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.

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.

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.

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.

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.

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.

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.

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.

Efficacy of selective alpha-1 blocker therapy in the treatment of acute urinary symptoms during radiotherapy for localized prostate cancer.

PURPOSE: To determine the efficacy of an alpha-1 adrenoreceptor blocking agent for acute urinary symptoms in patients treated with radiotherapy for localized prostate cancer. METHODS AND MATERIALS: Between 1987 and 1995, 743 patients with clinically localized prostate cancer were treated with 3D-CRT. A total of 275 (37%) patients developed Grade 2 acute urinary symptoms as defined by the RTOG morbidity scoring system. Terazosin hydrochloride (THC), a selective alpha-1 adrenoceptor blocking agent, was given to 119 (43%) patients for treatment of their urinary symptoms, whereas nonsteroidal anti-inflammatory medications (NSAID) were administered to 71 patients (26%). Thirty-one patients (11%) were treated with other medications, and 54 (20%) did not seek pharmacologic intervention for their urinary symptoms. Patients were monitored weekly to assess changes in urinary urgency, frequency, and nocturia. RESULTS: Treatment with THC resulted in a significant resolution of urinary symptoms in 79 of 119 patients (66%), while 26 (22%) had moderate improvement, and 14 (12%) had minimal to no response to this drug. In contrast, only 11 of 71 (16%) of the patients treated with NSAIDs experienced significant symptom relief, 20 (28%) had moderate improvement, and 40 (56%) had minimal to no response. The difference in the significant symptomatic improvement between THC and NSAID therapy (66% vs. 16%) was highly significant (p < 0.001). For patients treated with THC, a higher likelihood of significant symptom relief was observed in patients who did not receive neoadjuvant androgen ablation (p = 0.04) and in those who were younger than 65 years of age (p = 0.02). CONCLUSION: Alpha-1 selective adrenoceptor blocking agents are effective in ameliorating the acute urinary symptoms in patients receiving radiotherapy for localized prostate cancer. Although this was not a randomized prospective study, the data suggest that NSAIDs were less effective in relieving radiation-induced urinary symptoms.

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.

The use of a multi-leaf collimator for conformal radiotherapy of carcinomas of the prostate and nasopharynx.

We investigate the use of a multi-leaf collimator for conformal radiation therapy of carcinomas of the prostate and of the nasopharynx. Following verification of dose calculation algorithms for multi-leaf collimated fields using film dosimetry, we compute dose distributions for multi-field conformal treatment using fields shaped with either the multi-leaf collimator or conventional cerrobend blocks. We compare the two sets of treatment plans using graphical isodose displays, tissue specific dose volume histograms, tumor control probabilities, and normal tissue complication probabilities. We also incorporate setup errors into the calculated dose distributions to assess the effect of treatment uncertainties on the various criteria. Based on these comparisons, we conclude that for multi-field conformal radiotherapy for these two disease sites, the use of multi-leaf collimation is equivalent to that of conventional cerrobend blocks.

The biological basis for conformal three-dimensional radiation therapy.

The recent introduction of new computer technology for treatment planning and computer-driven treatment delivery systems, such as multi-leaf collimators and on-line verification systems, has accelerated the development of 3-dimensional (3-D) radiation therapy as a modality for curative cancer treatment. The goal of 3-D treatment planning is to conform the spatial distribution of the high radiation dose to the shape of the tumor contour while concomitantly decreasing the volume of the surrounding normal tissues receiving high radiation doses. The improved precision of tumor coverage and the exclusion of normal tissues should permit tumor dose escalation and may enhance local tumor control. It has been suggested that any survival gains derived from improvements in local control may be offset by the subsequent appearance of distant metastases arising from micrometastases already present at the time of initial diagnosis. However, clinical and laboratory studies indicate that failure to control the primary tumor at the time of initial treatment significantly increases the incidence of metastatic dissemination. This phenomenon is consistent with the hypothesis that the enhanced mitotic activity associated with the re-growth process of locally recurring primary tumors promotes the multi-step transformation of non-metastatic tumor cells into clonogens with metastatic potential, leading to increased overall rates of metastatic disease. These biologic considerations provide support for the need to focus attention on the identification of more effective therapeutic strategies designed to eradicate the primary local tumor completely at the time of initial therapy and serve as the rationale for clinical studies using 3-D conformal radiation therapy.

Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05.

PURPOSE: To determine if the addition of bromodeoxyuridine (BrdUrd) to radiotherapy prolongs survival when compared to radiotherapy alone in patients with brain metastases. METHODS AND MATERIALS: Seventy-two patients with brain metastases were randomized to 37.5 Gy in 15 fractions of 2.5 Gy or to the same dose with BrdUrd 0.8 g/m2 per day for 4 days of each of 3 weeks. Drug treatment was begun on Thursday or Friday before the first week of radiotherapy. Patients had a Karnofsky performance score of at least 70, a neurological function classification of 1 or 2, and any primary tumor except central nervous system (CNS), leukemia, or lymphoma. The primary was absent, controlled, or under active radiotherapy. Patients were free of other metastases. They were stratified by primary site (breast, lung or other), number of metastases (single or multiple) and age (< 60 vs. > 60). RESULTS: There was no significant difference between the two treatment arms (p = 0.904). The study was open from October 1989 to March 1993 and accrued 72 patients. Only one patient in the RT only arm remains alive. The two treatment arms were balanced with respect to all stratification variables. Toxicity due to radiotherapy was similar in both arms. BrdUrd caused significant Grade 4 and 5 hematologic and skin toxicity in five patients. Two patients died due to hematologic toxicity and one from a Stevens-Johnson type skin reaction. Phenytoin played a role in the skin reactions and ranitidine was associated with the hematologic deaths. Ranitidine was eliminated, BrdUrd was discontinued after any hematologic toxicity, and no further Grade 4 or 5 toxicities were seen. The median survival was 6.12 months in the radiotherapy group and 4.3 in the BrdUrd group (p = 0.904). Patients with solitary brain metastases had significantly better survival (p = 0.031). CONCLUSIONS: BrdUrd did not enhance the efficacy of the radiotherapy regimen tested, in spite of the fact that brain metastases have shown high labeling indices. The toxicity of this schedule of BrdUrd administration was apparently increased by ranitidine and phenytoin.

Induction chemotherapy plus three-dimensional conformal radiation therapy in the definitive treatment of locally advanced non-small-cell lung cancer.

PURPOSE: To evaluate our institution's experience using chemotherapy in conjunction with three-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS: From 1991 to 1998, 152 patients with Stage III non-small-cell lung cancer (NSCLC) were treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center. A total of 137 patients (90%) were surgically staged with either thoracotomy or mediastinoscopy. The remainder were staged radiographically. Seventy patients were treated with radiation therapy alone, and 82 patients received induction chemotherapy before radiation. The majority of chemotherapy-treated patients received a platinum-containing regimen. Radiation was delivered with a 3D conformal technique using CT-based treatment planning. The median dose in the radiation alone group was 70.2 Gy, while in the combined modality group, it was 64.8 Gy. RESULTS: The median follow-up time was 30.5 months among survivors. Stage IIIB disease was present in 36 patients (51%) in the radiation-alone group and 57 patients (70%) in the combined-modality group. Thirty-nine patients had poor prognostic factors (KPS < 70 or weight loss > 5%), and they were equally distributed between the two groups. The median survival times for the radiation-alone and the combined-modality groups were 11.7 months and 18.1 months, respectively (p = 0.001). The 2-year rates of local control in the radiation-alone and combined-modality groups were 35.4% and 43.1%, respectively (p = 0.1). Grade 3 or worse nonhematologic toxicity occurred in 20% of the patients receiving radiation alone and in 16% of those receiving chemotherapy and radiation. Overall, there were only 4 cases of Grade 3 or worse esophagitis. CONCLUSION: Despite more Stage IIIB patients in the combined-modality group, the addition of chemotherapy to 3D-CRT produced a survival advantage over 3D-CRT alone in Stage III NSCLC without a concomitant increase in toxicity. Chemotherapy thus appears to be beneficial, even in patients who are receiving higher doses of radiation therapy than are typically given with conventional techniques. Because locoregional failure remains a major challenge in patients with advanced disease, 3D-CRT in conjunction with chemotherapy may allow safe treatment to the dose levels required to further enhance local control.