Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials.

BACKGROUND: Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma. PURPOSE: This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials. METHODS: We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. RESULTS: The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients. CONCLUSIONS: This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis. IMPLICATIONS: The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.

Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in cancer patients.

Serum vitamin D3-binding protein (Gc protein) can be converted by beta-galactosidase of B cells and sialidase of T cells to a potent macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar moiety. Thus, Gc protein is the precursor of the macrophage activating factor (MAF). Treatment of Gc protein with immobilized beta-galactosidase and sialidase generates an extremely high titered MAF, Gc-MAF. When peripheral blood monocytes/macrophages of 52 patients bearing various types of cancer were incubated with 100 pg/ml of GcMAF, the monocytes/macrophages of all patients were efficiently activated. However, the MAF precursor activity of patient plasma Gc protein was found to be severely reduced in about 25% of this patient population. About 45% of the patients had moderately reduced MAF precursor activities. Loss of the precursor activity was found to be due to deglycosylation of plasma Gc protein by alpha-N-acetylgalactosaminidase detected in the patient's bloodstream. The source of the enzyme appeared to be cancerous cells. Radiation therapy decreased plasma alpha-N-acetylgalactosaminidase activity with concomitant increase of precursor activity. This implies that radiation therapy decreases the number of cancerous cells capable of secreting alpha-N-acetylgalactosaminidase. Both alpha-N-acetylgalactosaminidase activity and MAF precursor activity of Gc protein in patient bloodstream can serve as diagnostic and prognostic indices.

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.

Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413.

PURPOSE: This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%. MATERIALS AND METHODS: Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) < or = 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause. RESULTS: With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P =.022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P =.56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P =.008). No survival advantage has yet been seen. CONCLUSION: WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.

Misonidazole and unconventional radiation in advanced squamous cell carcinoma of the esophagus: a phase II study of the Radiation Therapy Oncology Group.

This is a report on Radiation Therapy Oncology Group (RTOG) Protocol No. 78-32, a Phase I/II prospective study aimed at determining tolerance, tumor response, and survival of squamous cell carcinoma of the esophagus treated with unorthodox fractionation radiotherapy combined with misonidazole. Misonidazole was administered by mouth 4 to 6 hr prior to radiation, at a dose of 1.0 to 1.25 Gm/.m2; blood levels were measured at about 4 hr after intake of the drug and reported in micrograms/ml. Radiotherapy was administered at 4 to 6 hr post-misonidazole dose and given with 400 rad fractions, alternating 2 or 3 times/week, up to 4,800 rad. A total of 43 patients were entered; 26 are evaluable for survival at 1 year post accession. Thirty patients (88%) received the planned radiation course. Twenty-eight patients (78%) received the planned misonidazole dosage. Tumor response, evaluable in 18 patients, showed a complete regression (C.R.) in only 2 patients (11%); and partial response (P.R.) in 6 patients (33%). Eight patients (44%) showed no tumor response to planned therapy. Toxicity was acceptable and in 38 evaluable patients only 4 reported (11%) nausea and vomiting, 7 reported mild paresthesias (18%). The median survival was only five months. In 26 patients evaluable for 1 year survival determination, only 1 survived (3.8%) this period. In view of the poor tumor response and low survival observed, we do not recommend that this particular fractionation regimen with misonidazole be used in a Phase III randomized trial in squamous cell carcinoma of the esophagus.

Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06.

From 1978 to 1983 the Radiation Therapy Oncology Group conducted a study to evaluate the role of elective pelvic lymph node irradiation in carcinoma of the prostate. Eligible patients were those with clinical Stage A2 (occult disease with more than 3 positive chips and poorly differentiated tumor) and Stage B without clinical (lymphangiogram) or biopsy evidence of lymph node involvement. The patients were randomized to receive 6.5 weeks of either prostatic bed irradiation only 6500 cGy at 180-200 cGy per treatment or pelvic node irradiation to 4500 cGy with a boost of 2000 cGy to the prostatic bed bringing the total dose to 6500 cGy. As of February, 1988, the median follow up has been 7 years and there were 445 analyzable cases who were evaluated for local control, incidence of distant metastases, ned (no evidence of disease) survival and survival. The results of the study revealed no statistically significant benefit of elective pelvic irradiation.

Correlation of radiotherapeutic parameters and treatment related morbidity--analysis of RTOG Study 77-06.

The current report is an updated and detailed analysis of treatment related morbidity in RTOG 77-06, a Phase III randomized study comparing prostatic irradiation versus pelvic irradiation followed by a prostatic boost, in patients with Stage A2 and B carcinoma of the prostate without evidence of nodal involvement. A total of 453 analyzable cases were accrued from 1978 to 1983, when the study was closed. All cases of treatment related morbidity were classified as to severity (using a clinical severity grading system). The data were then correlated with a number of radiotherapeutic parameters including treatment volumes (fields), doses, and techniques. Overall, pelvic irradiation, compared to prostate irradiation only, was not associated with a significantly increased incidence of treatment related morbidity. Within the range of pelvic doses used in this study a significant dose effect could not be detected. Total doses to the prostate of more than 7000 cGy were associated with an increased risk of rectal bleeding. Certain treatment techniques, (AP/PA irradiation of the pelvic lymphatics) were associated with an increased incidence of bowel complications.

Definitive radiotherapy in resectable (stage A2 and B) carcinoma of the prostate--results of a nationwide overview.

To evaluate the efficacy of definitive radiotherapy in a population of patients with carcinoma of the prostate who satisfy the customary selection criteria for radical prostatectomy, a nation-wide search was conducted. The assessed population consists of patients with clinical Stage A2 and B carcinoma of the prostate, negative staging lymphadenectomy, negative bone scan, and normal serum acid phosphatase. The search included patients from Stanford University, Washington University in St. Louis, those participating in the Radiation Therapy Oncology Group and a broad range of radiotherapy practices surveyed by the PCS (Patterns of Care Study). A total of 209 patients satisfying the selection criteria received definitive radiotherapy during the surveyed period. The end-point of analysis was the time to progression (distant metastases). The results of the analysis indicate a very low (less than 10%) probability of progression within the first 5 years after completion of treatment. Contrary to the recent report from the VA Uro-Oncology Group the study demonstrates a comparable outcome in radiotherapeutically and surgically treated patients.

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.

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.

Treatment-related morbidity in phase III RTOG studies of extended-field irradiation for carcinoma of the prostate.

The incidence, severity, time of onset, and clinical course of complications of treatment have been reviewed in the RTOG studies of extended field irradiation in carcinoma of the prostate. A total of 526 patients, entered between 1976 and 1980 and followed for a minimum of 18 months, comprised the study population. In most instances of treatment-related morbidity, the symptoms were recorded during the first several months to 1 year following completion of treatment. Late occurrences, however, were not uncommon in certain types of radiation-produced injuries, such as proctitis, hematuria, and urethral strictures. Resolution of symptoms has been observed in a large proportion of patients including those with late occurrences of treatment-related morbidity, although the probability and the pattern of resolution differed considerably from one type of morbidity to another. Symptoms of cystitis are more likely to abate than those of proctitis. In patients who develop symptoms of proctitis the probability of persistence of symptoms beyond the second year following occurrence has been estimated at 20%-30%. Hematuria and symptoms secondary to urethral strictures seem to be even more likely to recur or persist, while genital and leg edema remain chronic in the majority of patients.

Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification.

RTOG 77-06 and 75-06 were studies of nodal irradiation in prostate cancer, for which the status of nodes was determined by lymph node dissection (LND), lymphangiography (LAG), or computer assisted tomography (CT) based on investigator preference. Actuarial 5 year endpoints of survival, NED survival, local recurrence and distant metastasis have been determined by stage for 805 eligible patients with a comparison of pathologic vs clinical (imaging test) determined nodal status. Patients with pathologically negative lymph nodes show significantly improved 5 year survival (Stage T-2 (B) 84% vs 77%, Stage T-3,4 (C) 82% vs 65%) and NED survival (Stage T-2 (B) 72% vs 63%, Stage T-3,4 (C) 64% vs 44%) compared to patients clinically negative. Free of metastasis rates are increased in Stage T-3,4 (C) pathologic negative patients compared to imaging negative patients (75% vs 60%). A comparison of clinical positive versus clinical negative patients shows no difference in survival, NED survival or rate of metastasis, while a similar comparison of pathologic positive versus pathologic negative shows significant difference for all three endpoints (survival: Stage T-2 (B) 84% vs 61%, Stage T-3,4 (C) 82% vs 66%, NED survival: Stage T-2 (B) 72% vs 32%, Stage T-3,4 (C) 64% vs 32%; free of metastasis: Stage T-2 (B) 82% vs 64%, Stage T-3,4 (C) 75% vs 44%). The clinical determination of nodal status, therefore, has no prognostic value in contrast to pathologic determination and should not be used for stratifying patients in clinical trials. The CT scans often used to evaluate nodal status are more useful if delayed until they can be done as part of the treatment planning process where the CT has value. When imaging tests suggest positive lymph nodes in prostate cancer patients, the imaging finding is confirmed by biopsy.

Patterns of Care and RTOG studies in prostate cancer: long-term survival, hazard rate observations, and possibilities of cure.

PURPOSE: This study was undertaken to show the long-term survival and probability of cure of prostate cancer patients treated with external beam radiation in USA national surveys and in the prospective clinical trials of the RTOG. METHODS AND MATERIALS: Two national patterns of care surveys of patients treated in 1973 and 1978 are reported along with two RTOG prospective trials (7506 and 7706). Hazard rates represent the risk of death and are compared to the rate expected for a normal population. RESULTS: For patients with Stage A cancers, the survival is not different from the expected survival for any of the reported surveys. The hazard rate for death does not significantly exceed the expected hazard rate out to 15 years. For patients with Stage B cancer, there is a decrease in survival below expected and hazard rates show a continuing excess mortality as long as 15 years after treatment. For patients with Stage C cancers, there is a more rapid decrease in survival that then becomes parallel to the expected survival. Hazard rates indicate there has been a return to expected mortality at 15 years. CONCLUSION: These data make a strong argument for the long-term cure of prostate cancer by external beam radiation, and support the continued use and study of radiation therapy as a curative modality in prostate cancer. No similar national data is available for any other method of management.

Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01.

The Radiation Therapy Oncology Group (RTOG) conducted a Phase I/II study in hepatocellular cancer that closed on September 9, 1987 and some results presented previously. Here, 17 patient characteristics are evaluated to identify any of prognostic significance. Two hundred sixteen patients were entered and 198 (74% with metastases and/or previous chemotherapy) were evaluable. Treatment began with an induction regimen of external beam radiotherapy to the liver (21.0 Gy, 3.0 Gy/Fx, 10 MV photons, 4 days per week) with low-dose chemotherapy (5-Fluorouracil (FU), 500 mg, i.v.; Doxorubicin, 15 mg, i.v.) on treatment Days 1, 3, 5 and 7. In the later stages of these studies, 56 patients received external beam radiotherapy as hyperfractionated treatment (1.2 Gy twice daily, 4 hours separation, 5 days per week, 24.0 Gy total) with similar chemotherapy. One month following induction therapy, cycles of radiolabeled antibody therapy were given every 2 months. Each cycle was derived from a different species of animal and consisted of 30 mCi I-131 antiferritin, Day 0, and 20 mCi, Day 5. On Day -1, 5-FU, 500 mg, and Adriamycin, 15 mg, were administered. The overall median survival for the entire group, including previously treated patients, was 4.9 months. The median survival for alpha-fetoprotein (AFP) - patients not previously treated was 10.5 months. Median survival for all AFP - patients was 8.5 months and for all AFP + patients was 4.6 months (p = 0.006). Of the 17 pretreatment characteristics investigated for prognostic value Karnofsky Performance Score (KPS) (80-100 vs. less than 80) (p = 0.0001), presence/absence of ascites (p = 0.0002), bilirubin level (less than 1.5 vs. greater than or equal to 1.5) (p = 0.018), SGOT (less than or equal to 35 vs. greater than 35) (p = 0.001); alkaline phosphatase (less than or equal to 95 vs. greater than 95) (p = 0.008) were found to be significant independently using a multivariant regression model. The relative risk of dying for the unfavorable component of each of these characteristics was 2.2, 2.0, 1.5, 1.9 and 1.7, respectively. Good and poor prognostic groups were then defined and compared to a similar patient population (RTOG study 83-19) with confirmation of the validity of the model. When stratification for these overpowering clinical factors was incorporated, AFP status was again significant with a relative death rate 1.80 times higher for AFP+ patients. Our recommendations for structuring future prospective randomized trials are discussed and include stratification by AFP status.

Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials.

PURPOSE: Gleason score (GS), T stage, and pathologic lymph node status have been described as major independent predictors of death due to prostate cancer in men treated with external beam radiotherapy (XRT). In this analysis we combine these three factors to define prognostic subgroups that correlate with disease-specific survival (DSS) death from prostate cancer. METHODS AND MATERIALS: Men entered on one of four Radiation Therapy Oncology Group (RTOG) Phase III randomized trials between 1975 and 1992, for clinically localized prostate cancer (CAP) (n = 1557), were selected for this analysis. Patients were included if: 1) they were evaluable, and eligible for the trial; 2) they received no hormonal therapy with their initial treatment; and 3) follow-up was available. For this study a DSS event was declared if: 1) death was certified as due to CAP; 2) death was due to complications of treatment; or 3) death was from unknown causes with active malignancy. The median follow-up for patients treated on early and late RTOG studies exceeded 11 and 6 years respectively. Subgroups were identified based on their pretreatment GS, T-stage, and lymph node such that patients with similar risk of dying from prostate cancer were combined. RESULTS: By combining patients with similar DSS, four subgroups were identified. Risk Group 1 patients had a GS = 2-6, and T1-2Nx; Group 2: GS = 2-6, T3Nx; or GS = 2-6, N+, or GS = 7, T1-2Nx; Group 3: T3Nx, GS = 7; or N+, GS = 7, or T1-2Nx, GS = 8-10; and Group 4 patients were T3Nx, GS = 8-10, or N+, GS = 8-10. The 5-, 10-, and 15-year DSS was 96%, 86%, and 72%; 94%, 75%, and 61%; 83%, 62%, and 39%; and 64%, 34%, and 27% for Groups 1 through 4, respectively. CONCLUSIONS: Recognition of these four risk groups provides a basis for estimating the long-term DSS for men treated with XRT alone and should facilitate the design of future prospective randomized trials.

Predicting long-term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials.

PURPOSE: To assess the impact of short-term and long-term androgen suppression on the disease-specific and overall survival of 2200 men treated with radiotherapy on one of 5 prospective randomized trials when stratified by prognostic risk groups. METHODS AND MATERIALS: Between 1975 and 1992, 2742 men were treated for clinically localized prostate cancer on one of 5 consecutive prospective Phase III randomized trials. Patients were selected for this analysis if they were deemed evaluable and eligible for the trial, and if follow-up information was available. For this analysis patients were stratified into four previously described prognostic risk groups: Group 1 patients had a Gleason score (GS) = 2-6, and T1-2Nx; Group 2: GS = 2-6, T3Nx; or GS = 2-6, N+, or GS = 7, T1-2Nx; Group 3: T3Nx, GS = 7; or N+, GS = 7, or T1-2Nx, GS = 8-10; and Group 4 patients were T3Nx, GS = 8-10, or N+, GS = 8-10. The median pretreatment prostate-specific antigen (PSA) was 25 ng/ml for the 434 evaluable patients for whom this information was available. The median follow-up times for patients treated on early studies exceeded 11 years, and for more recent studies 6 years. RESULTS: Risk group 2 patients with "bulky" or T3 disease appeared to have a disease-specific survival benefit at 8 years with the addition of 4 months of goserelin and flutamide. Group 3 and 4 patients were noted to have an approximately 20% higher survival at 8 years with the addition of long-term hormonal therapy (p < or =0.0004). CONCLUSIONS: Based on this meta-analysis of RTOG trials, subsets of patients can be identified who either do not appear to benefit from the use of hormonal therapy, benefit from short-term hormonal therapy, or who benefit only from long-term hormonal therapy. These observations should be confirmed by prospective randomized trials before they can be considered conclusive. In the meantime, however, these observations provide rational guidelines for deciding who should receive hormonal therapy and for how long.

Failure patterns by prognostic group determined by recursive partitioning analysis (RPA) of 1547 patients on four radiation therapy oncology group (RTOG) studies in inoperable nonsmall-cell lung cancer (NSCLC).

PURPOSE: To identify groups of patients who might benefit from more aggressive systemic or local treatment, based on failure patterns when unresectable NSCLC was treated by radiation therapy (RT) alone. METHODS: From 4 RTOG trials, 1547 patients treated by RT alone were analyzed for patterns of first failure by RPA class defined by prognostic factors, including KPS, weight loss, nodal stage, pleural effusion, age and radiation therapy dose. All patients had NSCLC AJCC Stage II, IIIA, or IIIB, KPS > 50, with no previous RT or chemotherapy. Progressions in the primary (within irradiated fields), thorax (outside irradiated area, but within thorax), brain and distant metastasis other than brain were compared (2-sided) for each failure category by RPA. RESULTS: The RPA classes were 4 distinct subgroups that had significantly different median survivals of 12.6, 8.3, 6.3 and 3.3 months for Classes I, II, III and IV, respectively, (all groups, p = 0.0002). There were 583, 667, 249 and 48 patients in Classes I, II, III and IV, respectively. Primary failure was seen in 27%, 25%, 21% and 10% for Classes I, II, III, and IV, respectively (I vs. IV, p = 0.014; II vs. IV, p = 0.022). Distant metastasis, including brain metastasis, occurred at significantly higher rates among Classes I and II (58% and 54%) than in Classes III and IV (42% and 27%). A higher rate (58%) of death without an identifiable site of failure was found in Class IV than in Classes I, II and III (27%, 28% and 36%, respectively). CONCLUSIONS: The data suggest that physiologic compromise from the intrathoracic disease in Class IV patients is sufficient to cause death before specific sites of failure became evident. Clinical investigations using treatments directed at specific sites of failure could lead to improved outcome for Class I, II and, possibly, Class III patients. Inclusion of Class IV patients in clinical trials may obscure outcomes.

Irradiation with or without misonidazole for patients with stages IIIB and IVA carcinoma of the cervix: final results of RTOG 80-05. Radiation Therapy Oncology Group.

PURPOSE: The purpose of this study was to evaluate tumor response, progression-free survival, local tumor control, patterns of relapse, and toxicity in patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix treated with irradiation or irradiation and misonidazole. This is a report of the final results of the study. METHODS: This study was a prospective randomized Phase III trial performed by the Radiation Therapy Oncology Group (RTOG). Between August 1980 and November 1984, 120 patients with Stages IIIb and IVa squamous cell carcinoma of the cervix were randomized to receive either standard irradiation or standard irradiation and misonidazole. Irradiation consisted of 46 Gy to the pelvis plus a 10 Gy parametrial boost followed by intracavitary brachytherapy or external irradiation boost to the primary tumor. Misonidazole was administered at 400 mg/m2 daily, 2-4 h before irradiation. Patients in the 2 treatment groups were evenly distributed by stage, Karnofsky Performance Status, and positive para-aortic lymph nodes. RESULTS: Sixty-one patients were treated with irradiation alone, and 59 patients received irradiation and misonidazole. Complete response in the pelvis occurred in 44 (75%) of those treated with irradiation and in 38 (64%) of those treated with irradiation and misonidazole. The progression-free survivals were 22% at 5 years for the control group, and 29% at 5 years for the misonidazole group. At the time of last follow-up, 18 patients in the control arm were free of disease, and in the experimental arm, 19 were free of disease. The patterns of failure for those treated with irradiation alone were local-only in 9 patients, distant-only in 8 patients, and local and distant in 11 patients. The patterns of failure for those receiving irradiation and misonidazole were local-only in 3 patients, distant-only in 8 patients, and local and distant in 8 patients. The maximum toxicity experienced per patient was grade 3 in 18%, grade 4 in 8%, and no grade 5 toxicity for those treated with irradiation alone compared to 8%, 2%, and 2%, respectively, for the experimental arm. CONCLUSION: There were no statistically significant differences in pelvic response, disease-free survivals, patterns of failure, or toxicity for the irradiation alone group or for the irradiation and misonidazole group as administered in this study for patients with Stages IIIb and IVa squamous cell carcinoma of the uterine cervix.

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.

Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials.

PURPOSE: The influence of tumor site, size, and extent of surgery on the survival of patients with glioblastoma multiforme treated on three consecutive prospectively randomized Radiation Therapy Oncology Group trials employing surgery and irradiation plus or minus chemotherapy was studied. METHODS AND MATERIALS: Six hundred forty-five patients with a diagnosis of glioblastoma multiforme on central pathological review were analyzed for survival with respect to known prognostic factors, that is, age and Karnofsky Performance Status, as well as extent of surgery, site, and size. Surgical treatment consisted of biopsy only in 17%, partial resection in 64%, and total resection in 19%. Tumors were located in frontal lobe in 43%, temporal lobe in 28%, and parietal lobe in 25%. Maximum tumor diameter as determined on computed tomography or magnetic resonance imaging scans was less than 5 cm for 38%, between 5-10 cm for 56% and greater than 10 cm for 6% of patients. The extent of surgical therapy was the same for tumors greater than 5 or greater than 10 cm, whereas total resection was more often performed for tumors less than 5 cm. The extent of surgery did not appear to vary with age or site. RESULTS: Patients undergoing total resection had a median survival of 11.3 months compared to 6.6 months for patients with a biopsy only. A significant difference in median survival was also found for partial resection versus biopsy only treatment (10.4 vs. 6.6 months). There was no difference in survival for the different tumor sizes. Patients with frontal lobe tumors survived longer than those with temporal or parietal lobe lesions (11.4 months, 9.1 months, and 9.6 months, respectively) (p = 0.01). A Cox multivariate model confirmed a significant correlation of age, Karnofsky Performance Status, extent of surgery, and primary site with survival. The best survival rates occurred in patients who had at least three of the following features: < 40 years of age, high Karnofsky Performance Status, frontal tumors, and total resection (17 months median). CONCLUSION: We conclude that biopsy only yields inferior survival to more extensive surgery for patients with glioblastoma multiforme treated with surgery and radiation therapy.