Long-term results of a phase I/II study of high-dose thoracic radiotherapy with concomitant cisplatin and etoposide in limited stage small-cell lung cancer.

This report presents the results from a Mayo Clinic initiated phase I/II study exploring a potentially more aggressive local and systemic approach for treatment of limited-stage small-cell lung cancer (LSSCLC). Five patients with LSSCLC received three cycles of induction cyclophosphamide, etoposide, and infusion cisplatin chemotherapy. This was followed by accelerated hyperfractionated thoracic radiotherapy (AHFTRT) consisting of 30 Gy given as 1.5-Gy fractions twice daily with a 2-week break and then the AHFTRT was repeated. The AHFTRT was given concomitantly with daily oral etoposide and daily intravenous cisplatin. Prophylactic cranial radiation was delivered with the AHFTRT. After completion of the AHFTRT, patients received 4 cycles of oral etoposide maintenance chemotherapy. Follow-up of patients was continued until death or a minimum of 42 months. Three patients had severe toxic responses. No patients completed the entire protocol because of toxicity or progression during treatment. Three patients completed the majority of the protocol except for the four cycles of maintenance etoposide. Four of five patients achieved a complete response. There were two recurrences within the irradiated field, and distant metastases developed in four patients. Acute nonlymphocytic leukemia developed in one patient, who died 2 months later. No patient completed the entire protocol, because of toxicity or progression; therefore, this protocol cannot be recommended for the treatment of LSSCLC.

Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.

Attitude and disposition: Do they make a difference in cancer survival?

STATEMENT OF PROBLEM: Investigators have attempted to resolve the question: do psychosocial, emotional, and attitudinal factors have any effect on cancer survival? PURPOSE: This article presents a literature review and an overview of the developments in the mind-body connection to examine the influence of attitude in cancer survival. CONCLUSION: Even though a causal effect of emotional issues on the initiation and promotion of cancer is speculative, the effect of emotions on numerous medical conditions cannot be ignored.

A phase II study of high-dose cimetidine and the combination 5-fluorouracil, interferon alpha-2A, and leucovorin in advanced renal cell adenocarcinoma.

Cimetidine is an H2-receptor antagonist used in the management of peptic ulcer disease and other hypersecretory gastrointestinal disorders. This agent has intriguing immunomodulatory characteristics. A phase II trial of cimetidine in 19 patients with advanced malignant melanoma yielded an objective response rate of 16%. Having demonstrated that cimetidine is active in malignant melanoma, the authors conducted a phase II trial of cimetidine, 800 mg twice daily by mouth, in patients with advanced renal cell cancer. Among the 31 eligible patients, only one (3.2%) achieved a regression. It was a partial regression lasting 93 days. Median time to treatment failure was 83 days. The combination of interferon alpha-2A (IFL-RA) and 5-fluorouracil (5-FU) has been shown to be synergistic against experimental cell lines in vitro. Citrovorum factor (CF) added to 5-FU has been shown to improve objective tumor response compared with single-agent 5-FU in patients with advanced colorectal cancer. Fluorinated pyrimidines have shown some activity against renal cell cancer. We conducted a phase II trial of the combination of CF at 20 mg/m2 intravenous push followed by 5-FU at 325 mg/m2 intravenously daily for 5 days every week with interferon alpha-2A 5 x 10(6) units/m2 subcutaneously on days 1, 3, 5 in patients with advanced renal cell cancer. Among the 31 eligible patients, only two (6.5%) achieved a regression. Both were partial regressions. Median time to treatment failure was 84 days. Neither regimen is recommended for further testing in patients with advanced renal cell adenocarcinoma.

Combined levamisole with recombinant interleukin-2 (IL-2) in patients with advanced renal cell carcinoma: a phase II study.

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells is an antineoplastic modality in which immune-activated cells are administered to a host having cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested as having therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients who had advanced renal cell carcinoma. The regimen was IL-2 at 3 x 10(6) U/m2 daily x 5 plus LEV at 50 mg/m2 perorally three times a day x 5. Only one of the 22 eligible patients had a regression. It was a partial regression, 85 days in duration. The median time to treatment failure (refusal, progression, or off study because of toxicity) was 36 days. The only grade 4 toxicity reported was lethargy. This regimen is not recommended for further testing in patients who have advanced renal cell carcinoma.

The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study.

BACKGROUND: A three-arm Phase III randomized trial was performed to compare response rates, time to local or distant progression, and survival for patients with unresectable (Stage IIIA or IIIB) nonsmall cell lung carcinoma treated with standard fractionated thoracic radiotherapy (SFTRT) versus accelerated hyperfractionated thoracic radiotherapy (AHTRT) with or without combination etoposide and cisplatin chemotherapy. METHODS: This trial was initiated in 1992 by the North Central Cancer Treatment Group. Patients with Stage IIIA or IIIB nonsmall cell lung carcinoma were eligible. They were randomly assigned to either SFTRT (6000 centigray [cGy] in 30 fractions) or AHTRT (150 cGy twice daily to a total dose of 6000 cGy, with a 2-week break after the initial 3000 cGy); the AHTRT was given alone or with concomitant cisplatin (30 mg/m2, Days 1-3 and 28-30) and etoposide (100 mg/m2, Days 1-3 and 28-30). RESULTS: A total of 110 patients were entered on study. Eleven patients were declared ineligible or off study on the day of study entry. This analysis was confined to the 99 eligible patients. This article reports mature follow-up, because more than 80% of the patients have died. The median follow-up of living patients was 2.5 years. There were suggestions of improvement in the rates of freedom from local recurrence and survival for patients treated with AHTRT (with or without chemotherapy) as opposed to SFTRT (P = 0.06 and P = 0.10, respectively). The improvement in survival associated with AHTRT (with or without chemotherapy) was statistically significant for the subgroup of patients with nonsquamous cell carcinoma after adjustment for other potentially confounding factors (P = 0.02). No differences in freedom from systemic progression or survival were found in a comparison of AHTRT with chemotherapy and AHTRT without chemotherapy. CONCLUSIONS: These results suggest that treatment of Stage IIIA or IIIB nonsmall cell lung carcinoma with AHTRT with or without chemotherapy may improve freedom from local progression and survival as compared with SFTRT, especially for patients with nonsquamous cell carcinoma. The statistical powers to detect the observed differences in median time to local progression and survival were approximately 55% and 35%, respectively. Therefore, further investigation comparing SFTRT with AHTRT is warranted.

Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma.

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) is an antineoplastic modality in which immune-activated cells are administered to a host with advanced cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested to have therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients with advanced malignant melanoma. Nineteen patients were entered in the trial. They received IL-2 at 3 x 10(6) U/m2 subcutaneously daily x 5 plus LEV 50 mg/ m2 orally three times daily (p.o. t.i.d.) x 5. Patients were reevaluated at four-week intervals. None of the patients achieved a partial or complete regression (PR, CR). The median time to treatment failure (refusal, progression, or off study due to toxicity) was 56 days. Grade IV toxicities included vomiting (3 patients), lethargy (1 patient), and musculoskellar pain (1 patient). This regimen is not recommended for further testing in patients with advanced malignant melanoma.

Malignant melanoma: an emerging and preventable medical catastrophe.

The natural history of malignant melanoma, including the diagnosis, prognosis, and treatment options, is reviewed in an attempt to formulate appropriate management strategies. Awareness on the part of clinicians is important, inasmuch as early detection of malignant melanoma offers the best chance for improved survival. Most lesions are excised with a margin of 1 to 3 cm, and follow-up assessment intervals are based on the depth of the primary lesion. Follow-up usually consists of a medical history, physical examination, chest roentgenography, and hematologic and chemistry profiles. Routine use of sophisticated imaging studies is unnecessary because the yield from such an approach has been low. Patients with melanomas thicker than 1.6 mm and those with histologic evidence of involvement of regional lymph nodes are at risk for development of disseminated disease and may be candidates for adjuvant therapy. In patients with severe weight loss and poor nutrition because of advanced disease, analgesic agents, stool softeners, and appetite enhancers are palliative measures that should be considered.

Attitude and disposition: do they make a difference in cancer survival?

Psychosocial and spiritual factors influence a broad spectrum of medical and surgical disorders. The adverse effects of stress have been most clearly documented in cardiovascular disease. In cancer, unresolved questions include the following: Do emotional factors have a causal role in either initiating or promoting a malignant process, and can they possibly accelerate the dissemination of cancer? The literature, which consists of anecdotes, case-control methods, and randomized trials, is inconsistent and beset with major methodologic problems. Psychosocial interventions can be life enhancing in sharp contrast to the guilt-ridden programs of some alternative practitioners. A social support system and an element of spirituality and religion seem to be the most consistent predictors of quality of life and possible survival among patients with advanced malignant disease.

Etoposide-cisplatin and thoracic radiation therapy salvage of incomplete responders to a noncisplatin induction regimen for limited and extensive small-cell carcinoma of the lung.

Our purpose was to determine the ability of an etoposide-cisplatin (EP )-based regimen to salvage patients with limited and extensive small-cell lung cancer who are incomplete responders to cyclophosphamide-Adriamycin-vincristine-etoposide (CAVE) chemotherapy, and to determine the ability of thoracic radiation therapy (TRT) to salvage CAVE and EP incomplete responders. Fifty-eight patients with small-cell lung cancer (33, limited disease; 25, extensive disease) were entered on this Phase II study between November 1984 and December 1987. Patients received three cycles of CAVE chemotherapy, followed by two cycles of CEPi (cyclophosphamide-etoposide-cisplatin (infusional) and two cycles of CE (cyclophosphamide-etoposide) in conjunction with TRT and prophylactic cranial irradiation (PCI). The overall response rate to CAVE was 62% [5% complete response (CR), 57% partial response (PR) + regression (REGR)]. Of the patients who failed to achieve a CR with CAVE, 81% responded to CEPi (44% CR, 36% PR). Of the patients who did not achieve a CR with either CAVE or CEPi, 89% responded to TRT (65% CR, 24% PR + REGR). For the 33 patients with limited disease, the median survival time and 2-year survival rate were 16.1 months and 24%, respectively. The corresponding figures for the 25 patients with extensive disease were 9.8 months and 4%, respectively. Eleven of these 25 patients were "downstaged" to "limited disease" with CAVE + CEPi and then received TRT + PCI + CE. Their median survival time and 2-year survival rate were 12.6 months and 9%, respectively. The EP-based regimen CEPi and TRT were able to convert 44 to 65% of patients to a complete response who had failed to do so with non-EP induction chemotherapy. This study supports the use of an EP regimen with TRT as initial therapy for newly diagnosed small-cell lung cancer.

Infusion cisplatin chemotherapy and hyperfractionated thoracic radiotherapy for small-cell lung cancer.

Sixty patients, 29 with limited disease and 31 with extensive disease, received an infusion cisplatin-based chemotherapy regimen and, where applicable, subsequent hyperfractionated thoracic radiation therapy (HTRT). Of the patients with limited disease, the response rate was 100% (76% complete response); median survival 26.5 months; 1- and 2-year survival 90 and 55%, respectively. Of those with extensive disease,96% responded (36% complete response) with median survival 12.0 months and 1- and 2-year survival 48 and 29%, respectively. Thirty-five percent of extensive disease patients were downstaged to a "limited" status. with a median survival of 20.3 months. Grade IV leukopenia and thrombocytopenia were seen in 25 and 7% of patients, respectively, with one patient dying of radiation pneumonitis. Within the constraints of the study, infusion cisplatin-based chemotherapy and HTRT appear to be a safe and effective program for the treatment of small-cell lung cancer.

Neuroendocrine differentiation is an independent prognostic factor in chemotherapy-treated nonsmall cell lung carcinoma.

BACKGROUND: Neuroendocrine differentiation can be identified in 10-30% of patients with nonsmall cell lung carcinoma (NSCLC) by immunohistochemical or electron microscopic techniques. However, its clinical significance is not well established. METHODS: Tumors from 107 patients with Stage IIIA, IIIB, and IV NSCLC treated with cisplatin/etoposide with or without hydrazine in the North Central Cancer Treatment Group and Mayo Clinic protocols were analyzed immunohistochemically with antibodies to chromogranin A (CGA), Leu 7 (CD 57), and synaptophysin (SY). These results were compared with clinical outcomes. RESULTS: Keratin AE1/AE3, used as a control, was positive in 99.1% of cases; 34.6% had positive staining for at least 1 neuroendocrine marker, and 11.3% had positive staining for 2 or more markers. CGA was positive in 4.7%, Leu 7 in 18.7%, and SY in 24.3% of cases. A significant increase in survival was seen in patients with tumors expressing any one neuroendocrine marker or any combination of neuroendocrine markers (P < or = 0.01). There was no correlation between the presence of neuroendocrine differentiation and either response to chemotherapy or time to disease progression (P > 0.3), nor was there any correlation between chemotherapy response, time to progression, or survival with staining intensity or percent of cells positive per case. CONCLUSIONS: Neuroendocrine differentiation may be of prognostic significance in patients with advanced stage NSCLC treated with chemotherapy.

Utility of follow-up tests for detecting recurrent disease in patients with malignant melanomas.

OBJECTIVE: To determine the effectiveness of follow-up tests for signaling recurrences in patients with intermediate- and high-risk malignant melanomas treated with curative intention. DESIGN: Retrospective analysis of prospectively collected data. SETTING: North Central Cancer Treatment Group. PATIENTS: A total of 261 patients with resected local (> or = 1.69 mm) and regional nodal malignant melanomas who were enrolled in a single prospective adjuvant trial were studied. All patients were scheduled to be followed up monthly for 2 months, then every 2 months for the first year, every 4 months the second year, every 6 months the next 3 years, and annually thereafter, with each visit consisting of a history, physical examination, complete blood cell count, blood chemistry panel, and a chest x-ray. RESULTS: Of the 145 evaluable patients who developed recurrent melanomas, 99 patients (68%) developed symptoms that signaled the diagnosis of recurrent disease. Physical examination of asymptomatic patients led to the diagnosis of recurrent disease in 37 patients (26%). The other nine patients (6%) with recurrent disease had abnormal chest x-rays. Laboratory results were never a sole indicator of recurrent disease. CONCLUSION: The majority of recurrences following resection of primary melanomas are discovered by history and/or physical examination despite the frequent use of other follow-up tests. The present data indicate that routine blood analyses and chest x-rays have limited value in the postoperative follow-up of patients with resected intermediate- and high-risk melanomas.

Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma.

PURPOSE: We conducted a randomized prospective trial in selected patients with fully resected high-risk stage I and II malignant melanoma. PATIENTS AND METHODS: Interferon alfa-2a (IFN-alpha 2a) 20 x 10(6) U/m2 was administered three times each week for 12 weeks by the intramuscular route. Both the treatment group (n = 131) and the control group (n = 131) were evenly balanced with regard to relevant prognostic discriminants. RESULTS: The median disease-free survival (DFS) time was 2.4 years for the IFN-alpha 2a group and 2.0 years for the observation group (log-rank P = 0.19). The median survival times were 6.6 years for IFN-alpha 2a and 5.0 years for observation (log-rank P = .40). For stage I patients (n = 102), there was no apparent therapeutic advantage from IFN-alpha 2a therapy. The DFS for stage II patients was a median of 10.8 months in the control group versus 17 months in the treatment group. The overall survival time was 4.1 years for the treatment group versus 2.7 years for the control group. The differences in DFS for stage II patient were significant in a Cox model. These results must be interpreted cautiously because of subset analysis. A severe flu-like toxicity occurred in 44% of patients, 13% lost at least 10% of their baseline weight, and 45% experienced a worsening of Eastern Cooperative Oncology Group (ECOG) performance score. CONCLUSION: Our findings indicate trends that suggest a possible benefit for selected patients with high-risk malignant melanoma. The results will require further study in a larger patient population for confirmation.

Long term results of a phase I/II study of aggressive chemotherapy and sequential upper and lower hemibody radiation for patients with extensive stage small cell lung cancer.

BACKGROUND: A Phase I/II study of an aggressive six-drug chemotherapy regimen followed by the use of sequential hemibody radiation therapy as a possible non-cross-resistant systemic treatment was undertaken for patients with extensive stage small cell lung cancer. METHODS: The 20 enrolled patients received 7 cycles of cyclophosphamide-based chemotherapy. The first cycle consisted of cyclophosphamide, doxorubicin, etoposide, vincristine, and lomustine. Subsequent cycles used a regimen of doxorubicin alternating with cisplatin. Thoracic radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 5 and 6 (2000 cGy in five fractions during each week). Prophylactic cranial radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 2 and 3 (1700 cGy in 5 fractions during each week). After the 7 cycles, patients received 600 cGy upper hemibody radiation followed by 800 cGy lower hemibody radiation. RESULTS: Nineteen of 20 patients were evaluable for toxicity and response to treatment. Hematologic toxicity accounted for treatment delays or decreased doses in 16 of 19 patients. Thirteen patients completed the initial 7 cycles; progressive disease was the only reason for discontinuing treatment. Two patients had fatal hematologic complications after lower hemibody radiation. Three patients had severe or greater peripheral neurologic toxicity, two had severe central neurologic toxicity, and one had severe cardiac toxicity. Of 19 patients, 9 achieved a complete response; median survival was 11.5 months. Five-year progression free survival and 5-year overall survival were 27% and 16%, respectively. CONCLUSIONS: This aggressive regimen is feasible for patients with extensive stage small cell lung cancer; however, hematologic-related mortality after lower hemibody radiation suggests that future investigations should be initiated at lower initial doses of lower hemibody radiation. Long term survival of the patients suggests that sequential hemibody radiation treatment warrants further investigation.

Prophylactic cranial irradiation in limited-stage small cell lung cancer.

BACKGROUND: The role of prophylactic cranial irradiation (PCI) for patients with limited-stage small cell lung cancer (LSSCLC) remains a controversial issue. This study evaluated PCI in patients with LSSCLC who achieved a complete response to initial chemotherapy. METHODS: A retrospective case study of all nonprotocol patients with LSSCLC examined at our institution from 1982 to 1990 was performed. Of the 67 nonprotocol patients who were treated with combination chemotherapy (cyclophosphamide-based) and thoracic radiotherapy during those years, 43 achieved a complete response. Twenty-four patients received prophylactic cranial irradiation (PCI+) (25-36 Gy in 10-16 fractions), and 19 did not (PCI-) at the physician's or patient's discretion. RESULTS: The distribution of prognostic factors between the PCI+ and PCI- groups was well balanced. Of the PCI+ patients, the 2-year actuarial freedom from relapse in the central nervous system was 93% versus 47% for the PCI- patients (log rank analysis, P = 0.001). An initial central nervous system relapse developed in 2 of the 24 PCI+ patients as the only site of failure versus 7 of 19 PCI- patients (P = 0.003). The 2-year actuarial overall survival was 50% for the PCI+ patients versus 21% for the PCI- patients (P = 0.01). The addition of prophylactic cranial irradiation was the only significant factor contributing to an improvement in time to central nervous system relapse and survival for the PCI+ patients. There were five patients alive at the time of this report, and all received prophylactic cranial irradiation. None had cognitive or neurologic impairment. CONCLUSIONS: Prophylactic cranial irradiation may contribute to improved survival in patients with LSSCLC who achieve a complete response after chemotherapy and thoracic radiation therapy.

Pilot study of human recombinant interferon gamma and accelerated hyperfractionated thoracic radiation therapy in patients with unresectable stage IIIA/B nonsmall cell lung cancer.

PURPOSE: Gamma interferon has a wide range of properties, including the ability to sensitize solid tumor cells to the effects of ionizing radiation. The North Central Cancer Treatment Group has previously completed pilot studies of accelerated hyperfractionated thoracic radiation therapy (AHTRT) in patients with unresectable Stage IIIA/B nonsmall cell lung cancer (NSCLC). This Phase I study was designed to assess the toxicity of concomitant gamma interferon and AHTRT in a similar patient population. METHODS AND MATERIALS: Between December 1991 and May 1992, 18 patients with unresectable Stage IIIA/B NSCLC were treated with daily gamma interferon (0.2 mg subcutaneously) concomitant with AHTRT (60 Gy given in 1.5 Gy twice daily fractions). All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 with weight loss < 5%. Eight patients had Stage IIIA and 10 had Stage IIIB disease. RESULTS: Nine patients (50%) experienced severe, life-threatening, or fatal toxicities. Eight of the patients (44%) developed significant radiation pneumonitis, which was severe in six patients and fatal in two patients (11% treatment-related mortality). Two patients (11%) developed severe radiation esophagitis. With follow-up of 15-21 months, 2 patients are alive, and 16 have died. The median survival time and 1-year survival rate is 7.8 months and 38%, respectively. CONCLUSION: Gamma interferon appeared to sensitize normal lung tissue to the effects of radiation, as demonstrated by the high incidence of severe or fatal radiation pneumonitis. We do not recommend pursuing gamma interferon as a radiosensitizer in this setting.