Improved survival with recent Post-Transplant Lymphoproliferative Disorder (PTLD) in children with kidney transplants.

Post-transplant lymphoproliferative disorder (PTLD) has been associated with high mortality, but recent anecdotal survival appeared better. From 1988 to 2010, the NAPRTCS registry had 235 registered PTLD cases. We sent a special 25-point questionnaire study to the NAPRTCS centers with the most recent 150 cases to obtain additional follow-up data not collected in the master registry, our objective being to determine the recent outcomes after PTLD and determine prognostic factors. We received 92 completed responses, in which only 12 (13%) deaths were reported, 2 from nonmedical causes, 10 with a functioning graft. Kaplan-Meier-calculated patient survival was 90.6% at 1 year and 87.4% at 3, 4 and 5 years post-PTLD. Graft survival post-PTLD was 81.8% at 1 year, 68.0% at 3 years and 65.0% at 5 years. Seven patients received a retransplant after PTLD, with no PTLD recurrence reported. Using all 235 PTLD cases, the covariates associated with better patient survival were more recent year of PTLD diagnosis (adjusted hazard ratio AHR 0.86, p < 0.001), and with worse survival were late PTLD (AHR 1.98, p = 0.0176) and patient age above 13 at PTLD (AHR 3.43, p value 0.022). In children with kidney transplants, patient survival has improved with more recent PTLDs.

Linear growth patterns in prepubertal children following liver transplantation.

Factors impacting linear growth following pediatric liver transplantation (LT) are not well understood. This longitudinal analysis examines predictors of linear growth impairment in prepubertal children included in Studies of Pediatric Liver Transplantation. In 1143 children with serial measurements, mean height scores increased from -1.55 at LT to -0.87 and -0.68 at 24 and 36 months post LT with minimal subsequent catch up growth observed until 60 months. Subgroup analysis of height measurements at 24 months (n = 696), 33.8% were below 10th percentile at 24 months post LT. Multivariate analysis revealed linear growth impairment more likely in patients with metabolic disease (OR 4.4, CI: 1.83-10.59) and >18 months of steroids exposure (OR 3.02, CI: 1.39-6.55). Higher percentiles for weight (OR 0.80, CI: 0.65-0.99) and height (OR 0.62, CI: 0.51-0.77) at LT decreased risk. Less linear catch up was observed in patients with metabolic disease, non-Biliary atresia cholestatic diseases and lower weight and higher height percentiles prior to LT. Prolonged steroid exposure and elevated calculated glomerular filtration rate and gamma-Glutamyltransferase following LT were associated with less catch up growth. Linear growth impairment and incomplete linear catch up growth are common following LT and may improve by avoiding advanced growth failure before LT and steroid exposure minimization.

No evidence for lipid peroxidation in severe preeclampsia.

OBJECTIVE: This study was undertaken to address the role of oxidative stress in preeclampsia. STUDY DESIGN: We measured urinary 8,12-iso-iPF(2alpha)-VI, a chemically stable, free-radical catalyzed product, in a case control study of severe preeclampsia nested within the trial of Calcium for Preeclampsia Prevention. Cases included 29 women who developed severe preeclampsia and from whom urine had been obtained 10 to 20 weeks before the diagnosis of preeclampsia, 3 to 9 weeks before, and 1 day before through delivery. Controls did not develop hypertension or proteinuria and were matched to cases by center, gestational age at each of 3 corresponding urine collections, and date of enrollment. RESULTS: Urinary 8,12-iso -iPF(2alpha)-VI did not differ significantly between cases and controls before or at diagnosis of preeclampsia, nor did it vary with gestational age. CONCLUSIONS: These results call into question the importance of oxidative stress in the disease and the biochemical rationale for clinical trials of antioxidants to prevent and treat preeclampsia.

Does race influence survival for esophageal cancer patients treated on the radiation and chemotherapy arm of RTOG #85-01?

PURPOSE: In reported retrospective non-randomized trials of treatment of esophageal carcinoma, blacks have a lower survival from esophageal cancer than whites. None of these studies has accounted for the extent of disease, or the methods and quality of treatment. We reviewed the data that included only patients treated on the chemoradiation arm of the RTOG-8501 esophageal carcinoma trial to see if there were differences in overall survival between black and white patients receiving the same standard of care. METHODS AND MATERIALS: One hundred-nineteen patients, 37 blacks and 82 whites were evaluated who met the criteria for receiving chemoradiation of 5000 cGy and four courses of Cisplatin (75 mg/m2) and Fluorouracil (1000 mg/m2 for 4 days). RESULTS: Blacks had squamous histology only, with 86% of blacks having weight loss of 10 lbs. or more compared to 56% of whites (p = 0.001). In addition, blacks had larger tumors and more difficulty eating (p = 0.010). Overall, there was no difference in the Kaplan-Meier median survival estimate by race (p = 0.2757). Only when we limited the analysis to the "squamous histology" subgroup, stratified according to age >70 vs. <70 years (p = 0.0002), and nodal status (p = 0.0177) in a Cox regression model analysis, did race appear to be a significant factor (p = 0.0012). However, using the entire database, the age effect was found to be a "bimodal" effect, wherein the "youngest" (< age 60 years) and "oldest" patients (age > 70 years) did poorly. Because of the dramatic differences in the age and histology distributions between blacks and whites, this issue could not be resolved in the subset of squamous only who received chemoradiation. CONCLUSIONS: The increasing incidence of adenocarcinoma among white patients without a corresponding increase of this histology in blacks reflects a difference in diet and or lifestyle compared to blacks that deserves additional study. When treated aggressively with chemoradiation, race did not appear to be a statistically significant factor for overall survival.

Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG #77-06, a phase III study for T1BN0M0 (A2) and T2N0M0 (B) prostate carcinoma.

PURPOSE: To evaluate survival and time to metastatic disease in patients treated for localized prostatic carcinoma in a Phase III radiotherapy (RT) protocol, Radiation Therapy Oncology Group (RTOG) 77-06. Patients with T18N0M0 (A2) or T2N0M0 (B) disease after lymphangiogram (LAG) or staging laparotomy (SL) were randomized between prophylactic radiation to the pelvic lymph nodes and prostatic bed vs. prostatic bed alone. The outcome of both treatment arms, as well as a comparison of the LAG group, to that of the SL group, are updated. METHODS AND MATERIALS: A total of 449 eligible males were entered into RTOG protocol 7706 between 1978 and 1983. Lymph node staging was mandatory but at the physician's discretion; 117 (26%) patients had SL, while 332 (74%) had LAG. Follow-up was a median of 12 years and a maximum of 16 years. For those randomized to receive prophylactic pelvic lymph nodal irradiation, 45 Gy of megavoltage RT was delivered via multiple portals in 4.5-5 weeks, while all patients received 65 Gy in 6.5-8 weeks to the prostatic bed. RESULTS: There was no significant difference in survival whether treatment was administered to the prostate or prostate and pelvic lymph nodes. The SL group had greater 12-year survival than the LAG group (48% vs. 38%, p = 0.02). Disease-free survival was statistically significant, with 38% for the SL group vs. 26% for the LAG group (p = 0.003). Bone metastasis was less common in the SL group (14%) than the LAG group (27%) (p = 0.003). CONCLUSION: At 12-year median follow-up, there still was no survival difference in those patients treated prophylactically to the pelvic nodes and prostatic bed vs. the prostatic bed alone. Those patients not surgically staged with only LAG for lymph node evaluation were less accurately staged, as reflected by a statistically significant reduced survival and earlier metastases.

Fast neutron radiotherapy for locally advanced prostate cancer. Final report of Radiation Therapy Oncology Group randomized clinical trial.

Between June 1977 and April 1983 the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized trial investigating the use of fast neutron radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation or fast neutron radiation used in a mixed-beam (neutron/photon) treatment schedule. A total of 91 analyzable patients were entered into the study, and the two patient groups were balanced with respect to the major prognostic variables. Actuarial curves are presented for local/regional control and "overall" survival. Ten-year results for clinically assessed local control are 70% for the mixed-beam group versus 58% for the photon group (p = 0.03) and for survival are 46% for the mixed-beam group versus 29% for the photon group (p = 0.04). This study suggests that a regional method of treatment can influence both local tumor control and survival in patients with locally advanced adenocarcinoma of the prostate gland.

Malignant peripheral nerve sheath tumors (malignant schwannomas) in children.

We studied the clinical and pathologic features of 78 malignant peripheral nerve sheath tumors in children less than or equal to 15 years of age. There were 42 boys and 36 girls, with a median age of 10 years. The majority of the tumors (42, or 54%) were central or axial in location; the rest were peripheral. Sixteen patients (21%) had a history of von Recklinghausen's disease. Fourteen (18%) had a malignant peripheral nerve sheath tumor arising in a nerve trunk or a neurofibroma and were unassociated with von Recklinghausen's disease. Patients typically presented with a painful mass of variable duration. Tumors ranged from 2 to 33 cm (median, 7.5 cm) and demonstrated a wide histologic spectrum that included spindled, epithelioid, and primitive neuroepithelial-like cells as well as heterologous elements (11). Immunohistochemical staining revealed S-100 protein in 28 of 50 cases (56%) as well as vimentin (13 of 21 cases, or 62%), Leu 7 (22 of 49 cases, or 45%), actin (eight of 20 cases, or 40%), and keratin (seven of 27 cases, or 26%). Survival status was known for 57 patients (73%). Kaplan-Meier estimates revealed a median survival of 45 months. Half of the patients had local recurrences at 12 months, and half had metastases at 24 months, most commonly to lungs, followed by lymph nodes, liver, bone, soft tissue, and brain. Age greater than or equal to 7 years, male sex, presence of von Recklinghausen's disease, central location, larger tumor size, and tumors with greater than or equal to 25% necrosis were found to be potentially significant adverse prognostic indicators by univariate analysis. Multivariate analysis revealed that larger tumor size, age greater than or equal to 7 years, tumor necrosis greater than or equal to 25%, and von Recklinghausen's disease to be independent adverse prognostic factors.

Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315.

Between 1983 and 1987 the Radiation Therapy Oncology Group conducted a prospective phase II study to evaluate survival in primary non-Hodgkin's lymphoma of the brain treated with whole brain irradiation to 40 Gy and a 20 Gy boost to tumor plus a 2 cm margin. Forty-one patients are reported. Full follow-up is available on 35/41 who have died. Six are alive at 8.8-67.2 months from start of radiation therapy with a median followup of 53.9 months. Overall median survival was 11.6 months from start of radiation therapy and 12.2 months from diagnosis, with 48% surviving 1 year and 28% surviving 2 years. Karnofsky Performance Status and age were significant prognostic factors. Patients with a Karnofsky Performance Status of 70-100 had a median survival of 21.1 months compared to 5.6 months for patients with a status of 40-60 (p less than .001). Fourteen patients less than 60 years of age had a median survival of 23.1 months, while 27 patients greater than or equal to 60 years of age had a median survival of 7.6 months (log-rank p = .001). Disease recurred in the brain in 25/41 (61%) of the patients, (21/41 in the brain only and 4/41 in the brain plus distant metastases). Despite high dose and large volume irradiation, primary Central Nervous System lymphoma still exhibits excessive mortality, especially in older patients. This paradox of the relative radioresistance of primary Central Nervous System lymphoma remains unresolved.

Long-term survival in treated anaplastic astrocytomas. A report of combined RTOG/ECOG studies.

This report evaluates the long-term survival of patients with histologically confirmed anaplastic astrocytoma on several combined RTOG (Radiation Therapy Oncology Group) studies. Included in this analysis are the following studies: RTOG/ECOG (Eastern Cooperative Oncology Group) 74-01, RTOG 76-11, and RTOG 79-18, with the various treatment arms separated into radiation therapy (RT) only (47 patients) radiation therapy and chemotherapy (Chemo) (78 patients) and radiation therapy, chemotherapy, and misonidazole (Mizo) (24 patients). Pretreatment characteristics of age, prior surgery, performance status, and neurological function classification are identified. Median survival for patients treated with RT only is 3.0 years. Median survival for patients treated with RT + Chemo is 2.3 years, and for patients treated with RT + Chemo/Miso is 1.2 years. Five-year survival rates are 35% for patients treated with RT only, 29% for patients treated with RT + Chemo, and 24% for patients treated with RT + Chemo/Miso. Age and performance status have been identified in previous studies as important prognostic variables and are confirmed in this analysis. Patients treated with misonidazole had a significantly worse prognosis after adjustment for differences in prognostic factors. Addition of chemotherapy did not improve survival except in less favorable prognostic categories. In general, more aggressive treatment regimens are associated with decreased survival compared to conventional postoperative irradiation.

Results of the 1989 Association of Residents in Radiation Oncology survey.

To assess a variety of issues concerning physician-trainees in radiation oncology, a survey was conducted by the Association of Residents in Radiation Oncology (ARRO). Ultimately, 70% of residents responded to the survey. The survey identified perceived strengths as well as shortcomings in training programs. We conclude that residents are generally satisfied with their training. Future surveys are planned to expand this important database.

Mixed glioblastoma multiforme and sarcoma. A clinicopathologic study of 26 radiation therapy oncology group cases.

Twenty-six cases are reported of gliosarcoma (GS) retrieved from a series of 1479 glioblastomas (GBM) that were part of five consecutive, randomized Phase II or III malignant glioma protocols initiated by the Radiation Therapy Oncology Group between 1974 and 1983. The clinicopathologic features of these 26 cases, including actuarial survival times, were compared with the remaining 1453 GBM. The minimal qualitative and quantitative histologic criteria required to diagnose GS are presented. In most cases the sarcomatous component was a malignant fibrous histiocytoma; a minority were fibrosarcoma. No significant differences between GS and GBM were found with regard to age, sex, pretreatment Karnofsky performance status, tumor location, size, median survival (8.3 and 9.6 months, respectively), and actuarial survival. None of the treatment regimens, which included various combinations of radiation therapy and chemotherapy, improved the survival of GS over GBM. Selective involvement of the temporal lobe by GS was not found, and the frequency of GS was determined to be only 1.8% of all GBM.

Patterns and sites of failure in cervix cancer treated in the U.S.A. in 1978.

Patterns of Care Study (PCS) conducted the second survey of carcinoma of the cervix in 1978. The data of this survey are derived from 565 patient questionnaires completed from 120 randomly selected facilities. Through these surveys PCS has set out to establish a profile of the practice of radiation therapy in the United States as well as determine the survival, local control rates, patterns of recurrence, complications, and relationship of these events with dose. This study deals with the patterns and sites of failure and relationship with dose to the paracentral and lateral points previously defined. The breakdown of patients according to the stage was as follows: Stage I = 203, Stage II = 243, Stage III = 115, undertermined = 4. Twenty-three percent of the patients failed within the field of irradiation, whereas 9% failed outside of the irradiated field. The infield failure rate increased as a function of stage from 9% in Stage I to 23% in Stage II and 48% in Stage III. Distant metastasis was the first site of failure in 4% of patients with Stage I, 7% for Stage II, 9% for Stage III, and 6% for the entire group. The cervix and vagina were the first site of recurrence in 20% of the patients. The cervical/vaginal recurrence rate increased as a function of stage from 7% in Stage I to 21% in Stage II, and 37% in Stage III. An analysis of the cervical/vaginal recurrences as a function of the average total dose to the paracentral points showed a decreased recurrence rate as a function of dose within the range of less than 6500 to 7999 cGy. The recurrence rate at 4 years decreased from 34% with a dose of less than 6500 cGy to 14% with a dose of 7500-7999 cGy. Above this dose level, this correlation of dose with recurrence was not observed. This correlation was also absent when the patients were studied according to the stage of the disease. The relationship of parametrial/sidewall failure and average dose to the lateral point was studied also, but no correlation was found except for patients with Stage III disease. The disease-free survival was studied for the entire group of patients and for the different stages as a function of average paracentral dose: less than 7500 cGy, 7500 to 8500 cGy, and greater than 8500 cGy. The disease-free survival was lower for the patients in the less than 7500 cGy group.(ABSTRACT TRUNCATED AT 400 WORDS)

Results of the 1983 patterns of care process survey for definitive breast irradiation.

This report has documented the U.S.A. national averages for the results of the Process Survey for the 1983 Patterns of Care Study (PCS) for the processes of evaluation, work-up, and treatment for definitive breast irradiation. All women had been treated with definitive irradiation following breast-conserving surgery for early stage breast cancer. The data were collected from 191 patient charts which were randomly selected from five strata of radiotherapy practice to represent the U.S.A. national averages. Clinical and pathological characteristics of the primary tumor and regional lymph node status were similar to reported series as of 1983. Analysis of this Process Survey showed high compliance with the 1983 PCS standards of best current management of breast cancer. However, there was a wide variation in the technical delivery of the radiation fields and radiation doses used. There was good compliance with the use of documentation of the radiation treatments with simulation films, port films, implant films, and field descriptions. No systematic difference was seen amongst the various strata of radiotherapy practice. Although compliance with the majority of the parameters was relatively high, the small but important areas of lack of compliance with the standards of best current management document an incomplete transfer of technology to the radiation oncology community as a whole in 1983. Separate analysis for the outcome of treatment for these cases will be necessary to correlate process with outcome.

High energy (42-66 MeV reactions) fast neutron dose optimization studies in the head and neck, thorax, upper abdomen, pelvis and extremities.

Five hundred and fifty patients were entered into a set of dose-searching studies designed to determine normal tissue tolerance to high energy (42-66 MeV reactions) fast neutrons delivered in 12 equal fractions over 4 weeks. Participating institutions included: The Fermilab (66 MeV p+----Be), The University of Washington (50 MeVp+----Be), U.C.L.A. (45 MeVH-----Be), M.D. Anderson Hospital (42 MeVH-----Be), and The Cleveland Clinic (42 MeVp+----Be). Patients were stratified by treatment facility and then randomized to receive 16, 18 or 20 Gy for tumors located in the upper abdomen or pelvis, and 18, 20 or 22 Gy for tumors located in the head and neck, thorax or extremities. Following completion of the randomized protocols, additional patients were studied at the 20.4 Gy level in the head and neck, thorax and pelvis. Normal tissue effect scoring was accomplished using the RTOG-EORTC acute and late normal tissue effect scales. Acute Grade 3 + toxicity rates in the head and neck were 19% for 20/20.4 Gy and 20% for 22 Gy. Time adjusted late toxicity rates in the head and neck at 12 months were 15% for 20/20.4 Gy and 0% for 22 Gy. The 18 Gy treatment arm of the head and neck protocol was dropped early in the study after only two patients were accrued. For cases treated in the thorax, acute Grade 3 + toxicity rates were 6% for 18 Gy, 15% for 20/20.4 Gy and 7% for 22 Gy. Late toxicity rates at 12 months were 0% for 18 Gy, 11% for 20/20.4 Gy and 18% for 22 Gy. Acute Grade 3+ toxicity rates in the upper abdomen were 0% for 16 Gy, 8% for 18 Gy and 12% for 20 Gy. There were no Grade 3 + late toxicities in the upper abdomen. In the pelvis, acute Grade 3 + toxicity rates were 0% for 16 Gy, 3% for 18 Gy and 3% for 20/20.4 Gy. Late Grade 3 + toxicities at 24 months were 20% for 16 Gy, 5% for 18 Gy and 24% for 20/20.4 Gy. In extremities, acute Grade 3 + toxicity rates were 7% for 20 Gy and 21% for 22 Gy while at 12 months, late Grade 3 + toxicity rates were 14 and 35%, respectively. The 18 Gy treatment arm of the extremities protocol was dropped early in the study after only two patients were accrued. Factors associated with normal tissue effects in addition to treatment dose are discussed.

Radiation Therapy Oncology Group (RTOG) survival data on anaplastic astrocytomas of the brain: does a more aggressive form of treatment adversely impact survival?

The RTOG has sponsored several studies for malignant gliomas of the brain that have included tumors classified as either glioblastoma multiforme (GBM) or anaplastic-atypical astrocytoma (AAF) under the Nelson schema. Glioblastoma multiforme, the more aggressive histology, has done poorly under all forms of treatment having a typical median survival of 8-11 months. The less common and less aggressive anaplastic-atypical astrocytoma seems to show a survival that worsens with treatment more aggressive than standard radiotherapy. All patients in this report have had their tumors centrally reviewed by a RTOG neuropathologist and have had the diagnosis of anaplastic-atypical astrocytoma confirmed. We compare three patient groups: standard photon radiotherapy from the 60 and 70 Gy arms of RTOG 74-01/ECOG 1374 and from the 65 Gy control arm of RTOG 76-11; radiation therapy and chemotherapy from RTOG 74-01/ECOG 1374 (60 Gy + BCNU and 60 Gy + MeCCNU + DTIC) and from RTOG 79-18 (60 Gy + BCNU); and photon irradiation plus a neutron boost from RTOG 76-11 and RTOG 80-07. There are 47 analyzable cases treated with photons alone, 78 analyzable cases treated with photons + chemotherapy, and 38 analyzable cases treated with photons + neutron boost. Median survival for the three groups of patients is, respectively, 3.0 years, 2.3 years, and 1.7 years. Actuarial survival curves are presented for each subgroup of patients and then for the patient subgroups further broken down by major prognostic variables--age and Karnofsky performance status. In each "better prognostic category," the median survival decreased as the "aggressiveness" of the treatment increased. The implications of these findings for future clinical trials is discussed.

Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG phase III study for A2 and B prostate carcinoma.

Radiation Therapy Oncology Group (RTOG) protocol 7706 was a randomized Phase III study designed to test the value of elective (prophylactic) pelvic irradiation in addition to prostatic irradiation in patients with carcinoma of the prostate with no clinical evidence of tumor extension through the capsule. Eligible patients were those who had clinical Stage T1bNOMO (A2) or T2NOMO (B), who did not have curative surgery, and who had no evidence of lymph node metastases. Assessment of the regional lymphatics was mandatory but, at the discretion of the investigator, lymphangiography (LAG) or staging lymphadenectomy (SL) could be used. A total of 445 eligible and analyzable patients were entered in the study between 1978 and 1983 when the study was closed. The median follow-up was 7 years; minimum follow-up was 5 years. There were no significant differences in survival or local control whether treatment was administered to the prostate or to the prostate and pelvic lymph nodes. The nodal status for 117 (26%) patients was assessed by staging lymphadenectomy (SL) whereas for 328 (74%) patients it was assessed by lymphangiography (LAG). Pretreatment characteristics felt to have impact on survival were evaluated and found to be free of serious imbalance between the staging lymphadenectomy and lymphangiography groups. Compared to the lymphangiography group, the staging lymphadenectomy group showed better overall survival (87% to 76% at 5 years, p = .02), better disease-free survival (76% to 63% at 5 years, p = .008) and better metastases-free survival (88% to 82% at 5 years, p = .04). There was no difference between the groups in local control. The lymphangiography evaluation of pelvic nodes was clearly inferior for demonstration of the absence of pelvic node metastasis as reflected by reduced survival and increased metastasis.

Analysis of independent variables affecting survival after recurrence of prostate cancer.

Two hundred and sixty-six patients developed recurrence after external beam radiation therapy for Stage B or C prostate cancer. The median survival from the time of recurrence was 30 months, the 5-year actuarial survival was 22% and the 8-year actuarial survival was 13%. The original stage influences survival after recurrence. Median survival is 35 months for Stage B and 27 months for Stage C. Five-year actuarial survivals are 31% for Stage B and 16% for Stage C. The site of recurrence (infield or metastatic) influences survival after recurrence. Median survival is 33 months for infield and 25 months for metastatic. Five-year actuarial survival is 30% for infield and 17% for metastatic. The time of recurrence influences survival after recurrence, comparing survival in patients recurring in the first year after treatment, to patients recurring in the second or later years after treatment. Median survival after recurrence is 14 months for those who recur in the first year, 32 months for those who recur later. Histologic grade influences survival after recurrence. Median survivals are 49 months for well differentiated, 31 months for moderately differentiated, and 23 months for poorly differentiated. Cox regression analysis indicates that original stage, site of recurrence (local vs. metastatic), time of recurrence after therapy, and histologic grade are all independent variables influencing survival after recurrence (p = less than .01). This study supports the aggressive treatment of prostate cancer to prevent recurrence and provides a means of estimating prognosis for patients who suffer a recurrence of their prostate cancer after treatment.

Hormonal cytoreduction in locally advanced carcinoma of the prostate treated with definitive radiotherapy: preliminary results of RTOG 83-07.

RTOG 83-07 is a Phase II randomized protocol designed to compare the efficacy and toxicity of Megestrol vs Diethylstilbestrol (DES) used as cytoreductive agents prior to and during radiotherapy. The end-points of this study include tumor clearance rate, effect on serum testosterone, local-regional control, disease-free interval, and survival. Eligible patients were those with histologically confirmed locally advanced adenocarcinoma, clinical Stage B2 and C without regional lymph node involvement, or with lymph node involvement limited to the pelvis. Patients with medical conditions potentially predisposing to cardiovascular (thromboembolic) sequelae of endocrine therapy were not eligible. Patients were stratified by clinical stage, histological grade, and nodal status and were randomized to receive either Megestrol 40 mg PO tid or Diethylstilbestrol 1 mg PO tid. The drugs were started 2 months prior to initiation of radiotherapy and were continued throughout the radiotherapy course. Radiotherapy consisted of 44 to 46 Gy, 1.8 to 2 Gy per day to the regional lymphatics followed by a boost to the prostate consisting of 20 to 25 Gy, 1.8 to 2 Gy per day to a total of 65 to 70 Gy. Serum testosterone levels were recorded throughout the treatment course. Tumor response was assessed clinically and radiographically (CT scan). From March 1983 through June 1986 a total of 203 patients were accessioned to the study; 197 were analyzable. Correlation of the incidence of drug related toxicity and treatment arm assignment revealed a significantly higher incidence of complications in the Diethylstilbestrol (DES) arm. The most prominent were the differences in the incidence of gynecomastia (55% vs 7%) and fluid retention (21% vs 6%). The incidence of thromboembolic phenomena was comparable (8% vs 5% in the Megestrol arm). Although patients on the DES arm demonstrated a significantly greater median decrease in testosterone level, correlation of the treatment assigned to the rate of tumor regression and the incidence of complete response revealed no significant difference between the arms. At 3 years only 6.5% of the evaluable patients manifested evidence of local failure. The results of the study indicate comparable efficacy (using tumor clearance as an end-point) of DES and Megestrol. While DES appears more effective in suppressing testosterone it is also associated with a higher incidence of toxicity. The cytoreduction (using either DES, Megestrol, or an alternative regimen) concept remains to be tested in a Phase III study comparing it to radiotherapy alone.

Correlation of prostate-specific acid phosphatase and prostate-specific antigen immunocytochemistry with survival in prostate carcinoma.

Prostate-specific acid phosphatase, a secretory product of prostatic cells, may be a secondary product of the interaction of hormones with their receptor proteins. In this study we have examined two independent patient populations to see whether the intensity or extent of prostate-specific acid phosphatase and/or prostate-specific antigen staining correlated with survival and hormonal manipulation. One population of 24 patients was selected from patients undergoing surgical resection for adenocarcinoma Stage B or C at the Mayo Clinic. The second population of 123 patients was obtained from Radiation Therapy Oncology Group Protocols 75-06 and 77-06. Tissue from both populations was analyzed. In both populations, the intensity of prostate-specific acid phosphatase staining correlated with survival in a statistically significant manner. Staining with prostate-specific antigen was present in greater than 90% of specimens; data was therefore not analyzed. In those patients who subsequently relapsed and were subjected to hormonal manipulation, there appeared to be a higher likelihood of response to hormones with intense prostate-specific acid phosphatase staining.

The effect of dose on local control of prostate cancer.

Three patterns of care outcome surveys in prostate cancer totalling 1516 patients had been combined and analyzed for the effect of dose on infield recurrence. There are significant dose effects observed in the overall data (1516 patients, p = .003), Stage B cancers (725 patients, p = .004) and Stage C cancers (624 patients, p = .059). No dose effect was observed for Stage A cancers (168 patients, p = .217) within the dose range observed (5500 cGy to greater than 7000 cGy). For patients with Stage B cancer one may conclude that dose between 6000 cGy and 6999 cGy is appropriate. Patients treated to less than 6000 cGy show a highly significant increase in local failure. Patients treated to greater than 7000 cGy do not show a demonstrable improvement in local control, but do show an increase in complications. Patients with Stage C cancer appear to require dose that is equal or greater than 7000 cGy to obtain the best local control, and the potential increased morbidity of these high doses appears to be justified in this stage of the disease. Patients who have been given hormonal therapy more than 1 month prior to radiation therapy show an increase in local failure rate for all stages of cancer. This is presumed to be the selection of poor risk patients for adjuvant hormonal treatment or by referring non-responding hormone treated patients for radiation therapy. Histologic grade exerts a major influence on local failure for patients with Stage C disease (p = less than .001), identifying an important stratification point for prospective clinical trials and a sub-group for which it is important to develop strategies for improving local control. The policy of treating all stages of prostate cancer with the same dose is not supported by these data.