Rituximab-PECC induction followed by 90 Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of 90 Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after 90 Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of 90 Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.

Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial.

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B).

BACKGROUND: The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. PATIENTS AND METHODS: Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. RESULTS: A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). CONCLUSION: In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial.

BACKGROUND: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. METHODS: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. FINDINGS: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). INTERPRETATION: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. FUNDING: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA.

BACKGROUND: As rituximab combined with CHOP improves complete remission and overall survival in diffuse large B-cell lymphoma, intensified chemotherapy followed by autologous stem-cell transplantation has also been advocated for high-risk patients. The aim of this study was to establish whether or not combining rituximab with high-dose chemotherapy and auto-transplantation also benefits patient survival. DESIGN AND METHODS: The LNH2003-3 study was a phase II trial including diffuse large B-cell lymphoma patients with 2 or 3 International Prognostic Index factors. They received four cycles of intensive biweekly chemotherapy with rituximab, doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) followed by auto-transplantation in responding patients. Two hundred and nine patients under 60 years of age were included in the study and 155 responding patients underwent auto-transplantation. In addition, a case-control study was performed by matching (1:1) 181 patients treated with R-ACVBP with ACVBP patients not given rituximab but submitted to auto-transplantation from the previous LNH1998-3 trial. RESULTS: With a median follow up of 45 months, 4-year progression-free survival and overall survival were estimated at 76% (CI: 69-81) and 78% (CI: 72-83), respectively. There was no difference between patients with 2 or 3 International Prognostic Index factors. Four year progression-free survival was significantly higher in R-ACVBP than ACVBP patients (74% vs. 58%; P=0.0005). There was also a significant increase in 4-year overall survival (76% vs. 68%; P=0.0494). CONCLUSIONS: In high-risk diffuse large B-cell lymphoma patients, treatment with R-ACVBP followed by auto-transplantation results in a 78% 4-year overall survival which should be compared to other approaches.

Neoadjuvant transcatheter arterial chemoembolization and systemic chemotherapy for treatment of clear cell sarcoma of the kidney in children.

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is a rare and aggressive malignant renal tumor. We describe our experience with neoadjuvant transcatheter arterial chemoembolization (TACE) and systematic chemotherapy for the treatment of advanced CCSK in children. METHODS: Between January 2010 and December 2016, seven patients (3 boys and 4 girls; median 2.2 years) with advanced CCSK received preoperative TACE of renal artery and systemic chemotherapy. The chemoembolic emulsion for TACE consisted of cisplatin, pirarubicin, vindesine, and iodized oil. Preoperative systemic chemotherapy with vindesine, ifosfamide, and etoposide was administered three weeks after TACE. Nephrectomy was performed three weeks after systemic chemotherapy. After surgery, patients received radiotherapy and postoperative chemotherapy. RESULTS: No cardiotoxicity, renal insufficiency, or hepatic dysfunction was found in any patients. Grade II-III marrow suppression developed in four patients. One patient with tumor progress during neoadjuvant therapy failed to successfully undergo surgery and died. Six patients underwent nephrectomy after neoadjuvant therapy. Median follow-up period was 49.5 months (range, 11-83 months). Five patients have recurrence-free survival. One patient is still in postoperative chemotherapy after nephrectomy, radiotherapy and thoracoscopic resection of lung metastases. CONCLUSIONS: Neoadjuvant TACE and systemic chemotherapy appeared to be feasible in the treatment of advanced CCSK in this pilot study. THE TYPE OF STUDY: A case series with no comparison group. LEVEL OF EVIDENCE: Level IV.

Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support.

BACKGROUND: The efficacy of first-line intensive chemotherapy plus transplantation of autologous hematopoietic stem cells in adults with disseminated aggressive lymphoma is unknown. METHODS: We compared high-dose therapy plus autologous stem-cell support with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in a randomized trial. The patients were 15 to 60 years of age, had untreated aggressive lymphoma, and were at low, low intermediate, or high intermediate risk of death (i.e., a maximum of two adverse prognostic factors) according to the age-adjusted International Prognostic Index. The primary outcome was event-free survival at five years. RESULTS: Of 207 consecutive patients, 197 underwent randomization; 99 were assigned to receive CHOP, and 98 to receive high-dose chemotherapy plus stem-cell transplantation. Overall, 78 percent of the patients completed the assigned treatment; the median follow-up was four years. The estimated event-free survival rate (+/-SD) at five years was significantly higher among patients who received high-dose therapy than among patients who received CHOP (55+/-5 percent vs. 37+/-5 percent, P=0.037). Among patients with a high intermediate risk of death, according to the age-adjusted International Prognostic Index, the five-year survival rate was significantly higher after high-dose therapy than after CHOP (74+/-6 percent vs. 44+/-7 percent, P=0.001). CONCLUSIONS: High-dose chemotherapy with autologous stem-cell support is superior to CHOP in adults with disseminated aggressive lymphoma.

Razoxane and vindesine in advanced soft tissue sarcomas: impact on metastasis, survival and radiation response.

BACKGROUND: The treatment options in advanced soft tissue sarcomas (STS) are limited. In a pilot study, an antimetastatic and radiosensitizing treatment concept was explored. PATIENTS AND METHODS: Twenty-one patients with unresectable and/or oligometastatic STS received the drugs razoxane and vindesine supported by radiotherapy and surgery. Long-term treatment was intended in metastatic disease. Forty-one patients with comparable stages of STS treated with contemporary chemotherapy served as non-randomised controls. The prognostic parameters of the groups were comparable. RESULTS: In the study group, the median number of new metastases after 6 months was 0 (range, 0-40) and after 9 months likewise 0 (0-70). The corresponding numbers in the control group were 4.5 (range, 0-40) and 9 (0->100) (p<0.001). The progression-free survival at 6 months was 71% in the study group and 23% in the controls, and the median survival time from the occurrence of the first metastasis was 16 months versus 9 months. The rate of major responses under radiotherapy combined with razoxane and vindesine was 88%, and in the control group 62% (p=0.007). The combined treatment was associated with a low to moderate toxicity. CONCLUSION: The treatment combination inhibited the development of remote metastases in the majority of patients with STS and prolonged survival to some extent.

A phase II study of VEPA/FEPP chemotherapy for aggressive lymphoma in elderly patients: Japan Clinical Oncology Group Study JCOG9203.

The Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group conducted a phase II trial of LSG12 therapy for 45 elderly patients with aggressive lymphoma to clarify whether LSG12 reduces severe infection without lowering the complete response (CR) rate in comparison with LSG4. LSG12, which consisted of a regimen of vincristine, cyclophosphamide, prednisolone, doxorubicin, vindesine, etoposide, and procarbazine (VEPA/FEPP), excluded bleomycin and methotrexate of LSG4 therapy, reduced the dosages of doxorubicin and cyclophosphamide, and increased etoposide and procarbazine dosages instead. Inclusion criteria consisted of a patient age of 70 to 75 years, a World Health Organization performance status of 0 to 2, and acceptable organ function. The treatment was completed in 47% of the patients and terminated early for disease progression in 20% and for toxicity in 16%. The CR rate was 60% (95% confidence interval [CI], 44%-74%). The 5-year overall survival (OS) rate was 42% (95% CI, 27%-57%), and the median OS time was 4.3 years. Leukopenia of grade 3 to 4 occurred in 98% of the patients, and severe infection occurred in 9%. Eight patients with hepatitis C virus (HCV) antibody showed no severe hepatic toxicity and had a better CR or OS rate than the 37 HCV-negative patients. Although the outcomes of LSG12 met our expectations with a reduction in severe infection and equivalent CR and OS outcomes compared with LSG4 and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), the possibility of a regimen more beneficial than LSG12 for aggressive lymphoma in the elderly patient should be explored because of frequent hematologic toxicity and poor compliance in LSG12.

Fatal accidental intrathecal injection of vindesine.

A 25-year-old woman being treated for non-Hodgkin's lymphoma was accidentally given vindesine intrathecally. The error was recognized immediately and a spinal cord washing was performed through syringing with isotonic saline. However, the patient died 6 weeks later with increasing paralysis, which was followed by neurologic failure. The deceased was autopsied and the central nervous system was removed for a microscopic examination. The results showed microscopic lesions extending from the lumbar to the thoracic portion of the spinal cord, which included pseudocystic transformation of the cells, degeneration of myelin, and microhemorrhages. The brain was edematous and, in the cerebellum, the vermis showed a loss of granule and Purkinje cells. The authors compare this report on vindesine toxicity with cases in the literature involving vincristine. The treating physician admitted responsibility and was sentenced to both a fine and imprisonment.

Comparison of vindesine and prednisone and cyclophosphamide, etoposide, vindesine, and prednisone as first-line treatment for adult Langerhans cell histiocytosis: A single-center retrospective study.

OBJECTIVE: We compared the efficacy and clinical outcomes of vindesine and prednisone (VP) and cyclophosphamide, etoposide, vindesine, and prednisone (CEVP) regimens as first-line treatment for multisystem (MS) or multifocal single system (SS-m) adult Langerhans cell histiocytosis (LCH). METHOD: Clinical features, treatment response, and survival of adults with Langerhans cell histiocytosis treated at our center from January 2001 to January 2015 were reviewed retrospectively. RESULTS: Forty-five adult MS or SS-m LCH patients were treated (N=31, CEVP group; N=14, VP group). Both treatment groups had similar gender distributions, patient ages, and extent of disease. The non-active disease rate for both groups was 70.0% and 64.3% (P=0.775), respectively. Median follow-up was 74.9 (range: 2.8-183.6) months and recurrence rates were 71.0% and 78.6% (P=0.593), respectively. The need for second-line therapy was 64.5% and 71.4% (P=0.649), respectively, and mortality rates were 9.7% and 15.4% (P=0.586), respectively. Neutropenia occurred in 48.4% of CEVP-treated patients and 7.1% of VP-treated patients (P=0.008). CONCLUSIONS: CEVP or VP regimens for the treatment of adult SS-m or MS LCH showed similar efficacies, and both regimens were associated with high disease recurrence and the need for second-line therapy.

Phase II study of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer. Southern Osaka Lung Cancer Study Group.

PURPOSE: To evaluate the response rate, toxicity, and 2-year survival rate of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between July 1989 and October 1990, 65 patients with histologically or cytologically proven unresectable stage III NSCLC without T3N0-1M0 disease were entered onto this study. Sixty-one patients were eligible for response, survival, and toxicity analysis. Chemotherapy consisted of vindesine (3 mg/m2 on days 1, 8, 29, and 36), cisplatin (100 mg/m2 on days 1 and 29), and mitomycin (8 mg/m2 on days 1 and 29). Radiotherapy was administered for 3 weeks (2 Gy given 13 times, five fractions per week), followed by 10-day rest periods and then the previous schedule of radiotherapy repeated for 3 weeks. RESULTS: Of 61 eligible patients, 53 (86.9%) had a partial response (PR). The median response duration was 39.1 weeks (range, 8.4 to 163+). The median survival time was 16 months and the 2-year survival rate was 36.7%. Of 53 responding patients, 10 (16.4%) are alive and disease-free after 2 years. The major toxicity was leukopenia (> or = grade 3, 95%). Other toxicities of > or = grade 3 included thrombocytopenia (45%), anemia (28%), nausea/vomiting (16%), fever (11%), and esophagitis (6%). Treatment-related death occurred in two patients. One patient died of pulmonary toxicity (interstitial pneumonitis) and the other of esophagobronchial fistula with pulmonary infection. CONCLUSION: Concurrent radiotherapy plus chemotherapy with mitomycin, vindesine, and cisplatin (MVP) can be safely administered to patients with stage III NSCLC, with excellent response rates and 2-year survival rates.

Chemotherapy for adenocarcinoma of the lung (WHO III): A randomized study of vindesine versus lomustine, cyclophosphamide, and methotrexate versus all four drugs.

Two hundred seventy-nine patients with previously untreated nonresectable adenocarcinoma of the lung (ACL) entered a prospective randomized trial, comparing vindesine (VDS) to a combination of lomustine (CCNU), cyclophosphamide (CTX), and methotrexate (MTX), and to a regimen including all four drugs. Response assessment was possible in 218 patients, while 259 were evaluable for survival. Response rates were similar (22%, 23%, and 27%, respectively) as were median durations of response (15 weeks overall) and survival (29 weeks overall). Patients with dose-limiting toxicity had significantly higher response rate and longer survival than patients without toxicity. The major toxicity was peripheral neuropathy with VDS treatment and myelosuppression with the other two regimens. The VDS single-agent activity in ACL was confirmed, but addition of VDS to the three-drug regimen did not increase activity. Future studies of VDS in combination with other active agents, and comparison to a matched control group on supportive care, are indicated.

Randomized comparison of two combination regimens versus minimal chemotherapy in nonsmall-cell lung cancer: a Southeastern Cancer Study Group Trial.

Patients with advanced nonsmall-cell lung cancer (NSCLC), good performance status, and no prior chemotherapy were randomized to receive one of three regimens: intravenous vindesine (V) 3 mg/m2 every 2 weeks; V 3 mg/m2 weekly for 5 weeks, followed by a dose every 2 weeks plus mitomycin (VM) 20 mg/m2 day 1 and then 15 mg/m2 every 6 weeks; or V at the more intensive dose rate plus cisplatin (VC) 120 mg/m2 with forced diuresis on days 1 and 29 and then every 6 weeks. A total of 435 patients were enrolled in the trial, with 410 (94%) assessable for prognostic characteristics and survival. Among the 375 patients assessable for response, only 58 (15%) achieved objective response. Single-agent V every 2 weeks was inactive (response rate less than 1%), effectively acting as a no-treatment arm. Among assessable patients receiving VM, 33 (27%) responded; among patients receiving VC, 24 (19%) responded. There was no statistically significant survival difference among the treatment arms, with median survival among those treated with V 14.8 weeks, VM 20.4 weeks, and VC 24.7 weeks; VC achieved borderline significance (P = .06) compared with V. In a prognostic factor analysis, treatment was not a significant factor (P = .447) for survival. Thus, in this large multicenter trial, neither a high-dose cisplatin combination nor a noncisplatin regimen (VM) with a comparable response rate had a significant survival advantage over minimal chemotherapy. New approaches are needed in advanced NSCLC.

Rapidly alternating chemotherapy and hyperfractionated radiotherapy in the management of locally advanced head and neck carcinoma: four-year results of a phase I/II study.

PURPOSE: Treatment of locally advanced head and neck carcinoma by surgery and/or radiotherapy is associated with a high recurrence rate, poor survival, and, often, limitation in speech and swallowing functions. Because prolonged time of treatment might be detrimental for tumor control, we designed a study to develop a schedule of alternating radiotherapy and chemotherapy that should be administered over the shortest period of time and with the highest dose of radiotherapy as possible. PATIENTS AND METHODS: Following four successive steps of schedule modifications, regimens alternating split hyperfractionated radiotherapy (2.0 Gy/d times three over 30 to 40 days, to a total of 48 Gy to 60 Gy) and chemotherapy (cisplatin 80 to 100 mg/m2 and fluorouracil 1,000 mg/m2 by continuous infusion for 3 to 4 days, +/- vindesine 8 mg/m2 for two cycles) were administered in 91 patients with advanced squamous cell carcinoma of the head and neck. Adenectomy was performed for residual nodes and major surgery for progression only. RESULTS: The overall response rate was 95.6% (95% confidence interval [CI], 89.1 to 98.8), with 69.2% complete and 26.4% partial responses. Among partial responders, two patients were converted into complete responders by resection of a residual node. With a median follow-up duration of 45 months, distant mestastases occurred in 18% and a second primary tumor in 7.7% of patients. The median overall survival (OS) and progression-free survival (PFS) durations were 24 months and 17 months, respectively. At 4 years, the survival rate was 40%. All of the locoregional recurrences occurred within the first 15 months, in 14% and 73% of the complete and partial responders, respectively. Mucositis was the dose-limiting toxicity, with a World Health Organization (WHO) grade III and IV rate of 81% at a 60-Gy dose of radiotherapy, compared with 65% at 48 Gy or 54 Gy, which precluded further dose escalation. Leukopenia was severe in the first two steps of treatment, with WHO grade IV toxicity occurring in 41% of patients; however, this decreased to 10% when vindesine was deleted from the chemotherapy regimen in the last two steps. Late toxicity in 29% of patients was not different from that expected with radiotherapy alone. Among patients with resectable tumors, a 64% rate of organ preservation was obtained. CONCLUSION: We demonstrated that a full dose of hyperfractionated radiotherapy alternated with chemotherapy over 40 days could produce high antitumor activity. Mucositis was the dose-limiting toxicity, but this resolved completely within a median period of 6 weeks.

MOPP/EBV/CAD hybrid chemotherapy with or without limited radiotherapy in advanced or unfavorably presenting Hodgkin's disease: a report from the Italian Lymphoma Study Group.

PURPOSE: We explored the feasibility, toxicity, and preliminary results of a chemotherapy (CT) regimen, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), derived through hybridization, shortening, and intensification of a corresponding 10-drug alternating combination CAD/MOPP/doxorubicin, bleomycin, and vinblastine (ABV), effective in treatment of advanced Hodgkin's disease (HD). PATIENTS AND METHODS: Hybridization involved all drugs except CCNU and mechlorethamine, which were administered in alternating cycles; the length of therapy was reduced from nine to six cycles. The average projected drug doses during the six cycles were increased by 42%, with an overall 1.54 dose-intensification; epidoxorubicin was substituted for doxorubicin at equivalent tumoricidal doses. Radiotherapy (RT) was optional and its indications were limited. RESULTS: Eighty assessable patients with previously untreated, advanced or unfavorably presenting HD were treated in nine cooperating institutions between 1988 and 1991. RT was delivered to 22 patients. Remissions were complete (CR) in 75 patients (93%), partial in three (4%), and null in two (3%). The median relative dose-intensity was 0.71 for the overall regimen. Three of five patients who failed to achieve CR, and two of the four who relapsed, received lower relative dose-intensive cycles. Nonhematologic toxicity was acceptable, but there was considerable hematologic toxicity. Fatal gastrointestinal bleeding was seen in one patient. CONCLUSION: Caution is advised due to the short median follow-up period. Nevertheless, in addition to the excellent response rate, (1) the results were reached through abbreviation, intensification, and hybridization of an existing alternating regimen; (2) RT had limited use in this program, which may have contributed to lowering the risk of second tumors; and (3) the results were obtained in a multicenter study (a condition that often impairs results from clinical trials).

Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non-small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group.

PURPOSE: In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non-small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen. PATIENTS AND METHODS: One hundred eleven chemotherapy-naive patients, age < or = 70 years, with stage IIIB or IV NSCLC and a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM 1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57 patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally 150 mg three times daily (54 patients). In December 1996, randomization was stopped early, and an additional 30 patients were treated with the experimental regimen to obtain a more accurate estimation of its activity rate. RESULTS: Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms. CONCLUSION: The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.

Docetaxel: new indication. First-line treatment of non small-cell lung cancer: no advance.

(1) The reference first-line drug therapy for patients with non-operable non small-cell lung cancer is a combination of two cytotoxic agents, one of which is a platinum compound. The survival benefit is no more than a few months. (2) The docetaxel + cisplatin combination has now been authorised in France for first-line treatment of locally advanced and metastatic non small-cell lung cancer. Evaluation data includes the results of three comparative trials. (3) In one trial the docetaxel + cisplatin combination was no more effective than the docetaxel + carboplatin combination or the vinorelbine + cisplatin combination on either the survival time (9.4 to 11.3 months) or on other endpoints. (4) Similar results were obtained in a trial versus paclitaxel + cisplatin and gemcitabine + cisplatin (median survival time 8 months in each group). (5) In a trial versus vindesine + cisplatin, the median survival time was longer with docetaxel + cisplatin (11.3 versus 9.6 months). (6) It is difficult to analyse adverse effects in these unblinded trials. Globally, the docetaxel + cisplatin combination did not appear to be safer than the comparator combinations, particularly with regard to serious events. (7) Docetaxel, like paclitaxel, is infused intravenously every three weeks. The comparator combinations tested in the three clinical trials are infused once a week. (8) In practice, for first-line treatment of inoperable non small-cell lung cancer, the docetaxel + cisplatin combination is simply one of several options, and offers no advantages in terms of survival or adverse effects.

Comparison of Gefitinib versus VMP in the combination with radiotherapy for multiple brain metastases from non-small cell lung cancer.

The purpose of this study is to compare the efficacy and safety of Gefitinib versus VMP in combination with three-dimensional conformal radiotherapy (3D-CRT) for multiple brain metastases from non-small cell lung cancer (NSCLC). A total of 73 NSCLC patients with brain metastases from January 2010 to August 2013 were randomly divided into Gefitinib group (37 patients) and VMP chemotherapy group (36 patients). Patients in VMP group received VM-26 100 mg/day by intravenous injection, from day 1 to day 3, cisplatin 25 mg/m2 by intravenous injection, from day 1 to day 3. One cycle was defined as a 21-day therapy duration, with a total of 3 cycles; 2 cycles were used for consolidation. Patients in Gefitinib group received Gefitinib orally. Both groups received 3D-CRT, DT50 Gy/25f/35d from first day and target areas were treated with whole brain radiotherapy. The results of the study are listed below: There was no significant difference in the short-term effects of the two groups (P > 0.05). Median survival time (MST) of Gefitinib was 13.3 months whereas median survival time of VMP group is 12.7 months (P < 0.05). In Gefitinib group, we did not observe any difference of the median survival time between the patients with and without mutation EGFR. Toxicity of Gefitinib groups were characterized by rash, whereas chemotherapy resulted in hematologic toxicities, which included 6 cases of III/IV leucopenia (17.6 %), 3 cases of anemia (8.8 %), and 5 cases of thrombocytopenia (14.7 %), and non-hematological toxicity which was less serious symptoms for gastrointestinal disorders, hair loss, etc. These adverse reactions can be released after symptomatic treatment. No treatment-related deaths occurred. Two patients in VMP group quit due to IV leucopenia. Both oral Gefitinib and systemic VMP chemotherapy in combination with three-dimensional conformal radiotherapy (3D-CRT) could be used to treat brain metastases from non-small cell lung cancer. There were no difference in the short-term effects of the two groups, but long-term effect of Gefitinib group was slightly better than VMP group. Moreover, Gefitinib group showed low toxicity. All together, our finding implicated that Gefitinib is an effective method for patients with brain metastases from NSCLC.