John D. Earle

The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas

PURPOSE This article presents the American Brachytherapy Society (ABS) guidelines for the use of brachytherapy for patients with choroidal melanomas. METHODS Members of the ABS with expertise in choroidal melanoma formulated brachytherapy guidelines based upon their clinical experience and a review of the literature. The Board of Directors of the ABS approved the final report. RESULTS Episcleral plaque brachytherapy is a complex procedure and should only be undertaken in specialized medical centers with expertise in this sophisticated treatment program. Recommendations were made for patient selection, techniques, dose rates, and dosages. Most patients with very small uveal melanomas (<2.5 mm height and <10 mm in largest basal dimension) should be observed for tumor growth before treatment. Patients with a clinical diagnosis of medium-sized choroidal melanoma (between 2.5 and 10 mm in height and <16 mm basal diameter) are candidates for episcleral plaques if the patient is otherwise healthy and without metastatic disease. A histopathologic verification is not required. Small melanomas may be candidates if there is documented growth; some patients with large melanomas (>10 mm height or >16 mm basal diameter) may also be candidates. Patients with large tumors or with tumors at peripapillary and macular locations have a poorer visual outcome and lower local control that must be taken into account in the patient decision-making process. Patients with gross extrascleral extension, ring melanoma, and tumor involvement of more than half of the ciliary body are not suitable for plaque therapy. For plaque fabrication, the ophthalmologist must provide the tumor size (including basal diameters and tumor height) and a detailed fundus diagram. The ABS recommends a minimum tumor (125)I dose of 85 Gy at a dose rate of 0.60-1.05 Gy/h using AAPM TG-43 formalism for the calculation of dose. NRC or state licensing guidelines regarding procedures for handling of radioisotopes must be followed. CONCLUSIONS Brachytherapy represents an effective means of treating patients with choroidal melanomas. Guidelines are established for the use of brachytherapy in the treatment of choroidal melanomas. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose reporting policies. These guidelines will be modified as further clinical results become available.

Thoracic Radiation Therapy Alone Compared with Combined Chemoradiotherapy for Locally Unresectable Non-Small Cell Lung Cancer: A Randomized, Phase III Trial

OBJECTIVE To compare the survival of patients with medically inoperable or unresectable stage III non-small cell lung cancer treated with thoracic radiotherapy alone or in combination with chemotherapy. DESIGN Randomized, prospective phase III trial. SETTING Multi-institutional cooperative oncology group. PATIENTS A total of 121 patients were enrolled in the study, of whom 7 (5.8%) were ineligible. All patients were ambulatory and had measurable or evaluable disease. Before they were randomized, patients were stratified by ECOG performance score, histologic type, maximum tumor diameter, and NCCTG institution. INTERVENTIONS Radiotherapy consisted of a total of 5000 cGy in 5 weeks with a 1000 cGy boost in 5 fractions to a small tumor field. Combined modality therapy was MACC which is intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine (CCNU), on day 1 and 28. Chemotherapy was followed by identical thoracic radiotherapy 4 weeks after the second cycle of chemotherapy. Four weeks after thoracic radiotherapy was completed, patients received another two cycles of identical chemotherapy. Patients who had progression of disease after chest irradiation only were treated with MACC chemotherapy. MAIN RESULTS Major clinical responses were observed in 31 of 56 (55%; 95% Cl, 42% to 68%) patients treated with combination therapy and 37 of 58 (64%; Cl, 51% to 76%) treated with radiation only (P greater than 0.2). The median time to progression was 192 days with radiotherapy only compared with 199 days for combined modality therapy (P greater than 0.2). The median survival time was 313 days compared with 317 days, respectively (P greater than 0.2). The 1-, 2-, and 5-year survival rates after thoracic radiation only were 45% (Cl, 32% to 58%), 16% (Cl, 6% to 25%), and 7%. With chemoradiotherapy, the survival rates were 46% (Cl, 33% to 60%), 21% (Cl, 11% to 32%), and 5%, respectively. Myelosuppression was significantly greater for the combined modality therapy arm (P = 0.002). CONCLUSION Chemotherapy with MACC, in combination with thoracic radiotherapy, did not result in significant survival advantage compared with radiation alone (P greater than 0.2) in patients with medically inoperable or unresectable stage III non-small cell lung cancer.

Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients

In 33 patients undergoing operation and postoperative irradiation for intracranial ependymomas between January 1963 and December 1983, the tumor was grade 1 or 2 in 26 (79%) patients and grade 3 or 4 in 7 (21%). Operation consisted of only biopsy in 1 (3%), subtotal removal of tumor in 28 (85%), and gross total resection in 4 (12%). All patients received brain irradiation with a median dose of 4800 cGy. Seventeen (52%) patients also received spinal axis irradiation (median dose, 3000 cGy) which included 5 with high-grade tumors and 12 with low-grade infratentorial tumors. The relapse-free and overall survival rates at 5 years were 61% and 62%, respectively. Prognostic factors analyzed for statistically significant survival differences included age, sex, hydrocephalus, site, grade, extent of operation, extent of brain field, spinal axis irradiation, and brain dose. Grade was the only significant factor found: the 5-year survival of patients with low-grade ependymomas, 71%, was significantly better (p less than 0.04) than that of patients with high-grade ependymomas, 29%. Among the 31 patients evaluable for patterns of failure, treatment failed in 12 (39%) (10 only in the brain, 1 in the brain and spinal cord, and 1 only in the spine). All but one of the brain failures were at the site of the original primary lesion. Treatment failed in 4 of the 6 (67%) patients with high-grade tumor but in only 8 of the 25 (32%) with low grade tumor. Among the 7 low-grade infratentorial ependymomas treated with brain irradiation only, there was 1 treatment failure (in the spine; salvaged with further irradiation). Among the 12 patients with low-grade infratentorial tumors who received spinal axis irradiation, treatment failed in 1 (8%) (in the spine and also in the brain; patient subsequently died of disease). Nineteen (58%) patients remain alive; all but 2 of the patients who had recurrence died of their disease. This retrospective study suggests that: (a) patients with high-grade tumors have significantly poorer survival compared with those with low-grade tumors; (b) the main cause of death in ependymoma patients is intracranial failure at the primary site; and (c) craniospinal axis irradiation may not be necessary for patients with low-grade infratentorial ependymoma (localized irradiation alone may be adequate).

Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy).

PURPOSE A prospective Phase I dose escalation study was conducted to determine the maximally tolerated radiation dose in men treated with three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. This is a preliminary report of toxicity at Level III (79.2 Gy) on 3D Oncology Group/Radiation Therapy Oncology Group (RTOG) 9406. METHODS AND MATERIALS Between November 26, 1996 and October 1, 1998, 173 patients with clinically organ-confined prostate cancer (T1 and T2) were accrued to a Level III dose of 79.2 Gy. One hundred sixty-nine patients were available for analysis of toxicity. Patients were registered to two groups according to the risk of seminal vesicle invasion (SVI) on the basis of presenting PSA and Gleason score. Group 1 patients had a calculated risk of SVI <15%, and Group 2 patients had a risk of SVI > or = 15%. For Group 1 patients, the planning target volume (PTV) margins were 5-10 mm around the prostate only. For Group 2 patients, the same margins were applied to the prostate and seminal vesicles (PTV(1)) for the initial 55.8 Gy; then treatment volume was reduced to the prostate only (PTV(2)). To reduce the rectal dose on dose Level III, the minimum PTV dose was limited to 73.8 Gy, whereas the minimum gross target volume dose was 79.2 Gy, both in 44 fractions. The incidence of > or = 3 Grade late effects was compared to that in a similar group of patients treated on RTOG 7506 and 7706 studies. RESULTS Acute tolerance to 79.2 Gy was excellent with no patients experiencing > or = Grade 3 acute toxicity. The acute toxicity rate was comparable to that reported for previous lower dose levels. With the median follow-up of 3.3 years (range: 0.4-4.4 years), a total of 4 patients (2.4%) experienced Grade 3 late toxicity, three cases of which were related to the bladder, and one related to the rectum. There were no Grade 4 or 5 late complications noted during the period of observation. These results are also comparable to those reported at dose Levels I and II. The expected incidence of > or = 3 Grade 3 late toxicity was calculated using historical data from two previous RTOG prostate cancer trials, 7506 and 7706. The calculated risk accounted for the difference in follow-up duration between patients in this study and the historical experience. The observed rate of > or = Grade 3 late effects for Group 1 (two cases) is significantly lower (p = 0.0002) than the 17.6 cases that would have been expected from the historical control. The observed rate for Group 2 (two cases) was also significantly lower (p = 0.0037) than the 12.1 cases expected. CONCLUSION Based on excellent tolerance of 3D-CRT for stages T1 and T2 prostate cancer, further biological dose escalation has been pursued to Levels IV and V, 74 Gy and 78 Gy, respectively, at 2 Gy per day, in an attempt to reduce the total treatment duration. This trial has closed. A Phase III comparative RTOG trial is being developed to determine whether high-dose 3D-CRT improves efficacy.

Primary central nervous system non-hodgkin's lymphoma: Survival advantages with combined initial therapy?

PURPOSE Results of multiple radiation, chemotherapy, and combined treatment trials have shown that the fate of primary central nervous system lymphoma (PCNSL) patients is very different from that of patients with similarly treated systemic IE non-Hodgkins lymphoma. This study was designed to improve the survival of PCNSL patients by the use of combined initial therapy. METHODS AND MATERIALS Forty-six eligible primary PCNSL patients were treated with whole brain irradiation and adjuvant chemotherapy consisting of preirradiation cyclophosphamide-adriamycin-vincristine-prednisone (CHOP) and postirradiation high-dose cytosine arabinoside (HDAC) as part of an ongoing Phase II Mayo/North Central Cancer Treatment Group/Eastern Cooperative Oncology Group (M/NCCTG/ECOG) intergroup effort, which opened in April 1986. RESULTS This cohort consisted of 23 men and 23 women with median age 63.5 years (range 24 to 75 years). Only 5% were under age 40; 36% were age 40 to 59, 37% were age 60 to 69, and 22% were age 70 and over. Forty-six percent had good performance scores of ECOG 0-1 at time of study entry. Forty-six patients were evaluable for treatment outcome as of October 6, 1993. Of these, 10 were still alive. Estimated median survival and 21-month survival were 45.3 weeks and 29%, respectively. There were four early deaths ranging from Day 9 to Day 15 (three drug-related, one from other complications), and two CHOP responders died at 32 and 35 days, soon after Cycle 2 of CHOP (one probably drug-related, one from other complications). There was no significant difference in survival according to baseline performance status. However, survival was consistently worse for patients > 60 years old than for the younger patients (< or = 60 years). With deaths recorded for 21 of 21 older patients, but only 9 of the 14 younger patients, 21-month survival for older vs. younger was 14 vs. 50% based on the 35 patients who entered the study at least 21 months ago (p = 0.0365). Of the 46 patients evaluable for response, 63% had objective remissions on CHOP and another 20% remained stable. CONCLUSION Combined modality therapy in this study did not produce an overall survival advantage in treating PCNSL. The 50% 21-month survival of younger patients may be a reflection of age only.

Prostate-specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer.

PURPOSE This study was conducted to determine the value of prostate-specific antigen (PSA) as a pretherapy prognostic factor for localized prostate cancer treated with primary irradiation (RT). PATIENTS AND METHODS Between March 1987 and December 1990, 254 patients with pretherapy PSA determinations were treated for clinical stage A2 to C prostate adenocarcinoma. In conjunction with other prognostic factors, pretherapy PSA was evaluated to determine whether it had independent predictive value for disease outcome. RESULTS Pretherapy PSA was highly and directly correlated with clinical stage, tumor grade, and acid phosphatase level. With a median follow-up duration of 24 months, 241 patients (95%) were fully assessable for disease outcome. In these patients, PSA and tumor grade were the sole independent predictive factors for tumor relapse (ie, clinically determined and/or increasing PSA level). The combination of pretherapy PSA and tumor grade information defined groups of patients with distinctly different outcome. For patients in low- (favorable PSA and tumor grade), intermediate- (favorable PSA or tumor grade), and high- (adverse PSA and tumor grade) risk categories, the actuarial rates of survival free of tumor relapse or increasing PSA level were 94%, 77%, and 42% at 3 years, respectively (P < .0001). CONCLUSION Pretherapy PSA is a strongly independent prognostic factor for disease outcome following primary RT. The combination of adverse pretherapy PSA and unfavorable tumor grade identified a cohort of patients with a high risk of early treatment failure in whom combined modality therapy may be appropriately investigated.

Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: A report of radiation therapy oncology group 83-02

PURPOSE Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. METHODS AND MATERIALS One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. RESULTS The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL (p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. CONCLUSION The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis.

Radiotherapeutic management of adult intraspinal ependymomas

Twenty-two adults with ependymomas of the spinal cord were treated with surgery and postoperative radiation between January 1963 and December 1983. The median age was 47 years. Nineteen patients had grade 1 lesions, two had grade 2 and one grade 3. Ten patients had the myxopapillary histologic subtype (all grade 1) and 12 had the cellular variant. There were 15 distal cord lesions originating from the conus medullaris, filum terminale and/or cauda equina. The remaining seven lesions arose more proximally. Fourteen patients had localized lesions involving one to three vertebral segments, while the remaining eight had extensive ependymomas spanning six to thirteen vertebral segments. The median time from onset of symptoms to diagnosis was 3 years. Surgical treatment consisted of biopsy only in three patients, subtotal removal in eleven patients and total removal in eight patients. Radiation was given to the spine only in all cases. Five patients received whole spine radiation; seventeen received partial spine treatment, appropriate for the length of the primary lesion. The median dose was 5000 cGy (range 3600-5700 cGy). The disease free survival at 5 and 10 years was 81 and 71%, respectively. Overall survival at 5 and 10 years was 95%. Seven of twenty-two (32%) patients failed. Factors analyzed for prognostic significance included age, sex, histology, extent of primary, location of primary within the cord, extent of surgical resection and dose. Too few grade 2 and 3 patients precluded meaningful statistical analysis of grade as a prognostic factor. Neither age, sex, histology, extent of primary, location of primary, nor extent of surgical removal significantly affected disease free or overall survival (p greater than 0.05). Four of nineteen (21%) patients with grade 1 lesions failed, while all three patients with grade 2 and 3 lesions did so. Half of the eight patients with extensive ependymomas failed compared to three of fourteen (21%) with limited ones. Six of seventeen (35%) patients failed at doses less than or equal to 5000 cGy while only one of five (20%) failed at doses greater than 5000 cGy. Patterns of failure were analyzed for the seven patients who failed. Six of the seven failures (86% of the failure group, 27% of the overall group) were local, that is, within the initial radiation field at the site of the original tumor. A single patient (grade 2) failed in the posterior fossa while remaining NED in the spinal cord (a head CT scan at initial work-up was negative).(ABSTRACT TRUNCATED AT 400 WORDS)

Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma.

PURPOSE We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and PCNU with those of RT and carmustine (BCNU) in patients with malignant glioma. PATIENTS AND METHODS A total of 346 patients with histologically verified supratentorial grade 3 and grade 4 astrocytoma were studied. After surgery, patients were randomly assigned to receive RT 60 Gy in 30 fractions and either PCNU 100 mg/m2 or BCNU 200 mg/m2 every 7 weeks for 1 year and every 10 weeks for the second year. RT and chemotherapy were started within 72 hours of randomization and usually on the same day. Of 334 assessable patients, 72% had partial or radical resection and 71% had grade 4 tumors. Median age was 59 years, and 85% had performance scores of 0 to 2 (Eastern Cooperative Oncology Group [ECOG]). The follow-up duration of 51 living patients ranged from 10.3 to 63.2 months, with a median of 36.2 months. RESULTS The median survival duration in each group was 47 weeks, and median time to progression was 28 weeks. PCNU produced significantly more leukopenia and thrombocytopenia, whereas BCNU produced significantly more nausea, vomiting, and irritation. CONCLUSION PCNU has no therapeutic advantage at this dose and schedule and does not warrant further study as a single agent for patients with high-grade glioma.

Postoperative radiotherapy of supratentorial low-grade gliomas

Forty-nine patients with supratentorial low-grade gliomas underwent surgery (biopsy or subtotal resection) and postoperative radiotherapy at the Mayo Clinic between 1976 and 1983. The median, 5-, and 10-year overall survivals for the total group were 6.5 years, 62%, and 14%, respectively. Nine prognostic variables were examined for their possible association with survival, including age, sex, site, size, CT enhancement, histologic type, extent of resection, radiation volume, and radiation dose. Of these variables, only histologic type was significantly associated with survival. The estimated 5-year survival was 100% for the 5 patients with pilocytic astrocytomas, 83% for the 20 patients with oligodendrogliomas or mixed oligo-astrocytomas, and 40% in the 24 patients with ordinary astrocytomas (log rank p = 0.001). Other possible prognostic variables, such as radiation volume or total dose, showed no association with survival. Twenty-seven patients had a documented treatment failure. For the 20 patients in whom the pattern of failure could be determined, all failed within their radiation portals. Eleven patients had additional tissue obtained following suspected disease recurrence. Tumor was found in ten of these patients, and radionecrosis in one.