Diana B. Fischer

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.

Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse.

PURPOSE To evaluate the prognostic significance of ipsilateral breast tumor recurrence (IBTR) with respect to the subsequent development of distant metastasis. MATERIALS AND METHODS Between January 1970 and December 1989, 973 patients with invasive breast cancer were treated with conservative surgery and radiation therapy at Yale-New Haven Hospital. The median follow-up time as of December 1993 was 8.6 years. A number of prognostic factors were tested as possible predictors of distant metastases, including whether a patient experienced IBTR. IBTRs were broken down by time to recurrence to determine whether the breast recurrence-free interval had any prognostic relevance with respect to the development of distant metastasis. RESULTS As of December 1993, out of the entire population of 973 patients, 73 patients had developed IBTR and 134 had developed distant metastases. The overall actuarial survival rate at 10 years was .71 +/- .02, with a 10-year actuarial breast recurrence-free rate of .84 +/- .02 and a 10-year distant metastasis-free rate of .77 +/- .02. The overall distant metastasis rate was higher in patients who experienced IBTR compared with patients who had never experienced IBTR. Furthermore, the time to IBTR had a significant effect on distant metastases. Of 32 patients who developed an IBTR within 4 years of original diagnosis, 16 (50%) developed distant metastases. In contrast, of 41 patients who developed later breast relapses (> 4 years from original diagnosis), only seven (17%) developed distant metastases (P < .01). Of 32 patients who developed early breast relapse, the 5-year survival rate following breast relapse was .50 +/- .01, compared with a 5-year post-breast relapse survival rate of .78 +/- .10 among 41 patients with later breast relapses (P < .05). CONCLUSION It appears that early IBTR is a significant predictor for distant metastases. Whether early breast tumor relapse is a marker for or cause of distant metastases remains a controversial and unresolved issue. Implications for adjuvant systemic therapy at the time of breast relapse are discussed.

Results of radical radiation therapy in clinical stage I, technically operable non-small cell lung cancer

From 1970 to 1983, 1,646 lung cancer patients were referred for treatment to the Hunter Radiation Therapy Center, Yale-New Haven Hospital. Forty-three patients had clinical Stage I non-small cell lung cancer felt to be surgically resectable but were treated with radical radiation therapy either for medical reasons (37 patients) or because the patient refused surgery (six patients). This group of clinical Stage I lung cancer patients is understaged by modern criteria since the majority of patients did not have thoracic CT scans and staging was based on fairly limited clinical and radiographic studies. The histological diagnosis was squamous cell carcinoma in 53% of the Stage I patients, adenocarcinoma in 25%, and other non-small cell histologies in 22%. All patients were treated with megavoltage irradiation and the mediastinum was treated in 88% of the patients. Eleven patients were treated with a continuous course (CC) and 32 patients received split course (SC) therapy based on physician preference. The CC consisted of a median fraction size of 200 cGy to a total median dose of 5900 cGy in 6-7 weeks. The SC used a median fraction site of 275 cGy to a total median dose of 5400 cGy over a 6-week period with a 2-week rest in the middle of treatment. The actuarial survival rate of the 43 clinical Stage I patients was 36% at 3 years and 21% at 5 years. Intrathoracic failures occurred in 39% of the patients. Despite the fact that the CC group was similar to the SC group in terms of age, histology, and tumor extent, the CC patients had a lower thoracic failure rate (2/11) versus 15/32), a longer median survival (51.6 months versus 27 months), and a better actuarial 5-year survival rate (45% versus 12%) when compared to the SC patients. Using Cox regression analysis to compare survival curves, the CC group had a significantly better survival compared to the SC group (p = .04).

Prognosis following local recurrence in the conservatively treated breast cancer patient

At Yale-New Haven Hospital conservative treatment of early stage breast carcinoma with lumpectomy and radiation therapy has been used with increasing frequency since the 1960s. We have reviewed our experience with specific reference to prognosis following local recurrence. Between January 1962 and December 1984 a total of 433 patients were treated with conservative surgery and radiation therapy using standard techniques. As of December 1989, with minimum evaluable follow-up of 5 years and a median follow-up of 8.21 years, there have been a total of 50 ipsilateral breast recurrences resulting in a 5-year actuarial breast recurrence rate of 8%. Extent of disease at the time of local recurrence was clinically categorized as localized (less than 3 cm without dermal involvement) or diffuse (greater than 3 cm and/or with dermal involvement). Seventy-two percent of the recurrences were at or near the original tumor site whereas 28% recurred elsewhere in the breast. At a median follow-up post recurrence of 5.0 years (range 0.3-16.9 years), the 5-year actuarial survival for breast recurrences was 59% and the 5-year disease-free survival was 65%. A number of clinical and pathological features at the time of original diagnosis as well as at the time of local recurrence were tested as possible prognostic indicators for survival following local recurrence. By univariate analysis, significant factors associated with survival following local recurrence included extent of local disease at the time of recurrence (p less than .01), time to local recurrence (p less than .03), with later recurrences doing better, and site of local recurrence (p less than .01), with recurrences elsewhere in the breast doing better. We conclude from this large single institutional experience with a median follow-up post-recurrence of over 5 years that patients experiencing a local recurrence in the conservatively treated breast have a relatively favorable prognosis. The prognostic factors correlating with survival and implications regarding adjuvant systemic therapy at the time of local recurrence are discussed.

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.

Pretreatment prognostic factors in carcinoma of the uterine cervix: a multivariable analysis of the effect of age, stage, histology and blood counts on survival.

From January, 1953 through December, 1977, 910 previously untreated patients with invasive carcinoma of the uterine cervix (Stages IB-IVB) were seen at Yale-New Haven Medical Center and affiliated hospitals. An extensive retrospective analysis was undertaken in an attempt to identify prognostically significant pretreatment factors. The patients studied were uniformly staged according to the current FIGO recommendations and the majority of patients had been treated under standardized protocols combining external beam radiation therapy and intracavitary radium. Pretreatment parameters, including prior medical illnesses, gross tumor characteristics, histology, and blood parameters were studied, employing stepwise Cox regression analyses to identify the possible effects of all factors and all two-way interactions among factors on survival, disease-free survival and freedom from local-regional failure, controlling for stage of disease. FIGO stage, patient age at diagnosis, pretreatment neutrophil count and hematocrit, uterine position, prior subtotal hysterectomy, histology, history of diabetes mellitus and number of pregnancies were all found to have prognostic significance. When other factors including stage of disease were controlled for, increased tumor size was associated with decrease disease-free survival and local-regional control rates.

Results of radiotherapy in control of stage I and II non-Hodgkin's lymphoma.

We retrospectively analyzed 114 patients with non‐Hodgkins lymphoma, clinical stages I and II, classified by the criteria of Rappaport and treated by radiotherapy alone. Of 84 patients classifiable, one‐third were nodular and two‐thirds diffuse lymphomas. Berkson‐Gage actuarial and relapse‐free survivals were determined for these two groups and for subgroups stratified by histology, stage, and by presence or absence of extranodal disease. Five year relapse‐free and overall survivals were 83% and 100%, respectively, for the nodular group and 37% and 59% for the diffuse group. Extranodal involvement was less frequent in the nodular (19%) than in the diffuse (52%) group, where it was associated with Stage IE disease and increased relapse‐free and actuarial survival. Histopathological subtype in the diffuse group (histiocytic versus combined lymphocytic poorly differentiated and mixed lymphocytic‐histiocytic) did not influence survival. Extranodal involvement and stage I disease were associated with better survival in the diffuse histiocytic group. Successful radiotherapy for all stages of disease, all histologies, was not correlated with extended versus involved fields, and 89% of the relapses in the entire series were by wide dissemination.

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.

Second Malignancies After Treatment of Early-Stage Breast Cancer: Lumpectomy and Radiation Therapy Versus Mastectomy

PURPOSE To determine the risk of second malignancies after lumpectomy and radiation therapy (LRT), and to compare it with that in a similar cohort of early-stage breast cancer patients undergoing mastectomy without radiation (MAST). PATIENTS AND METHODS Between January 1970 and December 1990, 1,029 breast cancer patients at our institution underwent LRT. A cohort of 1,387 breast cancer patients who underwent surgical treatment by mastectomy (MAST), and who did not receive postoperative radiation during the same time period, served as a comparison group. Second malignancies were categorized as contralateral breast versus nonbreast. In the cohort of patients undergoing LRT, a detailed analysis was carried out with respect to age, disease stage, smoking history, radiation therapy technique, dose, the use of chemotherapy or hormone therapy, and other clinical and/or pathologic characteristics. RESULTS As of March 1999, the median follow-up was 14.6 years for the LRT group and 16 years for the MAST group. The 15-year risk of any second malignancy was nearly identical for both cohorts (17.5% v 19%, respectively). The second breast malignancy rate at 15 years was 10% for both the MAST and LRT groups. The 15-year risk of a second nonbreast malignancy was 11% for the LRT and 10% for the MAST group. In the subset of patients 45 years of age or younger at the time of treatment, the second breast and nonbreast malignancy rates at 15 years were 10% and 5% for patients undergoing LRT versus 7% and 4% for patients undergoing mastectomy (P, not statistically significant). In the detailed analysis of LRT patients, second lung malignancies were associated with a history of tobacco use. There were fewer contralateral breast tumors in patients undergoing adjuvant hormone therapy, although this did not reach statistical significance. The adjuvant use of chemotherapy did not significantly affect the risk of second malignancies. CONCLUSION There seems to be no increased risk of second malignancies in patients undergoing LRT using modern techniques, compared with MAST. Continued monitoring of these patient cohorts will be required in order to document that these findings are maintained with even longer follow-up periods. With nearly 15 years median follow-up periods, however, these data should be reassuring to women who are considering LRT as a treatment option.