Daniel S. Kapp

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.

Oral cavity and oropharyngeal cancer in a younger population. Review of literature and experience at Yale

Oral cavity and oropharyngeal cancer in younger adults is a rare entity with an incidence of 2.7% among 1014 patients seen or treated at the Department of Therapeutic Radiology, Yale‐New Haven Medical Center between 1958 and 1980. Although there are reports of contrastingly divergent therapeutic experiences, the authors contend that even early stage cancers frequently fail definitive therapy with a rampant course, causing a rapidly fatal outcome. The three‐year actuarial survival was a mere 17% at Yale. The authors speculate that younger adult oral cavity and oropharyngeal cancers are possibly related to a genetic disorder or immunodeficiency, and recommend aggressive surgical and radiotherapeutic approaches combined with possible adjuvant immunotherapy.

Ependymomas of the spinal cord

Many patients with spinal cord ependymomas (SCE) undoubtedly benefit from post-operative radiation therapy; however, because of the wide variability in the total doses given, the optimal post-operative dose for SCE remains unclear. Several recent papers recommend total doses of 4000 rad to 5000 rad in 4 1/2 to 6 weeks. Unfortunately, only a small number of patients reported in the literature have been consistently treated to these high dose recommendations. Nine consecutive adult patients with SCE have been treated in a consistent way at Yale-New Haven Hospital with total doses of approximately 4500 rad to 5000 rad at 180 rad to 200 rad per day. The acute and chronic morbidity from such treatment has been minimal and no patient has had a local recurrence at 8 months to 8 years following treatment.

Adjuvant therapy in mixed mullerian tumors of the uterus

We report 54 patients with mixed mullerian tumors of the uterus treated at Yale-New Haven Hospital from 1962 to 1983. Seven had previous pelvic irradiation. Twenty-five neoplasms were homologous and 29 were heterologous. The mainstay of therapy was surgery and radiation. By FIGO criteria 9 patients had stage IA disease, 31 stage IB, 6 stage II, and 8 patients had clinical extrauterine disease. Ten of forty-six patients (23%) with FIGO stage I and II disease had extrauterine disease found at surgery. No patient with extrauterine disease had prolonged survival. The 2-year disease-free survival with stage IA was 66%, with stage IB surgically confirmed 32%, and for stage II 33%. Surgically advanced disease in clinical stage I and II patients and recurrence were associated more frequently with a heterologous histology (67%). The small uterus with a less than 10-cm cavity had a better prognosis. Among 29 surgically confirmed stage I and II patients, 83% of recurrences appeared within 2 years (mean 16 months +/- 7 months). Patients who received both intracavitary radiation and external beam developed only 17.6% pelvic recurrence but this reduction in local recurrence was not associated with significant improved long-term survival. Six of eight patients treated with cis-platinum, Adriamycin, and dimethyl triazeno imidazole carboximide for persistent disease or for recurrence showed response for 4 to 24 months, none complete. Five patients were treated by radiation, surgery, and adjuvant chemotherapy (4 with Adriamycin-Cytoxan, 1 with Adriamycin-platinum). Four of the five (80%) are disease free from 36 to 60 months. These data and the experience of others support the need for a clinical trial with adjuvant platinum and Adriamycin in this disease.

High-dose fraction radiation therapy for intracranial metastases of malignant melanoma: A comparison with low-dose fraction therapy

Malignant melanoma is considered unresponsive to conventional radiation therapy when it is delivered at a daily dose rate of 130–300 rad/fraction. Previous studies have suggested that this is in part due to a large shoulder on the radiation survival curve and that higher dose fractions might be beneficial. High‐dose fraction therapy is effective for local control of cutaneous, lymph node, and soft‐tissue metastases. Results in 46 patients treated with high‐ or low‐dose fractions for intracranial metastases over the last decade in the Melanoma Unit and Department of Radiotherapy at Yale have been examined. Twenty‐six patients received high‐dose fraction therapy, generally 600 rad/fraction/week to 2400–3600 rad; 20 patients received low‐dose fraction radiotherapy with 125–400 rad/fraction daily. All patients were given steroids, and most received chemotherapy. Results in both groups were similar. Comparison of high‐ and low‐dose fraction patients revealed: improvement in 38 and 35%, respectively, stability in 23 and 25%, and deterioration in 38 and 40%. Median survival was three months in the high‐dose fraction group and 21/2 months in the low‐dose fraction group. Presence of hepatic metastases had no significant influence upon median survival in patients who received high‐dose fraction radiotherapy. In patients receiving low‐dose fraction, survival was 21/4 months with and three months without hepatic metastases. Death in most patients resulted from progression of central nervous system disease. Side effects, especially headache, were more prominent in the high‐dose fraction group. However, in no instance did side effects require discontinuation of therapy. The greater ease of delivery for weekly high‐dose fraction radiotherapy outweighed any other difference between the regimens.

Subsequent malignancies associated with carcinoma of the uterine cervix: Including an analysis of the effect of patient and treatment parameters on incidence and sites of metachronous malignancies

The incidence and sites of metachronous malignancies were retrospectively determined from the records of 763 patients seen at Yale University medical Center and affiliated hospitals with previously untreated, invasive carcinoma of the uterine cervix from 1953-1972. These patients were treated predominantly with radiation therapy; follow-up status was known for periods of 5-25 years or until time of death in over 96% of the patients. Forty-four patients had second malignancies noted at least 6 months after the initial cervical cancer was diagnosed. The expected incidence of second malignancies was determined from the Connecticut State Tumor Registry data controlling for year of diagnosis of the cervical cancer, patient age, sex, and time at risk (person-years exposure). To correct for any error in estimation of second malignancies introduced by the existence of a latency period for the development of a second cancer, the expected incidence of malignancies was also computed for 5-year time intervals following the cervical cancer. No significant increase in second malignancies was found (observed/expected-44/36) for the entire follow-up period nor for any individual 5-year interval. However, a statistically significant increase in lung cancer and vulva-vaginal cancer was noted and a significant decrease in breast cancer was observed. Cox regression analyses were performed to study the effect of total radium exposure and total external beam treatment, adjusting for other factors. No statistically significant increased risks were found.

Prognostic factors and sites of failure in figo Stage I, Grade 3 endometrial carcinoma

The results of therapy and patterns of failure were analyzed for 60 patients with Stage I, Grade 3 endometrial cancer seen at Yale-New Haven Hospital between 1960 and 1980. Fifty-eight patients were treated with a combination of surgery and radiation; one was treated with surgery only; and one received radiation only. The overall absolute 5-year survival rate was 72.9% with poorer prognosis noted for patients greater than 65 years of age, older at time of their menopause, and with Stage IA disease. Of the 14 patients who recurred, distant sites were involved in 93% (13/14), with the lung the most common site of distant failure (5/14), followed by the upper abdomen (4/14). Pelvic sites were involved in 43% (6/14) of the treatment failures. The use of pelvic external beam radiation resulted in a reduction in pelvic recurrences, but did not improve overall survival. The predominance of distant failures despite pelvic radiation suggests the possibility of early vascular and transcoelomic spread in Stage I, Grade 3 endometrial adenocarcinomas. Thorough exploration of the upper abdomen, paraaortic nodes, and the obtaining of pelvic washings for cytology at the time of initial surgery, are recommended in addition to chest CT scans to help identify those patients with occult metastases. Prospective randomized trials in Stage I, Grade 3 patients employing adjuvant cytotoxic chemotherapy, hormonal therapy, and/or whole abdominal-pelvic radiation, should be considered in an attempt to improve survival in high-risk patients.

Fallopian tube carcinoma

Twenty-one patients with fallopian tube carcinoma from Yale-New Haven Medical Center are reviewed. Most patients who died of disease did so in the first two years after diagnosis, even following complete resection, clearly indicating the need for adjuvant therapy. Negative second-look surgery did not provide assurance of permanent remission. There was a high recurrence rate with Stage I and completely resected Stage II and III disease (8 of 14 patients). Some recurrences occurred late, up to nine years after initial diagnosis. We recommend whole abdomino-pelvic radiation if no disease greater than 2 cm3 bulk exists after surgery. Chemotherapy may be an alternative to radiation as primary adjuvant treatment in early stage disease. Chemotherapy for unresectable disease or recurrent disease has shown palliation with occasional prolonged survival but no patient with recurrent disease survived longer than two years.

Glioblastoma multiforme: Treatment by large dose fraction irradiation and metronidazole☆

In an attempt to overcome the possible radioresistance of glioblastoma multiforme related to the large shoulder on the in vitro survival curves and to sensitize hypoxic tumor cells, a treatment protocol was instituted at Yale University Medical Center and affiliated hospitals, using large dose fraction irradiation therapy in conjunction with the hypoxic cell sensitizer metronidazole. Nineteen patients with biopsy-confirmed, previously untreated, cerebral grade IV glioblastoma multiforme were, following surgery, irradiated once a week at 600 rad per fraction, 3.5 to 4 hours after ingestion of metronidazole, 6 gm/m2. A total of 7 treatments were employed, with all patients maintained on antiseizure medications and corticosteroids. Metronidazole levels were determined prior to each treatment and patients were followed closely clinically and with serial computerized tomography (CT) scans. The treatment was well tolerated, in general, with no untoward side effects related to the high dose fraction irradiation. The majority of the patients experienced varying degrees of gastrointestinal upset lasting up to several hours following metronidazole administration. Three patients died of pulmonary emboli. One patient experienced moderately severe ototoxicity. A median survival of 9.4 months was obtained for all 19 patients, suggestive of a prolongation of survival compared to historical controls treated with conventionally fractionated radiation or with unconventional radiation fractionation schemes and metronidazole or misonidazole.

Intense eosinophilic stromal infiltration in carcinoma of the uterine cervix: A clinicopathologic study of 14 cases

Stromal responses to tumor, usually characterized by the intensity of the lymphoplasmacytic infiltration, have been felt to be of prognostic significance in a wide range of neoplasms. Little attention has been focused on stromal reactions composed primarily of infiltration by eosinophilic leukocytes. We describe here the clinical and histopathological findings in 14 patients with invasive carcinoma of the uterine cervix in whom pronounced eosinophilic infiltration was observed in the stroma in the initial diagnostic biopsy material. These patients tended to have early stage disease, had associated increased lymphoplasmacytic stromal response, and were somewhat younger than the patients lacking this intense eosinophilic infiltration. A suggestion of improved survival was noted in patients with intense stromal eosinophilia treated primarily with radiation therapy.