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Schwaab, L. M., C. W. Niman, and E. G. Gisel. "Comparison of Chewing Cycles in 2-, 3-, 4-, and 5-Year-Old Normal Children." American Journal of Occupational Therapy 40, no. 1 (January 1, 1986): 40–43. http://dx.doi.org/10.5014/ajot.40.1.40.
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Susiyah, Susiyah, and Subawi Subawi. "Upaya Meningkatkan Kedisiplinan Anak Usia 3-4 Tahun Melalui Simulasi Lalu Lintas." Golden Age: Jurnal Ilmiah Tumbuh Kembang Anak Usia Dini 3, no. 1 (April 1, 2019): 29–42. http://dx.doi.org/10.14421/jga.2018.31-03.
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This study aims to determine the discipline of children at KB Puri Siwi Tamansari Academic Year 2016/2017 and find out the improvement of children's discipline through playing traffic simulations at KB Puri Siwi Tamansari Academic Year 2016/2017. This research method uses a type of classroom action research. This research was conducted in two stages, namely cycle I and cycle II. The subjects of this study were Puri Siwi Play Group students aged 3-4 years Tamansari Tlogowungu Pati as many as 16 students. The results of this study indicate that traffic simulations to improve child discipline are carried out with two cycles, the first cycle is carried out by simulating traffic signs with micro equipment, sikus II is carried out by simulating traffic signs with macro equipment. The results of data analysis and observations through traffic simulations showed an increase from the pre-cycle of 30% of children who completed their discipline, rising in the first cycle to 56.7%. That is, an increase of 24%. And in the second cycle increased to 81% and an increase of 25%. The results achieved in the second cycle had met the intended completeness target, namely 80% of all children scored with a complete category of 85. This increase in the average value proved the success of traffic simulations can improve children's discipline.
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Susmini, Susmini. "Upaya Meningkatkan Kecerdasan Naturalis Anak Usia 3-4 Tahun Melalui Bermain Kreatif Berbasis Area." Golden Age: Jurnal Ilmiah Tumbuh Kembang Anak Usia Dini 3, no. 1 (April 1, 2019): 17–28. http://dx.doi.org/10.14421/jga.2018.31-02.
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This study aims to determine the naturalist intelligence of children aged 3-4 years in Amanah Family Planning Guwo Tlogowungu Pati 2016/2017 academic year. 2) and to determine the increase in naturalist intelligence of children aged 3-4 years in Amanah Guwo KB Tlogowungu Pati 2016/2017 school year through area-based creative play. This research method uses a type of classroom action research. This research was conducted in two stages, namely cycle I and cycle II. The subjects of this study were students of Amanah Play Group aged 3-4 years Guwo Tlogowungu Pati as many as 20 students. The results of this study indicate that area-based creative play to improve children's naturalist intelligence is carried out with two cycles, the first cycle is carried out by opening 4 areas. The second cycle is done by opening 5 game areas. The results of data analysis and observation through area-based creative play showed an increase from the pre-cycle of 35% of children who completed their naturalist intelligence, increasing in the first cycle to 61%. That is, an increase of 30%. In cycle II it increased to 80% and there was an increase of 85%. The results achieved in the second cycle had fulfilled the intended completeness target, namely 80% of all children scored with a complete category of 85. This increase in the average value proved the success of area-based creative play to improve children's naturalist intelligence.
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Erb, John, Nils Chr Stenseth, and Mark S. Boyce. "Geographic variation in population cycles of Canadian muskrats (Ondatra zibethicus)." Canadian Journal of Zoology 78, no. 6 (June 1, 2000): 1009–16. http://dx.doi.org/10.1139/z00-027.
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We investigated the dynamic properties of population cycles in Canadian muskrats (Ondatra zibethicus). Ninety-one historic time series of muskrat-harvest data obtained from the Hudson's Bay Company Archives were analyzed. Most series were 25 years in length (19251949) and were distributed primarily throughout five ecozones. For each series, we estimated period length and coefficients for a second-order autoregressive model. Estimated period length varied between 3 and 13 years, with 3- to 5-year periods located in Subarctic-Arctic ecozones. We hypothesize that the 4-year cycles are largely a result of predation by red fox (Vulpes vulpes), which exhibit 4-year cycles in Arctic regions. The remaining ecozones generally averaged 89 years in period length. However, the relative contributions of direct and delayed density dependence varied along a latitudinal gradient. We hypothesize that both social and trophic interactions are necessary to produce the observed dynamics, but that shifts in the nature of mink predation were responsible for the changes in the relative contribution of direct and delayed density dependence. Essentially, there is a tension between population-intrinsic and trophic interactions that may bound the length of the cycle.
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Holmengen, Nina, and Knut Lehre Seip. "Cycle lengths and phase portrait characteristics as probes for predator–prey interactions: comparing simulations and observed data." Canadian Journal of Zoology 87, no. 1 (January 2009): 20–30. http://dx.doi.org/10.1139/z08-134.
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In this paper we explore the cyclic interactions of prey–predator systems by examining the relationship between cycle lengths of both species and the strength of their interaction. As a probe of interaction strength, we use the degree of counter-clockwise rotation in phase plots with the prey on the x axis and the predator on the y axis. We compare the results from a 25-year time series from the Hudson’s Bay Company data on American mink ( Neovison vison (Schreber, 1777)) and muskrat ( Ondatra zibethicus (L., 1766)) with results from three simulation models. We found that the strength of interaction (rotation range: –0.4 to 1.1 rad/year) was strongest when the two cycle lengths were similar and that it increased with the amplitude of the cycles (cycle range: 4–10 years). The time difference between prey and predator cycles that corresponded to the highest interaction strength was 2–3 years. Similar results were obtained with simulation models; the most complex Hanski model showing the overall best fit with observations. However, none of the models were able to reproduce long ranges of stable cycles by only changing one of their parameters at a time (ranges 2–4 years), whereas the observed range of stable cycles was 4–10 years.
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Murillo, Edgar, Maria Nambo, Agustin Aviles, Natividad Neri, Alejandra Talavera, Martha Gonzalez, Claudia Castañeda, Sergio Cleto, and Judith Huerta. "Treatment of Indolent Lymphomas with 3 CNOP- 4 COPB." Blood 104, no. 11 (November 16, 2004): 4594. http://dx.doi.org/10.1182/blood.v104.11.4594.4594.
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Abstract Frequently recurrences and progressive resistance to chemotherapy characterize indolent lymphomas. The use of anthracyclines has been improved the response rate and the disease free survival, however, its use in elderly patients is controversial because the related toxicities. We analyze the use of a chemotherapy regimen with a short course of anthracycline. Material and Methods: We included patients with untreated indolent lymphomas according to the WHO classification. The chemotherapy regimens were 3 cycles of CNOP (cyclophosphamide 600 mg/m2 day 1, mitoxantrone 10 mg/m2 day1, vincristine 1.4 mg/m2 day 1 and prednisone 50 mg/m2 days 1–5) every 21 days, followed by 4 cycles of COPB (cyclophosphamide 800 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, a bleomycin 10 U/m2 day 1 and prednisone 50 mg/m2 days 1–5) every 14 days. Results: In an intent to treat 75 patients were valuable, 37 females and 38 males, median age was 56 (range 28–84), the histological variants were: follicular grade 1 and 2 (45 patients), lymphoma/leukemia of small well differentiated lymphocytes (6 patients), mantle cell lymphoma (1 patient), nodal marginal zone lymphoma (4 patients), lymphoplasmocytic lymphoma (1 patient), indolent lymphoma not otherwise characterized (12 patients), 61 patients (81.3%) had bulky disease, 57 patients (76%) had advanced disease (stage III and IV). According to the IPI: low risk (28 patients), low intermediate (21 patients), high intermediate (14 patients), and high (12 patients). A total of 488 cycles were administrated, 82 (16.8%) cycles had hematologic toxicities: 30 cycles grade 1, 29 cycles grade 2, 18 cycles grade 3, and 5 cycles grade 4. Filgrastim was needed in 20 patients (43 cycles). 58 patients had gastrointestinal toxicity (29 grade1, 26 grade 2, 3 grade 3), 61 patients had neurological toxicity (47 grade 1, 13 grade 2, 1 grade 3). 14 patients (18.7%) required hospitalization, 7 patients due to toxicity related chemotherapy and 6 due to tumor progression. The overall response rate was 84% (63 patients): Complete response 33 patients (44%), unconfirmed complete response 6 patients (8%), partial response 24 patients (32%). Failure to treatment occurred in 11 patients (14.7%). Adding radiotherapy 12 more patients were converted to complete response for a total of 45 patients (60%). With a median of follow up of 24 months (range 3–62 months) 10 patients (13.3%) relapsed, 13 (17.3%) patients died (8 due to tumor progression and 3 related to toxicity of the regimen). The actuarial 5-year disease free survival was 71% and the overall survival 86%. Conclusions: This chemotherapy regimen provides an effective alternative for the treatment of indolent lymphomas even in advanced or bulky disease. This regimen is well tolerated for elderly patients and has a good safety profile. It is necessary a long time of follow up to establish the importance of the regimen in free disease survival and in overall survival.
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Kane, R. P. "Prediction of solar cycle 24 based on the Gnevyshev-Ohl-Kopecky rule and the three-cycle periodicity scheme." Annales Geophysicae 26, no. 11 (October 21, 2008): 3329–39. http://dx.doi.org/10.5194/angeo-26-3329-2008.
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Abstract. An examination of the maximum yearly values of the conventional sunspot number Rz of all cycles revealed fluctuations of various intervals in the high periodicity region (exceeding 11 years), namely 2 cycles (Hale, 22 years), 3 cycles (TRC, three-cycle) and longer intervals. The 2-cycle spacings had the smallest amplitudes. According to the G-O (Gnevyshev-Ohl) rule (Gnevyshev and Ohl, 1948), the even-numbered series of the maxima of annual mean Wolf sunspot numbers Rz are followed by higher amplitude odd-numbered series. Kopecky (1950) generalized this relation to annual mean Wolf numbers corresponding to equivalent phases of the adjacent even-odd 11-year cycles. Therefore, we would call it the G-O-K rule. For the data of 28 cycles (cycle −4 to cycle 23), it was found that four pairs (~29%) from the fourteen even-odd pairs showed failure of the G-O-K rule. In the remaining ten pairs, the magnitudes of the odd cycles were well-correlated with the magnitudes of the preceding even cycles, but it was impossible to tell whether it would be a normal pair following the G-O-K rule or a possible case of failure. A much stronger sequence was the three-cycle sequence (TRC, low, high, higher). The 2-cycle oscillations were embedded into the TRC until the G-O-K rule failures occurred as in cycle 23. The patterns of cycle 17 (low), 18 (high), 19 (higher); 20 (low), 21 (high), 22 (higher) were noticed and used by Ahluwalia (1995, 1998) to predict a low value for cycle 23, which was accurate. However, in the earlier data, the preceding sequence (14, 15, 16) was rather uncertain, and before that for seven cycles (cycles 8-14), there were no TRC sequences at all. During the twelve cycles −4 to 7, there were only three isolated TRC sequences (one doubtful). In view of this chequered history of TRC, it is doubtful whether the present TRC pattern (cycles 17–23) would persist in the near future. Spectral analysis showed that in the first half (cycles −4 to 9), larger periodicities (reminiscent of the Gleissberg cycle of ~80 years) prevailed. but in the latter half, periodicities were different (3-year cycle was predominant) and the matching was not good. In particular, the points for the recent cycles 21, 22 seemed to deviate considerably from the constructed series, thus introducing unreliability in predictions for the future by using extrapolation of periodicities.
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Krygier, G., A. Sosa, A. Blanco, K. Lombardo, C. Castillo, A. Dutra, S. Cabrera, E. Savio, I. Muse, and G. Sabini. "ABV (doxorubicin [Adriamycin], bleomicin and vincristine) polychemotherapy regimen in HIV Kaposi’s Sarcoma: Uruguaian 10-year experience." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9559. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9559.
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9559 Background: Kaposi’s sarcoma is the most common malignancy among HIV patients and is considered to be one of the AIDS defining conditions. This abstract illustrates our 10 year experience with the treatment of 32 Kaposi’s sarcoma HIV patients with the same therapeutic approach. Methods: Between 04/95 and 03/05 we recruited 32 previously untreated patients that were diagnosed with Kaposi’s sarcoma and treated at the Servicio de Oncologia Clinica (Universitary Clinicas Hospital) in Montevideo. All of them received the same iv polychemotherapy plan (Adriamycin 10mg/m2, Bleomycin 10 U/m2 and Vincristine 1.4 mg/m2, every two weeks until tumor progression or severe toxicity). Results: 21 of the patients were good risk ones and the remaining 11 were poor risk patients (AIDS Clinical Trials Group staging classification). CD4 levels varied from 6 to 780/ml and the viral load ranges were 240 to 89000 copies. The patients received an average of 10.2 (4–21) polychemotherapy cycles. Grade 3–4 myelotoxicity was reported in 5 patients delaying the onset of the subsequent cycles. Grade 2 neurotoxicity was seen in 7 patients after 4, 5, 6, 8, 10, 11 and 13 cycles of ABV, changing vincristine for vinblastine (4mg/m2 every two weeks) in these patients. All the patients achieved a partial response with improvements in CD4 levels and viral load. 13/32 patients experienced a relapse (3–29 months after last chemotherapy cycle). 3 patients were retreated with paclitaxel 135 mg/m2 with 2/3 new partial responses of shorter duration. 5 patients received 4 additional ABV cycles achieving a new partial response. 5 patients refused further treatment dying due to progressive disease. One relapsed patient developed a second malignancy (High grade Non Hodgkin lymphoma) dying three months later. Conclusions: These data suggest that ABV regimen is still an effective treatment option for HIV-Kaposi’s sarcoma, specially in the undeveloped countries in which the cost of other better internationally approved options (liposomal doxorubicin and daunorubicin) makes them unaccesible for the majority of the population. No significant financial relationships to disclose.
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Duric, V., P. Francis, J. Simard-Lebrun, A. Chan, J. Chirgwin, V. Harvey, A. Sullivan, R. Simes, A. S. Coates, and M. Stockler. "Preferences for adjuvant chemotherapy (ACT) in early breast cancer: The benefits needed to make extended treatment with docetaxel, doxorubicin, and CMF worthwhile." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 6528. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.6528.
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6528 Background: Small benefits are judged sufficient to make ACT worthwhile by women who have had either 6 cycles of CMF or 4 cycles of AC. We sought to determine the benefits needed to make longer and more intensive regimens worthwhile. Methods: 293 women who completed ACT 3 to 39 months earlier were presented 4 hypothetical scenarios based on known survival times (5 and 15 years) and rates (65% and 85% at 5 years) without ACT using validated, standardised interviews. 179 were in a randomized trial (BIG 02–98) testing addition of docetaxel (T) to a standard regimen including doxorubicin (A) and classical CMF; 114 were treated outside of the trial at the same centres. Women also rated their recollections of health-related quality of life during ACT. Results: The median age was 55 (range 25 to 78), 36% had a college or university degree, and 62% had dependants. The regimens (and their duration) in the trial were: 4 cycles of A or AC then 3 cycles of CMF (24w) in 31% of the women; 4 cycles of AT followed by 4 cycles of CMF (24w) in 29%; and 3 cycles of A then 3 cycles of T then 3 cycles of CMF (30w) in 40%. The regimens outside of the trial were: 4 cycles of AC (12w) in 52%; 6 cycles of CMF (24w) in 20%; and 4 cycles of AC then 3 cycles of CMF (24w) in 23%. A 2% gain in 5-year survival rates or a 6-month gain in survival duration was judged sufficient to make ACT worthwhile by 62–67% of women. Gains of more than 5% in 5-year survival rates or more than 2 years in survival duration were judged necessary to make ACT worthwhile by 10–20% of women. Women's preferences were strongly associated with the aversiveness of their treatment. Women who had more problems with physical well-being, coping with treatment, and nausea or vomiting judged larger benefits necessary to make their ACT worthwhile (p<.0001). Preferences were unaffected by chemotherapy regimen, duration, context in a trial, age, time between treatment and interview, and social circumstances (p>.2). Conclusions: As in previous studies, small benefits were judged sufficient to make ACT worthwhile, even if it lasted 6–7 months, and included docetaxel, doxorubicin and CMF. No significant financial relationships to disclose.
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Deng, Yanhong, Pan Chi, Ping Lan, Lei Wang, Weiqing Chen, Long Cui, Daoda Chen, et al. "Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial." Journal of Clinical Oncology 37, no. 34 (December 1, 2019): 3223–33. http://dx.doi.org/10.1200/jco.18.02309.
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PURPOSE In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results. METHODS Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). RESULTS In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% ( P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% ( P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% ( P = .971 by log-rank test), respectively. CONCLUSION mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.
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Wadasadawala, T., R. Jalali, A. Munshi, T. Gupta, N. Kalyani, H. Menon, R. Sarin, and A. Goel. "Five-year survival data in newly diagnosed glioblastoma treated with radiotherapy along with concurrent and adjuvant temozolomide." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e13009-e13009. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e13009.
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e13009 Background: We report 5-year survival data in patients with newly diagnosed glioblastoma treated with radiotherapy along with concurrent and adjuvant temozolomide (TMZ). Methods: Between March 2001 to April 2008, 81 patients with newly diagnosed histopathologically proven glioblastoma underwent surgery followed by external radiotherapy to a total dose of 60 Gy in 30 fractions over 6 weeks. Concurrent oral TMZ (75 mg/m2) was given daily with RT followed by adjuvant TMZ for 5 days every 28 days for six cycles (150 mg/m2 for the first cycle and 200 mg/m2 for rest of the cycles). Patients were monitored clinicoradiologically as per standard practice. Results: Patients aged between 11–73 years with a median age of 49 years (60 males, 21 females). Forty per cent of patients underwent a gross total resection of tumour, 44% had partial resection, and 16% an open or stereotactic biopsy only. 79% of the patients had a post-operative Karnofsky Performance Score (KPS) of >80. All six adjuvant cycles were completed in 68%. The 2-, 3-, 4-, and 5-year survival was 34%, 24%, 11%, and 11%, respectively (95% CI 14.03–21.96). The median overall and progression-free survival was 18 (2–92 months) and 16 months (2–72 months), respectively. On multivariate analysis, completion of all six cycles of adjuvant TMZ was associated with significantly better survival (p = 0.000). Neurological performance score (NPS) of 2–3 (p = 0.06) and Recursive Partitioning Analysis class V (p = 0.093) showed a trend towards poorer outcome. Treatment was generally well tolerated with only 2.5% of patients developing grade 3 anemia, leucopoenia, and neutropenia. Grade 3 or 4 thrombocytopenia was seen in 5% patients. Conclusions: Concurrent radiotherapy and TMZ followed by adjuvant TMZ results in encouraging survival even at a long follow-up. No significant financial relationships to disclose.
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Kularatne, B. Y., B. E. Ayres, D. Mukherji, N. Watkin, W. Lam, M. Perry, and L. M. Pickering. "Chemotherapy for squamous cell carcinoma of the penis: An 8-year, single-institution experience." Journal of Clinical Oncology 29, no. 7_suppl (March 1, 2011): 222. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.222.
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222 Background: Penile cancer is a rare malignancy affecting approximately 400 men per year in the United Kingdom. There are relatively limited data regarding the role of chemotherapy, although it may be considered in the adjuvant setting for high-risk disease and for palliation of metastatic disease. Methods: Patients treated with chemotherapy between June 2002 and March 2010 were identified from our prospectively maintained institutional database. Regimens were recorded and toxicity documented according to the Common Toxicity Criteria version 4.0. Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 until 2009 and then version 1.1. Results: Twenty patients received chemotherapy either for adjuvant treatment (n=6) or for metastatic disease (n=14). Median age was 59 (range 33-80). Different regimens were used over the time period. In the adjuvant setting 4-6 cycles of chemotherapy were planned and all patients received cisplatin in combination with 5-FU or capecitabine. Five (83%) completed planned treatment with no grade 3 or 4 toxicities. One patient stopped after 2 cycles due to deteriorating renal function. Patients remained disease free at up to 22 months follow-up. In the metastatic setting, 10 patients received cisplatin and capecitabine, 1 cisplatin and 5-FU and 1 carboplatin and capecitabine. Of these 12 patients, 2 (17%) had partial response as their best response, 4 (33%) had stable disease (SD) and 6 (50%) had progressive disease (PD). Three patients (25%) experienced pulmonary embolism, 1 of whom died. Two (17%) developed grade 3 neutropenia. One patient received carboplatin, methotrexate and bleomycin with PD after 3 cycles and developed grade 3 neutropenia, stomatitis, and diarrhea. One patient received 3 cycles of paclitaxel, ifosfamide, and cisplatin with SD and no grade 3 or 4 toxicities. Conclusions: Combination chemotherapy can be delivered with acceptable toxicity in the adjuvant setting. In the metastatic setting response rates were disappointing and treatments were associated with greater toxicity. New treatments are urgently required to improve outcomes in this difficult malignancy. [Table: see text]
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Mai, Hai-Qiang, Xiao Yun Li, Hao-Yuan Mo, Guo Ling, Dong-Hua Luo, Rui Sun, LiTing Liu, et al. "De-intensified chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma based on plasma EBV DNA: A phase 2 randomized noninferiority trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 110. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.110.
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110 Background: The cisplatin-based chemoradiotherapy (CCRT), given at a dose of 100 mg/m2 for 3 cycles during radiotherapy, is the major treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). As several retrospective studies showed that receiving a cumulative cisplatin dose of 200 mg/m2 can bring survival benefits to NPC patients, we sought to test the non-inferiority of 2-cycle concurrent cisplatin over 3-cycle in locoregionally advanced NPC with Epstein-barr virus (EBV) DNA levels < 4000 copies/ml. Methods: We did a non-inferiority, phase 2, randomised controlled trial. Patients were enrolled with stage III–IVB NPC, EBV DNA levels < 4000 copies/ml, aged 18–70 and adequate haematological, renal, and hepatic function. Eligible patients were randomly assigned (1:1) to receive 2 or 3 cycles of cisplatin-based CCRT. Patients in the 2-cycle group were scheduled to receive 100 mg/m2 cisplatin given every 3 weeks concurrently with radiotherapy, and patients in the 3-cycle group received 100 mg/m2 cisplatin given every 3 weeks for 3 cycles. Randomization was done by a computer-generated random number code with a block size of six, stratified by clinical stage III or IV. The primary endpoint was 3-year progression-free survival (PFS), with a non-inferiority margin of 10%. This study was registered with ClinicalTrials.gov, ID. NCT02871518. Results: Between September 2016 and October 2018, 342 patients were enrolled, of whom 332 were randomly assigned to receive 2 or 3 cycles of cisplatin. 314 (94.6%) patients completed protocol-defined cycles of chemotherapy. After median follow-up of 33.6 months, 20 (12.0%) patients in the 2-cycle group and 17 (10.2%) patients in the 3-cycle group had tumor progression, and the 3-year PFS rates were 88.0% and 90.4% respectively, with a difference of 2.4% (95%CI -4.3 to 9.1, Pnon-inferiority < 0.001). In the per-protocol analysis, 3-year PFS was 88.5% in the 2-cycle group and 90.6% in the 3-cycle group, with a difference of 2.1% (95% CI –4.7 to 8.9; Pnon-inferiority= 0.001). No significant difference was observed concerning OS, LRRFS and DMFS. The grade 3 or 4 acute adverse events were recorded in 113 (68.1%) patients in the 2-cycle group and 116 (69.9%) patients in the 3-cycle group. Patients in the 3-cycle group was observed to have significantly more hyponatremia. Besides, patients in the 3-cycle group presented with more grade 1 or 2 dry mouth, dysphagia, weight loss, fatigue, constipation, fever, mucositis and dermatitis. More grade 3 or 4 anorexia, mucositis and dermatitis were also recorded in the 3-cycle group. No patients died from treatment-related toxicities. Conclusions: IMRT plus 2 cycles of concurrent 100 mg/m2 cisplatin could be an alternative option for patients with low-risk locoregionally advanced NPC. Further phase III studies are needed to validate the findings of this study. Clinical trial information: NCT02871518.
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Solomon, Scott R., Melhem Solh, Xu Zhang, Stacey Brown, Katelin C. Jackson, H. Kent Holland, Lawrence E. Morris, and Asad Bashey. "Prospective phase 2 trial of ixazomib after nonmyeloablative haploidentical peripheral blood stem cell transplant." Blood Advances 4, no. 15 (August 10, 2020): 3669–76. http://dx.doi.org/10.1182/bloodadvances.2020001958.
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Abstract Proteasome inhibition results in extensive immunomodulatory effects that augment natural killer cell cytotoxicity and inhibit aspects of T-cell, B-cell, and dendritic cell function. We performed a phase 2 study that examined the effects of ixazomib for graft-versus-host disease (GVHD) prophylaxis (up to 12 cycles) with posttransplant cyclophosphamide and tacrolimus after standard nonmyeloablative haploidentical donor transplantation (HIDT). Ixazomib was started on day +5 (4 mg on days 1, 8, and 15 of a 28-day cycle), with dose reductions allowed in future cycles for toxicity. All patients received peripheral blood stem cells. Twenty-five patients were enrolled with a median age of 62 years (range, 35-77 years) who had acute leukemia (4), myelodysplastic syndrome (7), non-Hodgkin lymphoma/Hodgkin lymphoma/chronic lymphocytic leukemia (8), and myeloma (6). The hematopoietic cell transplant comorbidity index was ≥3 in 68% of the patients. After a median follow-up of 33.5 months, the cumulative incidence of relapse/progression at 1 year was 24% and 44% at 3 years, which failed to meet the statistically predefined goal of decreasing 1-year risk of relapse. Engraftment occurred in all patients with no secondary graft failure, and 3-year nonrelapse mortality (NRM) was 12%. Cumulative incidence of grade 3 to 4 acute GVHD was 8%, whereas moderate-to-severe chronic GVHD occurred in 19%. Nineteen patients survive with an estimated 1-year overall survival (OS) of 84% and 3-year OS of 74%. Hematologic and cutaneous toxicities were common but manageable. The substitution of ixazomib for mycophenolate mofetil (MMF) post-HIDT results in reliable engraftment, comparable rates of clinically significant GVHD, relapse and NRM, and favorable OS. This trial was registered at www.clinicaltrials.gov as # NCT02169791.
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Palumbo, Antonio, Francesca Gay, Patrizia Falco, Claudia Crippa, Vittorio Montefusco, Francesca Patriarca, Fausto Rossini, et al. "Bortezomib As Induction Before Autologous Transplantation, Followed by Lenalidomide As Consolidation-Maintenance in Untreated Multiple Myeloma Patients." Journal of Clinical Oncology 28, no. 5 (February 10, 2010): 800–807. http://dx.doi.org/10.1200/jco.2009.22.7561.
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PurposeTo evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients.Patients and MethodsNewly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m2on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m2on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m2(MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate).ResultsA total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%).ConclusionBortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.
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Kawamura, M., K. Eguchi, Y. Izumi, K. Kobayashi, H. Sakaguchi, and T. Koike. "The docetaxel (DOC) and gemcitabine (GEM) combination as adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC): A multi-institutional phase II trial." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 17157. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17157.
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17157 Background: As clinical phase II studies with non-platinum doublet for adjuvant chemotherapy after complete resection of NSCLC has been scarcely reported, this clinical study was designed to evaluate the toxicity profile and the efficacy of the adjuvant chemotherapy with non-platinum doublet of DOC+GEM. Methods: Eligibility criteria included: completely resected NSCLC, pathological stage II and IIIA, younger than 76 years old, and performance status 0–1. Patients treated preoperatively were excluded. Treatment consisted of DOC, 60 mg/m2, on day 8, and GEM, 1000 mg/m2, on day 1, 8, and 15 every 4 week (4 cycles). Dose of GEM was decreased to 800 mg/m2 after the initial 21patients because interstitial pneumonitis (IP) occurred in 3 among them. Results: Between August 2000 and August 2002, 35 patients (M/F: 21/14) were enrolled. The median age was 62 years (range 47–74) were enrolled with 5 patients (14.3%) over the age of 70. 34 patients had ECOG PS of 0. 28 patients had adenocarcinomas, 6 had squamous cell carcinomas, and one had adenosquamous carcinoma. Pathological stages were stage IIA in 5 patients, stage IIB in 1 and stage IIIA in 29 (82.9%). All patients received at least one cycle of chemotherapy. 29 patients received 3 cycles of chemotherapy and 23 (66%) completed 4 cycles. The main grade 3/4 toxicity (according to WHO scale) consisted of leukocytopenie (n = 19, 54.3%), thrombocytopenia (n = 3, 8.6%), appetiteloss (n = 4, 11.4%), dyspnea (n = 3, 8.6%), and vomiting (n = 1, 2.9%). IP, which caused dyspnea in these 3 patients, were well treated with steroid and suspension of chemotherapy. There was no treatment related death. Median follow-up period was 52 months. The 4 year recurrent free survival rate was 42.9% and the 4 year survival rate was 65.8%. Conclusions: Non-platinum doublet regimen with DOC+GEM as adjuvant chemotherapy for the NSCLC patients with complete resection was feasible and showed good compliance besides IP. No significant financial relationships to disclose.
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Toyama, Kazuhiro, Toshiaki Takezaki, Akira Honda, Yasunori Kogure, Akira Chiba, Fumihiko Nakamura, Kumi Nakazaki, and Mineo Kurokawa. "Optimal Cycles of Bendamustine-Plus Rituximab Therapy for Indolent B Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 5242. http://dx.doi.org/10.1182/blood-2019-124597.
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Backgrounds Although bendamustine-plus rituximab therapy (BR) is considered as one of the standard therapy for several indolent B cell lymphomas, the optimal cycles of BR is not still uncovered. To elucidate the optimal cycles of BR, we performed a single center retrospective study of patients with indolent lymphoma treated with BR. Methods All patients with follicular lymphoma (n=40), lymphoplasmacytic lymphoma (n=11) and mucosa associated lymphoid tissue lymphoma (n=6) who underwent BR in our institute in the period between April 2011 and September 2017 were included in this study. The clinical information including the number of repeated cycles, overall survival (OS), progression free survival (PFS), laboratory findings, backgrounds, and the response to BR were analyzed retrospectively. Rituximab was administered at day 1 and bendamustine was administered at day 1 and 2, or 2 and 3, in each 28 days cycle. In the study cohort, the number of repeated cycles was allowed up to 6. The cessation of BR was allowed after 4 cycles in the patients with response to BR, according to the discretion of attending physicians. The dosage of bendamustine was reduced to 67% and 50% in 70 to 79 years and not less than 80 years, respectively. All patients in this study were prescribed trimethoprim-sulfamethoxazole combination or pentamidine for the prevention of pneumocystis pneumonia, and acyclovir for the prevention of herpes zoster. Results In total 57 patients, the median age was 65 years (range, 37 to 83). Thirty four were male, and 23 were female. Three patients were newly diagnosed and 54 were relapsed or refractory patients. The median observation period was 51.7 months (5.1 to 83.6). The overall response rate was 86.0% (CR 54.4% and PR 31.6%). The median number of repeated cycles of BR was 4 (1 to 6). There was no significant correlation between patient characteristics and the number of repeated cycles of BR. All patients were stratified by their number of repeated cycles of BR. The early cessation group (n=17) was identified that the number was from 1 to 3, and the late cessation group (n=40) was identified that the number was from 4 to 6. The 5-year OS rates in early and late cessation groups were 56.1% and 87.0%, respectively. The 5-year PFS rates in early and late cessation groups were 31.4% and 50.6%, respectively. Both 5-year OS and PFS rates in late cessation group were significantly longer than that in early cessation group (p=0.011 and p<0.01, respectively). In late cessation group, the number of the patient who underwent 4 cycles of BR (4 cycles group) was 21, and the number of the patient who underwent 5 or 6 cycles of BR (over 4 cycles group) was 19. The 5-year OS rates in 4 cycles group and over 4 cycles group was 85.7% and 85.2%, respectively. There was no significant difference between these groups in the 5-year OS rates (p=0.58). The 5-year PFS rates in 4 cycles group and over 4 cycles group was 71.8% and 31.0%, respectively. The 5-year PFS rates in 4 cycles group were significantly longer than that in over 4 cycles group (p<0.01). The most common reason of the cessation of BR was adverse event (n=15). BR were stopped in 9 patients who achieved response after 4 or 5 cycles, and in 8 patients who became relapsed or refractory. Conclusions Our study indicated that the outcome of the patients with indolent lymphoma who stopped BR after 4 cycles was not inferior to that of the patients who stopped BR after 5 or 6 cycles. The results suggest that the cessation of BR after 4 cycles may be permissible in the patients with response to BR. Disclosures Toyama: Celgene K.K.: Speakers Bureau; Chugai Pharmaceutical Company: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau. Nakamura:Astellas Pharma Inc.: Speakers Bureau. Kurokawa:Shionogi & Co., Ltd: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Consultancy, Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Sumitomo Dainippon Pharma Co.,Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Yakult Honsha Company: Speakers Bureau; Pfizer Japan Inc.: Research Funding; Teijin Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Shire Japan K.K.: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; Celgene K.K.: Consultancy, Speakers Bureau; MSD K.K.: Consultancy, Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Bioverativ Japan ltd.: Consultancy.
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Bogani, Giorgio, Laura Matteucci, Stefano Tamberi, Valentina Arcangeli, Antonino Ditto, Giuseppa Maltese, Mauro Signorelli, et al. "The Impact of Number of Cycles of Neoadjuvant Chemotherapy on Survival of Patients Undergoing Interval Debulking Surgery for Stage IIIC–IV Unresectable Ovarian Cancer: Results From a Multi-Institutional Study." International Journal of Gynecologic Cancer 27, no. 9 (November 2017): 1856–62. http://dx.doi.org/10.1097/igc.0000000000001108.
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ObjectivesNeoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) may be a valuable treatment option in advanced ovarian cancer when primary cytoreduction is not feasible. However, a consensus on the ideal number of NACT cycles is still lacking. In the present investigation, we aimed to evaluate how number of cycles of NACT influenced patients' outcomes.MethodsData of consecutive patients undergoing NACT and IDS were retrospectively reviewed in 4 Italian centers, and survival outcomes were evaluated.ResultsOverall, 193 patients were included. Cycles of NACT were 3, 4, and at least 5 in 77 (40%), 74 (38%), and 43 (22%) patients, respectively. Patients undergoing 3 cycles experienced a similar disease-free survival (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.89–1.65; P = 0.20) but an improved overall survival (HR, 1.64; 95% CI, 1.05–2.4; P = 0.02) in comparison to patients receiving at least 4 cycles. Five-year overall survival was 46% and 31% for patients having 3 and at least 4 cycles. Ten-year overall survival was 26% and 18% for patients having 3 and at least 4 cycles (HR, 1.70; 95% CI, 1.13–2.55; P = 0.009). Using multivariate analysis, we observed that only Eastern Cooperative Oncology Group performance status correlated with overall survival (HR, 1.76; 95% CI, 1.2–2.49; P = 0.001). In addition, a trend toward worse overall survival was observed for patients with residual disease at IDS (HR, 1.29; 95% CI, 0.98–1.70; P = 0.06) and patients receiving at least 4 cycles (HR, 1.76; 95% CI, 0.95–3.22; P = 0.06).ConclusionOur data underline the potential implication of number of cycles of NACT before IDS. Further prospective studies are warranted to assess this correlation.
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Suidan, Rudy S., Qin Zhou, Alexia Iasonos, Roisin E. O’Cearbhaill, Dennis S. Chi, Kara C. Long Roche, Edward J. Tanner, John Denesopolis, Richard R. Barakat, and Oliver Zivanovic. "Prognostic Significance of the Number of Postoperative Intraperitoneal Chemotherapy Cycles for Patients With Advanced Epithelial Ovarian Cancer." International Journal of Gynecologic Cancer 25, no. 4 (May 2015): 599–606. http://dx.doi.org/10.1097/igc.0000000000000389.
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ObjectivePhase 3 trials have demonstrated a survival advantage for patients with optimally debulked epithelial ovarian cancer who received intravenous (IV) and intraperitoneal (IP) chemotherapy compared with IV therapy alone. This was despite a significant proportion of patients in the IV/IP arms not completing all 6 planned cycles. Our objective was to evaluate the prognostic significance of the number of IV/IP cycles administered.Methods/MaterialsData were analyzed for all patients with stage III to IV epithelial ovarian cancer who underwent optimal primary cytoreduction followed by 1 or more cycles of IV/IP chemotherapy from January 2005 to July 2011 at our institution. A landmark analysis was performed to associate progression-free survival (PFS) and overall survival (OS) with the number of IV/IP cycles given.ResultsWe identified 201 patients; 26 (13%) received 1 to 2 cycles of IV/IP chemotherapy, 41 (20%) received 3 to 4 cycles, and 134 (67%) received 5 to 6 cycles. The 5-year PFS for patients who received 1 to 2, 3 to 4, and 5 to 6 cycles was 18%, 29%, and 17%, respectively. The 5-year OS for patients who received 1 to 2, 3 to 4, and 5 to 6 cycles was 44%, 54%, and 57%, respectively. There was no significant difference in PFS (P= 0.31) or OS (P= 0.14) between the 3 groups. The most common reason for discontinuing IV/IP therapy was treatment-related toxicity (77%). Postoperative complications were the most common reason for not initiating IV/IP therapy (42%) in patients who subsequently transitioned to it.ConclusionsWe did not detect a significant survival difference between patients who received 1 to 2, 3 to 4, or 5 to 6 IV/IP chemotherapy cycles. Women may still derive a survival benefit if they receive fewer than 6 IV/IP cycles.
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Hosein, Peter J., Daniel Morgensztern, Francine Coleman, Gail Walker, Maricer Escalon, Joseph Rosenblatt, and Izidore S. Lossos. "High Remission Rates and Prolonged Progression Free Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma Treated with R-MACLOIVAM-T." Blood 112, no. 11 (November 16, 2008): 3597. http://dx.doi.org/10.1182/blood.v112.11.3597.3597.
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Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable subtype of B-cell non-Hodgkin lymphoma characterized by median progression-free survival (PFS) and median overall survival (OS) of only 1.5 and 3–4 years respectively. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a need for novel therapeutic approaches for this entity. Methods: We conducted a single-arm phase II study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO1996;14:925). The study size of 22 patients was based on precision of a two-sided 95% confidence interval for the 18-month progression free survival rate. Eligible subjects had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS ≤ 2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures as well as esophagogastroduodenoscopy and colonoscopy. Prior to initiating thalidomide maintenance, subjects were enrolled in the STEPS® program. Cycle 1 consisted of R-MACLO: rituximab 375 mg/m2 IV on day 1, doxorubicin 45 mg/m2 IV on day 1, cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2/day on days 2–5, vincristine 1.5 mg/m2 on days 1 and 8 capped to 2mg, methotrexate 1.2 g/m2 IV on day 10 over 1 hour followed by 5.52 g/m2 IV over 23 hours followed by leucovorin 36 hours later. G-CSF was begun on day 13. When the ANC was >1.5×109/L, cycle 2 with R-IVAM was begun: rituximab 375 mg/m2 IV day 1, cytarabine 2 g/m2 IV every 12 hours on days 1 and 2, etoposide, 60 mg/m2 on days 1–5 and ifosfamide 1.5 g/m2 on days 1–5 with mesna. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, subjects were re-staged and responses were assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide 200 mg/day until MCL relapse or intolerable toxicity. Results: Accrual started in 4/2004 and ended in 3/2008 when the planned 22 subjects were enrolled. All subjects were evaluable for toxicity and 21 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage 3 disease with bone marrow involvement in 19 and gastrointestinal involvement in 10. Distribution according to IPI: 0–1 factor, 3; 2 factors, 8; 3 factors, 8; and 4 factors, 3. Twenty subjects had diffuse variant and 2 had blastic variant. Nineteen subjects completed all 4 cycles of therapy; treatment was stopped in 2 subjects after 2 and 3 cycles respectively, and one subject died during the first cycle. Of the 21 subjects completing 2 cycles of therapy, 20 achieved CR and one PR. Two subjects relapsed at 9 and 33 months respectively, while 19 remain relapse free after median follow-up of 25 months (range 5–51). With a total follow-up of 545 months, the estimated relapse rate is 4.4 per 100 patients per year. There were two deaths: 1 from sepsis on cycle 1 day 8 and the other in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL. Common severe toxicities were grade 3–4 neutropenia, thrombocytopenia and anemia in 33%, 19% and 17% of R-MACLO cycles and in 50%, 88% and 68% of R-IVAM cycles respectively. There were 14 bacteremias in 82 cycles, 12 of which were after R-IVAM therapy. Six episodes of reversible grade 1–2 renal toxicity occurred after methotrexate. The thalidomide maintenance dose was reduced in 6 subjects due to grade 3–4 neutropenia and reduced or stopped in 8 subjects because of grade 3–4 peripheral neuropathy. Patients remain under follow-up for relapse and survival. Conclusions: R-MACLO-IVAM-T results in a high overall response rate of 100% (95% CR and 5% PR) and a low relapse rate. At a median follow-up of 25 months, median PFS and OS were not reached. The 2-year actuarial PFS of 94% compares favorably with previously reported 2-year actuarial PFS of 40% and 67% for CHOP-like regimens without and with upfront bone marrow transplantation (Blood2005;105: 2677). The contribution of thalidomide maintenance to this outcome requires additional study. A multicenter clinical trial is suggested.
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Gastwirt, Jaime P., Mark A. Ahlman, Christopher Melani, Stefania Pittaluga, Kieron Dunleavy, Andrea Nicole Lucas, Seth M. Steinberg, Elaine S. Jaffe, Wyndham Wilson, and Mark Roschewski. "Response-Adapted Therapy in HIV-Associated Diffuse Large B-Cell Lymphoma: Updated Results of a Prospective Phase II Study of Short-Course-EPOCH-RR." Blood 134, Supplement_1 (November 13, 2019): 4080. http://dx.doi.org/10.1182/blood-2019-122450.
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Background: Response-adapted therapy aims to minimize toxicity while maintaining efficacy. Patients with HIV-associated lymphomas are at increased risk for complications and minimizing treatment is advantageous. In 33 patients with HIV-associated diffuse large B-cell lymphoma (DLBCL), we previously reported a 5-year freedom from progression (FFP) and overall survival (OS) rate of 84% and 68%, respectively, with 79% of patients receiving only 3 cycles of short course EPOCH-RR (Dunleavy, 2010). In that study, treatment duration was based on an interim FDG PET-CT scan comparing global reduction of SUV to baseline. Herein, we report an updated analysis including an additional 22 patients and investigate the predictive value of interim PET scans using modern Lugano response criteria. Methods: Eligible patients had untreated HIV-associated DLBCL with adequate organ function. All performance status and stages were eligible, including CNS involvement. Pre-treatment evaluation included bone marrow biopsy, lumbar puncture, CT and PET scan, and brain MRI/CT if indicated. Infusional EPOCH was delivered every 21 days with rituximab on days 1 and 5 (SC-EPOCH-RR) without dose-adjustment for a minimum of 3 and maximum of 6 cycles. HIV antiretroviral therapy (ART) was held until completion of systemic chemotherapy. Treatment response was determined by CT and PET imaging after 2 cycles, with restaging imaging performed consecutively after each cycle. Patients that had a global PET decrease > 50% compared to pre-treatment PET, were treated with only 1 additional cycle. Patients who did not decrease > 50% on PET, continued treatment until there was < 25% reduction in bidimensional products on serial CT imaging. Active CNS disease was treated with twice weekly intrathecal (IT) methotrexate until CSF clearance followed by maintenance IT therapy. All other patients received prophylactic IT methotrexate starting on cycle 3 for 8 doses. The primary endpoint of the study was progression-free survival (PFS). Independent and blinded review of PET scans using Lugano response criteria (Deauville score 1-3 = negative, score 4-5 = positive) was performed by a nuclear medicine specialist (M.A.). Results: Fifty-five patients were enrolled between March 2001 and February 2019. Median age was 42 (range, 9-60) and 85% were male. Ann Arbor stage was III/IV in 84% and 71% had a high-intermediate or high IPI score. Six (11%) patients had CNS involvement, and 6 (11%) had bone marrow involvement. Median CD4 count was 210 cell/m3 (range 0-1192). Cell-of-origin by Hans classified 69% as GCB and 22% were EBV positive. 31 patients were tested for MYC rearrangement by FISH and 5 (16%) were positive. Patients received a median of 3 cycles of therapy; 1 (2%) patient received only 1 cycle, 2 patients (4%) received 2 cycles, 45 patients (82%) received 3 cycles, 3 (5%) patients received 4 cycles, and 4 (7%) patients received 5 cycles. After a median potential follow-up of 12.6 years, 5-year FFP, PFS and OS were 76.0%, 64.3% and 71.8%, respectively [Figures 1, 2]. Two patients progressed during therapy, while 11 patients relapsed after therapy - all within 12 months of treatment completion. Of 18 deaths on study, 6 were due to disease progression and 12 died from causes unrelated to lymphoma or treatment. Of forty-seven patients with interim (post-cycle 2) PET scans, 30 (64%) became PET negative after 2 cycles. The 5-year PFS was not different in patients who achieved interim PET negativity: 73.4% versus 62.7% (p = 0.14 for comparison of entire PFS curves) [Figure 4]. Of the 13 total patients who progressed or relapsed, 5 were negative on interim PET. Conclusion:Response-adapted SC-EPOCH-RR therapy is effective for HIV-associated DLBCL and many patients are cured with only 3 cycles of therapy. Interim PET scans after 2 cycles using Lugano criteria did not reliably predict clinical outcomes. Further studies investigating the role of circulating tumor DNA (ctDNA) for genotyping and predicting clinical outcomes are planned. This work was supported by the Intramural Research Program of NCI. Disclosures Dunleavy: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.
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Ahn, J., S. Kim, B. Son, S. Ahn, and W. Kim. "Adjuvant CAF versus AC followed by paclitaxel for operable breast cancer with 4 or more involved axillary lymph nodes: Retrospective analysis." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10610. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10610.
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10610 Background: Recently, adjuvant AC followed by paclitaxel has improved disease-free survival (DFS) or overall survival (OS) of node-positive breast cancer. Although adjuvant TAC, as compared with FAC, significantly improves DFS and OS rate in node-positive breast cancer, AC→T has not been yet compared with FAC. Since 2001, we discussed the options of adjuvant CAF versus AC→T with patients who had 4 or more positive axillary nodes. We evaluated the efficacies of adjuvant CAF and AC→T, retrospectively. Methods: Between September 2001 and July 2004, a total of 1,394 patients underwent surgery and received adjuvant chemotherapy. Among them, 253 (18.1%) patients had 4 or more than axillary nodes and received either six cycles of CAF (n = 116) or 4 cycles of AC→T) (n = 137). The medical records and pathologic data of these patients were reviewed, retrospectively. Results: Median age of all patients was 46 years (range, 22∼76 years). The two groups were well balanced in terms of demographic and tumor characteristics. With a median follow-up period of 24 months (range, 6∼90 months), 49 (19.4%) patients had disease recurrence including 27 (23.3%) in CAF group and 22 (16.1%) in AC→T group (p = 0.155). The 3 year-DFS rate was 68.3% in CAF group and 71.1% in AC→T group (p = 0.9366), and the estimated 3-year OS rate was 90.3% and 92.3%, respectively (p = 0.8237). There was no significant difference in 3-year DFS rate according to hormone-receptor status. Febrile neutropenia occurred in 11 (9.6%) patients in CAF group and 7 (5.1%) patients in AC→T group (p = 0.222). Conclusion: Our data suggest that there is no significant difference in DFS or OS rates between six cycles of CAF and 4 cycles of AC followed by 4 cycles of paclitaxel as adjuvant chemotherapy in patients with 4 or more than involved axillary nodes. However, long-term follow-up period and prospective studies are needed to define better regimen. No significant financial relationships to disclose.
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Topp, Max S., Johannes Duell, Gerhard Zugmaier, Michel Attal, Philippe Moreau, Christian Langer, Jan Krönke, et al. "Anti–B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma." Journal of Clinical Oncology 38, no. 8 (March 10, 2020): 775–83. http://dx.doi.org/10.1200/jco.19.02657.
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PURPOSE The anti–B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/104 bone marrow cells by flow cytometry. RESULTS Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year. CONCLUSION In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.
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Harrington, Constance A. "Retrospective shoot growth analysis for three seed sources of loblolly pine." Canadian Journal of Forest Research 21, no. 3 (March 1, 1991): 306–17. http://dx.doi.org/10.1139/x91-038.
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Height growth by year and by individual cycle on the terminal shoot was reconstructed from stem analysis for 45 loblolly pine (Pinustaeda L.) trees that were 35 years old. Sample trees represented three seed sources (Clark County, AR; Livingston Parish, LA; and Onslow County, NC), each of which had been planted at three installations (Arkadelphia, AR; Poplarville, MS; and New Bern, NC) located in the general geographic area where one of the seed sources had been collected. Stem analysis was facilitated by the development of a staining technique that enhanced recognition of the boundaries between individual height-growth cycles and between years. Both annual height growth and number of cycles produced varied with tree age, seed source, and installation. Number of cycles produced per year ranged from two to seven; maximum annual production of cycles per seed source was achieved between ages 3 and 10 years. Even between ages 30 and 35, trees still exhibited polycyclic behavior, producing two to five cycles annually. Annual height growth was greatest between ages 4 and 15; height growth declined with age more rapidly than annual number of cycles. The relationship at each installation between cumulative height and cumulative number of cycles showed that the tallest seed source (Onslow in all cases) was the one that had produced the greatest number of cycles. Shorter trees at the poorest site resulted from lower numbers of cycles produced and, particularly after the production of 50 to 65 cycles, shorter mean cycle length. For all three seed sources, mean height was greatest at the installation where the trees produced the most cycles. Height-growth curves for two of the installations crossed, demonstrating differences in height-growth patterns related to site characteristics.
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Short, Nicholas James, Hagop M. Kantarjian, Susan Mary O'Brien, Farhad Ravandi, Deborah A. Thomas, Guillermo Garcia-Manero, Naval Guastad Daver, et al. "Updated results of a phase I/II study of inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) as frontline therapy for older patients with acute lymphoblastic leukemia." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 7014. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.7014.
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7014 Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody-toxin conjugate that is effective in patients (pts) with relapsed/refractory ALL. Given the poor tolerance of elderly pts to intensive chemotherapy, we evaluated the safety and efficacy of low-intensity chemotherapy (mini-hyper-CVD) plus InO as frontline treatment for older pts with newly diagnosed ALL. Methods: Pts ≥60 years of age with newly diagnosed Ph-negative pre-B ALL received mini-hyper-CVD (no anthracycline, dose reductions of cyclophosphamide, dexamethasone, MTX and Ara-C). Pts received InO 1.3-1.8 mg/m2 on day 3 of cycle 1 and 0.8-1.3 mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Results: 47 pts have been treated, 4 of whom were in CR at enrollment. Median age was 68 years (range, 60-81) and median CD22 expression was 97% (range, 72-100%). Among 43 pts evaluable for response, 41 (95%) achieved CR or CRp (CR, n = 36, CRp, n = 5). 1 pt achieved CRi and 1 did not respond. MRD negativity by 6-color flow cytometry was achieved in 31/41 pts (76%) after 1 cycle and in 44/46 pts (96%) overall. Median times to platelet and ANC recovery in cycle 1 were 23 and 16 days, respectively, and for subsequent cycles were 22 and 17 days, respectively. Prolonged thrombocytopenia ( > 6 weeks) occurred in 37 pts (79%). 4 pts (9%) developed VOD, 1 after allogeneic stem cell transplant (ASCT) and 3 unrelated to ASCT. Only 1 pt developed severe VOD. Among 46 responders, 6 (13%) relapsed, 3 (7%) underwent ASCT in CR1, 27 (59%) remain on treatment or have completed maintenance, and 10 (22%) died in CR/CRp. With a median follow-up of 24 months, the 3-year continued remission and OS rates were 72% and 54%, respectively. Compared to a historical cohort of older pts treated with hyper-CVAD ± rituximab (n = 79), mini-hyper-CVD + InO resulted in significantly higher 3-year OS (54% vs 31%; P = 0.007). Conclusions: Mini-hyper-CVD plus InO is safe and effective in elderly pts with newly diagnosed ALL and appears to improve outcomes compared to hyper-CVAD in this population. Clinical trial information: NCT01371630.
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Advani, Ranjana H., Alison J. Moskowitz, Nancy L. Bartlett, Julie M. Vose, Radhakrishnan Ramchandren, Tatyana A. Feldman, Ann S. LaCasce, et al. "Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results." Blood 138, no. 6 (April 7, 2021): 427–38. http://dx.doi.org/10.1182/blood.2020009178.
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Abstract This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.
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Straus, David J., Brandelyn Pitcher, Lale Kostakoglu, John C. Grecula, Eric D. Hsi, Heiko Schoder, Sin-Ho Jung, et al. "Initial Results of US Intergroup Trial of Response-Adapted Chemotherapy or Chemotherapy/Radiation Therapy Based on PET for Non-Bulky Stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)." Blood 126, no. 23 (December 3, 2015): 578. http://dx.doi.org/10.1182/blood.v126.23.578.578.
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Abstract Introduction Interim positron-emission tomography (PET) following 1-3 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in newly-diagnosed, non-bulky stage I and II HL patients (pts) is a useful biomarker that predicts relapse rates of ≤10% for PET- pts. Relapse rates are higher in pts who are PET+ (J Clin Oncol 2014 32: 2705-11; N Engl J Med 2015 372: 1598-607). Interim PET thus provides an opportunity to minimize treatment for the majority of pts who are interim PET - and only intensify treatment for those who are PET+. This strategy could reduce short and long term treatment toxicity for the majority of pts. To test this hypothesis, the US Intergroup conducted a phase II clinical trial, CALGB/Alliance 50604, for newly-diagnosed non-bulky stage I and II HL pts. Methods Between 5/15/10 and 5/4/12, 164 previously untreated pts with non-bulky stages I/II HL were enrolled. Pts received 2 cycles of ABVD followed by PET. Deauville scores 1-3 were negative (≤ liver uptake), while scores of 4-5 were positive, based on central review. PET- pts received 2 more cycles of ABVD, and PET+ pts received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escalated BEACOPP) + 3060 cGy involved-field radiation therapy (IF RT). Prophylactic growth factor use was permitted only after grade 3/4 febrile neutropenic events, with or without infection. Results Median age was 31 years (18-58). There were 88 males and 76 females. Pt. stages were IA (16), IB (4), IIA (90), IIB (35), IIAE 4, and IIBE (3). All pts were PET+ prior to treatment. 144/164 patients had cycle 2 PET and adequate follow-up for assessment: 131 (91%) were PET- and 13 (9%) PET+. Of 20 not analyzed, 13 were excluded (6 never treated and 2 treated with < 2 cycles) and 7 had insufficient follow up. At a median follow-up time of 2 years, 8/131 (6%) PET- pts relapsed or progressed with an estimated 3-year progression-free-survival (PFS) of 92%. 4/13 (31%) PET+ pts. failed (3 relapsed, 1 suicide) with an estimated 3-year PFS of 66%. By Cox model, observed hazard ratio comparing PET- and PET+ PFS for pts is 6.04 (1.82, 20.08). It is likely that the trial will meet the primary objective of 3-year PFS of at least 85% (79%, 92%) for PET- pts treated with 2 additional cycles of ABVD. It is unlikely that the results will meet secondary objective of improving the 3-year PFS of PET+ pts treated with 2 cycles of escalated BEACOPP + IF RT to the pre-set level considered to be of clinical interest in comparison with PET- pts treated with 2 additional cycles of ABVD (HR< 3.84). There was 1 death (suicide). Toxicity for all pts was minimal: Neutropenia: 29% grade 3 and 42% grade 4; Febrile neutropenia: 5% grade 3; Decreased CO diffusing capacity: 1% grade 3; Decreased left ventricular ejection fraction: 1% grade 3; Sensory neuropathy: 2% grade 3 and 1% grade 4; Motor neuropathy: 1% grade 4. Conclusions These early results confirm interim PET as a potential biomarker for prediction of relapse with ABVD in patients with non-bulky, stages I/II HL. Importantly, this study demonstrates that defining PET- as Deauville scores of 1-3 results in only 9% of pts. remaining PET+ after 2 ABVD cycles and excellent PFS for the PET-majority. More intensive treatment with 2 cycles of escalated BEACOPP and IF RT for the 9% of pts who are interim PET+ will be unlikely to improve 3-year PFS to the level considered to be of clinical interest in this trial. Interpretation may be limited by small numbers and lack of randomized control comparison. Fortunately, exciting new treatment approaches may provide an opportunity to improve outcomes for the minority of interim PET+ pts in the future. Kaplan Meier Plot of PFS for PET-negative and PET-positive patients For Alliance for Clinical Trials in Oncology, Eastern Cooperative Oncology Group, and Southwest Oncology Group; Supported in part by U10CA180821, U10CA180820, and U10CA180888 Figure 1. Figure 1. Disclosures Straus: Millenium Pharmaceuticals: Research Funding. Hsi:Abbvie: Research Funding; Cellerent Therapeutics: Research Funding; Eli Lilly: Research Funding; Onyx: Honoraria; Seattle Genetics: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Cheson:Gilead: Consultancy, Research Funding; Teva: Research Funding; Celgene: Consultancy, Research Funding; Ascenta: Research Funding; Astellas: Consultancy; Pharmacyclics: Consultancy, Research Funding; Spectrum: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy, Research Funding; MedImmune: Research Funding. Bartlett:Janssen: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Millenium: Research Funding; Celgene: Research Funding; Gilead: Consultancy; Seattle Genetics: Consultancy, Research Funding.
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Sehn, Laurie H., Kerry J. Savage, Paul Hoskins, Richard Klasa, Tamara Shenkier, Nicholas Voss, Don Wilson, and Joseph M. Connors. "Limited-Stage Diffuse Large B-Cell Lymphoma (DLBCL) Patients with a Negative Pet Scan Following Three Cycles of R-CHOP Can Be Effectively Treated with Abbreviated Chemoimmunotherapy Alone." Blood 110, no. 11 (November 16, 2007): 787. http://dx.doi.org/10.1182/blood.v110.11.787.787.
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Abstract Four cycles of CHOP chemotherapy has been shown to be sufficient treatment for low-risk elderly patients with limited-stage DLBCL, eliminating the need for radiation therapy (Bonnet et al, JCO 2007). FDG-PET scanning is an effective prognostic tool that may identify chemo-sensitive patients (regardless of age or clinical risk factors) who can appropriately be treated with abbreviated chemoimmunotherapy alone. Patients: Beginning in 2005, we have recommended that all prospective patients with limited-stage DLBCL (stage I/II, no B-symptoms, mass < 10cm) treated in British Columbia (BC) undergo a PET scan following 3 cycles of R-CHOP; PET-negative patients should then receive one additional cycle of R-CHOP (total 4 cycles R-CHOP), while PET-positive patients receive involved-field radiation therapy (IFRT). Clinical characteristics of the first 50 patients are as follows: median age 67 y (range 31–88); 56% male; 62% stage I, 38% stage II; 4% PS>1; 6% elevated LDH; 58% at least 1 extranodal site, 10% >1 extranodal site. Stage-modified IPI risk factors: 22% 0; 70% 1–2; 8% 3–4. Median follow-up is 17 mos (range 4–26). Results: 37 patients (74%) were PET-negative and 13 patients (26%) were PET-positive after 3 cycles of R-CHOP. No clinical factors were found to be predictive of PET status. Of the 37 PET-negative patients, 35 completed treatment with one additional cycle of chemoimmunotherapy, 1 received IFRT due to poor chemotherapy tolerance, and 1 died of toxicity before receiving any more treatment. Only 1/37 PET-negative patients has relapsed (alive with lymphoma after salvage therapy). All 13 PET-positive patients received IFRT, with 3 relapses and 2 deaths from lymphoma to date. Although longer follow-up is necessary, the 2-year estimated Kaplan-Meier progression-free survival is 91% overall (97% and 75% for PET-negative and PET-positive patients, respectively, p=0.09). (see figure) The 2-year estimated Kaplan-Meier overall survival is 97% for PET-negative and 69% for PET-positive patients, p=0.1. Conclusion: Patients with limited-stage DLBCL who are PET-negative after 3 cycles of R-CHOP can be effectively treated with abbreviated chemoimmunotherapy alone (4 cycles R-CHOP), avoiding the long-term toxicity of radiation while preserving excellent lymphoma control. Figure Figure
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von Tresckow, Bastian, Heinz Haverkamp, Boris Böll, Dennis A. Eichenauer, Stephanie Sasse, Michael Fuchs, Peter Borchmann, and Andreas Engert. "Impact Of Dose Reduction Of Bleomycin and Vincristine In Patients With Advanced Hodgkin Lymphoma Treated With Beacopp: A Comprehensive Analysis Of The German Hodgkin Study Group (GHSG) HD12 and HD15 Trials." Blood 122, no. 21 (November 15, 2013): 637. http://dx.doi.org/10.1182/blood.v122.21.637.637.
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Abstract Introduction BEACOPPescalated is the standard treatment for advanced Hodgkin Lymphoma (HL) within the German Hodgkin Study Group (GHSG) and other cooperative groups. Bleomycin and vincristine cause significant acute and long-term toxicity and are frequently discontinued during the course of therapy. However, the impact of dose reduction of these drugs on outcome and tolerability of BEACOPP has not been systematically assessed. Thus, we performed a retrospective analysis of patients treated within the GHSG trials HD12 (8xBEACOPPescalated versus 4xBEACOPPescalated plus 4xBEACOPPbaseline) and HD15 (8xBEACOPPescalated versus 6xBEACOPPescalated versus 8xBEACOPP14) trials for advanced stages. Methods Based on the intention-to-treat analysis, characteristics and outcome of patients receiving the full number of cycles of HD12 and HD15 were analyzed with respect to bleomycin and/or vincristine discontinuation. Progression-free survival (PFS) and overall survival (OS) were estimated from end of chemotherapy according to the Kaplan-Meier method and compared between groups using the log-rank test. To compare differences in patient characteristics, Fisher's exact test was used for rates and Wilcoxon's rank-sum test was used for continuous parameters. Receiver operating characteristic (ROC) analyses were performed in patients who had an event or were followed for at least 2 years after therapy. Results 3309 (89.4%) of patients received the full number of planned cycles and had complete chemotherapy documentation available. Bleomycin was discontinued in 10.5% and vincristine in 21.7% of cases. All other drugs had discontinuation rates less than 1.5%. 157 (4.7%) of patients received ≤4 cycles of bleomycin and 218 (6.6%) of patients received ≤3 cycles of vincristine; these were compared to patients with >4 cycles of bleomycin (3152 patients [95.3%]) and >3 cycles of vincristine (3091 patients [93.4%]). Discontinuation of bleomycin or vincristine was more frequent in patients aged 50 or older (4.4% and 7.4% with ≤4 cycles of bleomycin in patients <50 and ≥ 50 years, respectively, p=0.001; 6.2% and 9.5% with ≤3 cycles of vincristine in patients <50 and ≥ 50 years, respectively, p=0.015). More female patients had vincristine discontinued (8.4% and 5.5% female and male patients, respectively, with ≤3 cycles, p=0.001) whereas there was no significant difference between female and male patients regarding bleomycin discontinuation (p=0.6). After a median follow-up of 59 and 67 months for PFS and OS, respectively, there was no significant PFS or OS difference in patients with ≤4 or >4 cycles of bleomycin (6-year PFS-difference 0.3% [95%CI -5.7 to 6.2%]; 6-year OS-difference 0.4% [95%CI -3.7 to 4.5%]; Figure 1A). Similarly, there was no significant PFS or OS difference in patients with ≤3 or >3 cycles of vincristine (6-year PFS-difference -1.6% [95%CI -6.4 to 3.2%]; 6-year OS-difference 1.9% [95%CI -2.5% to 6.3%]; Figure 1B). To assess if the number of bleomycin and vincristine cycles received had an impact on 2-year PFS and OS, ROC analyses were performed. However, failure could not be predicted irrespective of the number of cycles chosen as cutpoint. Detailed analyses and comparisons of patient characteristics, dose delivery of chemotherapy and toxicity will be presented. Conclusion Bleomycin and vincristine discontinuation due to drug-specific side effects seemed to be safe in this setting. Given the limitations of this retrospective analysis, our data suggest that bleomycin and vincristine may have a limited role in the BEACOPP regimen. Disclosures: von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.
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Sohn, B., D. Yoon, S. Kim, D. Lee, S. Kim, J. Huh, J. Lee, and C. Suh. "Outcomes in patients with primary gastric diffuse large B-cell lymphoma after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e19543-e19543. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19543.
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e19543 Background: The optimal therapy for primary gastric diffuse large B- cell lymphoma (DLBCL) still needs to be defined. The aim of this study was to investigate the patient's outcomes after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) treatment in primary gastric DLBCL in a single institution. Methods: We searched AMC Registry for Non-Hodgkin's Lymphoma and found 26 patients with primary gastric DLBCL, who received R-CHOP as first-line chemotherapy. Ten of 26 patients had localized disease. Remaining patients had disseminated disease. R-CHOP was repeated every 21 days in all patients. Results: Overall, complete response (CR) was observed in 20 of 26 patients (76.9%). Three-year event free survival (EFS) and overall survival (OS) was 76.5% and 75.0%, respectively. After analyses of 10 patients with localized disease, we found that these patients had received a total 38 cycles, with a median of 3 cycles per patient. Of 10 patients, one patient had 2 cycles of R-CHOP, 4 had 3 cycles, and one had 4 cycles, all 6 patients above followed by consolidation radiotherapy. Remaining one patient and 4 patients had 5 cycles and 6 cycles of R-CHOP, respectively. In patients with localized disease, CR was observed in 10 of 10 patients (100%), and both 3-year EFS and OS was 100% (10 of 10 patients). In analyses with 16 patients with disseminated disease, all patients had received a total 91 cycles, with a median of 6 cycles per patient. In these patients, two patients had radiation therapy after R-CHOP, one patient had CR before consolidation radiation therapy, and another had partial response before radiation therapy. CR after R-CHOP treatment was observed in 10 of 16 patients (62.5%), partial response in 3 patients, stable disease in 1 patient, and progressive disease in 1 patient. Three-year EFS and OS was 61.1% and 57.8% in patients with disseminated disease. Conclusions: R-CHOP regimen showed a promising result in primary gastric DLBCL. Combination with rituximab in CHOP regimen showed excellent prognosis especially in patients with localized disease. In localized disease, CR was 100%, 3-year EFS and OS was 100%. In disseminated disease, CR was 62.5%, 3-year EFS and OS was 61.1% and 57.8%. No significant financial relationships to disclose.
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Palumbo, Antonio, Sara Bringhen, Davide Rossi, Maide Cavalli, Roberto Ria, Silvia Gentilini, Francesca Patriarca, et al. "Overall Survival Benefit for Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance with Bortezomib-Thalidomide (VMPT-VT) Versus Bortezomib-Melphalan-Prednisone (VMP) in Newly Diagnosed Multiple Myeloma Patients." Blood 120, no. 21 (November 16, 2012): 200. http://dx.doi.org/10.1182/blood.v120.21.200.200.
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Abstract Abstract 200 Background: In a multicenter phase 3 randomized trial, VMPT-VT was superior to VMP for response rates, progression-free survival and time to next treatment (Palumbo A, et al. J Clin Oncol 2010). Here we report an updated analysis on survival after 4 years of follow-up. Methods: Patients (N=511) were randomly assigned to receive nine 6-week cycles of VMPT-VT (induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day up to 2 years) or VMP alone. After the inclusion of 139 patients, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). Results: After a median follow-up of 47.2 months, median OS was not reached in the VMPT-VT arm and was 58.2 months in the VMP arm; 5-year OS rates were 59.3% and 45.9%, respectively (HR 0.74, p=0.04), with 26% reduced risk of death for patients receiving VMPT-VT (Figure-panel A). This benefit was more evident in patients younger than 75 years (5-year rates 67.8% for VMPT-VT vs 49.9% for VMP, HR 0.63, p=0.01, Figure-panel B) and in patients in complete response (CR) after induction (5-year rates 81.4% for VMPT-VT vs 48.2% for VMP, HR 0.38, p=0.006, Figure-panel C) while no significant differences were evident in patients with standard- or high-risk features detected by FISH (HR 0.99, p=0.99). A 1-year landmark analysis for patients completing induction was performed: the 4-year OS was 64.6% in the VMPT-VT group and 49.7% in the VMP group, with 33% reduced the risk of death for patients receiving VT maintenance (HR 0.67, p=0.02). Forty-nine percent of VMPT-VT and 70% of VMP patients relapsed and received subsequent salvage therapies; there was no difference in survival from relapse in the two groups (2-year OS rates 40.7% vs 50.2%,HR 1.11, p=0.54). The median duration of VT maintenance was 23.8 months. During VT maintenance 7% of patients experienced grade 3–4 peripheral neuropathy, 5% grade 3–4 hematological toxicity, 3% grade 3–4 infection and 12% discontinued due to adverse events. Second primary malignancies were reported in 7/254 patients in the VMPT-VT group and 7/257 patients in the VMP group. These corresponded to incidence rates of 0.9 and 1.05 per 100 patient-years, respectively, and were consistent with background incidence rates in the general population (aged 65–74 years 1.9, aged ≥ 75 years 2.3, SEER database). Conclusions: VMPT-VT significantly prolonged OS compared with VMP, especially in patients younger than 75 years and in patients achieving CR after induction. In patients 67–75 years of age, VMPT-VT reduced the risk of death by 37% and it should be considered a new standard of care. Disclosures: Palumbo: Celgene: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Janssen: Advisory Board Other, Consultancy, Honoraria. Bringhen:Janssen: Honoraria; Celgene: Honoraria. Gentilini:Janssen: Honoraria; Celgene: Honoraria. Patriarca:Janssen: Honoraria. Guglielmelli:Janssen: Honoraria; Celgene: Honoraria. Musto:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Petrucci:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Consultancy, Research Funding, Scientific Advisory Board Other; Celgene: Consultancy, Research Funding, Scientific Advisory Board, Scientific Advisory Board Other.
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Evens, Andrew M., Kenneth R. Carson, Chadi Nabhan, Borko Jovanovic, Paul Barr, Lilia Gallot, Irene Helenowski, Paolo F. Caimi, Stephanie A. Gregory, and Leo I. Gordon. "Integration of Rituximab and Liposomal Doxorubicin (DOXIL®) Into CODOX-M/IVAC for HIV-Negative and HIV+ Adults with Untreated Burkitt's Lymphoma (BL): Results of a Prospective Multicenter Phase II Study." Blood 118, no. 21 (November 18, 2011): 2669. http://dx.doi.org/10.1182/blood.v118.21.2669.2669.
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Abstract Abstract 2669 Background: The survival of adult BL has improved with intensification of multi-agent chemotherapy, although 2-year survival rates remain <65–70%. Efforts to improve survival, as well as decrease treatment-related toxicities are needed. Further, there are no prospective clinical studies to date that have examined the addition of rituximab into the CODOX-M/IVAC regimen. Methods: Eligible patients for this investigator-initiated, 5-site phase II clinical trial included: newly diagnosed BL and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and BL (according to WHO 2008 definition) regardless of HIV status. Eligibility for HIV+ patients included: no evidence of multi-drug resistant HIV infection or concurrent AIDS defining illness and CD4 count >350/mcL. Patients were classified as low risk (LR) if they had all of the following factors present: 1) normal LDH, 2) stage I/II disease, 3) ECOG performance status (PS) <2, and 4) no mass >10 cm. All other patients were “high risk” (HR). LR patients received 3 consecutive cycles of CODOX-M, while HR patients received 4 alternating cycles of CODOX-M and IVAC. For CODOX-M, methotrexate 3.0 gram/m2 i.v. was used. Further, liposomal doxorubicin (40 mg/m2) was utilized in lieu of doxorubicin (day 1 of all CODOX-M cycles), while intravenous rituximab (500 mg/m2) was added to days 0 and day 8 of each CODOX-M cycle and days 0 and 6 of IVAC cycles. In addition, as a corollary analysis, frequent assessment of ejection fraction (EF) was performed in all patients (baseline, s/p 2 cycles, and 4 weeks after completion of therapy). Results: Twenty-five patients (22 male and 3 female) enrolled from March 2007 through April 2011. The median age was 44 years (range, 23–70 years). Furthermore, 5 (20%) patients were >60 years. All patients had classical BL, while 1 patient had concomitant BCL-2 expression. There were 20 HR and 5 LR patients; 3 of the HR and 1 LR patient were HIV+, while the remaining patients were HIV-negative. Median PS at study entry was 1, while PS=2 in 6 (24%) patients. Further, 3 (15%) HR patients had + central nervous system disease (2 parenchymal, 1 leptomeningeal). Additionally, 7 (35%) HR patients had bulky disease >10 cm (2 (10%) with dominant mass >20cm), 8 (40%) of all patients had bone marrow involvement, and 15 (75%) had an elevated LDH. 24 of 25 patients were evaluable for toxicity and response/survival. Therapy was completed at a median of 13.5 weeks (range, 11–20) for HR patients and a median of 10 weeks for LR (range, 9–12). With respect to toxicity, myelosuppression was overall comparable (58% of patients experienced grade 4 thrombocytopenia with only 4% grade 4 anemia) to prior CODOX-M/IVAC data, while the incidence of mucositis also appeared similar to prior reports (38% grade 3, 13% grade 4). Other clinically relevant grade 3 toxicities included neutropenic fever (33%), transaminitis (33%), diarrhea (8%), elevated creatinine (8%), and seizure (4%). Notably, there was no grade 3 or 4 neuropathy. After 2 cycles of therapy, two grade 2 and two grade 3 cardiac events were noted (all depressed EF, no clinical evidence of congestive heart failure). The two grade 3 events occurred in a 70-year-old and 69-year-old man, both with HR disease, and the latter with history of myocardial infarction. Among all patients, the median change in EF at baseline vs study end was: −2% (range, −22% to +11%). In terms of outcomes, the response rate after 2 cycles of therapy was 100% with a 67% complete remission (CR) rate. At a median follow-up of 24 months, the 2-year PFS and OS rates for all patients were 86% and 86%, respectively (LR 2-year PFS and OS both 100%; and HR 2-year PFS and OS both 82%). Furthermore, the 2-year PFS and OS rates for HR, HIV-negative patients were 91% and 91%, respectively (see Figure 1), while the disease-specific survival (DSS) for this subgroup of patients was 100%. Of the 3 deaths on trial, 2 were due to progressive disease in HIV+ HR patients, while the 3rd was a 71 year-old HIV-negative HR subject who died in CR at 14 months from unknown causes. Conclusions: Altogether, the integration of rituximab and liposomal doxorubicin into CODOX-M/IVAC for adult BL was feasible and associated with similar tolerability compared with prior reports. Additionally, this regimen was associated with excellent survival rates, especially for HIV-negative BL. Disclosures: Evens: Ortho-Biotec: Research Funding. Off Label Use: Doxil in the treatment of Burkitt's lymphoma. Carson:Genentech: Speakers Bureau. Nabhan:Genentech: Research Funding, Speakers Bureau. Gregory:Genentech: Advisory Board. Gordon:Genentech: Consultancy, Speakers Bureau.
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Liu, Yunpeng, Xiujuan Qu, Jinglei Qu, Jingdong Zhang, and Jing Liu. "Optimal cycles of fluoropyrimidine-based adjuvant chemotherapy for patients with resectable gastric cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15160-e15160. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15160.
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e15160 Background: Although several clinical trials have suggested that postoperative adjuvant chemotherapy could improve survival, there has no study on the optimal cycles of treatment. This retrospective analysis was carried out to evaluate the outcomes of gastric cancer patients treated with 5-6 cycles of FU-based treatment as compared to a cohort treated with 3-4 cycles or 7-8 cycles. Methods: We retrospective identified 254 patients with stage IB-IIIC gastric cancer who received 3-8 cycles of adjuvant chemotherapy after gastrectomy with D1 or D2 lymphadenectomy. The endpoint was overall survival. Factors associated with prognosis were also analyzed. Results: Of the 254 patients, 74 patients treated with 3-4 cycles, 112 patients treated with 5-6 cycles and 68 patients treated with 7-8 cycles. The 3-year OS rates for 3-4 cycles, 5-6 cycles and 7-8 cycles cohort was 56.6%, 73.9% and 67.7%, respectively. Patients who received 5-6 cycles were more likely to have better OS than those received 3-4 cycles (p=0.003), two further cycles of treatment did not improved OS (p=0.885). In the multivariate analysis, cycles of chemotherapy were associated with OS independent of clinical covariates (p=0.008). Subgroup analysis was suggested that for patients with older adult (age ≥60), FU-platinum combined chemotherapy, stage III, poorly differentiation, and gastrectomy with D2 lymph node dissection, 5-6 cycles of adjuvant chemotherapy was associated with a statistically significant benefit of OS (P<0.05). Conclusions: Our result indicated that 5-6 cycles of adjuvant chemotherapy may lead to a favorable outcome for gastric cancer patients following primary surgical treatment. In view of the limited resources of medication, reduced incidences of toxicity and better quality-of-life with shorter duration of treatment, optimal cycles of adjuvant treatment should be explored further.
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McHugh, Deaglan Joseph, Samuel Funt, Deborah Silber, Andrea Knezevic, Sujata Patil, Devon O'Donnell, Stephanie Tsai, et al. "Adjuvant etoposide plus cisplatin (EP) for pathologic stage (PS) II nonseminomatous germ cell tumor (NSGCT)." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 567. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.567.
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567 Background: The risk of relapse after primary retroperitoneal lymph node dissection (RPLND) for patients (pts) with PS IIA NSGCT is 10-20% and increases to over 50% for pts with PS IIB NSGCT. Cisplatin-based chemotherapy reduces the relapse risk to approximately 1%. Standard adjuvant chemotherapy regimens consist of 2 cycles of EP or 2 cycles of bleomycin plus EP (BEP). Methods: From March 1989 to April 2016, 156 pts with PS II NSGCT seen at Memorial Sloan Kettering Cancer Center and assigned to two cycles of EP chemotherapy following RPLND were included. Pts from a prior analysis (Kondagunta, JCO, 2004) were included with updated survival outcomes and expanded histopathologic parameters. Each cycle consisted of cisplatin 20mg/m2 and etoposide 100mg/m2 administered on days 1 to 5 at 21-day intervals. Demographics, histopathologic features, therapeutic and survival outcomes were recorded. Results: Median age was 28 years (range 15-52). 30 pts (19%) had pN1 disease, 122 (78%) pN2 disease and 4 (3%) pN3 disease. Median number of positive lymph nodes was 3 (range 1-37) and median size of the largest positive node was 2.0cm (range 0.4-7.0cm). 69 pts (45%) had extranodal tumor extension. Embryonal carcinoma, seminoma, mature teratoma and yolk sac were the predominant histological subtypes in the RPLND pathology in 115 (90%), 8 (6%), 4 (3%) and 1 (1%) pts respectively. 150 pts (96%) received 2 cycles of EP, 5 (3%) received 1 cycle of EP and one received 4 cycles of EP due to a transient marker increase following his first cycle. Dose delays occurred in 54 (38%) pts, mostly due to neutropenia (44/54 delays). With a median follow-up of 9 years, 2 pts (1 pN2 and 1 pN3) relapsed; both achieved a complete response to paclitaxel, ifosfamide and cisplatin (TIP), remaining disease-free at 65 and 143 months respectively. 3 pts died, all unrelated to GCT or treatment, for 10-year relapse-free and overall survival rates of 98% and 99%, respectively. Conclusions: This is the largest series reported to date on adjuvant chemotherapy with EP for PS II NSGCT. With 100% disease-specific survival and acceptable toxicity, these data confirm the efficacy of 2 cycles of EP and suggest that inclusion of bleomycin (e.g. BEP) in this setting is not necessary.
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Malpass, T. W., K. McGonigle, M. Roberston, P. Weiden, and H. G. Muntz. "Mature results of a phase II study of intraperitoneal topotecan as consolidation therapy in ovarian cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 5570. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5570.
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5570 Background: Previous studies with intraperitoneal (IP) topotecan have shown 20 mg/m2 to be well tolerated. This study evaluated the feasibility, safety, and effectiveness of IP topotecan as consolidation therapy for ovarian cancer. Methods: Patients with stage III/IV ovarian (or primary peritoneal) cancer in clinical complete response after cytoreduction and IV chemotherapy with carboplatin and paclitaxel who had benign findings or minimal persistent disease (<= 1 cm diameter) documented at second-look surgery were eligible. IP topotecan 20 mg/m2 was administered once every 21 days for 4 to 6 cycles. Dose reduction was based on grade 3–4 toxicities. Hematopoietic growth factors were used at the discretion of the treating physician. Results: Twenty patients were enrolled (18 ovarian and 2 peritoneal cancers). Sixteen patients received 4 cycles, 3 patients received 6 cycles, and 1 patient withdrew by personal request after 1 cycle. Of the total 83 cycles, 10 (12%) were delayed due to slow recovery of neutropenia, and 22 (27%) were administered with does reductions due to prior grade 3–4 myelosuppression. Mean delivered dose was 18 mg/m2. Major toxicities included episodes of neutropenia (6 grade 3; 3 grade 4) and thrombocytopenia (7 grade 3; 2 grade 4). Filgrastim was administered to 75% of patients in 51 (61%) cycles, and epoetin alfa was administered to 30% of patients in 20 (24%) cycles. Other adverse events (grade 1 or 2) that occurred in approximately half of patients included nausea and abdominal distension. Median progression-free survival was 24 months from second-look surgery (Kaplan-Meier, 95% CI 14–34 months). Sixteen patients (80%) are alive after median of 42 months from second look surgery (range, 29 to 62 months), with 4.5 year estimated overall survival of 84% (95% CI 68–100%) measured from original diagnosis. Conclusion: Consolidation IP topotecan 20 mg/m2 every 3 weeks for 4–6 cycles is feasible and well tolerated. Progression-free and overall survival in this pilot study compare favorably with results expected for advanced ovarian cancer. Future investigation of IP topotecan is warranted, both as consolidation therapy and salvage therapy for advanced ovarian cancer. No significant financial relationships to disclose.
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Fields, Paul, Andrew Webb, Christopher FE Pocock, William Townsend, Paul Smith, Amy Kirkwood, Nadjet El-Mehidi, et al. "First Analysis of a Phase II Study of Rituximab-Gemcitabine, Cyclophosphamide, Vincristine and Prednisolone (R-GCVP) for Diffuse Large B Cell Lymphoma (DLBCL) Patients Considered Unsuitable for Anthracycline Containing Chemo-Immunotherapy. An NCRI Lymphoma Clinical Studies Group Trial." Blood 118, no. 21 (November 18, 2011): 1634. http://dx.doi.org/10.1182/blood.v118.21.1634.1634.
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Abstract Abstract 1634FN2 Introduction: The treatment of patients with DLBCL who are unsuitable for anthracycline containing chemotherapy remains a clinical challenge. Gemcitabine is a nucleoside analogue which has proven efficacy in the relapse setting in both non Hodgkin's and Hodgkin's lymphoma. We therefore developed a protocol incorporating Gemcitabine in a first line approach combined with CVP-R chemo-immunotherapy in DLBCL patients considered unfit for anthracycline containing chemotherapy. Methods: We performed a prospective, multicentre phase II trial in patients with DLCBL who were considered unfit for anthracycline containing chemo-immunotherapy. Eligibility criteria included ejection fraction < 50%, or ejection fraction ≥ 50% but with the presence of attendant significant co-morbidities (including: ischaemic heart disease, hypertension, diabetes mellitus), and ECOG PS 0–3. Patients received 6 cycles of Rituximab (375 mg/m2 IV D1), Cyclophosphamide (750mg/m2 IV D1), Vincristine (1.4 mg /m2 IV D1), Prednisolone (100mg, orally D1–5) and Gemcitabine IV D1 and D8. The Gemcitabine dose, if tolerated was sequentially escalated from 750mg/m2 in cycle 1 to 875mg/m2 in cycle 2 to 1000mg/m2 in cycle 3 with the dose maintained at 1000mg/m2 for cycles 4–6. Cycles were repeated every 21 days with growth factor support administered on day 9 of each cycle (pegfilgrastrim 6mg s/c).The primary endpoint was to achieve an overall response rate of > 40% assessed by CT scan at the end of treatment according to the Cheson criteria. Secondary endpoints were progression free survival and overall survival. Results: 62 patients were recruited from 32 UK sites over a 28 month period from April 2008 to July 2010. 66% were male. Median age was 76 years (range 52–90), 48 (77%) were > 70 years. 43 (69%) had stage III/IV disease and 46 (72%) had high – intermediate or high IPI (3–5) disease. ECOG performance status was ≥ 2 in 50% patients. Left ventricular ejection fraction (LVEF) was < 50% in 28 patients (45%). The 34 patients with LVEF ≥ 50% had significant co-morbidities, 22 (65%) had multiple co-morbidities. 44 (70%) received ≥ 3 cycles of treatment, reasons for early termination of treatment in the remaining 18 patients were progression (n=2), toxicity (n=5), death (n=6) patient choice (n=1) and other (n=4). 29 patients (47%) received the full 6 cycles. A total of 250 treatment cycles were delivered. Of the 44 patients who received ≥ 3 cycles of treatment, the dose of Gemcitabine was escalated to the full dose (1000mg/m2) in 67%. Day 8 Gemcitabine was delivered in 215/250 (86%) cycles of treatment. The overall response rate (CR/CRu/PR) at end of treatment for all 62 patients was 60%. For patients who received ≥ 3 cycles of treatment (n =44) the ORR was 79.5% at the end of treatment. There was no significant difference in ORR between those with LVEF <50% and those with LVEF ≥ 50% (71% vs 53%, p=0.155). At a median follow up of 18.2 months the 1 year progression free survival rate for all patients was 52.9% (95% CI 39.4–64.8). The 1 year overall survival (OS) rate is 62.4% (95% CI 48.5–73.6). For the group with LVEF <50% OS was 70.8% (95% CI: 48.4, 84.9) and LVEF group ≥ 50% OS was 55.9% (95% CI 37.1–71).Grade 3/4 haematological toxicity was observed in 54.1% patients. Grade 3/4 infection was observed in 24.6% of patients. The death rate observed related to infection for the whole cohort was 11%. Conclusion: This multicentre trial demonstrates that the R-GCVP regimen delivers excellent overall response rates with durable remissions in a group of patients where anthracycline use was precluded. The efficacy attained in this difficult group of patients provides a platform for testing the regimen in subsequent randomised phase II and phase III studies to confirm its efficacy. Disclosures: No relevant conflicts of interest to declare.
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Reece, Donna E., Giovanni Piza, Suzanne Trudel, Mariela Pantoja, Christine Chen, Joseph R. Mikhael, Vishal Kukreti, and Keith Stewart. "A Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone for Relapsed/Refractory Multiple Myeloma." Blood 108, no. 11 (November 16, 2006): 3536. http://dx.doi.org/10.1182/blood.v108.11.3536.3536.
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Abstract Bortezomib (btz) has established efficacy in relapsed/refractory multiple myeloma (MM) patients (pts). Combinations of btz and other agents can produce even higher response rates. We have reported that oral cyclophosphamide (CY) + prednisone (P) produced partial remissions (PR) in 41% and a median progression free survival (PFS) of 18.6 mos in MM pts who had progressed after ASCT. We now report a phase I trial adding btz to CY + P in 27 patients with relapsed/refractory MM. CY was given p.o. once weekly on days 1, 8, 15, and 22 of a 28 day cycle while P 100 mg was given every other morning. CY was given before btz on appropriate days. A total of 8 cycles was planned. The median age was 59 yrs (48–74); 16 were male. Ig subtypes were: IgG (19 pts), IgA (4 pts), kappa light chain (4 pts). The median number of prior regimens was 2 (1–6); all had undergone prior ASCT and 59% had received thalidomide and/or lenalidomide. The median pretreatment β2-microglobulin was 228 nm/L (114–875), albumin 38 g/L (30–46) and creatinine 86 nmol/L (58–153). The dose escalation scheme and toxicity with cycle 1 is shown below: Table 1. Dose levels and toxicity Dose Level N CY dose (mg/m2) Btz dose (mg/m2) Gr 3–4 Toxicity (cycle 1) *Community acquired pneumonia without neutropenia; ** protocol amended to exclude G-CSF for 2 weeks before study entry. 1 6 150 0.7 d 1,8,15 2 CAP* 2 3 300 0.7 d 1,8,15 0 3 3 300 1.0 d 1,8,15 1 ↓ PO4 4 6 300 1.0 d 1,4,8,11 1 ↓ANC**; 1 ↑ AST/ALT 5 6 300 1.3 d 1,4,8,11 1 N/V 6 3 300 1.5 d 1,8,15 0 All the above toxicities above were gr 3 except for 1 transient episode of gr 4 hypophosphatemia. Dose limiting toxicity was not seen. The median number of protocol cycles given per pt was 7 (1–8); 1 pt chose to continue therapy and has received 15 cycles. Toxicities in cycles 2–8 were generally mild. Episodes of infection included shingles (5), gr 3 respiratory infection (6) and febrile neutropenia (2). A total of 168 cycles have been administered; the dose of CY was reduced in 5 cycles due to neutropenia (↓ANC) (3), thrombocytopenia (1) or increased AST/ALT (1), while the btz dose was decreased in 4 cycles due to gr 2 peripheral neuropathy (PN) (1) or ↓ANC (3). 12 pts have completed all 8 cycles, 5 are on therapy and 7 have progressed after a median of cycles 3 (1–7). 3 stopped protocol therapy (physician choice in 1 pt with minimal response, gr 2 PN in 2 pts (after 7 cycles at dose levels 2 and 5) including the pt with prior btz dose reduction. 14/15 pts treated at dose levels 4–6 (effective btz doses) were evaluable for response after receiving at least 2 cycles. Best response was CR/nearCR in 6 (43%) and PR in 7 (50%) for an overall response rate of 93%. The median follow-up is 12 mos (1–20). 6 pts have progressed after stopping therapy. The median PFS is 11 mos, while the median overall survival (OS) has not been reached. The actuarial 1 year OS and PFS are 83% (95% CI 61–93%) and 47% (95% CI 24–68%), respectively. 7 of 10 planned additional pts have entered the phase II portion of the trial at dose level 6. 3 have completed at least 2 cycles; 2 are in CR/near CR while one is in PR. We conclude: Btz 1.5 mg/m2 can be given safely on a convenient weekly schedule days 1, 8 and 15 of a 28 day cycle in combination with full dose oral CY + P in relapsed/refractory MM pts; preliminary response rates at this dose level include 4/6 (67%) CR/near CRs and 1/6 (17%) PR.
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., SUJATI. "UPAYA MENINGKATKAN KREATIVITAS ANAK USIA 3-4 TAHUN MELALUI MEDIA POPING (POHON PISANG) DI PPT MADANI KLAMPIS NGASEM SURABAYA." MOTORIC 4, no. 1 (June 28, 2020): 139–46. http://dx.doi.org/10.31090/m.v4i1.1023.
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The current phenomenon in the education system only emphasizes cognitive abilities. In connection with this, the researchers conducted research by developing the creativity of children in the 3-4 year age group at PPT Madani. The purpose of this study is to increase the creativity of students using POPING (banana tree) media.The type of research used was the design of Kemmis and Mc Taggart and carried out in two cycles. The data collection technique used was observation to determine the fluency and originality aspects and interviews to find out flexibility and elaboration. Data analysis techniques in this study are qualitative descriptive and quantitative description of percentages.The improvement results are shown in cycle I and cycle II are known to increase from 50% to 85%. It can be concluded that students' creativity in making toys from POPING (banana tree) is very high.
Keywords: creativity, POPING (banana tree)
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Jasielec, Jagoda K., Tadeusz Kubicki, Noopur Raje, Ravi Vij, Donna Reece, Jesus Berdeja, Benjamin A. Derman, et al. "Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma." Blood 136, no. 22 (November 26, 2020): 2513–23. http://dx.doi.org/10.1182/blood.2020007522.
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Abstract In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10−5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.
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Moliterni, A., M. Mansutti, D. Aldrighetti, L. Merlini, L. Zuccarino, M. Bari, A. Farris, P. Mariani, S. Fava, and L. Gianni. "Anthracycline-based sequential adjuvant chemotherapy in operable breast cancer: Five-year results of a randomized study by the Michelangelo Foundation." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 535. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.535.
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535 Background: Anthracycline-based sequential chemotherapy significantly improves efficacy outcomes compared to CMF alone. Methods: 806 eligible patients with operable breast cancer were enrolled into a randomized study (ratio 1:1:1:1) of sequential chemotherapy. In a 2×2-type design patients were allocated to first receive 4 cycles of AT (doxorubicin, A 60 mg/m2 iv + paclitaxel, T 200 mg/m2 as 3 h inf q 3wks) or EV (epirubicin, E 75 mg/m2 iv + vinorelbine, V 25 mg/m2 iv D1,8 q3wks) followed either by 4 monthly cycles of iv CMF or 6 cycles of q3w T alone (100 mg/m2 as 1h inf D1,8). Tamoxifen was recommended for 5 yr after chemotherapy in patients with HR+ tumors. Patients with tumors > 2 cm in diameter were allowed to start primary chemotherapy with 4 cycles of either AT or EV followed by surgery and postoperative systemic treatment as detailed above. Aim of the study was to test the role of T vs V when combined with an anthracycline during the first 4 cycles of the regimen as well as the role of CMF vs T during the last 4 cycles. Results: At a median follow-up of approximately 48 months, the 5 year freedom from progression (FFP) and overall survival (OS) for the main endpoints were as in the Table : The four treatment sequences were fairly well tolerated, with only 1 treatment-related death after EV. Type and severity of hematological toxicities were similar in all treatment arms. The incidence of reversible G2–3 neurotoxicity was 21.9% after AT, 5.3% after EV and 29.1% after sequential T. Chemical phlebitis was more frequent after EV (6.5%) then after AT (0.3). Conclusions: The results indicate that vinorelbine-epirubicin and classical CMF when appropriately used in a sequential modality for high-risk breast cancer are as valid and less neurotoxic an option of adjuvant therapy than the more widely used taxane-containing adjuvant regimens. Supported in part by Bristol-Myers Squibb, Pierre Fabre and Pharmacia. [Table: see text] [Table: see text]
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Fumoleau, Pierre, Pierre Kerbrat, Pascale Romestaing, Pierre Fargeot, Alain Brémond, Moïse Namer, Simon Schraub, et al. "Randomized Trial Comparing Six Versus Three Cycles of Epirubicin-Based Adjuvant Chemotherapy in Premenopausal, Node-Positive Breast Cancer Patients: 10-Year Follow-Up Results of the French Adjuvant Study Group 01 Trial." Journal of Clinical Oncology 21, no. 2 (January 15, 2003): 298–305. http://dx.doi.org/10.1200/jco.2003.04.148.
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Purpose: To evaluate the duration and dose intensity of epirubicin-based regimens in premenopausal patients with lymph node-positive breast cancer. Patients and Methods: Between 1986 and 1990, 621 patients with operable breast cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75). All patients in the three arms received chest wall irradiation at the end of the third cycle. Results: After a 131-month median follow-up, the 10-year disease-free survival (DFS) was 53.4%, 42.5%, and 43.6% (P = .05) in the three arms, respectively. Pairwise comparisons demonstrate that 6 FEC 50 was superior both to 3 FEC 50 (P = .02) and to 3 FEC 75 (P = .05). The 10-year overall survival (OS) for the 6 FEC 50 arm was 64.3%, for the 3 FEC 50 arm it was 56.6%, and for the 3 FEC 75 arm, it was 59.7% (P = .25), respectively. Pairwise comparisons demonstrate that 6 FEC 50 was more effective than 3 FEC 50 (P = .10). Cox regression analysis demonstrates that OS was significantly better in the 6 FEC 50 than in the 3 FEC 50 arm (P = .046). No severe infections (grade 3 to 4), acute cardiac toxicity, or deaths from toxicity have been observed. Only five patients developed delayed cardiac dysfunctions, and three patients developed acute myeloblastic leukemia. Conclusion: After a long-term follow-up in an adjuvant setting, the benefit of six cycles of FEC 50 compared with three cycles, whatever the dose, is highly significant in terms of DFS. As regards OS, the group receiving six cycles of FEC 50 has significantly better results than the group receiving three cycles of FEC 50.
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Woyach, Jennifer Ann, Kerry Anne Rogers, Seema Ali Bhat, James Stewart Blachly, Mojgan Jianfar, Melanie M. Frigault, Ahmed M. Hamdy, et al. "Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Three-year follow-up." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 7500. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7500.
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7500 Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor. This Phase 1b/2 trial evaluated acalabrutinib with the CD20 antibody Ob in TN and R/R CLL. Methods: Patient (pts) with TN and R/R (≥1 prior therapy) CLL were eligible. In 28-day cycles, acalabrutinib was given at 100 mg BID or 200 mg QD PO (n=15; all switched to 100 mg BID) until progressive disease (PD); Ob was given in standard fashion for 6 cycles starting with Cycle 2. The primary endpoints were overall response rate (ORR) and safety. Minimal residual disease (MRD) was assessed using flow cytometry (sensitivity 10-4). Results: 19 TN and 26 R/R pts were treated; median age of all pts was 61 y (range 42-76). Pt characteristics, disposition, efficacy and MRD are in the Table. Common adverse events (AEs; any grade) were upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%) and dizziness (47%). Common Gr 3/4 AEs were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight and cellulitis (9% each). There were 2 (4%) Gr 3 bleeding events (hematuria, muscle hemorrhage) and 1 (2%) Gr 3 atrial fibrillation event. Conclusions: Acalabrutinib plus Ob was well tolerated and yielded high response rates that were durable and deepened over time in TN and R/R CLL patients. Clinical trial information: NCT02296918. [Table: see text]
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Schild, Steven E., James A. Bonner, Shauna Hillman, Timothy F. Kozelsky, Antonio P. G. Vigliotti, Randolph S. Marks, David L. Graham, et al. "Results of a Phase II Study of High-Dose Thoracic Radiation Therapy With Concurrent Cisplatin and Etoposide in Limited-Stage Small-Cell Lung Cancer (NCCTG 95-20-53)." Journal of Clinical Oncology 25, no. 21 (July 20, 2007): 3124–29. http://dx.doi.org/10.1200/jco.2006.09.9606.
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Purpose To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). Patients and Methods A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). Results Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. Conclusion This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.
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Legrand, Ollivier, Maria B. Vidriales, Xavier Thomas, Charles Dumontet, Anne Vekhoff, Rodica Morariu-Zamfir, John Lambert, Jesus F. San Miguel, and Jean-Pierre Marie. "An Open Label, Dose Escalation Study of AVE9633 Administered as a Single Agent by Intravenous (IV) Infusion Weekly for 2 Weeks in 4-Week Cycle to Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia (AML)." Blood 110, no. 11 (November 16, 2007): 1850. http://dx.doi.org/10.1182/blood.v110.11.1850.1850.
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Abstract AVE9633/huMy9-6-DM4 is an immunoconjugate composed of a humanized monoclonal IgG1 antibody, huMy9-6, which specifically targets the CD33 antigen, conjugated through a disulfide link to the maytansine derivative DM4, a potent tubulin inhibitor. The CD33 antigen is expressed on the surface of myeloid cells. After the conjugate is bound to the CD33 antigen it is internalized and the cytotoxic is released within the target cell. We report preliminary results of the ongoing phase I dose escalation study of AVE9633 in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 and Day 8 of a 28-day cycle. To date, dose levels of 30 (n=1), 50 (n=3), 75 (n=3), 105 (n=3) and 130 (n=3) mg/m2 on Day 1 and Day 8 have been investigated. Patients received 1 (n=2), 2 (n=5), 3 (n=2) and 4 (n=4) cycles of AVE9633. No dose-limiting toxicity was noted so far. Nine patients experienced mild to moderate infusion reactions, mostly on Day1 of Cycle1. One patient at 130 mg/m2 presented grade 3 ALT elevation of 3 days duration. Free DM4, measured by LC/MS/MS was detectable at 105 and 130 mg/m2 in the range of 5 to 10 ng/mL. AVE9633/huMy9-6-DM4 exposure (measuring, by ELISA method, all antibodies containing at least one molecule of DM4) increased proportionally with the administered dose. Using Flow Cytometry Assay, saturation and down regulation of CD33 on peripheral and marrow blasts were observed from the dose of 50 mg/m2. There was one CRp in a 68-year old woman with refractory AML, achieved after 4 cycles of AVE9633 given at 105 mg/m2 × 2, with a 4-month continuing CRp as of 7/07 (she is receiving AVE9633 105 mg/m2 once monthly). One PR occurred in a 81-year old woman with refractory AML after one cycle at 130 mg/m2 × 2, persistent after the second cycle (third cycle is ongoing). Two patients had >50% decrease in bone marrow blasts, at 105 mg/m2 × 2 (from 25% to 8% after two cycles) and at 130 mg/m2 × 2 (from 35% to 9% after one cycle). One additional patient at 75 mg/m2 × 2 presented clearance of peripheral blasts by Day 10 of Cycle1. Mean DM4/IgG on the surface of peripheral blasts (available for one patient at 130 mg/m2) progressively decreased after the infusion, from 3.09 on day 1 to 0.28 on Day 8, and then increased to 2.64 after the second infusion of AVE9633 on Day 8. These preliminary results show that AVE9633 is well tolerated, with manageable safety profile, allowing outpatient treatment. Evidence of anti-leukemia activity was observed in 5 patients. The study is continuing with the evaluation of 150 mg/m2 × 2. Evaluation of closer drug administrations which might enhance efficacy appears warranted.
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Palumbo, Antonio, Sara Bringhen, Davide Rossi, Valeria Magarotto, Francesco Di Raimondo, Roberto Ria, Massimo Offidani, et al. "A Prospective, Randomized, Phase III Study of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Versus Bortezomib, Melphalan and Prednisone (VMP) in Elderly Newly Diagnosed Myeloma Patients." Blood 112, no. 11 (November 16, 2008): 652. http://dx.doi.org/10.1182/blood.v112.11.652.652.
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Abstract Background: In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Methods: Newly diagnosed myeloma patients (N=393) older than 65 years, from 58 centers in Italy, were randomly assigned to receive VMPT (N=193) or VMP (N=200). Initially, patients were treated with nine 6-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–42, followed by bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (bortezomib 1.3 mg/m2 days 1,8,15,22 in cycles 1–9). Primary end-point was progression-free survival (PFS). Results: Patient characteristics were similar in both groups: median age was 71 years, 23% of patients were aged > 75 years. Patients who received at least 1 cycle were evaluated: 152 patients for VMPT (62 received bortezomib bi-weekly infusion and 90 weekly infusion) and 152 patients for VMP (62 received bortezomib bi-weekly infusion and 90 weekly infusion). Data were analyzed in intention-to-treat. The very good partial response (VGPR) rate was higher in the VMPT group (55% versus 42%, p=0.02), including a CR rate of 31% in the VMPT group and 16% in the VMP group (p=0.003). In the subgroup treated with weekly infusion of bortezomib, VGPR was 59% for VMPT and 37% for VMP (p=0.004), including 28% CR for VMPT and 10% for VMP (p=0.004). Subgroup analyses did not show any statistical difference between responses and either age, B2-microglobulin or chromosomal abnormalities, such as del13, t(4;14), t(14;16) and del17. After a median follow-up of 13.6 months, the 2-year PFS was 83.9% in the VMPT group and 75.7% in the VMP group (HR=0.73, 95% CI 0.38–1.42, p=0.35). In patients who received weekly infusion of bortezomib, the 2-year PFS was 86.8% in the VMPT group and 78.1% in the VMP group (HR=0.65, 95% CI 0.24–1.8, p=0.41). In patients who achieved CR after induction, the 2-year PFS was 100% for VMPT and 79% for VMP (p=0.02). The 3-year overall survival (OS) was 89.5% in the VMPT group and 88.7% in the VMP group (HR=1.02, 95% CI 0.43–2.46, p=0.96). The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%), infections (14% vs 10%), and gastrointestinal complications (7% vs 8%), respectively. The weekly infusion of bortezomib significantly decreased the incidence of grade 3–4 peripheral neuropathy (9% for VMPT and 3% for VMP). Conclusion: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. The weekly infusion of bortezomib significantly reduced the incidence of grade 3–4 peripheral neuropathy without influencing outcome. Table. Complete responses, progression-free survival and peripheral neuropathy in all patients and in those who received weekly infusion of bortezomib VMPT group (n=152) VMP group (n=152) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) CR rate (%) 31 28 16 10 2-year PFS (%) 84 87 76 78 Grade 3–4 peripheral neuropathy (%) 18 9 12 3
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Tocque, K., and R. C. Tinsley. "The influence of desert temperature cycles on the reproductive biology of Pseudodiplorchis americanus (Monogenea)." Parasitology 103, no. 1 (August 1991): 111–20. http://dx.doi.org/10.1017/s0031182000059357.
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Pseudodiplorchis americanus has an extremely brief opportunity for transmission, restricted to less than 24 h in the year when the host (Scaphiopus couchii) enters water to breed. This strict annual cycle means that invading worms have 1 year to complete reproductive development. Despite this, a large proportion of the parasite suprapopulation is not prepared for transmission at the time of host breeding. The present study correlates detailed soil temperatures for one field site in S.E. Arizona, spanning 3·5 years, with laboratory data on parasite growth and reproductive development at a series of controlled temperatures. Development is totally inhibited at 16°C. Optimal growth and development occurs at 25°C and is slower at both 20°C and a diurnal cycle fluctuating between 20 and 34°C (mean 27°C) (simulating summer temperatures experienced by host and parasite). The effective period for accumulation of infective stages by P. americanus in any one season varies according to the timing of the summer rains in consecutive years. Between 1985 and 1988, the interval between host breedings varied from 11 to 13 months and the period when temperatures were above 20°C varied from 4 to 5·5 months per year. Since the first month post-infection (p.i.) consists of pre-reproductive development, first-year worms have only 3–4·5 months to produce infective larvae. In the shortest seasons, these worms may not be able to complete reproductive preparation in time for the first opportunity for transmission. In different parts of the geographical distribution of S. couchii, different cycles of temperature, rainfall and host breeding occur; varying temperature regimes represent an important abiotic control of P. americanus reproductive biology and transmission.
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Micciolo, Rocco, Christa Zimmermann-Tansella, Paul Williams, and Michele Tansella. "Seasonal variation in suicide: is there a sex difference?" Psychological Medicine 19, no. 1 (February 1989): 199–203. http://dx.doi.org/10.1017/s0033291700011156.
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SynopsisSeasonal variation in suicide in Italy for the years 1969–81 has been assessed in males and females by means of harmonic analysis. Cyclical fluctuations in the number of suicides, reasonably consistent over the 13 years of the study, have been observed in both sexes. Seasonal harmonics accounted for 65·3 and 48·4% of the variance in male and female suicides respectively. While in males the only important seasonal harmonic was the first (one cycle per year), in females there was an important first harmonic and a second harmonic (two cycles per year). In both sexes the peak of the first harmonic occurred in May, while in females the subsidiary peak occurred in October–November.
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Deotare, Uday, Marwan Shaheen, Joseph M. Brandwein, Bethany Gill, Suzanne Kamel-Reid, Karen W. L. Yee, Anna Rydlewski, et al. "Predictive Value of Molecular Remissions Post Consolidation Chemotherapy in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemias – a Single Centre Analysis." Blood 124, no. 21 (December 6, 2014): 3693. http://dx.doi.org/10.1182/blood.v124.21.3693.3693.
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Abstract Background: Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). Although this group represents a favorable cytogenetic AML subgroup, 30-40% of these patients nevertheless relapse after standard intensive chemotherapy. The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered as 2-4 repetitive cycles. Here we present retrospective data from a single centre, on this favourable AML subgroup. Methods: We analyzed retrospectively the outcome of 80 sequential patients with CBF-AML (46 t(8;21), 34 inv(16)/t(16;16)) treated over a 13 year period from 2000-2012. The median age was 48 years (range 20-80) with a median white cell count of 13x109/L(range 1-426x109/L). All patients underwent induction chemotherapy consisting of daunorubicin (60 mg/m2/d x 3 days) and continuous infusion cytarabine (100 or 200 mg/m2/d x 7 days, for ages <60y and ≥60y, respectively). Patients in CR then received 3 cycles of consolidation chemotherapy which included high dose cytarabine (3 or 1.5 g/m2 on days 1, 3 and 5, for ages <60y and ≥60y, respectively) with daunorubicin 45 mg/m2 on days 1 and 3 added during cycle 1. Results: Ninety percent of patients achieved morphological complete remission (CR) post induction, but 33.3% of these remained molecularly positive by quantitative reverse transcriptase polymerase chain reaction (qR-PCR). The majority of patients (93.6%) subsequently achieved molecular negativity by qR-PCR after the 3rd consolidation cycle. With a median follow-up of 5 years, the estimated 5-year relapse free survival (RFS) was 58% and 5-year overall survival (OS) was 66%. This is in keeping with the earlier AMLSG and UK MRC studies. Only 21% of patients relapsed and the median time to relapse was 10 months. Of the 16 patients who relapsed, 7 underwent allogeneic hematopoietic cell transplantation (HCT) from HLA- matched sibling or unrelated donors, and of these, 4 remain alive and in remission with a median follow up of 8 years. While relapse occurred in 2 of the 4 patients who did not achieve a molecular CR after 3 cycles of consolidation, 13 of 16 relapsing patients had been in a molecular CR after final consolidation and one patient was not evaluated. Therefore, molecular remission post consolidation does not guarantee long term disease free survival. Further molecular analyses and the roles of additional mutations in predicting relapse will be presented. Conclusion: Sustained remissions can be achieved in patients with CBF AML after 3 cycles of high dose cytarabine consolidation, but post consolidation molecular remission does not necessarily preclude relapse. Comprehensive molecular profiling may be better in predicting relapse risk in this group of patients. Table1: Patient characteristics & response N=80 Sex 45 M : 35 F Median age, years (range) 48 (20-80) WBC at diagnosis (x106 cells/L) (range) 13 (1-426) Cytogenetics t(8;21) inv16/t(16;16) 46 (58%) 34 (42%) Response post-induction chemotherapy CR Primary refractory 72 (90%) 8 (10%) Number of consolidation cycles (range) 3 (2-4) Molecular CR post –induction Yes No Not evaluated 16 (20%) 32 (40%) 32 (40%) Molecular CR post –consolidation –cycle 3 Yes No Not evaluated 59 (74%) 4 (5%) 17 (21%) Relapse Yes No Unknown 16 (20%) 59 (74%) 5 (6%) Median time to relapse, months (range) 10 (6-17) Median time to follow up, y (range) 5 (0.5-11.5) Figure 1 : Overall and Relapse free survival in CBF-AML patients. Figure 1 :. Overall and Relapse free survival in CBF-AML patients. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.
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Hügli, A., D. Moro, B. Mermillod, M. Bolla, P. Alberto, H. Bonnefoi, and R. Miralbell. "Phase II Trial of Up-Front Accelerated Thoracic Radiotherapy Combined With Chemotherapy and Optional Up-Front Prophylactic Cranial Irradiation in Limited Small-Cell Lung Cancer." Journal of Clinical Oncology 18, no. 8 (April 8, 2000): 1662–67. http://dx.doi.org/10.1200/jco.2000.18.8.1662.
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PURPOSE: To investigate the feasibility and outcome of bifractionated, up-front thoracic radiotherapy (TR) (45 Gy in 30 fractions of 1.5 Gy twice daily over 3 weeks) combined with chemotherapy (CT) (six cycles of cisplatin and etoposide) and optional low-dose, up-front prophylactic cranial irradiation (18 Gy in 10 fractions of 1.8 Gy twice daily over 5 days) in limited small-cell lung cancer. PATIENTS AND METHODS: CT (etoposide 100 mg/m2 for 3 days and cisplatin 25 mg/m2 for 3 days) was started on day 8 or 15 after the first TR treatment. In the five subsequent cycles, cisplatin was given as a single 100-mg/m2 dose on day 1 every 4 weeks. A total of 52 patients were entered (41 men and 11 women); the median age was 55 years (range, 33 to 67 years). World Health Organization performance status was 0 in 34 patients, 1 in 16 patients, and 2 in two patients. Thirty-six patients (69%) received the full planned six cycles of CT. RESULTS: All treated patients were assessable for response. Thirty-one patients (60%) achieved a complete response, and 16 (30%) had a partial response. One-, 3-, and 4-year survival rates were 74% (95% confidence interval [CI], 60% to 84%), 34% (95% CI, 21% to 49%), and 32% (95 CI, 16% to 46%), respectively. The median survival time was 18 months. Event-free survival at 1 year was 45% (95% CI, 32% to 58%) and at 3 years, 30% (95% CI, 18% to 44%). The main radiation-related acute toxicity was esophageal: 38% of the patients experienced grade 3 or 4 acute toxicity. CT was well tolerated. Although grade 3/4 neutropenia was observed in 86% of the patients, only 4% presented with associated fever. Grade 3/4 nausea and vomiting was seen in 35% of patients. CONCLUSION: This trial demonstrates that up-front accelerated TR associated with CT is feasible, has acceptable toxicity, and shows considerable long-term survival potential.
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Schmitz, Norbert, Maike Nickelsen, Marita Ziepert, Matthias Haenel, Peter Borchmann, Andreas Viardot, Christina Nickenig, et al. "Aggressive Chemotherapy (CHOEP-14) and Rituximab or High-Dose Therapy (MegaCHOEP) and Rituximab for Young, High-Risk Patients with Aggressive B-Cell Lymphoma: Results of the MegaCHOEP Trial of the German High — Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)." Blood 114, no. 22 (November 20, 2009): 404. http://dx.doi.org/10.1182/blood.v114.22.404.404.
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Abstract Abstract 404 Comparison of conventional chemotherapy with high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) administered to young, high-risk patients with aggressive B-cell lymphoma as part of first-line therapy gave conflicting results; none of the randomized studies used rituximab (R) in combination with conventional or HDT. In March 2003 we started a randomized phase III study for young (18-60 years), high-risk (age-adjusted IPI 2 or 3) patients with aggressive lymphoma. For patients with B-cell lymphomas this study compared 8 cycles of CHOEP-14 (CHOP + etoposide 300 mg/m2 given every 2 weeks) with MegaCHOEP. The MegaCHOEP program used cyclophoshamide (1500 mg/m2 in cycle 1; 4500 mg/m2 in cycles 2 and 3; 6000 mg/m2 in cycle 4), doxorubicin (70 mg/m2 in all cycles), vincristine (2 mg, all cycles), etoposide (600 mg/m2 , cycle 1; 960 mg/m2 , cycles 2 and 3; 1480 mg/m2, cycle 4), and prednisone (500 mg, all cycles) to be administered every 21 days. Hematopoietic stem cells were harvested after cycles 1 and 2 and reinfused after HDT cycles 2, 3, and 4. Feasibility, safety, and efficacy of MegaCHOEP + / - R have been described (Glass et al. Blood 2006 and BMT 2006). The phase III study originally had four arms (8 × CHOEP – 14, 8 × CHOEP – 14 and 6 × R, MegaCHOEP, and MegaCHOEP and 6 × R). Treatment arms without R were closed in June 2004 because other studies (e.g the MInT study) had shown major improvement in outcome parameters when R was added to chemotherapy. The study continued comparing 8 × CHOEP – 14 and 6 × R (375 mg/m2) with MegaCHOEP and 6 × R (375 mg/m2). At the time of this analysis 346 patients (pts) had been recruited; 216 pts. (median age 48 years, LDH > N 97 %, stage III or IV 96%, ECOG > 1 35%) had been randomized until 07 / 07 and were availabel for this planned interim analysis ( 8 × CHOEP – 14 + 6 × R, n = 91; MegaCHOEP + 6 × R, n = 94; 8 × CHOEP – 14, n = 15; MegaCHOEP, n = 16). Major toxicities included mucositis, diarrhea, and infections all of which were significantly more frequent in the MegaCHOEP arm of the study. Treatment – related deaths occurred in 5 / 94 pts. ( 5.3%) in the MegaCHOEP arm and in 1 / 91 pts. (1.1 %) in the R – CHOEP arm (p = 0.211). Surprisingly, the 3 – year event – free survival ( EFS : time from randomization to either disease progression, no CR / CRu at the end of treatment, initiation of salvage therapy, relapse or death from any cause) was better after conventional than after HDT / ASCT: 71.0% after 8 × CHOEP-14 + 6 × R vs. 56.7 % after MegaCHOEP + 6 × R (p = 0.050). After a median observation time of 29 months the estimated 3-year overall survival was 83.8 % after 8 × CHOEP – 14 + 6 × R and 75.3 % after MegaCHOEP + 6 × R (p = 0.142). Progression – free survival was 76.0 % after 8 × CHOEP – 14 + 6 × R and 64.6 % after MegaCHOEP + 6 × R (p = 0.119). A comparison of the rituximab-containing treatment arms (8 × CHOEP 14 + 6 × R and Mega CHOEP + 6 × R) with the chemotherapy – only arms (8 × CHOEP -14 and MegaCHOEP) revealed a 27.1 % difference in the 3-year EFS-rate ( p = 0.003 ) pointing to the unexpectedly high efficacy of R particularly in untreated, young, high-risk patients with aggressive B-NHL. These data were presented to the members of the study group and the data safety and monitoring committee who decided to stop the MegaCHOEP arm of the study. In conclusion, 8 × CHOEP -14 + 6 × R gave excellent results in young, high-risk patients with untreated aggressive B cell lymphoma. The 3-year EFS and OS are the best ever reported for this group of patients. MegaCHOEP + 6 × R was no better than aggressive conventional chemotherapy regarding any of the study endpoints; EFS (primary endpoint of the study) was significantly worse. Because of higher toxicity and inferior survival the MegaCHOEP arm was discontinued. HDT / ASCT has no role to play as part of first-line therapy for patients with high-risk aggressive B cell lymphoma if rituximab is combined with aggressive conventional chemotherapy. Disclosures: Schmitz: Roche: Honoraria, Research Funding. Nickelsen:Roche: Honoraria. Trümper:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Research Funding. Glass:Roche: Honoraria, Research Funding.