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.

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 with radiation therapy in clinical stage I and II breast cancer. Results of a 20-year experience.

Conservative surgery and radiation therapy have been increasingly utilized at Yale-New Haven (Conn) Hospital since the 1960s. This analysis represents our experience from 1962 to 1982, with a total of 281 patients having a minimum assessable follow-up of five years and a median follow-up of 7.4 years. Five- and ten-year actuarial survivals were 83% and 67%, respectively. The actuarial breast recurrence-free rate was 91% at five years and 80% at ten years. Of 31 patients having recurrences in the breast alone, the actuarial five-year survival following recurrence was 48%. Twenty-eight (90%) of these 31 recurrences were salvageable with mastectomy or repeated wedge resection. Patients experiencing an early breast recurrence (less than three years) following initial treatment had a poorer prognosis than patients having recurrences later.

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 1960's, 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.

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 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.

Radiation therapy for squamous cell carcinoma of the esophagus.

Between 1965 and 1981, 119 patients with squamous cell carcinoma of the esophagus were treated with radiation therapy with curative intent. Radiation was employed in combination with surgery and delivered pre- and/or postoperatively in 20 patients (17%). The remainder received radiotherapy alone. The overall survival rate was statistically higher in patients who had surgery and radiation compared to the group receiving radiation alone. The one-, two-, and five-year survival rates of patients receiving combined treatment vs radiotherapy alone were 65% vs 35%, 25% vs 14%, and 15% vs 6%. Age, total radiation dose, and inclusion of the supraclavicular areas in the radiation portals did not impact on outcome. Other prognostic factors are discussed. Long term survivors were noted to be at substantial risk for the development of a second epidermoid malignancy in the upper aerodigestive tract. Cumulative risk at five years was approximately 25%.

Malignant biliary obstruction: intracavitary treatment with a high-dose-rate remote afterloading device.

A new technique of intracavitary brachytherapy for malignant biliary obstruction is presented. The technique involves the use of a high-dose-rate remote afterloading device, which offers all the advantages of conventional brachytherapy with the added benefit that the dose can be delivered in a single treatment over a few minutes. The potential problems associated with conventional brachytherapy are thereby minimized.

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.

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.

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. Megavoltage radiotherapy is a viable treatment option in this disorder.

Differential effect of cycloheximide on normal tissue tolerance and tumor control in irradiated rats.

The effect of the protein synthesis inhibitor cycloheximide (CHM) on normal tissue tolerance and tumor control in the rat following single doses of radiation has been studied. We have previously shown that the drug protects against skin damage when administered prior to irradiation of the hind limbs. It does not protect against six-month lethality when given prior to irradiation of the kidneys. In the present studies protection of rat bone marrow as evidenced by 30-day lethality was observed when CHM was given prior to whole-body irradiation. When CHM was given to rats bearing the BA1112 tumor, it had no protective effect on radiocurability. Therapeutically favorable differential protection of rapidly proliferating normal tissue over tumor can be achieved when CHM is administered prior to single radiation doses in the rat. This effect is most likely due to inhibition of protein synthesis and resultant interruption of the cell cycle in proliferating normal tissue. Further studies are required to determine the clinical applicability of CHM.

Effect of cycloheximide on skin and renal radiation tolerance in the rat.

The effect of cycloheximide (CHM) on skin and renal radiation tolerance in the rat has been studied. When administered 24 hr prior to a range of single radiation doses to the hind limbs, the drug protected against skin damage. When administered at intervals of 45 min to 100 hr prior to single-dose irradiation of the kidneys, no protection against renal injury, as manifested by blood pressure, urine creatinine level, and lethality, was observed. CHM-induced alteration in the cell cycle may confer radioprotection to a rapidly proliferating cell renewal system such as the skin and exert no radioprotective action in slowly proliferative tissue such as kidney.

High fractional dose irradiation of advanced head and neck cancer. Implications for combined radiotherapy and surgery.

Short-course, high fractional dose radiation therapy was compared with the conventional protracted radiation schedule in the treatment of advanced (stages III and IV) head and neck cancer. Sixty-four patients with surgically unresectable squamous cell carcinoma were randomized to receive either 6,000 to 7,000 rad in six to seven weeks or 4,000 to 4,800 rad in two to three weeks. The palliative benefits of irradiation were comparable in the two treatment arms, and complete tumor regression was observed in the majority of patients in both groups. There was no difference between the groups with regard to either short-term normal tissue radiation reaction or long-term complications. High fractional dose irradiation appears to yield results equivalent to those of conventionally fractionated radiation therapy in advanced head and neck cancer and deserves further study both as primary treatment and in combination with surgery.

Role of radiation therapy in gastrointestinal cancer.

The intradiation techniques in the last several decades has resulted in a wider application of radiation therapy to the treatment of gastrointestinal cancer. Controlled and uncontrolled clinical trials have shown benefit for preoperative and/or postoperative irradiation in carcinoma of the rectum and rectosigmoid. Endocavitary radiation techniques have been employed successfully in early, accessible rectal cancers as an alternative to abdominal perineal resection. High-dose external beam irradiation with and without concomitant chemotherapy has produced encouraging results in locally advanced, unresectable pancreatic carcinoma. Benefit for radiotherapy in locally advanced gastric carcinoma has been demonstrated as well. In carcinoma of the esophagus, radiotherapy has resulted in long-term control in selected patients and also has been employed with modest success in combination with surgery. Interstitial radiation techniques, intraoperative electron beam therapy, and fast neutrons, heavy charged particles, and other forms of high linear energy transfer radiation are being investigated and may eventually find greater application.