Bleomycin,vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma

This EORTC multicentre study analysed the efficacy and tolerability in patients with metastatic uveal melanoma of BOLD chemotherapy in combination with recombinant interferon alpha-2b. The dose of bleomycin was 15 mg on days 2 and 5, of vincristine 1 mg/m(2) on days 1 and 4, of lomustine 80 mg on day 1, and of dacarbazine (DTIC) 200 mg/m(2) on days 1-5, given every 4 weeks for a minimum of two cycles. Subcutaneous (s.c.) interferon alpha-2b at a dose of 3 x 10(6) IU was initiated on day 8 of the first cycle, and continued at a dose of 6 x 10(6) IU three times per week after 6 weeks. A median of two cycles were administered to 24 patients (median age 60.5 years). None achieved an objective response (0%; 95% Confidence Interval (CI): 0-14), 2 (8.3%) remained stable, 20 showed progression, and 2 (8.3%) were invaluable. The median progression-free survival was 1.9 months (95% CI: 1.8-3.4) and overall survival 10.6 months (95% CI: 6.9-16.4). Overall survival improved with increasingly favourable pretreatment characteristics (median, 14.7 versus 6.9 versus 6.0 months for Helsinki University Central Hospital (HUCH) Working Formulation stages IVBa, IVBb and IVBc, respectively; P=0.018). Grade 3 alopecia and neurotoxicity occurred in 13% of the patients. This multicentre study did not confirm earlier reports that BOLD with human leucocyte or recombinant interferon would induce at least 15% objective responses in metastatic uveal melanoma.     

Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study.

High response rates in patients with metastatic melanoma have been achieved with combination chemoimmunotherapy. A response rate of 62% in 45 patients has been reported for treatment with dacarbazine, bleomycin, vincristine, lomustine (BOLD) plus interferon alpha (IFN-alpha). We conducted a multicentre phase II study to confirm these results. Melanoma patients with distant metastases were treated as outpatients with dacarbazine 200 mg m(-2) on days 1-5, vincristine 1 mg m(-2) on days 1 and 4, bleomycin 15 mg on days 2 and 5 i.v. and lomustine 80 mg orally on day 1, repeated every 4 weeks. IFN-alpha-2b was initiated s.c. on day 8 at 3 MU daily for 6 weeks, and 6 MU t.i.w. thereafter. Forty-three patients entered the study. The median number of metastatic sites was three (range 1-5), and 81% of patients had visceral metastases. Nine patients had brain metastases, and seven patients were systemically pretreated. Among the 41 patients that were evaluable for response, the response rate was 27% (95% CI 14-3%), with one complete and ten partial remissions. The response rate in 25 previously untreated patients without brain metastases was 40% (95% CI 21-61%). Median duration of response was 6 (range 2-14+) months; median overall survival was 5 (1-26) months. The main toxicity was malaise/fatigue. We confirm that BOLD plus IFN-alpha has activity in metastatic melanoma. The lower response rate in our study compared with the previous report is probably related to patient selection, as in the previous study 46% of patients had stage III disease, whereas all our patients had stage IV disease, which is associated with a worse prognosis.     

Uveal melanoma: natural history and treatment options for metastatic disease

In order to evaluate the natural history, prognostic parameters and treatment modalities for metastatic uveal melanoma, a review of the clinical data from the current literature was performed based on a Medline database search. Uveal melanoma represents approximately 5% of all melanomas. It is a distinct clinico-pathological entity, differing in many aspects from cutaneous melanoma. The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver. The most Important prognostic parameters for primary uveal melanoma are tumour diameter, the patient's age and gender, histological features and tumour location. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma. So far only the BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon-alpha has been shown to produce an objective tumour response in approximately 20% of previously untreated patients. For metastatic disease localized to the liver, intra-arterial application of fotemustine or carboplatin or chemoembolization with cisplatin have shown useful activity, resulting in a response in up to 40% of patients. Selected patients may benefit from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has not shown consistent activity in metastatic uveal melanoma. In conclusion, patients with uveal melanoma metastatic to the liver should undergo one of the local treatment options. Carefully selected patients with extrahepatic disease or patients failing local treatment may benefit from systemic therapy using the BOLD regimen combined with interferon.     

A prognostic model and staging for metastatic uveal melanoma

BACKGROUND: To identify factors that independently contribute to overall survival in Stage IVB uveal melanoma and to subcategorize by prognosis. METHODS: Data of 91 consecutive patients who died of metastatic uveal melanoma in 1985-2000 were analyzed by Kaplan-Meier and Cox regression analysis. Main covariates were participation in annual review, symptoms, Karnofsky index, metastatic burden, liver function tests, and age. Time on chemotherapy was modeled as a confounder. A working formulation for staging patients according to predicted survival was designed. RESULTS: Of the 91 patients, 85% underwent annual liver imaging and function tests, 63% were asymptomatic, and 73% received chemotherapy. The median survival period was 8.4 months (95% confidence interval [CI], 6.3-11.8). Karnofsky index, largest dimension of the largest metastasis, metastatic burden, serum transaminase, lactate dehydrogenase, and alkaline phosphatase (AP) levels, and time on chemotherapy were strongly (P < 0.001) associated with survival. Symptoms (P = 0.031) and regular review (P = 0.081) were weakly associated with survival. Karnofsky index (P = 0.013), the largest dimension of the largest metastasis (P = 0.003), and serum AP level (P = 0.042) retained independent significance, adjusting for time on chemotherapy. Predicted median survival calculated for relevant covariate combinations was divided into three periods (> or =12 months vs. 6-11 months vs. < 6 months). Observed median survival for Stage IVBa was 14.9 months (95% CI, 11.7-21.3), for Stage IVBb 8.9 months (95% CI, 2.7-13.7), and for Stage IVBc 2.0 months (95% CI, 1.0-3.7). CONCLUSION: The model and working formulation for categorization can be tested as an aid in patient counseling and as a tool in design and analysis of clinical trials.     

Serum VEGF-C is associated with metastatic site in patients with malignant melanoma

Vascular endothelial growth factor-C (VEGF-C) is involved in lymphatic metastatic spread. Metastatic site is a prognostic factor in melanoma. We assessed whether serum levels of VEGF-C are associated with metastatic sites or prognosis in patients treated for stage IV melanoma. The study included 64 patients, who received dacarbazine or four-drug chemotherapy (dacarbazine, vincristine, bleomycin and lomustine; BOLD) both combined with interferon-alfa. Serum samples for VEGF-C were analyzed by ELISA. The patients (n =22) with only skin and subcutaneous metastases had significantly lower mean VEGF-C levels (1 643 pg/ml) then the patients (n =42) with other distant metastases (2 584 pg/ml, Mann-Whitney, p =0.033). VEGF-C levels above the median (1 590 pg/ml) were significantly related to deep lymph node involvement (OR 3.763; 95% CI 1.038 - 13.646, p =0.034). There were no other significant associations between VEGF-C levels and tumour burden, nor were the levels significantly related to the response to therapy or survival. Those eight patients, who had received previous adjuvant IFN-alfa therapy had lower mean VEGF-C levels (1 738 pg/ml) as compared to those 56 patients without previous IFN-alfa therapy (2 335 pg/ml, ANOVA, p =0.026). This is the first study exploring serum VEGF-C in melanoma. VEGF-C might be involved in the deep lymphatic dissemination and progression of melanoma metastasis.     

Lomustine (chloroethylnitrosourea [CCNU]), ifosfamide, bleomycin, vincristine, and cisplatin (CIBO-P) is an effective regimen for patients with poor prognostic refractory or multiple disease recurrent aggressive non-Hodgkin lymphoma

BACKGROUND: The current study was designed to assess the activity and safety of a novel combination therapy for patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS: Forty-three consecutive patients with recurrent or refractory aggressive NHL were treated with lomustine (chloroethylnitrosourea [CCNU]; 60 mg/m2 on Day 1), ifosfamide (1.5 g/m(2 on Days 1, 2 and 21, 22), bleomycin (5 mg/m2 on Days 1, 5 and 21, 25), vincristine (1.4 mg/m2 on Days 1, 8 and 21, 28), and cisplatin (25 mg/m2 on Days 3, 4, 5 and 23, 24, 25), every 42 days (CIBO-P regimen). RESULTS: Thirty-nine patients (91%) were evaluable for response. The median patient age was 63 years. Thirty-five percent of the patients had received > or = 2 lines of previous chemotherapy and 40% had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall objective response rate was 77% (95% confidence interval [95% CI], 63-90%), including 19 (49%) complete (CR) and 11 (28%) partial responses. CIBO-P induced responses in primary refractory disease and in patients treated for second or subsequent disease recurrences. A CR with previous therapy was the most important factor associated with a significantly higher CR rate. The median duration of response was 6 months (95% CI, 4.4-7.7 months) and the median survival duration was 10.7 months (95% CI, 5.9-18.1 months). Five patients (11.6%) remained disease free for > or = 24 months. By multivariate analysis, a CR with previous therapy and average dose intensity of CIBO-P drugs were independent prognostic factors for time-to-treatment failure, whereas a CR with previous therapy and serum lactate dehydrogenase were independent predictors for survival. Myelosuppression was the most frequent serious complication of this regimen. However, none of the patients had hemorrhage with thrombocytopenia, and only 2 patients (5%) had febrile neutropenia. CONCLUSIONS: In the current study, CIBO-P was a novel, highly active, and safe combination therapy for patients with refractory disease with a poor prognosis or for patients with multiply recurrent aggressive NHL.     

Phase II trial of cisplatin, gemcitabine and treosulfan in patients with metastatic uveal melanoma

Gemcitabine plus treosulfan (GeT) is under investigation in metastatic uveal melanoma. In this phase II trial, cisplatin was added to a GeT regimen to investigate the efficacy and toxicity of two alkylating agents in combination with gemcitabine. Patients received 30 or 40 mg/m of cisplatin, 1000 mg/m of gemcitabine and 3000 mg/m of treosulfan on days 1 and 8. Therapy was repeated on day 29. A maximum of six cycles was administered. Nineteen patients were included in the trial, of whom 17 were evaluable for response. No objective response was observed; seven patients (41%) had stable disease and 10 (59%) progressed. The median progression-free survival of all 19 patients was 3.0 months [95% confidence interval (CI), 1.8-3.1]; the median overall survival was 7.7 months (95% CI, 1.9-13.8). Grade 3 and 4 thrombopenia and leucopenia occurred in eight and nine of the 19 patients, respectively. The addition of cisplatin to the GeT regimen results in excessive haematological toxicity without improvement in efficacy.     

DTIC, CCNU, bleomycin and vincristine (BOLD) in metastatic melanoma

Treatment of 91 consecutive patients having metastatic, Stage IV melanoma who had not received any previous chemotherapy was begun between January 1977 and April 1978. The therapy included bleomycin (B) at 7.5 units subcutaneously in the first course and 15 units in subsequent courses on days 1 and 4; vincristine or Oncovin (O) at 1 mg/m2 intravenously on days 1 and 5; CCNU or lomustine (L) at 80 mg/m2 p.o. on day 1 and DTIC (D) 200 mg/m2 intravenously on days 1 through 5. Evaluable patients (72) were those who had measurable tumours in the viscera and on the skin. Seven patients (9%) responded with complete tumor regression (CR), 22 (31%) with partial regression (PR) (50% or more tumor regression), 12 (17%) with stabilization of disease, and 31 (43%) with progression of the disease. Patients who responded with CR, PR, and stable disease (41 patients) had a median survival of 67 weeks, while those who did not respond (31 patients) had a median survival of 20 weeks (P < .0001). Overall median survival was 31 weeks. The bleomycin-Oncovin-lomustine-DTIC (BOLD) regimen is an effective alternative treatment for metastatic melanoma; there is good tumor response and prolongation of survival in the responding patients. Its overall toxicity is mild to moderate.     

Low-dose continuous chemotherapy for metastatic melanoma: a phase II trial

The prognosis of patients with metastatic melanoma remains poor and there is a need to develop new regimens with low toxicity. We investigated a novel outpatient regimen combining oral and intravenous chemotherapy with daily subcutaneous bleomycin. Twenty-nine chemotherapy-naive patients with metastatic melanoma were treated with a novel regimen consisting of low dose lomustine, daily subcutaneous bleomycin, chlorambucil, methotrexate and vinblastine with tamoxifen for an 8 week cycle (LBCMVT-56). A median of two cycles were given until disease progression or grade 3/4 toxicity. Five out of 29 (17%) patients had an objective response, of whom two (7%) had a complete response and remain progression-free after 2 years of follow-up. The median overall survival was 7.3 months. A symptomatic response was seen in 11 out of 29 patients (38%). Toxicity was acceptable, with grade 3/4 haematological toxicity seen in 25% of cycles, infection requiring intravenous antibiotics in 11% of cycles, and pulmonary toxicity seen in 4% of cycles. Hospitalization was required in 21% of the patients at some point during the treatment, most commonly for neutropenic sepsis. LBCMVT-56 chemotherapy is a novel outpatient regimen producing occasional durable complete responses in a patient group with a poor prognosis. The median survival is similar to that obtained with dacarbazine, though the toxicity is greater.     

Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study

The aim of this randomized four-arm phase III study was to evaluate whether there is a difference in activity between regimens containing dacarbazine and regimens without dacarbazine in metastatic melanoma, whether there is a dose-effect relationship for dacarbazine, and whether non-dacarbazine-containing aggressive regimens are in any way superior to non-aggressive ones. A total of 219 patients with metastatic cutaneous melanoma were included in this study; 196 of them were evaluable for activity. The patients were randomized into four treatment arms: arm A (standard dose dacarbazine arm), vincristine 1.4 mg/m2 on day 1, carmustine (BCNU) 60 mg/m2 on day 1, and dacarbazine 300 mg/m2 per 24 h on days 2-5; arm B (high-dose dacarbazine arm), vincristine and BCNU as in arm A and dacarbazine 600 mg/m2 per 24 h on days 2-5; arm C ('aggressive' regimen without dacarbazine), vindesine 3 mg/m2 on day 1, bleomycin 7 mg/m2 per 24 h on days 1-4, and cisplatin 30 mg/m2 per 24 h on days 5-8; arm D ('non-aggressive' regimen without dacarbazine), BCNU 100 mg/m2 on day 1 and procarbazine 90 mg/m2 per 24 h on days 1-10. The four arms were well balanced with regard to patient- and disease-related characteristics. On an intend-to-treat basis, the response rate was 11 out of 49 (22%) in arm A, nine out of 47 (19%) in arm B, 16 out of 63 (25%) in arm C and nine out of 60 (15%) in arm D. There was a large overlap between the 95% confidence intervals and no significant differences in the response rates between the four arms. Median survival in the four treatment arms was 4, 5, 6 and 4 months, respectively, again with no significant differences. Median survival for responders (8, 11, 10 and 13 months, respectively) in all four arms was significantly longer than in non-responders (4, 3, 5 and 4 months, respectively). Arms A, B and C were significantly more toxic compared with arm D, which was for all practical purposes devoid of toxicities. The efficacy of all four regimens thus appeared comparable both in terms of response rate and survival. Responders in all four arms achieved a survival benefit. There does not seem to be a dose-effect relationship for dacarbazine in metastatic melanoma. Chemotherapy from arm D, might be well suited for 'fragile' or elderly patients due to the lack of toxicity.     

Bleomycin, vincristine, lomustine, and DTIC chemotherapy for metastatic melanoma

Forty-six consecutive, evaluable patients with a diagnosis of metastatic melanoma without prior chemotherapy were treated with bleomycin, vincristine, lomustine, and DTIC (BOLD). Treatment was repeated every 28 days for two cycles. Complete restaging then was performed, and response to treatment was determined. Of the 46 patients, five (11%) achieved a complete response, five (11%) achieved a partial response, nine (19%) obtained disease stabilization, and 27 (59%) had progressive disease. If four patients who died of rapidly progressive disease are included, the response rate drops to 20%. Overall median survival was 6 months. These results are inferior to the 40% and 46% response rates reported by other investigators. The modest response rate toxicity and expense of the regimen do not support its use in metastatic melanoma except, perhaps, in selected patients with soft tissue and/or lung metastasis.     

A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma.

BACKGROUND: Several trials demonstrated efficacy of the gemcitabine/treosulfan (GeT) combination in metastatic uveal melamoma. This randomized phase II trial compared the GeT combination versus treosulfan alone (T) in this rare disease. PATIENTS AND METHODS: Chemotherapy-naive patients with proven metastatic uveal melanoma were randomly assigned to receive 1000 mg/m(2) of gemcitabine plus 3500 mg/m(2) of treosulfan (GeT) or 3500 mg/m(2) of T. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. Primary end point was rate of responses and disease stabilizations. RESULTS: Forty-eight patients were randomized. Seven confirmed stable diseases (SDs) and one partial remission (PR) were observed in 24 patients treated with the GeT regimen, whereas no PR and only three SDs were observed in the T arm (P = 0.08). Median progression-free survival (PFS) was 3 months (95% CI 1.1-4.9) and 2 months (95% CI 1.7-2.3) in the GeT and T arm (P = 0.008, log-rank). Six and 12 months PFS was 34.8% and 17.9% and 16.7% and 0% always favoring the GeT arm. CONCLUSIONS: This first randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over T.     

Complete remission of brain metastases in three patients with stage IV melanoma treated with BOLD and G-CSF

BACKGROUND: Brain metastases are the most life-threatening among the secondary localizations of melanoma for their unresponsiveness to the surgical, radiotherapeutic and/or chemotherapeutic treatments. METHODS: Accidentally, we observed a complete response (CR) in a patient undergoing chemotherapy with bleomycin, vincristine or Oncovin, CCNU or lomustine, dacarbazine (BOLD) regimen for metastatic melanoma including brain metastases, who was also treated with G-CSF to manage a concomitant leukopenia. After this observation, seven more patients with stage IV melanoma with brain metastases were treated with BOLD regimen repeated every 6 weeks with administration of G-CSF in the intervals. RESULTS: Three patients presented CR (37.5%). Two patients stopped the treatment after two courses for evident progressive disease (25%). The other three patients showed stable disease (SD: 37.5%). Median duration of SD was 24 weeks. Among the eight patients, six (75%) achieved clinical benefit. Median time to progression was 8.5 months (range 0-74+ months). Median survival was 12.5 months (range 4-74+ months). Two patients are still alive and disease-free after 74 and 57 months, respectively. CONCLUSION: We believe that the brilliant CR, the long duration of the disease-free intervals and the long survival in at least three of eight patients should encourage further research on BOLD with G-CSF for the treatment of advanced melanoma.     

The prognostic role of CD4+ and CD8+ lymphocytes during chemoimmunotherapy in metastatic melanoma

We have observed that an early increase in the CD4+/CD8+ ratio of metastatic melanoma patients during chemoimmunotherapy is the most favourable independent prognostic factor. In this study, 87 patients with metastatic melanoma were monitored for peripheral blood lymphocyte subsets (CD4+ and CD8+) before and during chemoimmunotherapy (dacarbazine, vinblastine, lomustine and bleomycin or dacarbazine alone plus interferon-alpha) to confirm our previous observation. Blood samples were systematically obtained from patients who received either of these chemoimmunotherapies. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using monoclonal antibodies OKT4 (CD4+, T-helper cells) and OKT8 (CD8+, T-suppressor cells). The overall response rate was 46.5%, and the median overall survival was 9.3 months. Patients with pre-treatment CD4+ levels above the mean level, who later responded to therapy, had a median survival of 28.1 months vs. 10.2 months for responders with low pre-treatment CD4+ levels (P=0.053, log-rank test). Responders with decreasing CD8+ levels had a median survival of 27.8 months vs. 10.8 months for responders with increasing CD8+ levels (P=0.04, log-rank test). Similarly, responding patients with an increasing CD4+/CD8+ ratio had a median survival of 28.1 months vs. 10.5 months for those with decreasing ratios (P=0.002, log-rank test). Non-responders showed no difference in median survival irrespective of low or high pre-treatment CD4+ lymphocytes, increasing or decreasing CD8+ levels, or increasing or decreasing CD4+/CD8+ ratios. This follow-up study confirms that the monitoring of CD4+ and CD8+ lymphocytes may provide important predictive and prognostic information in metastatic melanoma patients receiving chemoimmunotherapy.     

A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma

Uveal melanoma is relatively uncommon accounting for fewer than 5% of all melanoma cases. Localized tumours are curable by local therapy but a significant percentage of patients go on to have a relapse with metastatic disease. Uncertainty remains concerning the level of activity of dacarbazine in uveal melanoma as opposed to that in the cutaneous form. Recently, a possible role for treosulfan in uveal disease has been reported. A phase II study was therefore undertaken to assess the objective response rate of the combination of dacarbazine and treosulfan in previously untreated patients with metastatic uveal melanoma. All patients received dacarbazine 850 mg/m and treosulfan 8 g/m(2) every 21 days up to a maximum of six cycles. Fifteen patients enrolled in the study. As expected, the major toxicities were haematological (particularly thrombocytopaenia) but the treatment was generally well tolerated. No responses were seen; however, disease stabilization was achieved in two patients. Median progression free survival from the start of chemotherapy was 12 weeks and median overall survival was 30 weeks. This study, using the combination of dacarbazine and treosulfan, while well tolerated, did not confirm earlier reports suggesting treosulfan is active in uveal melanoma.     

Second malignancies after chemotherapy and radiotherapy for Hodgkin disease

The purpose of this preliminary study was to determine the incidence of second malignancies after combined-modality therapy for adults with Hodgkin disease and relate it to the details of initial treatment. We retrospectively studied 286 patients ranging in age from 16 to 88 years with stage I or II Hodgkin disease who were treated between 1980 and 1995 with chemotherapy followed 3 to 4 weeks later by radiotherapy. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone was used in 161 cases, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 67 cases, Adriamycin, bleomycin, vinblastine, and dacarbazine in 19 cases, lomustine, vinblastine, procarbazine, and prednisone/doxorubicin, bleomycin, dacarbazine, and lomustine in 18 cases, and other chemotherapeutic regimens in the remaining 21 cases. The median radiotherapy dose was 40 Gy given in 20 daily 2-Gy fractions. Median follow-up of surviving patients was 7.4 years. There were 2,230 person-years of observation. Significantly increased relative risks (RR) were observed for acute myeloid leukemia (RR, 69.3; 95% CI, 14.3-202.6) and melanoma (RR, 7.3; 95% CI, 1.5-21.3). The 5-, 10-, and 15-year actuarial risks of acute myeloid leukemia were 0.8%, 1.3%, and 1.3%, respectively. Patients treated with MOPP had the highest 15-year actuarial risk of leukemia (1.6%). The 5-, 10-, and 15-year actuarial risks of solid tumors were 1.9%, 9.3%, and 16.8%, respectively. Consolidative radiotherapy to both sides of the diaphragm resulted in a trend toward an increased risk of solid tumors relative to radiotherapy to only one side of the diaphragm (p = 0.08). In an effort to reduce the risk of second malignancies, we have stopped using the alkylating agents nitrogen mustard and procarbazine and elective paraaortic and splenic radiotherapy after chemotherapy.     

A phase II study of hyperfractionated accelerated radiotherapy (HART) after induction cisplatin (CDDP) and vinorelbine (VNR) for stage III non-small-cell lung cancer (NSCLC)

PURPOSE: The purpose was to assess the feasibility and efficacy of hyperfractionated accelerated radiotherapy (HART) after induction chemotherapy for Stage III non-small-cell lung cancer. METHODS AND MATERIALS: Treatment consisted of 2 cycles of cisplatin 80 mg/m(2) on Day 1 and vinorelbine 25 mg/m(2) on Days 1 and 8 every 3 weeks followed by HART, 3 times a day (1.5, 1.8, 1.5 Gy, 4-h interval) for a total dose of 57.6 Gy. RESULTS: Thirty patients were eligible. Their median age was 64 years (range, 46-73 years), 24 were male, 6 were female, 8 had performance status (PS) 0, 22 had PS 1, 9 had Stage IIIA, and 21 had Stage IIIB. All but 1 patient completed the treatment. Common grade > or =3 toxicities during the treatment included neutropenia, 25; infection, 5; esophagitis, 5; and radiation pneumonitis, 3. The overall response rate was 83%. The median survival was 24 months (95% confidence interval [CI], 13-34 months), and the 2-year overall survival was 50% (95% CI, 32-68%). The median progression-free survival was 10 months (95% CI, 8-20 months). CONCLUSION: Hyperfractionated accelerated radiotherapy after induction of cisplatin and vinorelbine was feasible and promising. Future investigation employing dose-intensified radiotherapy in combination with chemotherapy is needed.     

Phase II trial of cyclophosphamide,vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma

BACKGROUND: In this Phase II study, the authors assessed the toxicity and anti-tumor activity of a combination of oral cyclophosphamide, oral low-dose dexamethasone, and intravenous vincristine (CVD) in patients with metastatic androgen-independent prostate carcinoma (AI-PCa). METHODS: Patients with histologic proof of adenocarcinoma of the prostate progressing despite adequate hormonal therapy and adequate organ function were treated with oral cyclophosphamide, 250 mg/daily (Days 1-14); intravenous vincristine, 1 mg daily (Days 1, 8, 15); and oral dexamethasone, 0.75 mg twice a day (Days 1-14) in 28-day cycles. Study endpoints were toxicity, rate of prostate specific antigen (PSA) decline > 50%, and/or measurable disease response. RESULTS: Fifty-two (95%) of 55 registered patients were evaluable. The majority (65%) of patients had received prior chemotherapy. The median number of treatment cycles given was two (range, one-seven cycles). Twenty-nine percent of the patients were found to have a > 50% decline in PSA level compared with baseline levels, and 25% of the patients with bidimensionally measurable soft-tissue or visceral disease were found to have a partial response. The median progression-free survival duration was 10 weeks, and the median overall survival duration was 10.6 months. There were no thromboembolic events, and hematologic and nonhematologic toxicity was minimal. CONCLUSIONS: CVD was found to be an active and well-tolerated regimen for AI-PCa. The low toxicity profile makes CVD a useful treatment option for patients with significant comorbidities and high risk for treatment-related toxicity, especially thromboembolic events and myelotoxicity.     

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study

BackgroundThe BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAF^V600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3.Patients and methodsPatients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m² every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.ResultsBetween 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98];P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96);P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.ConclusionsVemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.ClinicalTrials.govNCT01006980.     

A phase II study of neoadjuvant biochemotherapy for stage III melanoma

BACKGROUND: Phase II studies of biochemotherapy (combining interleukin-2, interferon-alpha, and multiagent chemotherapy) have reported high response rates and a significant number of durable complete responses in patients with metastatic melanoma. METHODS: A pilot Phase II study was performed to explore the safety and activity of neoadjuvant biochemotherapy in patients with Stage III melanoma. Forty-eight patients were enrolled between April 1996 and May 1999. The median age of the patients was 46 years (range, 19-70 years). Two cycles of biochemotherapy were administered prior to and after complete lymph node dissection. Each cycle was comprised of cisplatin, 20 mg/m2 intravenously (i.v.), on Days 1-4; vinblastine, 1.6 mg/m2 i.v., on Days 1-4; dacarbazine, 800 mg/m2 i.v., on Day 1; interleukin-2, 9 x 10(6) IU/m2/day i.v. over 24 hours, on Days 1-4; and interferon-alpha, 5 x 10(6) IU/m2/day subcutaneously, on Days 1-5, every 3 weeks. Twelve patients did not have measurable disease. All patients were evaluable for toxicity and survival. RESULTS: Clinical responses were observed in 14 of 36 patients (38.9%) with measurable disease, including 13 partial responses (36.1%) and 1 complete response (2.8%). Complete pathologic responses were noted in 4 patients (11.1%). Toxicity, although severe, was manageable and typically short-lived. There were no treatment-related deaths reported. At a median follow-up of 31 months, 38 of the 48 patients (79.2%) were alive and 31 patients (64.6%) remained free of disease progression. CONCLUSIONS: Neoadjuvant biochemotherapy appears to have promising activity in patients with Stage III melanoma. A larger multicenter study currently is underway to explore this approach further.