Roberta Lawrence

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.

Estrogen and progestin receptor levels as prognosticators for survival in endometrial cancer.

The survival of 213 postmenopausal patients with primary endometrial cancer was analyzed as a function of clinicopathologic features and cytosol steroid receptor levels. Estrogen receptor (ER) levels (P = 0.008) and progestin receptor (PR) levels (P = 0.0001) were negatively correlated with grade. ER and PR levels were positively correlated with each other (P = 0.0001), but neither was correlated with age. In 187 patients with stages I and II, ER positivity (greater than or equal to 20 fmole/mg cytosol protein (cp] was statistically associated with grade (P = 0.007); and PR (greater than or equal to 7 fmole/mg cp) was statistically associated with grade (P = 0.001). Univariant analysis revealed that survival for the early endometrial cancer patients was significantly dependent upon ER status (P = 0.0003), PR status (P = 0.0016), and grade (P = 0.0002). Multivariant analysis of ER status, PR status, age, and grade showed that the ER status was a significant prognostic factor for survival (P = 0.0168), even if the positivity of the PR status was defined at greater than or equal to 50 fmole/mg cp. If ER status was divided at 0-19, 20-100, and greater than 100 fmole/mg cp, survival was significantly different between the low range group and the other two groups. If PR status was divided at 0-6, 7-50, and greater than 50 fmole/mg cp survival was significantly different between the first two groups and the high range group. Thus, survival in these endometrial cancer patients was better predicted by ER status than grade.

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.

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.

Combination chemotherapy for advanced breast cancer. Two regimens containing adriamycin

Forty‐eight women with advanced metastatic carcinoma of the breast were treated with one of two combination chemotherapy regimens: 1) adriamycin and cyclophosphamide or 2) adriamycin, cyclophosphamide, methotrexate and 5‐fluorouracil. The response rate in the two‐drug treatment group was 50% and in the four‐drug treatment group, 55%. The median duration of response was ten months in both treatment groups. Dramatic responses were seen in patients with visceral metastases. Patients who responded to chemotherapy had a significantly longer survival than nonresponders (p<0.01). The long interval between adriamycin doses (six weeks) in the four drug regimen did not adversely effect the response rate—an important finding in view of the dose‐related cardiac toxicity of this agent.

The effective use of combined modality therapy for the treatment of patients with Hodgkin's disease who relapsed following radiotherapy.

FROM 1969 TO 1977, 124 PATIENTS with advanced staged Hodgkins disease were entered into a treatment protocol which consisted of three cycles of drugs (nitrogen mustard, vincristine, vinblastine, prednisone, and procarbazine) followed by radiation (1500–2000 rad) to previous sites of known disease. After completion of radiation therapy, two more drug cycles were given. There were 63 newly diagnosed patients with Stage IIIB and IVA or B disease and 61 patients who had relapsed from prior radiotherapy. The median follow-up is now in excess of 5 years. Of the relapsed patients, 86.9% entered a complete remission and 90.6% of these patients have remained in complete remission from 1 to 10 years. In comparison, 81% of the newly diagnosed patients entered a complete remission and 78.4% of these patients continue free of disease from 1 to 11 years. These differences were not statistically significant. The 10-year actuarial disease-free survival—79.8% for the 61 relapsed patients compared to 65.6% for the 63 newly diagnosed patients—was not significantly different either. The 10-year actuarial survival for the 40 patients who had relapsed to IIIB and IVA or B was 71.3% and approximated more closely those of newly diagnosed IIIB and IVA or B patients. This drug-radiotherapy protocol is very effective for the treatment of patients who have relapsed from previous radiotherapy.

Temperature elevation during brachytherapy for carcinoma of the uterine cervix: Adverse effect on survival and enhancement of distant metastasis☆

Possible effects of fever during intracavitary radiation therapy on patient survival, local-regional control or metastatic spread of disease were analyzed in a group of 398 patients with previously untreated, invasive carcinoma of the uterine cervix, managed with a combination of external beam irradiation and intracavitary radium (ICR) applications at Yale-New Haven Medical Center and affiliated hospitals from January 1953 through December 1977. Cox step-wise proportional hazard models were used to test for the influence of elevated temperatures during ICR placements, controlling for the influence of other pretreatment patient parameters, including FIGO stage, age, blood count, prior supracervical hysterectomy and number of prior pregnancies. Increasing maximum temperatures noted during ICR placements were associated with: decreased patient survival (p = 0.014) and increased frequency with time of distant metastasis as the initial sites of treatment failure (p = 0.038). When patients were dichotomized on the basis of maximum temperature during ICR, distant metastasis as the initial site(s) of treatment failure was noted twice as frequently in patients with maximum temperatures greater than or equal to 101.0 degrees F (12.5%; 10/80 patients) than in those with maximum temperatures less than 101.0 degrees F during ICR placement (6.3%; 20/318 patients). No statistically significant differences were noted between the two groups in their distributions by stage, age, histology, year of diagnosis, or pretreatment hemoglobin, and the sites of distant metastasis and time course for clinical detection were similar in both groups. These results are in agreement with prior clinical studies in cancer of the uterine cervix which noted a poor prognosis in patients with cancer of cervix who developed fever during treatment. In addition, the finding of an association between an increased frequency of distant metastasis and temperature elevation during the ICR provides, for the first time, clinical data supporting the reports of an alteration or enhancement of distant metastasis following the application of whole body hyperthermia in murine, rabbit and canine tumors.

Circannual rhythms in steroid receptor concentration in gynecologic and breast cancers

Both estrogen and progestin receptor concentrations vary in a predictive temporal pattern for breast cancer; in epithelial ovarian cancer a temporal rhythmic pattern is suggested for estrogen receptor concentration only. No pattern for either receptor is seen for endometrial cancer.

The effect of surgical resection of experimental “primary” adenocarcinoma of the colon on survival and incidence of metastases

The effect of surgical resection of “primary” tumors classified by size at the time of resection has been studied in two tumor cell lines derived from di‐methylhydrazine‐induced colonic neoplasms in the Buffalo strain rat. Surgical treatment of colon cancer in the rat yields results similar to those for human carcinoma. Some of the smallest tumors resected were associated with metastases and this finding suggests a need for effective postoperative adjuvant therapy. The incidence of metastases and the size of the tumor were inversely related to survival, e.g., the smaller the tumor or the sooner the excision, the greater the survival of the animal. The operated animal model studied here could prove to be very useful for evaluating various forms of systemic therapy for the control of micrometastases associated with colonic neoplasms.