Joseph B. Weissberg

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.

A clinical and histopathologic analysis of the results of conservation surgery and radiation therapy in stage I and II breast carcinoma

One hundred eighty women with clinical Stage I or II operable breast carcinoma were treated by radiotherapy following local tumor excision at Yale‐New Haven Hospital through 1980. With a median follow‐up time of 6.9 years, the actuarial 5‐year overall and disease‐free survival rates were 82% and 78%, respectively. The 5‐year actuarial breast‐recurrence‐free survival rate was 92%. Several clinical‐histopathologic features and treatment parameters were assessed for their significance as predictors of local breast failure or distant relapse. Cox lifetable regression analysis showed that patients with clinical Stage II carcinomas had significantly worse overall and relapse‐free survival rates, but clinical stage alone had no effect on the rate of breast recurrence. Furthermore, a decrease in overall and disease‐free survival was evident when necrosis was present in the tumor or when patients had an infiltrating lobular carcinoma. Breast recurrence‐free survival was also influenced adversely by the presence of these two tumor features, especially when either tumor necrosis or infiltrating lobular carcinoma was found in conjunction with clinical Stage II lesions. Other histologic features such as grade, vascular invasion, perineural invasion, or the presence of an intraductal component of carcinoma did not affect outcome, nor did the treatment techniques employed appear to have a differential effect.

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.

Conservative surgery and radiation therapy in breast carcinoma: Local recurrence and prognostic implications

Conservative surgery with radiation therapy has been used with increasing frequency at Yale-New Haven Hospital since the late 1960s, resulting in a minimum evaluable follow-up time of 5 years on 278 patients treated prior to 1982. The radiation therapy technique generally encompassed treatment to the breast and regional lymph nodes of 4600 cGy with an electron beam boost to the tumor bed of 6400 cGy. Axillary dissection was performed in 19%, adjuvant chemotherapy in 7.3%, and adjuvant hormonal therapy in 5.7%; 65% were clinical Stage I and 35% were clinical Stage II. As of July 1987, with a minimum evaluable follow-up of 5 years and a median follow-up of 7.46 years, the actuarial 5- and 10-year survival for all 278 patients was 83% and 67%, respectively. The breast recurrence-free rate was 91% at 5 years and 80% at 10 years. Whereas the 5-year survival was significantly greater for clinical Stage I patients (91% vs 68%, p = .01), the breast recurrence-free rates did not significantly differ between clinical Stage I & II (93% vs 88%). There were 31 patients who failed in the breast alone as the first site of failure; 67% were at or near the primary site whereas 33% were distinctly removed from the primary site. Salvage mastectomy was performed in 25 patients, repeat wedge resection in two patients, and biopsy only in four patients. Axillary nodes were positive in five (33%) of 15 evaluable patients undergoing axillary dissection at the time of recurrence. The 5-year actuarial survival following local recurrence for the 31 patients was 48% at a mean follow-up of 5.06 years. The local recurrences were further subclassified into localized breast recurrences (LBR), defined clinically as greater than 3 cm and/or with dermal involvement. The 22 patients experiencing localized breast recurrences tended to occur later (median time to recurrence 4.3 years) than the nine patients experiencing a diffuse breast recurrence (median time to recurrence 2.9 years). At last follow-up, three (14%) of the 22 localized breast recurrences had subsequently failed distantly and none had subsequent local failure, whereas four (44%) of nine diffuse breast recurrences had subsequent distant failure and five (55%) of the nine diffuse breast recurrences experienced further local disease. The 5-year actuarial survival following salvage treatment was 90% for the localized breast recurrences and only 13% for the diffuse breast recurrences.

A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: A RTOG randomized study (#79-04)

A randomized prospective trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer, misonidazole (MISO), used as an adjunct to high fractional dose radiotherapy in the management of unresectable Stage III and IV squamous cell carcinomas of the oral cavity, oropharynx and hypopharynx. From June 1979 to February 1983, 42 patients were randomized with 40 patients available for analysis. In the radiotherapy (RT) only group, 19 patients received a short course of high fractional dose radiotherapy with 400 rad per day, 5 days per week, to a total of 4400 to 5200 rad. In the radiotherapy plus misonidazole group (RT + MISO) 21 patients received the same radiotherapy plus 1.5 gm/m2 of misonidazole 3 times a week for a total of 7 doses. The observed side effects associated with misonidazole were: persistent numbness and paresthesia (1 patient), transient peripheral nerve paresis and persistent paresthesia (1 patient), and nausea and vomiting (2 patients). The treatment related morbidities were similar in both groups. Acute mucositis was seen in 4 of 19 patients in the RT group and 3 of 21 patients in the RT + MISO group. Acute airway obstruction requiring tracheotomy was seen in 2 patients with massive tumor in the base of tongue (1 in each group). Severe dysphagia requiring NG tube feeding was seen in 3 patients in the RT + MISO group and 3 patients in the RT group. The initial complete response rate in the RT group was 53%, versus 48% in the RT + MISO group. The estimated 2-year loco-regional control rates were 10% for RT alone and 17% for RT + MISO (no significancy). These results indicate that the addition of misonidazole does not improve the efficacy of high fractional dose radiotherapy for management of unresectable head and neck carcinomas. However, high fractional dose radiotherapy can be administered for the management of advanced head and neck carcinomas with acceptable morbidity and thus, is a useful regimen for future clinical trials of hyperbaric oxygen or new hypoxic cell sensitizers.

Randomized trial of conventional versus high fractional dose radiation therapy in the treatment of advanced head and neck cancer

A prospectively randomized clinical trial was undertaken to compare conventionally fractionated radiation therapy and high fractional dose irradiation in the treatment of advanced, surgically unresectable head and neck squamous cell carcinoma. Sixty-four patients were entered into the study between 1973 and 1979 and were randomized to receive either 200 rad daily to total tumor doses of 6000-7000 rad in 6-7 weeks, or 400 rad daily to a total of approximately 4400 rad in 2-3 weeks. The distribution of patients between the two fractionation schedules was comparable regarding site of the primary tumor, extent of disease, degree of histologic differentiation and performance status. Twenty-nine of 31 (94%) patients in the 200 rad group and 29 of 33 (88%) in the 400 rad group has Stage IV disease. Twenty-six in the former group and 30 in the latter completed radiation therapy as planned. Acute skin and mucosal reactions occurred earlier in patients treated with 400 rad daily, but were of equivalent intensity and well within acceptable levels in both groups. No increase in late adverse effects was seen with high daily doses. Palliation of tumor-related symptoms and extent of tumor control were comparable in the two groups. Actuarial five year disease-free survival rates were approximately 10% in both treatment groups with a mean follow-up period of 5 1/2 years. We conclude that high fractional dose irradiation is equivalent to conventionally fractionated radiation therapy in the treatment of advanced head and neck cancer.

A technique for interstitial nasopharyngeal brachytherapy

Two patients have recently been seen with recurrent epidermoid carcinoma in the nasopharynx. Both have achieved local control and are disease-free after a brachytherapy procedure. Here we describe our technique for interstitial nasopharyngeal brachytherapy.

Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes ☆

PURPOSE Approximately 5% of cancer patients given radiation therapy exhibit severe injuries to the noncancerous tissue in the radiation field. Striking clinical sensitivity to ionizing radiation has been observed frequently in ataxia-telangiectasia (A-T) homozygotes. This study was undertaken to test the hypothesis that heterozygous carriers of a mutated gene for A-T may represent a substantial proportion of all patients who suffer severe radiation toxicity. METHODS The medical records of all A-T heterozygotes treated with radiation therapy for breast or prostate cancer were compiled from an ongoing study of mortality and cancer incidence in A-T families. Diagnostic, treatment, and follow-up records were reviewed. Acute and long-term radiation complications were scored according to Radiation Therapy and Oncology Group criteria. RESULTS There were no instances of soft tissue necrosis or other apparent serious injuries to normal tissues of two A-T heterozygotes with prostate carcinoma and 11 with breast carcinoma who received moderate-to-high doses of conventionally fractionated radiation therapy by megavoltage techniques. CONCLUSION There is no evidence that abnormal clinical radiosensitivity occurs in A-T heterozygotes receiving conventionally fractionated radiation therapy for breast or prostate cancer.

The role of radiation therapy in carcinoma of the extrahepatic bile ducts

Carcinoma of the extrahepatic bile ducts is uncommon, and the primary management has been largely surgical. Radiotherapy for this disease has received minimal attention, although recent innovations have prompted increased interest. We report a retrospective review of 34 patients treated with radiotherapy between 1967 and 1982. The five-year survival rate was 6%, and the median survival was 11 months. Patient characteristics, treatment techniques, and outcome for the entire group, as well as selected subgroups are discussed. Two patients treated by interventional radiographic techniques, external irradiation, and transcatheter intracavitary brachytherapy are presented in detail. The current surgical, radiotherapeutic, and chemotherapeutic literature is reviewed.

Radiotherapy in sarcoidosis of the larynx: Case report and review of the literature†

Sarcoidosis infrequently involves the larynx, but resultant airway obstruction will often prompt the need for therapeutic intervention. Systemic and intralesional corticosteroids as well as various surgical approaches have been advocated. We report a case of a 36‐year‐old man with biopsy proven laryngeal sarcoidosis. The patient became refractory to corticosteroids and was treated with megavoltage radiotherapy as an alternative to tracheostomy. A gradual and complete clinical recovery was observed. The radiation techniques are presented, and the literature regarding laryngeal sarcoidosis is reviewed. Megavoltnge radiotherapy is a viable treatment option in this disorder.