Combination Of Dacarbazine Research Articles

Synergistic inhibitory effects of the oxyresveratrol and dacarbazine combination against melanoma cells.

Various therapies have been developed to target malignant melanoma, which is associated with a high mortality rate worldwide. Although dacarbazine (DTIC) is employed for treating melanoma, it is associated with several side effects. Hence, patients with melanoma are co-treated with additional drugs to mitigate the side effects of DTIC. In the present study, synergistic therapeutic effects of the DTIC/oxyresveratrol (ORT) combination were examined using the human malignant melanoma WM-266-4 cell line. Treatment with ORT and DTIC inhibited the proliferation of WM-266-4 cells. Compared with those in the ORT- and DTIC-treated groups, the proportion of cells arrested at the S phase, as well as apoptotic rates, were increased in the ORT and DTIC co-treatment group. In WM-266-4 cells, synergistic proliferation-inhibitory activities of the ORT/DTIC combination were assessed based on cell viability and migration, antioxidant capacity, cytokine production, cell cycle arrest, apoptotic rate and protein expression through WST-1 assay, wound healing assay, flow cytometry and western blotting. Furthermore, the expression levels of proteins, including NOTCH, involved in the pathogenesis of solid cancers, such as melanoma, were examined. Overall, the ORT/DTIC combination synergistically promoted cell cycle arrest at the S phase and the apoptosis of WM-266-4 cells. Thus, this combination treatment may serve as a novel therapeutic strategy for treating malignant melanoma.

Animal-type malignant melanoma associated with nevus of Ota in the orbit of a Japanese woman

We present a patient with an animal-type malignant melanoma associated with the nevus of Ota in the orbit who showed a good prognosis after a combination of orbital extirpation, chemotherapy, stereotactic radiotherapy, and gamma knife. A 42-year-old Japanese woman presented with two tumors, one pathologically diagnosed as right-sided intraconal animal-type malignant melanoma and the other intracranially, presumed to be of the same pathogenesis and both were considered to have arisen from the nevus of Ota. She underwent an extirpation of the orbit, chemotherapy (DAV therapy, which is a combination of dacarbazine, nimustine, and vincristine), stereotactic radiotherapy (54 Gy in 27 fractions), and gamma knife (marginal dose was 17 Gy, target volume was 0.2 ml). She has been alive for 33 months since the extirpation, with no sign of local recurrence, new metastasis, nor enlargement of the intracranial tumor. Not just combination therapy but also the low malignancy of animal-type melanoma may have contributed toward the good prognosis.

Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study

Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. AstraZeneca.

Sorafenib and dacarbazine in soft tissue sarcoma: a single institution experience

Background: To report on the anti-tumour activity and toxicity of sorafenib combined with dacarbazine in patients with pre-treated advanced soft tissue sarcoma (STSs).Methods: From November 2009 to December 2010, 17 patients affected by STSs who had failed two or more regimen of chemotherapy, with a performance status ≤ 2 and measurable disease were consecutively enrolled in the present case series. Sorafenib was administered at 400 mg b.i.d. continuous dosing in combination with dacarbazine, 300 mg/m2 for three consecutive days every 21 days until disease progression or intolerable toxicity.Results: Fourteen patients were evaluable for response. Three patients stopped treatment early and were not evaluable for response. One of them died for not disease-dependent reason, the other two went off-study due to rapid clinical worsening, without performing radiologic evaluation. No complete responses were registered. As by RECIST, partial responses (PR) were observed in three patients (21%), stable disease (SD) in six patients (43%) and progressive disease (PD) in five patients (36%), with a clinical benefit rate (RECIST PR+SD > 6 months) of 64%. The median time of progression was 20 weeks (range: 9 – 34 weeks) and the median overall survival was 43 weeks (range: 17 – 65 weeks). The main toxicities were neutropenia (36%), thrombocytopenia (36%), hypertension (36%), fatigue (50%) and skin reactions (57%). Five patients required dose reductions (both dacarbazine and sorafenib) for toxicity and three patients required only sorafenib reduction for dermatologic reactions. One patient was taken off-study because of severe sorafenib-related dermatologic toxicity.Conclusions: Sorafenib and dacarbazine combination seems to be an active and safety regimen in pre-treated STSs. A Phase II trial is ongoing in patient affected by selected sarcoma subtypes.

BEVATEM: Phase II single-center study of bevacizumab in combination with temozolomide in patients (pts) with first-line metastatic uveal melanoma (MUM): First-step results.

8546 Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 470 MUM pts, median OS was 13 months, ranging from 3 to 12 and 21 months for best supportive care, systemic treatment and surgery groups respectively, stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma. Intravitreal application of antiangiogenic agents is used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental uveal melanoma. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and bevacizumab. Methods: Phase II study, modified 2-step Fleming plan; with expected 6-month progression-free survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 35 pts are to be recruited for a power of 94% (α and β risk 3 and 6%). After the first 17 pts, the study will be continued and another 18 pts will be enrolled in the second step if ≥3 evaluable pts show stable disease or response. Primary endpoint: 6-month PFS according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then Bevacizumab maintenance until toxicity or progression. Results: From May 2010 to January 2011, 17 pts were enrolled according to the first step of the study: 3/17 achieved disease control at 6 months, second step is on going with 26/35 pts already recruited. One patient with minor response in liver and lung metastases is under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as good as expected. Liver perfusion CT study showed decrease in blood flow and blood volume before lesion size decrease in one stable patient. Conclusions: BEVATEM study in first line MUM pts is on going, showing promising results in the first step of 17 pts.

Highlights of This Issue

Improving risk classification of children with neuroblastoma is an important challenge in pediatric oncology. Through one of the largest microRNA (miRNA) expression studies on cancer biopsies, De Preter and colleagues developed a 25-miRNA signature that identifies neuroblastoma patients with increased risk for adverse outcome. This classifier is independent of currently used risk factors and enables further patient stratification within the current highrisk subgroup. Importantly, the 25-miRNA signature performs equally well in archived formalin-fixed, paraffin-embedded material as it does in fresh frozen samples. Results were confirmed in 2 independent patient cohorts and indicate that use of the miRNA signature can substantially improve risk stratification of patients with neuroblastoma.The insulin-like growth factor 1 receptor (IGF-1R) is a potential new therapeutic target. Unfortunately, a suitable biomarker predictive for anti-IGF-1R therapy response is not available. Fleuren and colleagues investigated whether indium-111-labeled R1507 (111In-R1507) immuno-SPECT, a novel noninvasive, in vivo screening method to visualize membranous IGF-1R expression and accessibility, can be used to predict IGF-1R treatment response in Ewing sarcoma and osteosarcoma. This novel imaging technique could clearly distinguish among high, modest, and nonresponsive xenografts, whereas conventional techniques could not. This new technique may therefore enable the selection of patients susceptible to IGF-1R targeted therapy and monitor treatment response.Ever since its approval in 1976, dacarbazine has represented the standard of care for the treatment of patients with metastatic melanoma; however, only a minority of melanoma patients responds to dacarbazine treatment. This article presents clinical evidence that the combination of dacarbazine with the tumor-targeting immunocytokine L19-IL2 (a biopharmaceutical agent consisting of the human recombinant antibody L19, specific to the alternatively-spliced EDB domain of fibronectin, fused to human interleukin-2) is well tolerated in patients with metastatic melanoma and can induce long-lasting objective responses in a subset of patients.Examination of epidermal growth factor (EGFR) mutations is a diagnostic routine for treatment of lung cancer that involves the use of EGFR tyrosine kinase inhibitors. Because it is difficult to obtain primary lesions, especially in patients with progressive disease, a noninvasive procedure is desirable. Taniguchi and colleagues used BEAMing (beads, emulsion, amplification, and magnetics) to detect EGFR mutations in circulating tumor DNA. In addition to its high sensitivity, BEAMing can estimate the extent to which the activating mutation alleles have been converted into resistant alleles. Because BEAMing and next-generation sequencers are based on the same technologic principle, we can predict how next-generation sequencers will detect mutations in circulating tumor DNA based on the findings from this study.

Fermented wheat germ extract - nutritional supplement or anticancer drug?

BackgroundFermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-α and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE.Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies.ConclusionIn conclusion, available data so far, justify the use of FWGE as a non-prescription medical nutriment for cancer patients. Further randomized, controlled and large scale clinical studies are mandatory, to further clarify the value of FWGE as a drug component of future chemotherapy regimens.

Phase I safety study of lenalidomide and dacarbazine in patients with metastatic melanoma previously untreated with systemic chemotherapy

This phase I trial assessed the maximal tolerated dose (MTD) of dacarbazine in combination with lenalidomide in metastatic melanoma. Cohorts of three to six patients with metastatic melanoma without brain metastases were enrolled at each of three dose levels of dacarbazine: 600 mg/m², 800 mg/m², and 1000 mg/m² administered intravenously every 3 weeks. Lenalidomide (25 mg/day) was administered orally for 14 days followed by a 7-day rest. Safety was assessed every 3 weeks, and tumor response was evaluated every 6 weeks. An additional 10 patients were enrolled in an expansion cohort at MTD level. Twenty-eight chemotherapy-naive patients were enrolled. The MTD was determined to be dose level 2 (800 mg/m²). Three patients experienced a grade 4 adverse reaction; two pulmonary emboli and one cerebral ischemia. Two patients had a deep venous thrombosis. Of 27 patients assessable for disease response, two experienced a complete response and four experienced a partial response. The median overall survival was 10.6 months (range 1.6-46.0+ months). One patient had a small brain lesion at the baseline; 10 additional patients developed brain metastasis at 0-10.8 months after completion of study therapy. The combination of dacarbazine and lenalidomide is safe and well tolerated in patients with metastatic melanoma. Clinical activity was seen at the MTD level. Additional measures to prevent brain metastasis are needed for patients who achieve a response.

Evaluation of paclitaxel and dacarbazine combination in metastatic melanoma

20005 Background: Metastatic melanoma has a poor prognosis, with less than 11 months median survival rate from the diagnosis of distant metastasis. Response rates for both dacarbazine and paclitaxel as single therapy are around 20%. High levels of S100 protein were found in the serum of patients with metastatic melanoma. Methods: The purpose of this study was to determine the safety and efficacy of Paclitaxel + Dacarbazine combination in metastatic malignant melanoma. Secondary we want to evaluate the correlation between serum level of S100 protein and therapeutic response. 63 patients were included between January 2005 and December 2006. The median age was 54 years. Patients could have prior adjuvant immunotherapy. Performance status was ECOG 0 - 2. Metastatic sites were: liver - 29 patients; lung - 19 patients; soft tissue - 11 patients; lymph nodes - 9 patients; bone - 6 patients. Treatment schedule: Paclitaxel 175 mg/sqm on day 1 and Dacarbazine 400 mg/sqm/day on days 1, 2, repetead at 3 weeks for six cycles. Serum S100 was determined at start, every two chemotherapy cycles, and in follow-up visits (every three month). Results: All patients were evaluable for toxicity and 61 patients were evaluable for efficacy. Main grade 3–4 toxicity was: hematology 12 patients, no neutropenic fever, neuropathy 8 patients, emesis 9 patients. Overall response rate was 23.8% (15 patients partial response); 23 patients had stable disease and 25 patients had progressive disease. 59 patients had elevated S100 levels. The highest were among patients with liver metastasis. The responders registered decrease of more than 50% in S100 level. Conclusions: Our results suggest that the combination is not significant superior to single agent therapy. The regimen was well tolerated, with no treatment related serious adverse events. Serum levels of S100 were correlated with the treatment efficacy and could be used for easy follow-up. No significant financial relationships to disclose.

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

To compare results of treatment with temozolomide or dacarbazine, in combination with an anthracycline, in dogs with relapsed or refractory lymphoma. Nonrandomized, controlled clinical trial. 63 dogs with relapsed or refractory lymphoma. Chemotherapy was administered in 21-day cycles. A combination of temozolomide and an anthracycline (doxorubicin or dactinomycin) was administered to 21 dogs and a combination of dacarbazine and an anthracycline was administered to 42 dogs. Efficacy and toxicoses were assessed. Results-Thirteen of the 18 (72%) dogs treated with the temozolomide-anthracycline combination and 25 of the 35 (71%) dogs treated with the dacarbazine-anthracycline combination had a complete or partial response. Median duration of response to rescue chemotherapy was 40 days (range, 0 to 217 days) for dogs in the temozolomide group and 50 days (range, 0 to 587 days) for dogs in the dacarbazine group. The incidence of high-grade hematologic toxicoses was significantly higher among dogs in the dacarbazine group than among dogs in the temozolomide group, but the incidence of gastrointestinal tract toxicoses was not significantly different between groups. There were no significant differences between groups in regard to proportion of dogs with a complete or partial response, duration of response to rescue chemotherapy, survival time following rescue chemotherapy, or overall survival time. Both combinations had promise in the treatment of dogs with relapsed or refractory lymphoma, although administration of temozolomide was more convenient than administration of dacarbazine and caused fewer hematologic toxicoses.

Durable responses and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma

7525 Background: CTLA-4 is a negative regulator of cytotoxic T cell responses and may contribute to tumor escape from immune surveillance. MDX-010 is an IgG1κ fully human monoclonal antibody that blocks CTLA-4 function and is being studied in patients with metastatic melanoma and other malignancies. The current Phase II study was conducted to determine the safety and efficacy of MDX-010 when given alone or in combination with dacarbazine in chemotherapy and vaccine naïve patients with unresectable metastatic melanoma. Dacarbazine is an FDA approved agent for metastatic melanoma with an approximate 10% objective response rate (ORR) but no demonstrable survival benefit. Long-term follow-up data on response duration and median progression-free survival for this Phase II study is now reported. Methods: Patients were randomized to receive MDX-010 at 3 mg/kg monthly x 4 (arm A; n=37) or MDX-010 in combination with dacarbazine 250 mg/m2 for 5 days monthly x 4 (arm B; n=35). Clinical response was measured by RECIST at week 12 and patients were followed every 3 months until disease progression. Results: In Arm A there were 2 PRs (ORR 5%) and 4 SD. In Arm B there were 2 CRs and 4 PRs (ORR 17%) as well as 4 SDs. Long-term durable objective responses and disease stabilization have been observed in both monotherapy and combination arms of the study. In Arm A the 2 PRs are continuing at 11.9+ and 14+ months and 1 patient with SD is ongoing at 18.2+ months. In Arm B the 2 CRs are continuing at 12.6+ and 16.3+ months, and 1 PR is ongoing at 16.7+ months. The median progression-free survival in Arm A is 82 days and 99 days in Arm B. Conclusions: MDX-010 alone or in combination with dacarbazine can induce durable (i.e., greater than 1 year) objective clinical responses in previously untreated patients with metastatic melanoma. Furthermore, the ORR observed in patients treated with the combination of dacarbazine and MDX-010 appears higher than that reported with dacarbazine alone. The combination of dacarbazine plus MDX-010 merits further study in patients with metastatic melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Medarex Medarex Medarex Medarex Medarex

215 Dacarbazine-vindesine vs dacarbazine-vindesine-cisplatinum in disseminated melanoma—a randomized phase III trial

In a phase III study of disseminated malignant melanoma performed in Sweden and Norway, 326 patients were randomized to receive treatment with the combination Dacarbazine (OTIC) and Vindesine (VDS) with or without addition of Cisplatin (CDDP). The study was designed to reveal a clinically significant survival difference when the three drugs were combined. DTIC was given i.v. at a dose of 250 mg/sqm days 1 to 5 every four weeks and VDS was given i.v. at a dose of 3.0 mg/sqm day 1 weekly. CDDP was given i.v. at a dose of 100 mg/sqm day 1 every 4 weeks. There was no statistical significant difference regarding total survival between the treatment arms (P = 0.22). What was clearly demonstrated was an increased toxicity in the treatment arm containing CDDP. Two hundred and sixteen patients were evaluable for response in compliance with the WHO criteria. With the DTIC-VDS regimen 9.9% patients obtained a complete remission and 10.8% patients a partial remission with an overall response rate of 20.7%. With the triple regimen DTIC-VDS-CDDP 16.2% patients obtained a complete remission and 15.2% patients a partial remission with an overall response of 31.4%. The difference in objective response rates observed between the treatment arms is not statistically significant (P = 0.1011). In conclusion this study did not show any significant increases in median survival time or objective response rate. The study has demonstrated a clinically significant increase in toxicity and we suggest that this triple regimen does not merit further use in patients with disseminated malignant melanoma, which earlier phase II studies have indicated.

Tamoxifen: is it useful in the treatment of patients with metastatic melanoma?

We have attempted to review the data regarding the activity of tamoxifen (TAM) to clarify the role of this agent in the treatment of metastatic melanoma. Using the Melvyl Medline system, we identified recent reports describing the results of clinical trials that used TAM either as a single agent or in combination with other cytotoxic agents. Additionally, we reviewed the abstracts from the 29th Annual Meeting of the American Society of Clinical Oncology held in May 1993. Numerous articles have reported an overall response rate of 47% (95% confidence limit, 39.25 to 54.75) when patients with metastatic melanoma are treated with the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and TAM (DBDT). Additionally, recent laboratory studies have reported that synergism between TAM and DDP is at least partially responsible for the success of this regimen. While TAM as a single agent is minimally active in treating patients with metastatic melanoma, when it is combined with DTIC, BCNU, and DDP, a marked improvement in the overall response rate is observed. Although a prospective randomized trial has yet to be completed, it appears that this four-drug combination has a higher overall and complete response (CR) rate when compared with single-agent DTIC. In light of the relatively modest toxicity observed with this regimen, the combination of DBDT represents a reasonable alternative to single-agent DTIC as first-line therapy for patients with metastatic melanoma.

進行期悪性黒色種におけるｃｉｓｐｌａｔｉｎ， ｄａｃａｒｂａｚｉｎｅ‐ｖｉｎｄｅｓｉｎｅ併用療法時に生じる悪心，おう吐に対する塩酸グラニセトロンの効果

Treatment for metastatic melanoma has not yet been established. But the current standard of therapy for metastatic melanoma consists of dacarbazine in combination with other agents. Especially, the combination cisplatin-vindesine-dacarbazine give rise to a high response rate in patients with advanced melanoma. Ten patients with advanced melanoma were treated with a 6-day triple drug chemotherapy regimen comprising cisplatin, dacarbazine and vindesine at the Department of Dermatology, National Cancer Center Hospital. Cisplatin was used in a dose of 80 mg/m2 on day 1, vindesine was used in a dose of 2 mg/m2 on day 2 and dacarbazine was used in a dose of 120 mg/m2 on days 2-6. The major toxicities of cisplatin-vindesine-dacarbazine chemotherapy were nausea and vomiting. Granisetron is a potent and selective 5-HT3 antagonists currently being developed, as an antiemetic for the treatment of chemotherapy induced nausea and vomiting. Granisetron was administered in a dose of 40μg/kg once a day by infusion over 30 minutes, showed an excellent antiemetic effects. Granisetron dramatically reduced or abolished the severe cisplatin-induced vomiting in the absence of any side effects.

Effective combination chemo/hormonal therapy for malignant melanoma: Experience with three consecutive trials

Our experience with the combination of dacarbazine, carmustine, cisplatin with and without tamoxifen is reported. In our initial study, with all 4 drugs, we had an overall response rate of 50% with a complete response rate of 15%. Due to a high incidence of deep venous thrombosis and the lack of effectiveness of tamoxifen as a single agent, we deleted tamoxifen from the regimen and treated another 20 patients. Surprisingly, the response rate decreased to 10%. We then re-incorporated tamoxifen into the regimen and treated 25 additional patients. In this third group of patients we experienced an objective response rate of 52% with a complete response rate of 8%. Overall, 65 patients have been treated: 45 with and 20 without tamoxifen. Twenty-three (51%) patients treated with tamoxifen have responded, with 5 (11%) patients achieving a complete response. Only 2 (10%) patients treated without tamoxifen have responded. Despite the improvement in the response rate, a corresponding increase in survival has not been seen. Patients treated with tamoxifen had a mean survival of 10.8 (SD 13.6) months compared with a mean survival of 9.8 (SD 7.3) months for those treated without tamoxifen. The absence of survival advantage for the tamoxifen-treated patients may be due to early failure in the central nervous system. In 48% of the responding tamoxifen-treated patients, the first site of failure was the central nervous system, while systemic disease was still responding.

Association between chemotherapy response and rate of disease progression in disseminated melanoma

Fifty-five evaluable patients with disseminated malignant melanoma were treated with the combination of dacarbazine (DTIC) 400 mg i.v. on days 1 to 3 and lomustine (CCNU) 50 to 80 mg m-2 orally on day 1 with intervals of 6 weeks as the first line chemotherapy. Three (5%) patients had complete and 6 (11%) partial response, and 7 (13%) patients had stable disease at least for 3 months. The patients with an objective response (n = 9) survived longer than the rest of the patients if the length of survival was calculated from the start of chemotherapy (P = 0.0006). However, the responding patients also had longer time interval from the diagnosis to the detection of distant metastases (P = 0.05), and survival time from disease progression following DTIC and CCNU therapy (P = 0.005). These findings suggest that patients with an objective response to DTIC-CCNU therapy have melanoma with a slow progression rate, and prolonged survival in such patients may in part result from the less aggressive biological nature of their tumours.

A phase I-II study of dacarbazine in combination with outpatient interleukin-2 in metastatic malignant melanoma

Because of encouraging response rates published with recombinant interleukin-2 (rIL-2) alone in metastatic malignant melanoma (MMM), dacarbazine (DTIC) and rIL-2 were sequentially combined to evaluate efficacy, toxicity, pharmacokinetics, and immunologic interaction. Thirty-two patients aged 18 to 67 years have received 127 courses of treatment. The dose of DTIC was 1.0 g/m2 as a 24-hour infusion every 28 days on day 1. Recombinant interleukin-2 (2.0, 3.0, 4.0, or 5.0 x 10(6) Cetus units/m2) was administered as a 30-minute infusion on days 15 through 19 and 22 through 26 of each 28-day cycle. Seven of 32 patients (22%) who received therapy had a remission, one complete and six partial. The complete response was in a lung mass. Partial responses were seen in lymph nodes, liver, and lung. The median duration of response was 4.7 months. One patient is in persistent partial remission of the liver for greater than 2 years. One patient had residual mediastinal disease resected after partial response and remains without evidence of disease for 18+ months. This regimen was generally well tolerated, did not create overlapping toxicity, and produced encouraging responses in visceral sites. This provides a framework for future combinations of chemotherapy with rIL-2 alone or in combination with other biologic response modifiers in an outpatient setting.

The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma.

The combination of dacarbazine (DTIC, 220 mg/m2) and cisplatin (DDP, 25 mg/m2) IV daily for 3 days every 3 weeks, carmustine (BCNU, 150 mg/m2) IV every 6 weeks, and tamoxifen (TAM, 10 mg orally twice daily) produced a 50% objective response rate in patients with metastatic melanoma. Associated with this treatment, there was a high incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE). In an effort to reduce this toxicity, this regimen minus TAM was studied, and the results are reported. Twenty of twenty patients are evaluable for response and toxicity. There was one complete response (CR) lasting 5+ months and one partial response (PR) lasting 4+ months for an overall response rate of 10% (95% confidence limits, 1.23% to 31.70%). Two patients exhibited a mixed response and three patients developed disease stabilization lasting 4 to 10 months. Toxicity was similar to the original study except that no patients developed DVT or PE. This statistically significant (Fisher's exact test [two-tail] P = 0.008) decrease in the response rate by comparison with that achieved with the TAM-containing regimen may signal an essential role of TAM in this regimen. TAM may be acting in synergy with cisplatin through its calcium channel-blocking properties. TAM should be included as described in the initial reports, and the patients should be carefully observed for vascular complications.

Combination of dacarbazine, mitomycin C, 5-fluorouracil and vincristine in advanced colorectal cancer.

Thirty patients with advanced measurable colorectal cancer received monthly courses of a combination of dacarbazine, mitomycin C, 5-fluorouracil, and vincristine (FIVMit-Or). Four of the patients had received prior chemotherapy. Two patients were not evaluable for response. Objective response was obtained in four patients. Severe toxicity was encountered in 11 patients. It is concluded that unlike the four-drug combination of 5-fluorouracil, DTIC, vincristine and BCNU (FIVB), the present regimen did not have significant antitumour activity in advanced colorectal cancer.

Combination of dacarbazine and mitomycin in advanced colorectal cancer.

Twenty evaluable patients with advanced measurable colorectal cancer received 3-week courses of a combination of IV dacarbazine 300 mg/m2/day from day 1 to day 5 and IV mitomycin 2 mg/m2/day from day 1 to day 5. Fourteen of these patients had had no prior chemotherapy and received two or more courses of this two-drug regimen. None of the patients achieved complete or partial response. Severe to life-threatening myelosuppression, was encountered in patients with prior radiotherapy and or prior chemotherapy, and/or in patients with a Karnofsky score less than or equal to 70. Hematologic toxicity was mild in the other patients. Nonhematologic toxic effects were generally mild to moderate and consisted essentially in nausea and vomiting. It is concluded that in our hands the regimen selected for this trial has no significant antitumor activity in advanced colorectal cancer.