Rose J. Papac

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.

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.

Distant metastases from head and neck cancer.

Distant metastases were detected in 52 (30.7%) of 169 patients with advanced head and neck cancer observed from 1968 until 1982. Both clinical and autopsy findings are included in the assessment. The occurrence of distant metastases was related to primary disease site, stage of disease at presentation, and development of infectious complications during the course of the disease. The duration of survival was unrelated to the development of metastases. The incidence of distant spread was low for patients with floor‐of‐mouth lesions (11.8%) and high for patients with advanced disease arising in some regions of the larynx (58.6%). Patients who experienced wound infections, pneumonia, or bacteremia had infrequent development of metastatic disease.

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.

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

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.

Biochemical and pharmacological studies with 1-β-d-arabinofuranosylcytosine in man

Abstract Cytosine arabinoside, labeled with tritium, was administered to five patients with far-advanced neoplasms. The analog was rapidly deaminated to uracil arabinoside; the latter accounted for between 86 and 96 per cent of the radioactivity excreted in the urine. Incorporation of tritium-labeled cytidine into DNA by suspensions of human leukemic leukocytes was inhibited in the presence of cytosine arabinoside. Although administration of cytosine arabinoside at therapeutic levels depressed the ability of leukemic leukocytes to incorporate cytidine into DNA in vitro , there was no correlation between the degree and duration of this effect and the clinical response to the drug. Tritium-labeled cytosine arabinoside entered human leukemic leukocytes very rapidly when incubated with the cells in vitro ; there was a small but significant incorporation of the analog into both DNA and RNA.

Spontaneous regression of cancer

Spontaneous regression of cancer is one of the most fascinating phenomena observed in medicine. It is generally regarded as inexplicable, although there are now some laboratory studies of regressed or regressing tumours, as well as new theoretical possibilities about mechanisms. In this review, the historical background, clinical features and possible mechanisms are discussed. The clinical aspects of the malignancies most often reported to undergo spontaneous regression, namely renal cell carcinoma, neuroblastoma, carcinoma of the breast, malignant melanoma and leukaemias/lymphomas, are reviewed. The prevalent view regarding the mechanism for spontaneous regression is the involvement of immunological factors in the host. Other mechanisms include hormonal changes, tumour necrosis, trauma and changes in blood supply. Recent. reports suggest other mechanisms such as apoptosis and differentiation to a benign tumour. Decreased telomerase activity has been reported in neuroblastomas that regress, and hypomethylation of DNA in retinoblastoma is a possibility. A role for cytokines and/or growth factors is also discussed. The significance of spontaneous regression is the demonstration of endogenous control of neoplastic growth. Spontaneous regression of cancer is defined as the complete or partial disappearance of malignant tumour in the absence of therapy that is capable of inducing anti-neoplastic effects. Most patients ultimately relapse, so it is not usually associated with cure of the malignant disease. The existence of spontaneous regression is often questioned; indeed, review of the literature reveals reported cases which do not represent malignant disease, instances in which documentation of metastases is questionable and some reported cases in which therapy may have played a role. In 1966, Everson and Cole published a classic monograph on this topic which included 176 well- documented cases of spontaneous regression of cancer published from 1900 until 1964, and listed criteria for the diagnosis (1). These are: documented histologic regression of biopsy-proven metastases; radiologic regression of

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

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.

Lymphocyte transformation in malignant lymphomas.

Peripheral blood leukocyte cultures with phytohemagglutinin (PHA) were studied in 19 patients with malignant lymphomas, classified as Stage IV. Thirteen patients had lymphosarcoma and 6 had reticulum cell sarcoma. Control subjects included both healthy and chronically ill subjects. Seventeen patients with Hodgkins disease were also studied. A wide range of responsiveness to PHA was observed in cases of lymphosarcoma with a median value for the group lower than that of control subjects. Correlation of lymphocyte transformation with PHA was noted with histologic type of lymphosarcoma, with duration of disease and with age of the patient. The most marked impairment of transformation generally occurred in patients with small cell lymphosarcoma, in patients with brief duration of disease and older age groups. There was little correlation between peripheral blood lymphocyte level and percentage transformation with PHA. In patients with reticulum cell sarcoma, PHA stimulation was quite markedly impaired. In Hodgkins disease, impaired transformation with PHA was related to stage of disease and peripheral lymphocyte levels. Patients with Stage IV disease showed decreased transformation as did patients with lymphopenia.

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.