Phase I trial of intravenous L-phenylalanine mustard plus the sensitizer misonidazole.

Misonidazole (MISO), a hypoxic cell radiosensitizer, has been shown in vivo to enhance tumor cell killing by melphalan (LPAM) with little or no enhancement of normal tissue injury. A Phase I trial was conducted using MISO p.o. 2 hr before i.v. LPAM. The highest doses used were the single maximum tolerated doses of MISO, 4 g/sq m, and LPAM, 0.6 mg/kg. Thirty-five patients were entered; 30 were evaluable for assessment of hematological toxicity, which was predicted to be the dose-limiting toxicity. The median age was 60 years (range, 28 to 72 years). Mild to moderate nausea and vomiting occurred in 80% of patients. Five developed serious hematological toxicity defined as nadir white blood cell count less than 1000/cu mm, platelets less than 20,000/cu mm or 4-week posttreatment white blood cell count less than 2000/cu mm, platelets less than 50,000/cu mm. Four of the toxicities occurred at the LPAM dose of 0.6 mg/kg but were independent of MISO dose. One patient died of infection. Two patients whose tumor demonstrated an objective response to therapy and 10 others with disease stabilization received additional courses. Four patients developed mild MISO neuropathy. Pharmacokinetic studies demonstrated that MISO did not appear to affect the pharmacokinetics of LPAM in plasma. Both LPAM and MISO can be given safely at their individual maximum tolerated dose. This combination will proceed to Phase II trials.

Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy.

PURPOSE: To assess the role of neoadjuvant androgen deprivation (NAAD) and transperineal interstitial permanent prostate brachytherapy (TIPPB) using a matched-pair analysis selected from a large cohort of patients undergoing TIPPB. PATIENTS AND METHODS: Six hundred twelve consecutive patients with clinically confined prostate cancer were treated between June 1992, and January 1997, with permanent ultrasound-guided TIPPB with either palladium-103 or iodine-125 as monotherapy or combined with external radiation. Patients with prostate glands >/= 60 g underwent treatment with NAAD before TIPPB to reduce the prostate volume (n = 163). The median duration of NAAD was 3.4 months before TIPPB (range, 1 to 8 months). To assess the benefit of NAAD, a matched-pair analysis was performed. The American Society of Therapeutic Radiology and Oncology Consensus Group definition of prostate-specific antigen (PSA) relapse-free survival (RFS) was used with the added caveat of an absolute increase of >/= 1.0 ng/mL. Differences in pretreatment PSA, Gleason scores, and stage were analyzed by Kaplan-Meier curves and the log-rank test. RESULTS: Two hundred sixty-three patients were matched, with a median follow-up duration of 46 months (range, 24 to 76 months). The actuarial 5-year PSA-RFS rate for all 263 patients is 86.5%. The 5-year PSA-RFS rate for patients treated with NAAD and TIPPB was 87.1% compared with 86.9% for those treated with TIPPB only (P =.935). Subgroup analysis by Gleason score groupings, pretreatment PSA, or stage of disease failed to identify any factors for which androgen ablation was beneficial. CONCLUSION: We were unable to identify any improvement with the addition of NAAD to TIPPB in patients with localized prostate cancer in this retrospective matched-pair analysis. Furthermore, there was no subset for which the addition of NAAD was found to be beneficial. Clarification of the role and duration of NAAD in patients with early-stage prostate cancer will require prospective data.

Radiation therapy for relapsed CNS germinoma after primary chemotherapy.

PURPOSE: To retrospectively evaluate the ability of radiation therapy to salvage patients with CNS germinoma who relapsed after treatment with primary chemotherapy on a multiinstitution trial that included carboplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS: Eight patients with CNS germinoma received carboplatin, etoposide, and bleomycin as their only nonsurgical treatment following their initial diagnosis. At the time of relapse each patient received high-dose cyclophosphamide (one to three cycles) followed by craniospinal irradiation (25.2 to 36 Gy) and a boost to the site of recurrent disease (45 to 54 Gy). Six of eight patients had disease at relapse that was more extensive than at diagnosis. One patient had magnetic resonance imaging (MRI) evidence of leptomeningeal enhancement in the cauda equina although CSF cytology was negative, and one patient had cytologic evidence of CSF involvement. The median time to relapse following primary chemotherapy was 17 months. RESULTS: Although myelosuppression was prolonged following the administration of preirradiation chemotherapy, all patients completed a continuous course of radiation therapy. With a median follow-up after radiation therapy of 32 months (range, 16 to 47 months), no failures have occurred. CONCLUSION: Radiation therapy has a proven record of efficacy in the treatment of intracranial germinoma and it remains the standard therapy with which others are compared for treatment response, local control, and overall survival. Arguments can be made for alternative approaches when patients face hormonal or neurocognitive dysfunction as a result of radiation therapy; however, any reduction in late effects will have to be weighed against the probability of survival if alternative approaches prove to be inferior.

Isotopic immunoglobulin: a new systemic therapy for advanced Hodgkin's disease.

Thirty-eight patients with advanced, progressive Hodgkin's disease who had relapsed from or who had not responded to treatment with at least two potentially curative combination chemotherapy regimens were entered into this phase 2 study. All patients received 131I antiferritin antibody administered intravenously (IV) at a dose of 30 mCi on day 0 and 20 mCi on day 5. Antibody was derived from rabbit, pig, and monkey species. Objective partial remission of measurable disease was recorded in 40% of patients. Symptomatic response was recorded in 77% of patients. Toxicity was restricted to bone marrow depression with thrombocytopenia greater than leukopenia. These responses are comparable to other reported phase 2 drugs in this patient population and subsequent trials of antibody free of radioactivity and antibody using a beta emitting isotope are being carried out to expand upon these results.

Significance of normal serum prostate-specific antigen in the follow-up period after definitive radiation therapy for prostatic cancer.

PURPOSE: To determine the prognostic significance of a normal serum prostate-specific antigen (PSA) level in patients with prostatic cancer with long-term follow-up evaluation after radiotherapy. MATERIALS AND METHODS: PSA information was available in 403 patients (38%) who were treated with pelvic lymph node dissection and retropubic radioactive iodine-125 implantation. One hundred eighty-two patients had a normal serum PSA level (< or = 4.0 ng/mL) the first time this test was conducted during the follow-up period, designated PSA-1. RESULTS: Among patients with PSA-1 values < or = 1.0 ng/mL, the 5-year PSA relapse-free survival rate was 85% compared with 27%, respectively, among those with PSA values in the higher range of normal (P < .00001). Multivariate analysis demonstrated that only a PSA-1 value greater than 1.0 to < or 4.0 (P < .00001) and grade II/III histology (P = .009) had a negative impact on continued PSA relapse-free survival. The only independent variable identified by a multivariate analysis to affect local relapse-free survival (LRFS) was a PSA-1 value greater than 1.0 to < or = 4.0 ng/mL (P < .004), while high-grade histology (P < .0001) and local failure (P < .001) were the only significant variables to affect distant metastases-free survival (DMFS). CONCLUSION: Patients with PSA values < or = 1.0 ng/mL are significantly less likely to have a subsequent relapse after therapy than those with levels greater than 1.0 to < or = 4.0 ng/mL. Continuously maintained PSA levels of < or = 1.0 ng/mL after treatment may serve as an end point for early evaluation of the efficacy of experimental radiotherapy protocols in prostate cancer.

Postoperative radiation for lung cancer metastatic to the brain.

PURPOSE: Although resection of single brain metastases and postoperative whole-brain radiation therapy (WBRT) improves survival, compared with treatment using WBRT alone, the value of postoperative WBRT after resection of brain metastases is controversial. We analyzed the largest reported series of lung cancer patients with resected brain metastases to evaluate the impact of postoperative WBRT. MATERIALS AND METHODS: Between 1974 and 1989, 185 patients with non-small-cell lung cancer (NSCLC) underwent resection of brain metastases. Patients who had received preoperative WBRT (23%, 42 of 185) were excluded. The remaining patients were divided into group A (no WBRT; n = 32), group B (patients received WBRT and were prognostically matched to group A; n = 32), and group C (all other WBRT patients; n = 79). Most patients received postoperative doses of 30 Gy in 10 fractions. Higher doses were used in 16% of group B and 18% of group C patients. RESULTS: Overall 5-year survival rates were as follows: group A, 12%; B, 8%; C, 16%. Overall brain failures occurred in 38% of patients in group A, 47% in group B, and 42% in group C. The use of WBRT (group A v groups B plus C) had no apparent impact on survival or on overall brain failure rates. In particular, no improvement in either of these parameters could be demonstrated when group B was compared with group A. Focal failure (defined as failure within the brain adjacent to the site of the resected brain metastases) occurred as follows: group A, 34% (11 of 32); groups B plus C, 23% (25 of 111) (P = .07). WBRT significantly reduced focal failure for patients with adenocarcinoma (group A, 33% [eight of 24]; groups B plus C, 14% [11 of 79]; P = .05). Nonfocal failure (anatomically distinct from the resected metastasis) occurred in 9% of patients in group A (three of 32), 21% in groups B plus C (23 of 111) (P = .07). CONCLUSION: Long-term survival is possible when NSCLC brain metastases are resected. Postoperative WBRT as used in this series only had an impact on the focal control of brain metastases and this effect was of borderline significance. The lack of conclusive benefit supports the need for ongoing randomized trials to test the value of adjuvant postoperative WBRT. Brain failures were relatively common in all three groups of patients, which suggests that doses greater than 30 Gy need to be studied.

Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy.

PURPOSE: To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years). RESULTS: The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = 10.0 ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = 0.5 ng/mL (P < .001), and clinical stage < or = T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = 10 ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001). CONCLUSION: For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies.

Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer.

PURPOSE: Several studies have defined risk groups for predicting the outcome after external-beam radiotherapy of localized prostate cancer. However, most models formed patient risk groups, and none of these models considers radiation dose as a predictor variable. The purpose of this study was to develop a nomogram to improve the accuracy of predicting outcome after three-dimensional conformal radiotherapy. MATERIALS AND METHODS: This study was a retrospective, nonrandomized analysis of patients treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1998. Clinical parameters of the 1,042 patients included stage, biopsy Gleason score, pretreatment serum prostate-specific antigen (PSA) level, whether neoadjuvant androgen deprivation therapy was administered, and the radiation dose delivered. Biochemical (PSA) treatment failure was scored when three consecutive rises of serum PSA occurred. A nomogram, which predicts the probability of remaining free from biochemical recurrence for 5 years, was validated internally on this data set using a bootstrapping method and externally using a cohort of patients treated at the Cleveland Clinic, Cleveland, OH. RESULTS: When predicting outcomes for patients in the validation data set from the Cleveland Clinic, the nomogram had a Somers' D rank correlation between predicted and observed failure times of 0.52. Predictions from this nomogram were more accurate (P<.0001) than the best of seven published risk stratification systems, which achieved a Somers' D coefficient of 0.47. CONCLUSION: The development process illustrated here produced a nomogram that seems to predict more accurately than other available systems and may be useful for treatment selection by both physicians and patients.

Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy.

PURPOSE: To determine any differences in outcome for patients with anaplastic astrocytoma (AA) treated with adjuvant carmustine (BCNU) versus procarbazine, lomustine, and vincristine (PCV) chemotherapy. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) database was reviewed for patients with newly diagnosed AA treated according to protocols that included either BCNU or PCV adjuvant chemotherapy. All patients were treated with radiation therapy. The outcome analysis included overall survival, taking into account patient age, extent of resection, Karnofsky performance status (KPS), and treatment group (BCNU v PCV). Stratified and nonstratified Cox proportional hazards models were used, as well as an analysis using matched cases between the groups. RESULTS: A total of 257 patients were treated with BCNU according to RTOG protocols 70-18, 83-02, and 90-06; 175 patients were treated with PCV according to RTOG protocol 94-04. All pretreatment characteristics except KPS were well balanced by treatment group; 61% of the BCNU group had a KPS of 90 to 100 compared with 73% of the PCV group (P =.0075). No statistically significant difference in survival was observed in any age group or by KPS or extent of surgery. The stratified analysis also showed no trends for improved survival by treatment group (P =. 40). The Cox model identified only age, KPS, and extent of surgery as important variables influencing survival, not treatment group. Matching cases between groups using age, KPS, and surgery resulted in 133 matched pairs. No difference in survival was observed (P =. 41). In a Cox model in which each matched pair is a strata, there was no difference between groups (P =.20). CONCLUSION: Using this retrospective analysis, there does not seem to be any survival benefit to PCV chemotherapy. Future phase III studies for patients with AA may need to consider whether BCNU or PCV is used in the control arm.

Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study.

PURPOSE: Radiation therapy for CNS germ cell tumors (GCT) is commonly associated with neurologic sequelae. We designed a therapeutic trial to determine whether irradiation could be avoided. PATIENTS AND METHODS: Patients received four cycles of carboplatin, etoposide, and bleomycin. Those with a complete response (CR) received two further cycles; others received two cycles intensified by cyclophosphamide. RESULTS: Seventy-one patients were enrolled (45 with germinoma and 26 with nongerminomatous GCT [NGGCT]). Sixty-eight were assessable for response. Thirty-nine of 68 (57%) achieved a CR within four cycles. Of 29 patients with less than a CR, 16 achieved CR with intensified chemotherapy or second surgery. Overall, 55 of 71 (78%) achieved a CR without irradiation. The CR rate was 84% for germinomas and 78% for NGGCT. With a median follow-up duration of 31 months, 28 of 71 patients were alive without relapse or progression. Thirty-five showed tumor recurrence (n = 28) or progression (n = 7) at a median of 13 months. Twenty-six of 28 patients (93%) who recurred following remission underwent successful salvage therapy. Pathology was the only variable predictive of survival. The probability of surviving 2 years was .84 for germinoma patients and .62 for NGGCT. Seven of 71 patients died of toxicity associated with study chemotherapy. CONCLUSION: Forty-one percent of surviving patients and 50% of all patients were treated successfully with chemotherapy only without irradiation. Chemotherapy-only regimens for CNS GCT, although encouraging, should continue to be used only in the setting of formal clinical trials.

Results of a phase II study using estramustine phosphate and vinblastine in combination with high-dose three-dimensional conformal radiotherapy for patients with locally advanced prostate cancer.

PURPOSE: To assess the feasibility and tolerance of neoadjuvant and concomitant estramustine phosphate and vinblastine (EV) with high-dose three-dimensional conformal radiotherapy (3D-CRT) for patients with unfavorable-risk prostate cancer. PATIENTS AND METHODS: Twenty-seven patients with unfavorable-risk prostate cancer were enrolled onto a prospective study to determine the feasibility of combining EV with 3D-CRT. Patients were eligible if any of the following requirements were satisfied: (1) Gleason score > or =8 and prostate-specific antigen (PSA) > 10 ng/mL; (2) Gleason score of 7 and PSA > 20 ng/mL; (3) clinical stage T3N0M0 disease with PSA > 20 ng/mL; (4) any patient with T4N0M0 disease; or (5) patients with TXN1MO disease. Therapy consisted of three 8-week cycles of EV and 8 weeks of 3D-CRT. Estramustine phosphate was given orally beginning on week 1 and continued until the completion of 3D-CRT. Each 8-week cycle of vinblastine consisted of 6 weekly intravenous injections followed by a 2-week rest period. Radiation therapy was administered using a three-dimensional conformal approach to a prescription dose of 75.6 Gy. The median follow-up was 26 months (range, 6 to 40 months). RESULTS: Twenty-three (85%) of 27 patients completed the entire course of therapy and were assessable for toxicities and biochemical outcome. Two patients (7%) developed grade 3 hematologic toxicity that resolved, and two patients (7%) developed grade 3 hepatoxicity, manifesting as persistent elevation of serum transaminase levels, necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The most prominent adverse effects from this regimen were mild to moderate (grade 1 to 2) nausea and fatigue related to estramustine. Mild peripheral edema was seen in 15% of patients and was treated with diuresis. 3D-CRT was tolerated well in these patients. Medications were required for relief of acute grade 2 rectal (gastrointestinal [GI]) and urinary (genitourinary [GU]) symptoms in 35% and 48% of patients, respectively. Three patients developed acute grade 3 GU toxicities. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. No late grade 3 or 4 GI toxicities were observed. The 2-year actuarial likelihoods of late grade 2 and 3 GU toxicities were 25% and 12%, respectively. No grade 4 GU toxicity was observed. CONCLUSION: Neoadjuvant and concomitant EV with high-dose 3D-CRT is well tolerated in patients with unfavorable-risk prostate cancer. Although the incidence of modest (grade 2) late GI and GU toxicities seem to be increased compared with 3D-CRT alone or in combination with androgen ablation therapy, no severe toxicities were encountered with this regimen.

Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer.

PURPOSE: To compare the prostate-specific antigen (PSA) relapse-free survival outcome and incidence of late toxicity for patients with early-stage prostate cancer treated at a single institution with either three-dimensional conformal radiotherapy (3D-CRT) or transperineal permanent implantation (TPI) with iodine-125 seeds. MATERIALS AND METHODS: Patients with favorable-risk prostate cancer, defined as a pretreatment PSA of less than or equal to 10.0 ng/mL, Gleason score of 6 or lower, and stage less than or equal to T2b, were selected for this analysis. Between 1989 and 1996, 137 such patients were treated with 3D-CRT and 145 with TPI. The median ages of the 3D-CRT and TPI groups were 68 years and 64 years, respectively. The median dose of 3D-CRT was 70.2 Gy, and the median implant dose was 150 Gy. Prostate-specific antigen relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up times for the 3D-CRT and TPI groups were 36 and 24 months, respectively. RESULTS: Eleven patients (8%) in the 3D-CRT group and 12 patients (8%) in the TPI group developed a biochemical relapse. The 5-year PSA relapse-free survival rates for the 3D-CRT and the TPI groups were 88% and 82%, respectively (P = .09). Protracted grade 2 urinary symptoms were more prevalent among patients treated with TPI compared with 3D-CRT. Grade 2 urinary toxicity, which was manifest after the implant and persisted for more than 1 year after this procedure, was observed in 45 patients (31%) in the TPI group. In these 45 patients, the median duration of grade 2 urinary symptoms was 23 months (range, 12 to 70 months). On the other hand, acute grade 2 urinary symptoms resolved within 4 to 6 weeks after completion of 3D-CRT, and the 5-year actuarial likelihood of late grade 2 urinary toxicity for the 3D-CRT group was only 8%. The 5-year actuarial likelihood of developing a urethral stricture (grade 3 urinary toxicity) for the 3D-CRT and TPI groups was 2% and 12%, respectively (P<.0002). Of 45 patients who developed grade 2 or higher urinary toxicity after TPI, the likelihood of resolution or significant improvement of these symptoms at 36 months from onset was 59%. The 5-year likelihood of grade 2 late rectal toxicity for the 3D-CRT and TPI patients was similar (6% and 11%, respectively; P = .97). No patient in either group developed grade 3 or higher late rectal toxicity. The 5-year likelihood of posttreatment erectile dysfunction among patients who were initially potent before therapy was 43% for the 3D-CRT group and 53% for the TPI group (P = .52). CONCLUSION: Both 3D-CRT and TPI are associated with an excellent PSA outcome for patients with early-stage prostate cancer. Urinary toxicities are more prevalent for the TPI group and subsequently resolve or improve in most patients. In addition to evaluating long-term follow-up, future comparisons will require detailed quality-of-life assessments to further determine the impact of these toxicities on the overall well-being and quality of life of the individual patient.

The treatment of hepatic metastases from colorectal cancer with radiation therapy alone or combined with chemotherapy or misonidazole.

In summary, whole liver RT alone is generally well tolerated and, in most cases, offers some palliative benefit. It is difficult to determine its ultimate impact on survival since many patients treated with this single modality have extra-hepatic disease. In addition, the dose of radiation which the liver can tolerate is not adequate to control gross disease. The addition of chemotherapy (systemic and/or intra-hepatic) appears promising. However, further follow-up and randomized trials need to be performed before this is known with certainty. The use of misonidazole in the dosages and techniques employed by the RTOG did not appear to enhance overall survival. More innovative techniques of delivering RT, including intraoperative brachytherapy, radiolabeled antibodies, and hyperfractionated external beam RT require further investigation in order to determine their efficacy.

Three-dimensional conformal radiotherapy and dose escalation: where do we stand?

Three-dimensional conformal radiotherapy is an effective means of delivering high doses of radiation with enhanced precision. Several institutions have gained substantial experience using this modality for patients with clinically localized prostate cancer. Reports from these centers have demonstrated not only excellent tolerance despite the administration of higher radiation doses, but improved biochemical and local control outcomes as well. Meticulous attention to treatment technique and dose volume histogram analysis are critical for the safe implementation of these higher doses. The emergence of intensity-modulated treatment planning has provided the opportunity at our institution to further escalate the radiation dose to 86.4 Gy while still respecting the surrounding normal tissue tolerance. Phase I studies will need to continue to define more clearly the maximal dose of radiation that can be delivered safely with this modality. Current studies indicate a direct correlation between dose and prostate-specific antigen (PSA) relapse-free survival response for patients with intermediate and high-risk prognostic features. These patients likely represent the ideal cohort for future studies designed to investigate the impact of dose on biochemical and disease-free survival outcome.

Preliminary results of conformal radiation therapy for medulloblastoma.

Radiation therapy for medulloblastoma consists of postoperative irradiation of the intracranial and spinal subarachnoid volume with an additional boost to the primary site of disease in the posterior fossa. The entire posterior fossa is usually included in the boost volume. Conformal radiation therapy techniques may be used to boost the primary site alone and substantially reduce the dose received by normal tissues, including the supratentorial brain, the middle and inner ear, and the hypothalamus. Using these techniques to irradiate only the tumor bed or residual tumor and not the entire posterior fossa represents a new paradigm in the treatment of medulloblastoma. In this study, we examine the use of conformal radiation therapy in the treatment of 14 patients with medulloblastoma. These patients were treated with multiple static, individually shaped, noncoplanar beams directed at the primary site after craniospinal irradiation. Excluding two patients who had previously received irradiation to the posterior fossa, the mean dose delivered to the primary site was 5715 cGy. Among the medulloblastoma patients (n = 10) who received immediate postoperative radiation therapy, no failures have occurred with a median follow-up of 42 months (range from 30 to 54 months). To demonstrate the differences in the distribution of dose to normal tissues when comparing conventional and conformal techniques, dose-volume histograms of the total brain, middle and inner ear, hypothalamus, and temporal lobe were created and presented for an example case. The neurologic, neuroendocrine, and neurocognitive outcome for patients with medulloblastoma may be influenced with the use of conformal radiation therapy. The use of these techniques should be formally tested in prospective studies of rigorously staged patients with failure rate monitoring.

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 facility's 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.

The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement.

PURPOSE: The effect of local and regional treatment on the development of distant metastases in patients with localized node negative and node positive carcinoma of the prostate is examined. METHODS AND MATERIALS: Distant metastases-free survival was evaluated in 1078 patients with Stage B-C node negative (733 patients) or node positive (345 patients) carcinoma of the prostate, staged with pelvic lymph node dissection and treated with retropublic 125I implantation at the Memorial Sloan-Kettering Cancer Center between 1970 and 1985. RESULTS: The 15-year actuarial distant metastases-free survival rate for the entire group of patients was 27%. Lymph node involvement was the most significant covariate affecting distant metastases-free survival, although local failure, stage, and grade were also independent variables. Distant metastases-free survival varied with the extent of lymph node involvement (N0 vs. N1, p < 0.0001; N1 vs. N2, p < 0.0001). However, the difference between N1 and N2 patients was due to a faster rate of development of distant metastases in N2 patients. The ultimate 10-year distant metastases-free survival rate was similar for the two patient groups (11% for N1 and 9% for N2). Local failure correlated with the metastatic outcome in patients with B-C/N0 disease (p < 0.00001), but not in N1 or N2 patients. Although distant metastases-free survival in locally controlled N1 patients was improved compared to N2 patients (p = 0.004), when stratified by primary tumor stage and grade, the differences were no longer significant. CONCLUSION: Essentially all node positive patients with carcinoma of the prostate will develop distant metastatic disease if followed for sufficiently long periods of time. This is consistent with the hypothesis that in such patients distant micrometastatic dissemination already exists at the time of initial diagnosis. The data suggest that clinical trials designed to test whether improvements in local therapy impact on survival should be restricted to node negative patients. The data also raise concerns regarding the therapeutic value of elective whole pelvic irradiation.

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.

Tolerance and early outcome results of postprostatectomy three-dimensional conformal radiotherapy.

PURPOSE: Three-dimensional conformal radiotherapy (3D-CRT) has been associated with a reduction in acute and late toxicity among patients treated for localized prostatic cancer. The purpose of this study is to assess the acute and late toxicity of 3D-CRT delivered to patients in the postprostatectomy setting and to analyze which factors predict for durable biochemical control in this group of patients. METHODS AND MATERIALS: Between 1988 and 1994, 42 patients were treated after prostatectomy with three-dimensional conformal radiotherapy. The median time from prostatectomy to radiotherapy was 11 months. Indications for treatment included a rising serum PSA level in 28 patients (65%) and positive surgical margins without a rising PSA level in 14 (35%). Twenty-five patients (60%) had pathologic stage T3 disease, and 32 (74%) had tumor at or close to the surgical margins. The median dose was 64.8 Gy, and the median follow-up time was 2 years. RESULTS: 3D-CRT in the postprostatectomy setting was well tolerated. Three patients (7%) experienced Grade II acute genitourinary toxicity and nine patients (21%) experienced Grade II acute gastrointestinal toxicity during treatment. No patient experienced Grade III or higher acute morbidity. The 2-year actuarial risk for Grade II late genitourinary and gastrointestinal late complications were 5 and 9%, respectively. In patients with existing incontinence, the incidence of worsening stress incontinence 6 months after treatment was 17%, which resolved within 12 months to its preradiotherapy level in four of six cases (66%). The overall 2-year postirradiation PSA relapse-free survival rate was 53%. The 2-year PSA relapse-free survival was 66% for patients with undetectable PSA levels in the immediate postoperative period compared to 26% for those with detectable levels of PSA after surgery (p < 0.006). Furthermore, for patients with preradiotherapy PSA levels of < or = 1.0 ng/ml, the 2-year PSA relapse-free survival was 74% compared to 17% of those with preradiotherapy PSA levels of > 1.0 ng/ml (p < 0.002). The resection margin status, presence of seminal vesicle involvement, Gleason score, and the preprostatectomy PSA level did not impact on PSA relapse-free survival. A Cox proportional hazards regression analysis demonstrated that a preradiotherapy PSA value of > 1 ng/ml (p < 0.002) was the most important covariate predicting for a rising PSA after radiotherapy. CONCLUSIONS: After prostatectomy, three-dimensional conformal radiotherapy is associated with minimal treatment-related morbidity. Patients with postprostatectomy, preradiotherapy PSA levels < or = 1.0 ng/ml, and those patients who had undetectable PSA levels in the immediate postoperative period are more likely to benefit from local adjuvant therapy.

The definition of biochemical failure in patients treated with definitive radiotherapy.

PURPOSE: The American Society for Therapeutic Radiology and Oncology (ASTRO) published a definition for biochemical failure following treatment of prostate cancer. Others have noted difficulties with interpreting this definition and recommended modifications to accommodate special recurrence patterns. We have compared various modifications to the original ASTRO definition on our series of 1213 patients treated with transperineal permanent prostate brachytherapy. METHODS AND MATERIALS: The ASTRO modifications we considered adjusted for (1) early censoring of nonrecurrent patients with rising prostate-specific antigen levels (PSA), (2) cumulative rather than consecutive rises (without a decrease) as evidence of recurrence, (3) both of the above, and (4) waiting 2 years before data analysis. The Kaplan-Meier method was used to compute the effects on recurrence rate for patients treated with and without neoadjuvant hormones. RESULTS: With the original ASTRO definition, freedom from recurrence in our series of men who did not receive neoadjuvant hormones was 83% at 4 years. All of the modifications considered had statistically insignificant effects on freedom from recurrence rates, varying from 80% to 83% at 4 years. Patients treated with neoadjuvant hormones also showed very little sensitivity to the recurrence definition employed. CONCLUSION: Early censoring of equivocal patients and counting cumulative rather than consecutive rises in PSA (without a decrease) had little empiric effect on the ASTRO recurrence rates. However, we favor the addition of both these modifications to the ASTRO definition on conceptual grounds for evaluating patients following any modality (radiation or surgery), whereby a trend over multiple PSA values is used to judge failure.