Lawrence H. Einhorn

Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in Patients With Metastatic Melanoma

PURPOSEnSeveral single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients.nnnPATIENTS AND METHODSnIn this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity.nnnRESULTSnMedian survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm.nnnCONCLUSIONnThere was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial.

PURPOSEnTo determine the response rate of cisplatin plus doxorubicin plus cyclophosphamide (PAC) in patients with limited-stage unresectable thymoma. In addition, this study was undertaken to determine the toxicity, progression-free survival, and overall survival of combined-modality therapy with PAC plus radiation therapy.nnnPATIENTS AND METHODSnPatients with a histologic diagnosis of limited-stage unresectable thymoma or thymic carcinoma were eligible. Further requirements included a Karnofsky Performance Score of > 60, no prior radiation to the chest, and adequate bone marrow, hepatic, and renal function. No patient had undergone chemotherapy previously. Patients received two to four cycles (repeated every 3 weeks) of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) followed by a total dosage of 54 Gy to the primary tumor and regional lymph nodes for patients with a stable, partial, or complete response to chemotherapy.nnnRESULTSnFrom November 1983 through January 1995, 26 patients were entered onto the trial. Three patients were ineligible on the basis of pathologic review (lung cancer, germ cell cancer, lymphoma). Toxicity, primarily hematologic, was mild, with only one early death due to a perforated abdominal viscus. Among the 23 assessable patients, there were five complete and 11 partial responses to chemotherapy (overall response rate, 69.6%). The median time to treatment failure was 93.2 months (range, 3 to 99.2+ months), and the median survival time was 93 months (range, 1 to 110 months). The 5-year survival rate is 52.5%.nnnCONCLUSIONSnPAC combination chemotherapy produces response rates in the management of patients with limited thymoma. Combined-modality therapy is feasible and associated with prolonged progressive-free survival. The benefit of combined-modality therapy over radiation therapy alone is suggested for patients with unresectable thymoma.

Chemotherapy for advanced thymoma preliminary: Results of an intergroup study

OBJECTIVEnTo determine the efficacy of combination therapy with cisplatin, doxorubicin, and cyclophosphamide alone or with radiotherapy for patients with extensive and those with limited unresectable thymoma.nnnDESIGNnNonrandomized, prospective phase I-II trial.nnnSETTINGnA Cooperative Oncology Group trial involving tertiary medical centers.nnnPATIENTSnTwenty of twenty-two patients with measurable, extensive or limited, unresectable thymoma were evaluable for response.nnnINTERVENTIONnPatients were given cisplatin, 50 mg/m2 body surface area, doxorubicin, 50 mg/m2, and cyclophosphamide, 500 mg/m2, on day 1, with cycles repeated every 21 days until progression or until the maximally tolerated total doxorubicin dosage (for example, 450 mg/m2) was reached. Intravenous hydration with normal saline was administered during treatment courses. For responding patients with limited disease, 4500 cGy was administered to primary tumors after the second cycle of chemotherapy and before the initiation of the third cycle.nnnMEASUREMENTS AND MAIN RESULTSnThree complete and eleven partial remissions were seen in 20 evaluable patients, for a total response rate of 70% (95% CI, 46% to 88%). The median duration of remission was 13 months with three patients remaining continuously disease free for over 2 years. The median survival time of all eligible patients was 59 months (CI, 22 months to infinity). Four patients developed infections, including listerial and aseptic meningitides, mucocutaneous candidiasis, and cryptococcal pneumonia, that were indicative of a defect in cell-mediated immunity.nnnCONCLUSIONSnCombination therapy with cisplatin, doxorubicin, and cyclophosphamide frequently produces objective remissions in patients with advanced thymoma. Further experience with this treatment regimen is warranted to clarify potential prognostic factors in patients with unresectable thymoma.

Small cell carcinoma of the lung

Small cell lung cancer is a common, usually fatal neoplasm. Although palliative therapy is available for the majority of patients, only a very small minority enjoy long-term survival. Ironically, this neoplasm is nearly entirely preventable and a successful antismoking program is desperately needed. Our efforts to understand the basic biology of this tumor should continue, and, hopefully, will eventually translate into improvements in therapy. In addition to following the leads provided by basic research, a concerted clinical research effort needs to continue to build upon the advances already achieved.

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Paul A. Bunn Jr., MD, John D. Minna, MD, Alexander Augustyn, PhD, Adi F. Gazdar, MD, Youcef Ouadah, BS, Mark A. Krasnow, MD, PhD, Anton Berns, PhD, Elisabeth Brambilla, MD, Natasha Rekhtman, MD, PhD, Pierre P. Massion, MD, Matthew Niederst, PhD, Martin Peifer, PhD, Jun Yokota, MD, Ramaswamy Govindan, MD, John T. Poirier, PhD, Lauren A. Byers, MD, Murry W. Wynes, PhD, David G. McFadden, MD, PhD, David MacPherson, PhD, Christine L. Hann, MD, PhD, Anna F. Farago, MD, PhD, Caroline Dive, PhD, Beverly A. Teicher, PhD, Craig D. Peacock, PhD, Jane E. Johnson, PhD, Melanie H. Cobb, PhD, Hans-Guido Wendel, MD, David Spigel, MD, Julien Sage, PhD, Ping Yang, MD, PhD, M. Catherine Pietanza, MD, Lee M. Krug, MD, John Heymach, MD, PhD, Peter Ujhazy, MD, PhD, Caicun Zhou, MD, PhD, Koichi Goto, MD, Afshin Dowlati, MD, Camilla Laulund Christensen, PhD, Keunchil Park, MD, PhD, Lawrence H. Einhorn, MD, Martin J. Edelman, MD, Giuseppe Giaccone, MD, PhD, David E. Gerber, MD, Ravi Salgia, MD, PhD, Taofeek Owonikoko, MD, PhD, Shakun Malik, MD, Niki Karachaliou, MD, David R. Gandara, MD, Ben J. Slotman, MD, PhD, Fiona Blackhall, MD, PhD, Glenwood Goss, MD, FRCPC, Roman Thomas, MD, Charles M. Rudin, MD, PhD, Fred R. Hirsch, MD, PhD*

Ifosfamide chemotherapy for pancreatic carcinoma

SummaryFrom April 1982 through February 1984, 29 patients with pancreatic cancer were treated with ifosfamide (1.25–1.5 g/m2 on days 1–5) +N-acetylcysteine (NAC) 2 g p.o. every 6 h on days 1–7 every 3 weeks. In responding patients without serious toxicity, subsequent courses of ifosfamide were escalated every 3 weeks by 0.25 g/m2 per day to a maximum of 2 g/m2 per day, with escalation of NAC to 12 g/day. Patients with KPS<50, serum creatinine or bilirubin>2 mg/d l, or obstructive uropathy were ineligible. The median age was 54 (range 36–78), median KPS 70, and median pretreatment weight loss 9 kg. Toxicity included nausea, vomiting, moderate myelosuppression, and occasional mental confusion. Hematuria (>11 RBC/HPF) developed in only 1/29 courses (17 patients) of ifosfamide at ≥1.75 g/m2 per day, and in 7/52 courses (27 patients) overall (13%). Of 27 evaluable patients 6 responded (22%), including 1 with complete response. The median survival was 6 months. Based upon these results, we are currently evaluating ifosfamide + 5-fluorouracil in pancreatic cancer.

Phase II clinical trial of oxaliplatin and bevacizumab in refractory germ cell tumors.

Background:Salvage chemotherapy has curative potential in germ cell tumors (GCTs). However, novel therapies are still needed for patients failing to be cured with standard salvage chemotherapy. Bevacizumab in combination with chemotherapy has clinical activity in many solid tumors. This is the first study of bevacizumab with oxaliplatin in refractory GCT patients. Patients and Methods:Patients with metastatic GCT with progressive disease after second-line or later salvage chemotherapy were eligible. Prior high-dose chemotherapy and paclitaxel and/or gemcitabine were required unless primary mediastinal nonseminomatous GCT or late relapse. Patients received oxaliplatin—85 mg/m2 and bevacizumab—10 mg/kg every 2 weeks for a maximum of 14 cycles. Results:Twenty-nine patients were enrolled and evaluated. Nine patients were late relapses and 5 had primary mediastinal nonseminomatous GCT. Median number of prior chemotherapy regimens was 4. There was no grade 4 and only 1 grade 3 toxicity. Although the primary endpoint of 12 months disease-free survival was not achieved, 8 patients (27.6%) had objective response including 1 complete remission. Median duration of remission was 5 months (range, 4 to 22 mo). Conclusions:Oxaliplatin plus bevacizumab was well tolerated in heavily pretreated GCTs with manageable adverse events. There was modest clinical activity but only 1 patient achieved complete remission.

Brain Metastases in Patients With Germ Cell Tumors: Prognostic Factors and Treatment Options—An Analysis From the Global Germ Cell Cancer Group

PURPOSEnTo define characteristics, treatment response, and outcomes of men with brain metastases (BM) from germ cell tumors (GCT).nnnPATIENTS AND METHODSnData from 523 men with BM from GCT were collected retrospectively from 46 centers in 13 countries by using standardized questionnaires. Clinical features were correlated with overall survival (OS) as the primary end point.nnnRESULTSnBM were present at initial diagnosis in 228 men (group A) and at relapse in 295 men (group B). OS at 3 years (3-year OS) was superior in group A versus group B (48% v 27%; P < .001). Multiple BM and the presence of liver or bone metastasis were independent adverse prognostic factors in both groups; primary mediastinal nonseminoma (group A) and elevations of α-fetoprotein of 100 ng/mL or greater or of human chorionic gonadotropin of 5,000 U/L or greater (group B) were additional independent adverse prognostic factors. Depending on these factors, the 3-year OS ranged from 0% to 70% in group A and from 6% to 52% in group B. In group A, 99% of patients received chemotherapy; multimodality treatment or high-dose chemotherapy was not associated with statistically improved survival in multivariable analysis. In group B, only 54% of patients received chemotherapy; multimodality treatment was associated with improved survival compared with single-modality therapy (hazard ratio, 0.51; 95% CI, 0.36 to 0.73; P < .001), as was high-dose compared with conventional-dose chemotherapy (hazard ratio, 0.41; 95% CI, 0.24 to 0.70; P = .001).nnnCONCLUSIONnMen with BM from GCT have poor OS, particularly if additional risk factors are present. High-dose chemotherapy and multimodality treatment seemed to improve survival probabilities in men with BM at relapse.

VP 16 plus ifosfamide plus cisplatin as salvage therapy in refractory testicular cancer

SummaryIn patients with refractory germ cell tumour who fail to achieve complete remission (CR) or which achieve CR but subsequently experience disease progression within 2 months of receiving cisplatin + vinblastine + bleomycin (PVB) the results of further treatment are poor. Similarly, third-line therapy after cisplatin with VP 16 salvage rarely produces clinically significant remission. From February 1983 to October 1984 we treated 53 patients with ifosfamide (1.2 g/m2 per day on days 1–5), VP 16 (75 mg/m2 per day on days 1–5), cisplatin (20 mg/m2 per day on days 1–5), andN-acetylcysteine (2.0 g p.o. every 6 h on days 1–7). This was repeated every 21 days for four to six cycles. One group of patients (group A, 20 pts) had achieved partial remission (PR) but still had nonresectable tumours after PVB therapy; a further group (group B, 4 pts) had achieved CR with PVB but then experienced disease progression within 2 months; the remaining patients (group C, 28 pts) had experienced disease progression after one or more salvage attempts, including therapy with cisplatin and VP 16. Of the original 53 patients, 51 were evaluable for response. Toxicity included moderate to severe myelosuppression in almost all patients, fever/sepsis in 8, creatinine ≥6 mg% in 4, and hematuria in 4 patients. There were no drug-related deaths. CR was attained in 17/51 patients (34%), these being 8/20 in group A, 1/4 in group B, and 8/28 in group C, and 10 patients have remained in CR for periods ranging from over 1 month to over 17 months. PR was achieved in 20 patients (40%), but their median duration of remission was only 2 months. We feel these results, obtained in a poorprognosis patient population, are sufficiently encouraging to warrant further study of this regimen, including investigation of its use as initial salvage therapy following PVB.

Clinical and genetic risk factors for adverse metabolic outcomes in north American testicular cancer survivors

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment-associated MetS requires further characterization.