Bowen E. Keller

Uterine sarcomas: natural history, treatment and prognosis.

Seventy‐three documented cases of uterine sarcoma were treated at the University of Rochester Strong Memorial Hospital from 1955 to 1975. Thirty‐three patients (45%) were treated with surgery only [S], 31 (43%) with surgery and radiation [S + R], and 9 (12%) with radiation alone [R]. A review of the literature with over 900 cases was also performed. Several important issues regarding these rare tumors are addressed, such as the prognosis of the several histologic variants, the role of radiation therapy in their management and what perhaps may constitute a comprehensive therapeutic approach. These tumors are characterized by local aggressiveness and early widespread dissemination. There are three main histologic varieties: mixed mesodermal sarcoma (MMS), leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS). Of the three, MMS was the most common, seen in 60% of the cases; LMS occurred in younger patients and tended to be localized to the uterine corpus (Stage I) in 80% of the instances. Tumor extent at diagnosis was the main prognosticator for survival in uterine sarcomas; patients with Stage I tumors had a significantly lower incidence of recurrences, as well as a better survival than patients with more advanced tumors. Stage‐by‐stage, there were no significant differences in survival among the pathologic variants. To ensure adequate staging, a surgical procedure is recommended first whenever possible. Adjuvant radiation therapy significantly improved disease controlability in the pelvis, although it may not have dramatically affected the final outcome. In addition to pelvic irradiation, some form of systemic therapy should be administered to decrease distant metastases.

Systeniic (half-body) radiation therapy: Response and toxicity

Abstract Systemic (half-body) Radiation Therapy (SHBRT) was employed in 40 patients with advanced cancer. The upper half body was irradiated in 23 patients; the lower half was irradiated in 12 (6 of these also received radiation to the upper segment); 5 patients received radiation to the middle segment (abdomen and pelvis). All patients received a single dose of 800 rad delivered at low dose rates (30–40 rad/min) with a 10 MeV iincer accelerator. The “acute radiation syndrome” occurred mainly with irradiation of the upper half of the body; it consisted of nausea and vomiting, increases in temperature and pulse rate and a drop in blood pressure. The onset of this syndrome occurred shortly after the procedure and sometimes lasted for up to 10 hr. In the last 6 patients treated a comprehensive premedication program which includes the administration of glucocorticoids, antiemetics and adequate hydration has reduced these acute symptoms to a minimum. Irradiation of one half of the human body is hematologically safe; blood counts return to normal within 6–8 weeks after the procedure. The main limiting factor of upper body irradiation is pulmonary toxicity; single doses of 800 rad (uncorrected for lung transmission) may lead to a 10–20% incidence of fatal radiation pneumonitis. Caution is advocated and the total dose proposed at the present time is 600–700 rad corrected for long transmission; minimal pulmonary toxicity has been reported with this dose. Systemic radiation therapy given for pain palliation achieves its goal in over 8096 of all patients. This pain relief is complete in over 40% of the patients and occurs dramatically within the first 24–48 hr. Furthermore, this technique has proved effective in reducing large tumor collections for a limited period of time (average of 3 months); pathologic confirmation of severe radiation damage inflicted on tumor cells has been obtained. This report analyzes Phase I-II (toxicity-response) studies in patients with overt metastases and speculates on the potential uses of this therapeutic modality for occult deposits.

Bone marrow regeneration and extension after extended field irradiation in Hodgkin's disease

The dose response data for bone marrow suppression, following localized irradiation as recorded in the literature, are 3,000 rads. Since doses from 3,500 rads to 4,500 rads are widely utilized in extended field irradiation, the probability of ablation of a major portion of the bone marrow compartment exists with the current techniques of treatment for Hodgkins disease. The ability of geographically mapping bone marrow distribution in a semiquantitative fashion is possible with modern radioisotope scanning procedures. 99mTc‐S colloid activity parallels 59Fe and can be used to reflect hematopoietic activity although a disparity between the RES and erythron compartments has been reported. Clinical evidence utilizing 99mTc‐S colloid bone marrow scanning techniques indicates that prolonged suppression of bone marrow occurs immediately following completion of segmental sequential irradiation in patients with Hodgkins disease and persists for a period of 1 or 2 years. New evidence is presented of partial to complete bone marrow regeneration at 4,000 rads range in 85% of the exposed bone marrow sites at 2 years if the doses are fractionated. Mechanisms of bone marrow recovery which are discussed include: increased hematopoietic production in shielded marrow sites, expansion of bone marrow space, and infield regeneration of bone marrow.

Uterine sarcomas. Analysis of failures with special emphasis on the use of adjuvant radiation therapy

There were 47 failures among 73 verified cases of uterine sarcoma reported at the University of Rochester Tumor Registry from 1955 to 1975; they constitute the subject of this report. Of 33 patients initially treated with surgery only [S], 19 patients (58%) failed; 20 of 31 patients (65%) treated with surgery and radiation [S + R] failed; 8 of 9 patients (89%) treated by radiation alone [R] failed. According to pathology, failures occurred in 33 of 44 patients (75%) with mixed mesodermal sarcomas (MMS), 7 of 20 patients (35%) with leiomyosarcoma (LMS), 4 of 6 patients with endometrial stromal sarcomas (ESS), and 3 of 3 patients with other types of sarcoma. Once corrected by stage, there were no significant differences in failure rates, spread patterns or survival among these main histologic variants. Twenty of 41 patients (56%) with Stage I tumors failed with an average failure time of 32 months. Twenty‐seven of 32 patients (84%) with Stages II, III, and IV tumor failed; their average failure time was only 9 months. The mean failure time for both the patients treated with [S] and [S + R] was 22 months; for patients treated by [R] it was 3 months. Isolated pelvic failures constituted only 4% of all failures, failures both in the pelvis and in distant sites, 49%, and distant metastases, 47%. There was a marked decrease in pelvic failures in patients treated with [S + R] when compared to those who received [S]. Adjuvant radiation proved to increase tumor control in the pelvis but did not influence the final outcome because over 90% of all failures developed distant spread outside the pelvis. The most common distant failures were in the upper abdomen (mainly omentum and peritoneum) and in the lungs. Lung metastases alone was the only site of failure in 16% of the instances. A comprehensive treatment approach based on the spread and failure patterns will be proposed.

Predictors of radiation response in lung cancer. A clinico-pathobiological analysis.

From February 1972 to July 1975, 200 lung cancer patients were seen at the University of Rochester Cancer Centers Division of Radiation Oncology; 40% had squamous cell tumors and 87.5% had advanced disease localized to the thorax. Of the 160 patients who completed treatment, 101 were treated with continuous therapy schedules, and 59 were treated with split‐course schedules; 40 patients did not complete treatment because of early metastatic disease or death. Radiation therapy was very effective in local tumor ablation. To assess local tumor response, doubling times were obtained in measurable lesions prior to treatment. The doubling times (DT) were 25 days for small cell cancers and 192 days for adenocarcinoma. More than 50% tumor shadow regression was a good prognosticator of local tumor response; this increased as the mean DT decreased. The order of kinetic increase in tumor ablation per histology was the opposite of the one‐year survival results because of the metastatic spread patterns of the different tumors. Survival rates in lung cancer emerge as simplistic and inadequate to explain local radiation effectiveness. Survival is conditioned by stage, histology, modality of treatment, total dose delivered, and local tumor response. Although the most effective treatment dose seems to be over 6000 rads, the most efficient schedules were split‐courses delivering lower tumor doses. This modality of treatment is proposed as the optimal schedule to be combined with other forms of therapy with the goal of achieving better survival.

THE MANAGEMENT OF CLINICAL STAGE I ENDOMETRIAL CARCINOMA

A retrospective analyses of 307 cases with clinical Stage I endometrial carcinoma was done in an attempt to determine the role of radiation therapy in the optimal treatment of this disease. A review of the modern literature with over 9000 cases served as a useful tool to corroborate inferences and conclusions. The present series has 155 patients (51%) treated with preoperative megavoltage external pelvic radiation with a variation in doses of less than 6%. Five‐year survival estimates (79%‐83%) in clinical Stage I endometrial carcinoma are similar among the several main treatment combination that are employed; they become a useless parameter for any comparison. The pelvic failure rate constitutes a more useful guideline in assessing the most adequate therapy. The pathologic grade of the tumor is the main prognosticator in endometrial carcinoma. Intimately related to the tumor grade is the depth of myometrial invasion of the carcinoma. The size of the uterus and/or its cavity carry less prognostic significance than traditionally thought. For grade I lesions, there is little error in diagnosis, few pelvic failures and excellent survival (96%); they could be approached with initial surgery and postoperative radiation reserved for selected patients. For grade 2 tumors, the error in diagnosis and the failure rate increases with an overall survival of 87%. For grade 3 tumors, the error in diagnosis and failure rates are quite high with a 5 year survival of only 70%. Preoperative radiation, especially external beam therapy, is suggested for grades 2 and 3 Stage I tumors. The use of this treatment modality yields only 3% pelvic failure and an overall 5 year survival of almost 90%.

Endometrial carcinoma: Analysis of failures with special emphasis on the use of initial preoperative external pelvic radiation

Abstract This paper analyzes in detail a total of 75 failures occurring among 364 patients with endometrial carcinoma. Approximately one half of all patients received preoperative external pelvic radiation for initial treatment. One-half of all failures occurred in the pelvis, the other half in distant sites. Failures in endometrial carcinoma are associated with a higher pathologic grade and clinical stage. An increase in grade and/or stage is associated with a higher incidence and depth of myometrial invasion and pelvic nodal involvement. The use of preoperative external pelvic radiation has eliminated vaginal recurrences in clinical Stages I and If and has reduced the overall incidence of pelvic failures to only 3%. Approximately one-third of patients with failures localized to the pelvis after initial surgery can be salvaged by the use of external pelvic radiation. Patients with distant metastases benefit significantly from therapy other than supportive measures.

Radiation therapy for tumors of the pineal region

Abstract This manuscript presents the results of treatment for 25 patients with tumors in the pineal region and related ectopic locations. Twenty two were treated with radiation therapy. Twelve patients died; autopsies were performed on 11 which allowed for a definition of the spread and failure patterns. A review of the literature with over 100 case studies was added to the present series in order to increase the significance of comparisons in failure rates by irradiated brain volumes and total doses delivered. The overall median survival for these patients was 10 years; at 5 years, 63% were alive and free of disease. The data suggests more than a 50% probability for tumors in these locations to extend by direct contiguity or by seeding along the third ventricle into adjacent supratentorial and infratentorial structures. The apparent tendency of some of these neoplasms to spread extensively within the cranium indicates the potential value of whole brain irradiation or at least the use of fields that are sufficiently large to encompass the entire ventricular system. In contrast, the low probability (≤5 10%) of metastasis to the spinal cord after adequate primary therapy does not indicate the routine use of elective spinal irradiation.

Tumor persistence as a predictor of outcome after radiation therapy of head and neck cancers

Abstract Tumor clearance or persistence was assessed at different time intervals during, at the completion of, and after radiation therapy in order to predict local control of failure in 144 cases of head and neck cancer. The rate of tumor clearance (TC) during treatment is less important than is complete tumor clearance in predicting for local control (LC). If tumor clearance occurred within one to three months following completion of treatment, local control could be predicted in cancers of the oral cavity, oropharynx and hypopharynx with approximately 80, 70 and 50% reliability, respectively. However, tumor persistence (TP) (evidenced by induration and surface irregularity) was a highly accurate predictor of failure (90–100%) at this assessment interval. Persistence of induration at the completion of treatment is inaccurate in the assessment of eventual local failure (LF), since local control eventually is achieved in 25–35% of the cases.

The assessment of tumor response to irradiation of lung cancer: Continuous versus split-course regimes

Abstract From February 1972 to July 1975, 200 lung cancer patients were seen in the University of Rochester Cancer Centers Division of Radiation Oncology; 40% had squamous cell tumors and 87.5% had advanced disease localized to the thorax. Of the 160 patients who completed treatment, 101 were treated with four different continuous therapy schedules; 59 were treated with three different split-course schedules. The patients who were treated with split-courses were compared with those who were treated continuously; those treated with split courses had higher nominal standard dose (NSD) ret doses, higher percentage of tumor resolution per histological type, milder radiation toxicity, decreased incidence of focal failures, and a better survival rate. Although, in order to achieve over 90% tumor sterilization, the most effective treatment dose seems to be above 6000 rad, the most efficient treatment schedules were split courses which delivered lower total tumor doses. Doubling times were obtained in measurable lesions to assess local tumor response. More than 50% tumor shadow regression was a good prognosticator of local tumor response; it increased as the mean DT decreased. One month after therapy, the survival rate associated with a tumor shadow of more than 50% was statistically better than that associated with tumors exhibiting less than 50% shadow regression. However, survival rates in lung cancer are simplistic and are inadequate to explain how local tumors are controlled by irradiation. A selective population of patients with cancers of the same stage and histology and with measurable lesions is the basis of a proposed study group to investigate local effectiveness of radiation therapy in primary lung cancers.