Steven A. Leibel

Carcinoma of the major and minor salivary glands. Analysis of treatment results and sites and causes of failures

Treatment results of 100 cases of previously untreated malignant epithelial tumors of the major and minor salivary glands were analyzed with respect to stage, treatment modality and histology. For carcinoma of the parotid gland, the 5‐ and 10‐year determinate survivals decreased from 88% and 83% for Stage I disease to 76% and 76% for Stage II, to 49% and 32% for Stage III and 0% for Stage IV disease. The 5‐ and 10‐year determinate survivals were 96% and 96% for mucoepidermoid carcinoma, 80% and 80% for acinic cell carcinoma, 72% and 62% for adenocarcinoma, 57% and 57% for squamous cell carcinoma, 65% and 29% for adenoid cystic carcinoma and 44% and 22% for undifferentiated carcinoma. Postoperative radiotherapy improved the local control rates of adenoid cystic carcinoma and advanced local disease, its effectiveness related directly to the extent of tumor present. Radiotherapy was highly effective for microscopic disease and the incidence of local recurrence was 14% for patients who received postoperative radiotherapy and 54% for those who did not when there was known microscopic disease at or close to surgical margin. No significant difference in response to radiotherapy was seen between the different histological types. Most failures occurred at the primary tumor site or at the site of distant metastasis, whereas failure in regional lymph nodes was uncommon. When the cause of failure could be determined, it most often appeared to have been tumor remaining at the surgical margin with no postoperative radiotherapy given. Cancer 40:2882‐2890, 1977.

Survival and quality of life after interstitial implantation of removable high-activity iodine-125 sources for the treatment of patients with recurrent malignant gliomas.

Between January 1980 and January 1988, 95 evaluable patients with recurrent, unifocal, supratentorial malignant gliomas were reirradiated with high-activity iodine-125 sources implanted directly into tumor in afterloaded, removable catheters using computerized tomography-directed stereotaxy. A tumor dose of 5270-15,000 cGy was delivered at a maximum distance of 0.5 cm from the rim of the contrast-enhancing mass seen on CT scans. The median survival for the 50 patients with anaplastic astrocytoma was 81 weeks and for 45 patients with glioblastoma multiforme it was 54 weeks. The 18- and 36-month survival rates for patients with anaplastic astrocytoma were 46% and 28%, respectively; the 18- and 36-month survival rates for patients with glioblastoma multiforme were 22% and 8%, respectively. Because of clinical deterioration, increasing steroid dependency, and increasing mass effect at the implantation site seen on CT scans, necrotic tissue was excised from 47 patients (49%) at craniotomy; in some patients, tumor was mixed with necrotic tissue. The survival of reoperated patients was significantly longer compared with patients who did not undergo this procedure. Serial determination of the Karnofsky Performance Score (KPS) showed that there was no significant deterioration for the group as a whole during the 6 months immediately after implantation. At 18 months, 33 of the patients were alive; KPS ranged between 50 to 90 (mean 79) and 67% were steroid dependent. At 36 months, 18 patients were alive; 17 patients were evaluable with KPS that ranged between 40 to 90 (mean 76) and 53% were steroid dependent. Eleven of the 17 evaluable long-term survivors had a KPS of 80 or higher with a mean of 87. Interstitial brachytherapy may provide long-term survival in selected patients with recurrent malignant gliomas who have been irradiated previously with conventional teletherapy. The quality of life in the majority of long-term survivors appears to be quite satisfactory. Further attempts to control tumor growth using this modality appear to be warranted.

The role of radiation therapy in the treatment of astrocytomas

One hundred forty‐seven patients with astrocytoma were treated between 1942 and 1967. There were 25 postoperative deaths. The 14 patients in whom the tumor was thought to have been completely removed were not irradiated and all survived 5 years or longer. Seventy‐one of the 108 patients with incompletely excised lesions received radiation therapy. The 5‐year survival rate for those with incomplete resection alone was 19%, compared to 46% when irradiation was given. Based on observations up to 20 years, after incomplete removal postoperative irradiation significantly prolonged useful life and may have lead to permanent control in some. There was no evidence of radiation damage. Most of these tumors were fibrillary astrocytomas, and the results apply particularly to this histologic type. Only 1 of 11 patients with gemistocytic astrocytoma survived 5 years. The survival rate for Grade I tumors was appreciably greater than for Grade II lesions; in both grades, it was improved by irradiation.

Patterns of care outcome studies: Results of the national practice in adenocarcinoma of the prostate☆

The Patterns of Care Study reviewed the processes and outcome of 682 patients with carcinoma of the prostate treated with radiation therapy from 1973-1976. The study and patient sampling were designed to reflect a valid representation of how prostate cancer is treated by radiation oncologists in the United States. The outcome results represent national benchmarks. The three year actuarial survival was 91% for Stage A, 88% for Stage B, and 76% for Stage C. The three year relapse free survival rate was 85% for Stage A, 77% for Stage B, and 59% for Stage C. The infield recurrence rates were: Stage A--4%, Stage B--9%, and Stage C--20%. Stage, grade, elevated serum acid phosphatase, Karnofsky performance status, previous hormonal therapy, age, and prior transurethral resection were identified by multivariate regression analysis to be important independent prognostic variables. Local control was related to the dose of the primary site, paraprostatic region, and pelvic sidewall. Local control was significantly improved if the facilitys best treatment equipment was a linear accelerator. Major complications occurred in 9% of patients with Stage A, 2% of Stage B, and 6% with Stage C disease. Complications were related to dose and treatment technique. The Patterns of Care Process Survey identified that only 60% of patients surveyed had the necessary pretreatment evaluation studies required for best current management of adenocarcinoma of the prostate. Variance occurred within each stratum of facilities sampled. Strict attention to the details of evaluation of therapy will help to enhance the delivery of optimal radiation therapy in the management of patients with carcinoma of the prostate.

Soft tissue sarcomas of the extremities. Survival and patterns of failure with conservative surgery and postoperative irradiation compared to surgery alone

Between 1960 and 1978, 81 patients received their primary treatment for localized soft tissue sarcomas of the extremities, buttock and shoulder at the University of California, San Francisco. Initial treatment consisted of surgery alone in 47 patients, planned conservative surgery followed by radiation therapy in 29 patients, and irradiation alone in five patients. The two‐ and five‐year determinate survival for all cases was 86% and 73%, respectively. The local control rate achieved with surgery alone was related to the extent of surgery. Eighty‐seven percent (14/16) of the patients undergoing amputation were locally controlled. Seventy‐two percent (8/11) were treated with wide en bloc resection and had local tumor control while only 30% (6/20) having simple excision were controlled. The local control rate with surgery and postoperative irradiation was 90% (26/29). No patients treated with radiation therapy alone were controlled. The development of distant metastases was significantly influenced by the grade of the primary tumor, and was independent of initial primary treatments, histologic type, and tumor site. Fifty‐three percent of patients with Grade III tumors developed distant metastases, while only 7% of patients with Grade I or Grade II disease developed distant spread. Distant metastases with or without control of the primary was the most common initial pattern of relapse in patients with combined treatment. The primary site was the most common site of failure in the group receiving surgery alone. The ultimate pattern of failure in both the surgery alone and combined groups was distant metastases with or without local control. This review suggests that local tumor control achieved with limb preserving conservative surgery and postoperative irradiation is superior to limited surgery alone. The survival and patterns of failure of patients undergoing radical surgery is comparable to combined treatment with the risk‐benefit ratio favoring the latter.

Patterns of care studies: dose-response observations for local control of adenocarcinoma of the prostate

Five hundred seventy-four patients with prostate cancer treated by external beam radiation therapy in the United States in 1973 to 1975 have been analyzed comparing radiation dose with in-field recurrence. Dose-response effects are observed for all cases (p = less than .05) and T-2 and T-3 tumors, but not for T-0, T-1 and T-4 tumors. For doses calculated at the center of the prostate, these observations suggest optimal control is obtained at no more than 6000 rad for T-0 and T-1 tumors; 6000-6500 rad for T-2 tumors; 6500-7000 rad for T-3 tumors; and that greater than 7000 rad is required only for T-4 tumors. The paraprostatic dose calculated at a point 4 cm lateral to the center of the prostate also shows a correlation of dose with infield failure for all cases (p = .01). Observations in individual T states suggest optimal control is obtained at no more than 6000 rad for T-0, T-1 and T-2 tumors, 6500-6999 rad for T-3 and greater than or equal to 7000 rad for T-4. These data suggest that for T-2 and T-3 cancers, extension in the periprostatic region must be treated. A comparison of central dose vs. stage indicates institutional policy rather than cancer volume determines the radiation dose used in treating prostate cancer. A change in institutional policies to treat with optimal doses as indicated by this study would result in an overall increase in local control and a decrease in complications.

Postoperative radiotherapy of primary spinal cord tumors

During the 30 year period from 1957 to 1986, 42 patients with primary tumors arising from the spinal cord or cauda equina received postoperative irradiation at the University of California, San Francisco. Twenty-one patients had ependymomas: 18 were localized to one site, and 3 diffusely involved the cord. There were 12 patients with low grade astrocytomas and 3 with highly anaplastic astrocytoma or glioblastoma multiforme. All astrocytomas were localized at presentation. In 6 cases tissue was insufficient to permit a histologic diagnosis. Thirty-nine patients (93%) received total radiation doses ranging between 45.0-54.7 Gy using standard fractionation. The 10-year actuarial disease-specific survival rate for patients with localized ependymoma was 93%; 33% of these tumors recurred locally. The corresponding rate for diffuse ependymomas was 50%; the spinal disease was controlled in all 3 patients, but one developed a cerebral metastasis despite prophylactic cranial irradiation. Low-grade astrocytoma patients had a 10-year actuarial disease-specific survival rate of 91%, with 33% of these tumors recurring locally. No patient with highly anaplastic astrocytoma or glioblastoma multiforme survived longer than 8 months; all of these tumors recurred locally, and two of the three also developed diffuse craniospinal axis metastases. Local recurrence for ependymoma was delayed as long as 12 years following treatment, while all but one astrocytoma failure occurred within 3 years of treatment. No significant dose-response relationship with respect to local control was noted for either localized ependymomas or low grade astrocytomas. One patient developed radiation myelitis after receiving 50.4 Gy with standard fractionation. These results indicate that patients who undergo postoperative irradiation for low grade spinal astrocytomas and localized spinal ependymomas achieve excellent survival. However, despite treatment with total radiation doses taken to the practical limit of spinal cord tolerance, local failure remains common.

Desmoid tumors: Local control and patterns of relapse following radiation therapy☆☆☆

Desmoid tumors are benign neoplasms, arising from musculoaponeurotic tissues, which tend to be locally infiltrative, resulting in a high rate of local recurrence following surgical resection. Nineteen patients with desmoid tumors underwent radiation therapy at the University of California, San Francisco, between 1970 and 1980. Fifteen patients were referred with local recurrence following one or more surgical resections. Three patients were referred for initial radiation therapy with unresectable tumors, and one patient received planned postoperative irradiation following subtotal tumor resection. At the time of treatment, 8 patients had nonresectable disease measuring greater than 10 cm. Five patients had residual tumor masses measuring 4 to 6 cm, and six had only microscopic disease following resection. The majority of patients were treated to a tumor dose of 50-55 Gy at 1.6 to 1.8 Gy per fraction. With a median follow-up of 8 years, 13 patients remained free of recurrent disease following radiation therapy. The 5 year relapse free survival was 72% with 10 patients continuing to be free of disease 5 to 11 years following therapy. Local control was not related to the amount of disease present at the time of treatment. Of the 6 patients who developed recurrent disease, only 1 patient had a true in-field recurrence. Four patients recurred at the margin of the radiation field 1 to 5 years following therapy. Of these four patients, 3 were successfully salvaged while 1 died as a result of tumor extension into a major vessel. One patient with an extensive mesenteric mass did not respond to therapy and died 1 month post irradiation. The patient with the in-field recurrence and 1 patient with a marginal recurrence were successfully treated with combination chemotherapy. Moderate dose radiation therapy to desmoid tumors can result in lasting local control when surgical resection is not possible. Post operative radiation can improve the rate of local control for patients with a high risk of recurrence. As desmoid tumors tend to be locally infiltrative, fields must be very generous to prevent marginal recurrence. Systemic chemotherapy offers an alternative to ablative surgery in the event of local failure following radiation therapy.

The Dissemination of Cancer by Transurethral Resection of Locally Advanced Prostate Cancer

In 1973 a study was done on 443 patients treated with radiation therapy for cancer of the prostate. An actuarial analysis was done on survival comparing patients whose cancer was diagnosed by transurethral resection of the prostate to those diagnosed by needle biopsy. This analysis indicated a doubling of recurrence and of deaths of patients diagnosed by transurethral resection of the prostate. This effect of transurethral resection of the prostate was observed in patients with T3 and T4 cancer of intermediate, poor or unstated differentiation. It was not observed in those with well differentiated cancer. The effect was not caused by a difference in the extent of cancer or a distribution of histologic subtypes between the 2 diagnostic groups. Therefore, it appears that transurethral resection of the prostate causes dissemination on locally advanced prostatic cancer and clinical studies are suggested to avoid or minimize this effect.

194 Hepatocellular cancers treated by radiation and chemotherapy combinations: toxicity and response: A radiation therapy oncology group study☆

Hepatocellular carcinoma is known to have a doubling time of approximately 41 days. This rapid cell division suggested that hyperfractionated radiation and chemotherapy might add an advantage in gaining remission of this malignancy. One hundred and thirty-five patients (70% with metastasis and/or previous treatment) were prospectively treated with single daily fractions to the liver (3.0 Gy external beam radiation, total dose 21.0 Gy), and chemotherapy for hepatocellular carcinoma. The low dose chemotherapy used in conjunction with the radiation was 2 hr before treatment on days 1, 3, 5, and 7 and consisted of Adriamycin, 15 mg IV and 5-FU, 500 mg IV. These patients were compared to a second group of 59 patients (80% with metastases and/or previous treatment) treated using the same chemotherapy regimen but using hyperfractionated whole liver external beam irradiation (1.2 Gy twice daily, 4 hr between treatments, 5 days per week to 24.0 Gy, 10 MV photons). Response was determined by CT scan tumor volumetric analysis. The response rate for the single daily fraction patient group was 22% and for the new hyperfractionated group, 18% (p = 0.68). Toxicity was evaluated by RTOG criteria. The grade 4 hematologic toxicity noted in the daily fraction patient group was 6%. Among 59 patients treated with the hyperfractionated liver irradiation, 2% experienced grade 4 hematologic toxicity. Esophagitis occurred in 1% of patients in the standard fractionation group and 19% in the hyperfractionated group (p = 0.0001). Grade 1-4 thrombocytopenia occurred in 49% of patients in the conventional group and 68% in the hyperfractionated group (p = 0.03). Normal liver volume changes with treatment were measured with CT scan tumor volumetric analysis. The hyperfractionated group experienced a median of 11 cc increase in liver volume and the conventional group a 46 cc decrease, but the difference was not significant. Hyperfractionated radiation did not demonstrate a significant benefit over standard daily radiation, but acute toxicity appeared to be higher.