Origins of cancer therapy.

This is a brief overview of the development of cancer therapy with a focus on systemic therapy. The modern era of chemotherapy developed at Yale University Medical School during World War II, a fact that has been generally unrecognized until recently. The observations preceding and involved in the discovery of effective drugs for cancer seem particularly pertinent for this anniversary year.

Follow-up recommendations for patients with American Joint Committee on Cancer Stages I-III malignant melanoma.

BACKGROUND: Guidelines for follow-up of melanoma patients are not established. In 1987, a follow-up protocol was instituted at the Yale Melanoma Unit to improve upon the detection of disease recurrence in patients with American Joint Committee on Cancer Stage I-III cutaneous melanoma. The follow-up protocol consists of a patient education program and a surveillance schedule based on stage of disease. METHODS: The authors retrospectively reviewed the records of 373 patients who were seen and followed according to the surveillance protocol in the Yale Melanoma Unit between January 1988 and December 1994 to determine 1) the time interval between the initial visit and recurrence; 2) the most common method of detecting recurrences; 3) whether the surveillance schedule or the patient detects more recurrences, i.e., asymptomatic recurrences versus symptomatic recurrences; 4) whether there is any survival difference between asymptomatic and symptomatic recurrences. RESULTS: The 5-year overall survival rates for Stage I, II, and III patients were 95%, 72%, and 52%, respectively. Of the 78 recurrences, 44 (56%) were detected by physician-directed surveillance examinations and 34 (44%) by patients. Most recurrences were found within the first (47%) or second (32%) year of follow-up. The estimated 6-month hazard rates for death or recurrence were 0.0044, 0.0088, and 0.0278 for Stage I, II, and III patients, respectively. The group of asymptomatic patients with recurrence had a survival advantage over the symptomatic recurrence group. In addition, patients with locoregional recurrence had better survival than those with distant recurrence. CONCLUSIONS: Although many recurrences arise rapidly and are recognized early by patients, in this study more than half were found by surveillance examinations before symptoms were manifest. Based on the hazard ratio for recurrences, the authors recommend the following surveillance schedules in addition to the patient education program for detection of recurrences: 1) Stage I, annually; 2) Stage II, every 6 months for Years 1-2 and annually thereafter; 3) Stage III, every 3 months for Year 1, every 4 months for Year 2, and every 6 months for Years 3-5; 4) at Year 6 and beyond, all patients should have surveillance annually, due to the risk of late recurrence and/or metachronous multiple primaries.

Renal cell carcinoma: a paradigm of lanthanic disease.

Renal cell carcinoma is characterized by varied and sometimes obscure manifestations, which include unusual metastatic sites and paraneoplastic and vascular syndromes. In this review, uncommon metastatic sites and their clinical significance are discussed, particularly the thyroid, nasal structures, vagina, and gastrointestinal sites. Paraneoplastic syndromes appear to be related predominantly to cytokines or immunologic mechanisms. Vascular syndromes are related to the tendency of the tumor to spread by direct venous extension and to complications related to the vascularity of the tumor or its metastases. The recognition of unusual manifestations of renal cell carcinoma is important because these syndromes may lead to the diagnosis. Moreover, paraneoplastic syndromes and vascular findings may not indicate unresectability or incurability.

Spontaneous regression of cancer: possible mechanisms.

Spontaneous regression of cancer is reported in virtually all types of human cancer, although the greatest number of cases are reported in patients with neuroblastoma, renal cell carcinoma, malignant melanoma and lymhomas/leukemias. Study of patients with these diseases has provided most of the data regarding mechanisms of spontaneous regression. Mechanisms proposed for spontaneous regression of human cancer include: immune mediation, tumor inhibition by growth factors and/or cytokines, induction of differentiation, hormonal mediation, elimination of a carcinogen, tumor necrosis and/or angiogenesis inhibition, psychologic factors, apoptosis and epigenetic mechanisms. Clinical observations and laboratory studies support these concepts to a variable extent. The induction of spontaneous regression may involve multiple mechanisms in some cases although the end result is likely to be either differentiation or cell death. Elucidation of the process of spontaneous regression offers the possibility of improved methods of treating and preventing cancer.

Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials.

PURPOSE: Two consecutive randomized trials were run at our institution using the bioreductive alkylating agent mitomycin as an adjunct to radiation therapy in an effort to improve outcome in patients with squamous cell carcinoma of the head and neck. METHODS: Between 1980 and 1992, two consecutive randomized trials using mitomycin (trial 1) and mitomycin with dicumarol (trial 2) as an adjunct to radiation therapy in patients with squamous cell carcinoma of the head and neck were conducted at our institution. The patients were stratified by intent of therapy, extent of disease, and primary tumor site. Within each strata, patients were randomized to receive radiation therapy with or without mitomycin (trial 1) or mitomycin/dicumarol (trial 2). RESULTS: A total of 203 patients were enrolled onto both trials, 195 of whom were eligible for analysis. Patients were equally balanced with respect to sex, age, extent of disease, primary site, radiation dose, and total duration of radiation treatment. Hematologic toxicities were more frequently noted in the drug-treated arms, but were acceptable with no drug-related treatment deaths. Nonhematologic toxicities were acceptable and not significantly different between the two arms. As of September 1995, with a median follow-up of 138 months, a statistically significant benefit occurred in the mitomycin arms with respect to cause-specific survival (0.74 +/- 0.05 v 0.51 +/- 0.05; P = .005), local recurrence-free survival (0.85 +/- 0.04 v 0.66 +/- 0.05; P = .002), and local regional recurrence-free survival (0.76 +/- 0.05 v 0.54 +/- 0.05; P = .003). No statistically significant difference in overall survival was obtained (0.48 +/- 0.05 mitomycin arms v 0.42 +/- 0.05 radiation alone). CONCLUSION: The bioreductive alkylating agent mitomycin is a safe and effective adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck. The statistically and clinically significant improvement in local regional relapse and cause-specific survival obtained support the use of mitomycin as an adjunct to radiation therapy in the management of squamous cell carcinoma of the head and neck.

Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma of the head and neck.

Porfiromycin (methyl mitomycin C) has been shown in laboratory studies to have increased preferential cytotoxicity to hypoxic cells and therefore may provide enhanced therapeutic efficacy over mitomycin C when used in combination with radiation therapy (RT). The purpose of the two clinical studies reported here is to evaluate the concomitant use of porfiromycin with RT in the management of squamous cell carcinoma of the head and neck. Between October 1989 and July 1992, 21 patients presenting with locally advanced stage III/IV squamous cell carcinoma of the head and neck were entered into a phase I toxicity trial evaluating porfiromycin as an adjunct to RT. Patients were eligible if they had biopsy documented squamous cell carcinoma of the head and neck with a low probability of cure by conventional means. Patients were treated with standard fractionated daily RT to a total median dose of 63 Gy, with porfiromycin administered on days 5 and 47 of the course of RT. Upon completion of this phase I trial, a phase III trial was initiated in November 1992 randomizing patients with squamous cell carcinoma of the head and neck to RT with mitomycin C vs. RT with porfiromycin. There is no radiation only arm in this current trial. To date, 75 patients have been entered on this trial and acute toxicity data are available on 67 patients (34 porfiromycin, 31 mitomycin C) who have completed their entire course of treatment. Median follow-up of the 21 patients enrolled in the phase I porfiromycin trial is 58.5 months. Of the 21 patients, 5 were treated at a dose of 50 mg/M2, 4 at 45 mg/M2, and the final 12 at 40 mg/M2, which appeared to result in acceptable acute hematological and nonhematological toxicities. As of December 1995, 14 of the 21 patients have died with disease and 7 remain alive and free of disease, resulting in a 5-year actuarial survival of 32%. Of the patients enrolled to date in the phase III randomized trial of mitomycin C vs. porfiromycin, there have been no statistically significant differences between the two arms with respect to white blood cell count (WBC), platelet, or hemoglobin nadirs. Acute nonhematological toxicities including mucositis, epidermitis, odynophagia, and nausea have also been comparable. Two patients in this current randomized trial died during treatment, apparently of nondrug-related causes. We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final analysis of the phase I trial, which revealed a 5-year no evidence of disease survival rate of 32% in patients with locally advanced disease and a low probability of cure, appears encouraging. We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next 2 years. Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT, are warranted.

Myelodysplasia. The clinical spectrum of 51 patients.

BACKGROUND: Over a 15 year period, the authors followed 51 male patients with myelodysplastic syndromes whose clinical findings, laboratory data, and evolution demonstrated a wide spectrum of disease. METHODS: The following characteristics were assessed: age at diagnosis, risk factors, clinical presentation, laboratory features, category of myelodysplasia, leukemic conversion, and overall survival. RESULTS: The clinical manifestations included hemolytic episodes in two patients, antibody-mediated thrombopenia in one, marked marrow fibrosis in two; thrombocytosis in three, and simultaneous lymphoproliferative disorders in two. There were 21 patients whose marrow was either normo- or hypocellular. Six patients presented with single cytopenia but not anemia. There were six instances of overlapping of the French-American-British classification. Eighteen patients progressed to acute leukemia and 1 to chronic myelomonocytic leukemia. CONCLUSIONS: These observations indicate that patients with myelodysplastic syndromes may have single cytopenia without anemia that progresses to acute leukemia and may, rarely, evolve into chronic myelomonocytic leukemia. The clinical aspects of these syndromes may include autoimmune phenomena and myeloproliferative features.

Bone marrow metastases. A review.

Although bone marrow examination is a common procedure in the evaluation of patients with cancer, its role and contribution have been questioned in recent years. This review deals with the clinical and biologic aspects of metastasis to the bone marrow. The discussion is focused on the common tumor types that involve marrow and the application of newer techniques for tumor detection in the marrow. Therapeutic and prognostic implications of bone marrow metastasis are significant in several clinical settings. The mechanisms by which tumor cells affect marrow function have not been completely defined.

Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: results from two randomized clinical trials.

PURPOSE: This study was undertaken to assess the benefit of mitomycin C as an adjunct to postoperative radiation therapy in patients with operable squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Between May 1980 and May 1991, 182 patients have been enrolled in two consecutive randomized clinical trials testing mitomycin C as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck. In both trials, patients were stratified by stage, disease site and intent of therapy. This subset analysis includes 113 patients entered into these two randomized trials treated with surgery and postoperative radiation therapy. In the first trial, patients were randomized to receive standard postoperative radiation therapy alone compared with postoperative radiation therapy with concomitant mitomycin C. In the second trial, patients were randomized to postoperative radiation therapy or postoperative radiation therapy with concomitant mitomycin C plus dicoumarol. RESULTS: As of November 1991, the 113 patients treated with surgery and postoperative radiation therapy in both trials had a median follow-up of 93 months. There have been a total of 12 local recurrences in the radiation therapy alone arm compared to 0 local recurrences in the radiation therapy/mitomycin C arm. There were eight regional recurrences in the radiation therapy alone arm compared with five regional recurrences in the mitomycin C arm. Patients in the mitomycin C arm experienced a superior 5-year actuarial local regional control rate (87% vs. 67%, p < .015) and a statistically significant disease-free survival benefit (67% vs. 44%, p < .03). Overall survival difference between the two arms (56% vs. 41%) has not reached statistical significance. CONCLUSIONS: We conclude from these prospectively designed randomized clinical trials that in patients with operable head and neck cancer treated with surgery and postoperative radiation therapy, concomitant administration of mitomycin C with radiation therapy will result in a statistically significant disease-free survival and local regional control benefit. We are currently investigating the value of other bioreductive alkylating agents as adjuncts to radiation therapy in patients with squamous cell carcinoma of the head and neck.

Hormonal therapy for metastatic renal cell carcinoma combined androgen and provera followed by high dose tamoxifen.

The purpose of this phase II study was to determine the effectiveness of hormonal therapy with combined high dose androgen and provera or tamoxifen in patients with advanced renal cell carcinoma. 30 patients with metastatic renal cell carcinoma received testosterone propionate 100 mg intramuscularly (i.m.) 5 times weekly plus provera 400 mg (i.m.) twice weekly until disease progression developed. 20 patients, most of whom had previously failed to respond to androgen and provera, received tamoxifen 100 mg/m2 daily. Of the 30 patients treated with androgen and provera, 3 (10%) developed partial responses of brief duration. 2 of 20 patients (10%) experienced tumour response with tamoxifen, one instance of complete disappearance of pulmonary metastases in a patient whose primary tumour was questionably persistent at post mortem and another case demonstrating disease stability. Combined hormonal therapy offers very little therapeutic advantage in advanced renal cell carcinoma. Tamoxifen, in high dose, exerts anti-tumour effects in a small cohort of cases.

A phase II trial of mitomycin C, 5-fluorouracil and radiation therapy in the treatment of unresectable non-small cell lung cancer.

We conducted a study evaluating the efficacy of simultaneous administration of 5-fluorouracil, mitomycin C, and X-irradiation in unresectable Stage III non-small cell lung cancer. Radiation was delivered in a split course to a total of 55 Gy. In the first course, radiation was administered daily in 250 cGy fractions for 12 treatments. Following a two week rest, an additional 10 treatments of 200 cGy fractions were delivered. Chemotherapy consisted of 10 mg/M2 of mitomycin C on day 1, and 1000 mg/M2 per day of 5-fluorouracil by continuous infusion on days 1 through 5 and 29 through 33. Twenty-one enrolled patients were evaluable. The overall response rate was 52% (95% confidence intervals 31-73%), with a median duration of response of 42 weeks. There were 5 complete responders (24%) and four of these patients remain disease-free with follow-up between 24-54 months. The median survival time for all patients was 59 weeks. For the complete responders the median survival time has not yet been reached, but is in excess of 42 months. Toxicity consisted of moderate stomatitis and myelosuppression. The sustained remissions obtained by 4 of 21 patients (18%) treated with concurrent mitomycin C, 5-fluorouracil and x-irradiation are encouraging and deserve further study.

Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer.

A randomized prospective clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region. One hundred and twenty patients with biopsy proven tumor of the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx were randomly assigned to receive or not receive mitomycin C; all other aspects were similar in the two treatment groups. One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years. Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups. Hematologic and pulmonary toxicity were observed in the drug treated patients. Actuarial disease-free survival at 5 years was 49% in the radiation therapy group and 75% in the radiation therapy plus mitomycin C group, p less than 0.07. Local recurrence-free survival was 66% in the radiation therapy group and 87% in the radiation therapy plus mitomycin C group, p less than 0.02. The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer. The drug improves local tumor control without enhancing normal tissue radiation reactions.

Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy.

Over the past decade, improvement in survival has developed for patients with small cell lung carcinoma (SCLC) due to treatment strategies that include: cyclic combination chemotherapy, thoracic irradiation, and prophylactic cranial irradiation. In this study, we assess the outcome of treatment with initial cyclic combination chemotherapy including: cyclophosphamide, VP 16-123 and methotrexate combined with radiotherapy (RT), 6000 cGY [corrected] to the thorax for patients with limited disease and 3000 cGy [corrected] for patients with extensive disease. Forty-six patients are evaluated: 26 patients with limited disease and 20 with extensive disease. In patients who received 6000 cGy [corrected], to thoracic lesions, in combination with chemotherapy, administered for 3 courses prior to and following RT, the rate of clinically detected failure in the thorax was 3.8%. Morbidity was considered acceptable, although the occurrence of encephalopathy in 6 of 19 cases who received cranial irradiation, 3000 cGy [corrected], and concomitant chemotherapy was a serious consequence. Control of the primary tumor achieved by the use of higher dose RT is shown to be superior to that observed at lower doses of RT. This suggests that for the small cohort of patients whose disease is truly limited at the time of diagnosis, therapeutic regimens, which include higher dose RT, could increase the number of long term survivors of SCLC.

Hodgkin's disease in married couples.

The case of a husband and wife who both developed Hodgkin's disease of the same cellular subtype is reported. This represents only the fifth reported case of marital Hodgkin's disease that is well-documented histologically. The relevant literature and potential implications are reviewed.

Hodgkin's disease, intracranial involvement. Report of a case and review of the literature.

Intracranial hodgkin's disease, an extremely uncommon finding, is reported in a 21-year-old man. This diagnosis, confirmed histologically, occurred in the presence of recurrent systemic disease, mixed cellularity type, which is typical for patients who have developed this complication. Review of the reported cases suggests there may be increasing incidence of intracranial involvement of Hodgkin's disease.

Medical aspects of head and neck cancer.

Certain medical aspects of advanced head and neck cancer observed in 191 patients referred to a medical oncology service over a 14-year period are presented in this review. While these tumors constitute an uncommon group of advanced neoplasms, the disability and impairment associated with this disease are great. Infections, folate deficiency, and hypercalcemia are frequent complications and generally detected. The occurrence of pulmonary tuberculosis, cardiovascular and neurologic sequelae were infrequent but may be generally under-recognized. Additionally, head and neck cancer patients were found to develop second malignancies in remote sites with surprising frequency as well as demonstrating the predilection to develop second primary tumors within the same area.