Marrow cytometry and prognosis in myeloma.

We have previously shown that flow cytometric analysis of acridine orange-stained bone marrow cells is useful for the objective enumeration and characterization of plasma cells from patients with myeloma, frequently exhibiting an abnormal DNA and an elevated RNA content. In this report on 77 previously untreated patients, we have investigated the biologic and prognostic implications of these quantitative tumor cell parameters. The degree of marrow involvement by tumor, both by microscopic and cytometric analysis, correlated with the clinically derived tumor mass stage. Examination of the product of relative tumor cell RNA content and marrow tumor infiltrate (as a measure of metabolic capacity for immunoglobulin production) in relationship to the myeloma protein concentration in the serum revealed differences in the efficiency of immunoglobulin production and/or catabolism. There was an inverse relationship between the degree of marrow tumor involvement and RNA index, suggesting a more aggressive behavior of myeloma in patients with a low tumor cell RNA content. Prognostically, high tumor cell RNA content identified patients with a high likelihood of response to both initial treatment (32 patients, P = 0.004) and salvage therapy (29 patients, P = 0.01). Favorable factors for survival were low clinical tumor mass stage (P = 0.07) and low marrow tumor infiltrate as determined morphologically (P = 0.04) and cytometrically (P = 0.004). Thus, the direct examination of marrow cellular DNA and RNA content permitted assessment of tumor burden and was useful in the prediction of response and survival.

Prognostic factors in metastatic breast cancer treated with combination chemotherapy.

Six hundred nineteen patients with metastatic breast cancer, treated with a combination of 5-fluorouracil, Adriamycin, and cyclophosphamide, or close variations of this program, with or without immunotherapy were analyzed retrospectively to identify those host, tumor, or treatment characteristics that might be of prognostic importance in predicting response to chemotherapy and survival from onset of the 5-fluorouracil-Adriamycin-cyclophosphamide treatments. Primary tumor characteristics such as size of primary, number of axillary nodes involved, stage at diagnosis, and type of surgery used for primary treatment were not found to be of prognostic significance. Host characteristics such as age, menstrual status, or family history of breast cancer were similarly unrelated to outcome. Non-Caucasian patients had a lower response rate and somewhat shorter survival than did Caucasians. Pretreatment weight loss, poor performance status, and abnormal biochemical and hematological values were of adverse prognostic significance. An estimate of total extent of disease based on criteria for rating extent of involvement at 12 potential sites was a much more important prognostic factor related to response and survival than actual sites of involvement or the traditional "dominant site" classification. There was a trend, however, for patients with bone involvement to have a longer survival than did patients with metastases to other organ sites. Shorter survival times were observed among patients exposed to extensive prior radiotherapy and those who failed to respond to prior hormonal treatment. The prognostic variables identified in this paper should be used for the design and comparison of clinical trials in the future.

Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II).

The need for a pretreatment staging system to accurately assess programs of therapy for the various sites and stages of childhood rhabdomyosarcoma has become apparent as detailed analyses of many factors affecting prognosis and treatment choices have been accomplished through the national cooperative trial, the Intergroup Rhabdomyosarcoma Study (IRS). Initiated in 1972, the IRS has thus far used a clinicopathologic grouping system that is based heavily on therapeutic decisions, particularly on whether or not excision is accomplished and the extent of such an operation. The major problem with this and several other staging classifications now in use is that they depend on pathologic data obtained after surgical treatment has been initiated or rejected. In addition, they do not consider histologic variations of this neoplasm which may be important in estimating prognosis. The large body of clinical data now accumulated in the IRS has provided an excellent opportunity for developing a database for evaluating the International Union Against Cancer (UICC) pretreatment staging system and also the potential for using histologic categories in the staging process. The records of 505 eligible patients entered into the IRS between 1978 and 1982 were used to determine the prognostic impact of a number of pretreatment factors. These included local invasiveness of the primary neoplasm on clinical examination, tumor size, clinical status of regional nodes, clinical or radiologic evidence of distant metastases, and favorable or unfavorable histologic categories. A retrospective assessment of the relationship of these pretreatment observations to survival experience has been carried out. This retrospective study indicates definite prognostic significance for all of the individual factors used on the UICC system except clinical status of regional nodes. Also, these data serve as a basis for considering the possibility of including favorable v unfavorable histology in the pretreatment staging system now being tested prospectively in the ongoing IRS protocols.

Clinical features and results of therapy for children with paraspinal soft tissue sarcoma: a report of the Intergroup Rhabdomyosarcoma Study.

Soft tissue sarcomas of the paraspinal region comprised 3.3% (56 of 1,688) of the patients entered and eligible on Intergroup Rhabdomyosarcoma Studies I (IRS-I) and II (IRS-II) (1972 to 1984). These lesions tended to be greater than 5 cm in diameter at diagnosis, invaded the spinal extradural space, and were of the extraosseous Ewing's sarcoma or undifferentiated sarcoma subtype in 55% (30 of 56) of the cases. Patients with tumors in clinical groups II, III, and IV were treated with radiotherapy (XRT) and vincristine-dactinomycin (VA) or VA plus cyclophosphamide (VAC) +/- doxorubicin. Clinical group I patients treated on IRS-II did not receive XRT, while those on IRS-I were randomized to receive VAC +/- XRT. Forty-four of the paraspinal patients (79%) achieved a complete response (CR) compared with 77% (1,260 of 1,632) for patients with disease in other sites. Twenty-seven patients (55%) subsequently relapsed (five local, three regional, four local and distant, and 14 distant). The proportion of patients surviving 5 years by clinical group (stage) from I to IV were 50%, 50%, 62%, and 27%, respectively. Paraspinal patients had somewhat poorer survival than patients with disease in other sites, both in IRS-I and IRS-II; the percentage of paraspinal patients surviving 5 years was 50% and 52% for IRS-I and IRS-II, respectively, whereas these percentages were 55% and 63% for patients with disease in other sites. Histology did not influence the CR rate, but unexpectedly, patients who had embryonal rhabdomyosarcoma (RMS) had the poorest overall survival rate. We concluded that patients with paraspinal lesions may require extended-field radiation therapy to reduce the high local failure rate and more intensive chemotherapy to achieve better local and systemic tumor control.

Multimodal therapy for the management of localized Ewing's sarcoma of pelvic and sacral bones: a report from the second intergroup study.

A total of 59 eligible patients with localized Ewing's sarcoma of the pelvic and sacral bones were entered into a multimodal Intergroup Ewing's Sarcoma Study (IESS-II) (1978 to 1982) and compared with a historical control series of 68 patients entered into an earlier multimodal Intergroup Ewing's Sarcoma Study (IESS-I) (1973 to 1978). High-dose intermittent multiagent chemotherapy (vincristine, cyclophosphamide, Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and dactinomycin) was given to all patients for 6 weeks before and for 70 weeks following local therapy. All patients who had a tumor biopsy or incomplete resection performed received a dose of 55 Gy to the tumor bed. With a median follow-up time of 5.5 years, two of 59 patients (3%) had a local recurrence, five patients (8%) had a local recurrence and metastases, and 17 patients (29%) developed metastases only. There was significant statistical evidence of an advantage in relapse-free survival (RFS) and survival (S) for patients on IESS-II versus IESS-I, P = .006 and P = .002, respectively. At 5 years, the comparison between IESS-II versus IESS-I was 55% versus 23% for RFS and 63% versus 35% for S.

The Third Intergroup Rhabdomyosarcoma Study.

PURPOSE: The ultimate goal of the Third Intergroup Rhabdomyosarcoma Study (IRS-III, 1984 to 1991) was to improve treatment outcome in children with rhabdomyosarcoma through clinical trials comparing risk-based protocols of surgery and multiagent chemotherapy, with or without irradiation. PATIENTS AND METHODS: One thousand sixty-two previously untreated, eligible patients who were entered onto the study after surgery were randomized or assigned to treatment by clinical group (I through IV), histology (unfavorable or favorable), and site of the primary tumor. Initial responses, progression-free survival (PFS), and survival (S) were the end points used in comparisons between randomized groups and between patients treated in IRS-III and IRS-II (1978 to 1984). RESULTS: The overall outcome of therapy in IRS-III was significantly better than in IRS-II (5-year PFS, 65% +/- 2% v 55% +/- 2%; P < .001 by stratified testing). Patients with group I favorable-histology tumors fared as well on a 1-year regimen of vincristine and dactinomycin (VA), as did a comparable group treated with VA plus cyclophosphamide (C) (5-year PFS, 83% +/- 3% v 76% +/- 4%; P = .18). Results for patients with group II favorable-histology tumors, excluding orbit, head, and paratesticular sites, were inconclusive regarding the benefit from addition of doxorubicin (ADR) to VA. Patients with group III tumors, excluding those in special pelvic, orbit, and other selected nonparameningeal head sites, fared much better on the more intensive regimens of IRS-III than on pulsed VAC or VAC-VADRC in IRS-II (5-year PFS estimates, 62% +/- 3% v 52% +/- 3%; P < .01); however, there were no significant differences in outcome among the groups treated in IRS-III. Patients with metastatic disease at diagnosis (clinical group IV) did not benefit significantly from the more complex therapies evaluated in IRS-III. CONCLUSION: Intensification of therapy for most patients in IRS-III, using a risk-based study design, significantly improved treatment outcome overall. The largest gain from this strategy was realized in patients with gross residual tumor after biopsy (clinical group III). It was also possible to decrease therapy for selected patient subsets without compromising survival.

Multivariate analysis of prognostic factors in metastatic breast cancer.

Univariate and multivariate analyses were conducted on data collected from the records of 619 patients with metastatic breast cancer in whom an Adriamycin-containing chemotherapeutic regimen was used. Using a forward, stepwise logistic regression procedure, several models or equations in which a small number of pretreatment factors were incorporated were generated and the probability of response to therapy was accurately predicted. The predictive ability of these models was tested retrospectively in 546 of the 619 patients from whom the data were derived and prospectively in a new population of 200 patients with metastatic breast cancer also treated with a therapeutically equivalent Adriamycin combination. Using similar univariate techniques, pretreatment factors were correlated with the length of survival after therapy. The proportional hazard model of Cox was used to develop a regression model relating survival to pretreatment characteristics in much the same manner as that of the response model. The total population of the initial group of patients was divided according to four levels of hazard ratio, and survival distributions were compared. This model also was tested progressively and its predictive capability was confirmed. The prediction of individual outcome is a valuable capability in the comparison of clinical trials and the continuing evaluation of biologic changes in patients with metastatic carcinoma; such a method is described in this paper.

A strategy for evaluation of new treatments in untreated patients: application to a clinical trial of AMSA for acute leukemia.

This clinical trial (DT7995) was designed to evaluate amsacrine (AMSA) plus cytosine arabinoside (ara-C), vincristine, and prednisone (OAP) therapy in previously untreated patients with adult acute leukemia and to investigate a new strategy for assignment of patients to treatment using estimated probabilities of complete remission (PPR) based on six prognostic factors. In the first stage of the trial, patients with unfavorable prognosis (PPR less than .40) received AMSA-OAP for remission induction and patients with favorable prognosis (PPR greater than or equal to .40) received Adriamycin [Adria Laboratories, Columbus, OH] plus OAP (Ad-OAP). As AMSA-OAP was found to be promising in patients with unfavorable prognosis, it was administered to relatively more favorable patients (PPR less than .60) in the second stage of the trial and to all patients in the third stage. There were 242 patients entered into study; 134 received AMSA-OAP and 108 received Ad-OAP. Outcomes were compared with 242 paired patients who received Ad-OAP therapy from 1973 to 1977. The estimated complete remission rate in previously untreated adults with acute leukemia is 61% for patients receiving Ad-OAP (95% confidence interval, 59% to 64%). Overall, the survival experience for the 242 patients on DT7995 was significantly better than that in the control series (P = .03), but there was no strong statistical evidence (P = .10) that the 134 patients receiving AMSA-OAP had better survival than control patients receiving Ad-OAP, with a median of 32 v 21 weeks, respectively. It is concluded that AMSA-OAP is equivalent to Ad-OAP in the induction of complete remissions (estimated complete remission rate, 61%) and that assignment of patients to treatment based on predicted prognosis is an ethical and efficient strategy for the evaluation of new therapies in previously untreated patients with acute leukemia.

Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study.

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II.

Two hundred fourteen eligible patients with previously untreated, localized Ewing's sarcoma of bone were randomized on IESS-II to receive Adriamycin (ADR; doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, vincristine, and dactinomycin by either a high-dose intermittent method (treatment [trt] 1) or a moderate-dose continuous method (trt 2) similar to the four-drug arm of IESS-I. Patient characteristics (sex, primary site, type of surgery) were stratified at the time of registration; these and other patient characteristics (age, time from symptoms to diagnosis, race) were distributed similarly between treatments. Surgical resection was encouraged, but not mandatory. Local radiation therapy was the same as for IESS-I. The median follow-up time is 5.6 years. The overall outcome was significantly better on trt 1 than on trt 2. At 5 years, the estimated percentages of patients who were disease-free, relapse-free, and surviving were 68%, 73%, and 77% for trt 1 and 48%, 56%, and 63% for trt 2 (P = .02, .03, and .05, respectively). The major reason for treatment failure for both treatment groups was the development of metastatic disease. The lung was the most common site of metastases followed by bone sites. The combined incidence of severe or worse toxicity (67%) was comparable between the treatments; however, severe or worse cardiovascular toxicity was significantly greater on trt 1. Tne only treatment-associated deaths (N = 3) were on trt 1 and were cardiac-related.

Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991.

PURPOSE: One hundred thirty of 2,792 patients (5%) registered on three Intergroup Rhabdomyosarcoma Study clinical trials (IRS-I, -II, and -III) from 1972 to 1991 had an extraosseous Ewing's sarcoma (EOE). We report here the results of multimodality therapy for this tumor. PATIENTS AND METHODS: The 130 patients were less than 21 years of age; 70 (54%) were males. Primary tumor sites were on the trunk in 41 patients, an extremity in 34, the head/neck in 23, the retroperitoneum/pelvis in 21, and other sites in 11. One hundred fourteen patients had no metastases at diagnosis. In 21 patients, the tumor was completely resected; in 30, the localized or regional tumor was grossly resected, and in 63 patients, grossly visible sarcoma was left behind. Sixteen patients (12%) had distant metastases at diagnosis. All patients were given multiagent chemotherapy and most received irradiation (XRT); none were treated with bone marrow transplantation. RESULTS: One hundred seven patients (82%) achieved a complete response. At 10 years, 62%, 61%, and 77% of the patients were alive after treatment on IRS-I, IRS-II, or IRS-III therapeutic protocols, respectively, similar to figures obtained in all IRS patients. At last follow-up evaluation, 42 patients had died of progressive tumor and one of infection. Survival at 10 years was most likely for patients with tumor that arose in the head and neck, extremities, and trunk, and for those who underwent grossly complete tumor removal before initiation of chemotherapy. For patients with localized, gross residual tumor, adding doxorubicin (DOX) to the combination of vincristine, dactinomycin, cyclophosphamide (VAC), and XRT did not significantly improve survival in 39 patients (62% alive at 10 years) compared with that of 24 patients treated with VAC and XRT without DOX (65% alive at 10 years, P = .93). CONCLUSION: This series indicated that EOE in children is similar to rhabdomyosarcoma (RMS) in its response to multimodal treatment. No benefit was apparent from the addition of DOX to VAC chemotherapy in patients with gross residual EOE.

Prediction of survival during induction therapy in patients with newly diagnosed acute myeloblastic leukemia.

Among 569 patients with newly diagnosed AML, 16% died in the 4 weeks following initiation of remission induction therapy. Eight pretreatment characteristics were found to be independently associated with 4-week survival: performance status, bilirubin, age, neutrophil count, fibrinogen, albumin, hemoglobin, and creatinine. A model incorporating these characteristics prospectively stratified a separate group of 198 patients into two comparably sized groups differing substantially in both 4-week survival rates (71% (95% confidence limits, 61-80%) vs. 91% (95% confidence limits, 83-96%] and in survival rates throughout remission induction. Characteristics associated with failure to survive 4 weeks were unassociated with resistance to therapy. This suggests that patients who fail to survive induction are qualitatively different than patients who survive induction but exhibit resistance to treatment. Different therapeutic strategies might be appropriate in the two groups. The model presented here can be used to identify patients at increased risk of death during remission induction.

Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome.

An analysis was conducted of clinical and laboratory variables associated with response to remission induction therapy and remission duration in 440 patients with acute myelogenous leukemia treated between 1975 and 1983. The complete remission rate was 259/440 (59%). Specific cytogenetic abnormalities such as t(8;21), t(15;17), and inv16 were found to be favorable for response to therapy and/or remission duration, whereas those with a normal (diploid) karyotype had an intermediate prognosis. All other karyotypic abnormalities were associated with lower response rates and short complete remission durations. The karyotypes were classified as favorable, intermediate, and unfavorable groups for response and remission duration after allowing for all the other observed clinical and laboratory values related to prognosis. The cytogenetic classification was prospectively validated in an independent test group of 130 patients treated between 1983 and 1986 and showed a consistent relationship to response and remission duration. Logistic regression and proportional hazard models developed from the initial 440 patients were prospectively evaluated in the test group of 130 patients. Clear stratifications of patients into good, intermediate, and poor risk groups were obtained in the prospective tests. The karyotype of the leukemia cells is an independent prognostic variable for response and remission duration in acute myelogenous leukemia.

The scientific basis of clinical trials: statistical aspects.

The objective of this paper is to delineate some of the advances in clinical oncology that have occurred since the 1950s in the context of methodological principles established by Dr. Emil J Freireich and colleagues. Four statistical aspects of the methodological developments in clinical trials are considered and illustrated by real examples: a quantitative approach to the design and analysis of clinical trials; the randomized controlled trial; the nonrandomized controlled trial; and the use of regression models in clinical studies.

Chemotherapy of acute leukemia: a comparison of vincristine, cytarabine, and prednisone alone and in combination with cyclophosphamide or daunorubicin.

Adults (274) with acute leukemia (AML) were randomly assigned to one of three treatment regimens: vincristine, prednisone, cytarabine--(1) 100 mg/sq m/day with cyclophosphamide (COAP); (2) 100 mg/sq m/day with daunorubicin (DOAP); and 200 mg/sq m/day (OAP). Cytarabine was infused continuously for five days. Patients entering complete remission randomly received maintenance treatment with COAP or OAP. For 197 previously untreated AML patients given COAP, DOAP, or OAP, remission rates were 37%, 35%, and 43%, respectively; median lengths, 40, 45, and 90 weeks; median survival, 7, 11, and 8 weeks. No statistically significant difference was found among treatments. Therefore, adding cyclophosphamide or daunorubicin, or using the COAP regimen with continuously infused cytarabine, produced no significant improvement over previously reported regimens. There was no significant difference in remission lengths in previously untreated AML patients maintained on OAP (median 81 weeks) or COAP (median 65 weeks).

Randomized trial of protected environment--prophylactic antibiotics in 145 adults with acute leukemia.

One hundred and forty-five adults with acute leukemia were randomized to receive remission induction therapy in or out of a protected environment (PE) with prophylactic antibiotics orally (PA) or systemically (SA). Sixty-three patients were randomized in PE and 82 outside a PE. The proportion of patients who survived long enough to receive an adequate trial was higher in the PE (97%) than out (82%) (P = .01). The complete remission (CR) rate was 71% in and 43% out of the PE (P less than .01). Fifty-five patients received PA and 90 received SA. The CR rates were 61% and 45%, respectively. Of the 145 patients, 73 (50%) developed 102 episodes of major infections. Twenty-six of 63 patients in the PE developed major infection compared to 47 of 82 outside a PE (P = .08). The incidence rate of 13% fatal infections in a PE was significantly smaller than the 28% rate outside a PE (P = .04). The number of days with infections at less than 500 neutrophils/mm3 was also significantly lower inside a PE than outside (P less than .01). When comparing patients receiving SA or PA, there was no statistically significant difference in the incidence of infections. Forty-one patients received OAP Chemotherapy and 104 received adriamycin-OAP plus BCG. The CR rate on OAP was 44% compared with 60% on Ad-OAP + BCG. Infection rates were 76% and 40%, respectively (P less than .01). The median survival time was 72 weeks for patients in PE compared with 42 weeks for patients outside a PE (P less than .01). The prophylactic antibiotic regimens were well tolerated by most patients. This prospective randomized study has demonstrated statistically significant advantages for a lowered risk of fatal infection, higher CR rate and longer survival of patients treated in a PE with prophylactic antibiotics compared with patients treated in a conventional hospital room. Also, there was evidence for the superiority of adriamycin-OAP + BCG treatment compared with OAP.

Necrotizing colitis in patients with cancer.

Necrotizing lesions of the colon occur in patients with malignancy. We identified 26 patients with cancer (23 with acute leukemia and three with solid tumors) who died from necrotizing colitis. Autopsies revealed three pathologic categories: pseudomembranous colitis in 69 per cent, agranulocytic colitis in 19 per cent and ischemic colitis in 12 per cent. Most died from sepsis. A comparison of characteristics was made with a control population matched for diagnosis, age, cause of death and duration of neoplasia. Nearly all patients in both groups had fever and were granulocytopenic secondary to chemotherapy. Most received antineoplastic and antimicrobial regimens during the month prior to their terminal illness. Abdominal pain and distention, stomatitis and necrotizing pharyngitis were frequently associated with colitis. Hyperbilirubinemia was a frequent late complication in those with colitis and the control group. Single and multiorganism septicemia were found more frequently in patients with colitis. As antemortem diagnosis was unusual, aggressive attempts at diagnosis are necessary to assess the true incidence of this disorder and the best therapy.

Hyperfractionated radiation in children with rhabdomyosarcoma--results of an Intergroup Rhabdomyosarcoma Pilot Study.

PURPOSE: The Intergroup Rhabdomyosarcoma Study (IRS) Group initiated a pilot study (IRS IV-P) of hyperfractionated radiation (HF XRT) with chemotherapy to test the feasibility and toxicity of this combined modality approach in children with localized but nonresected (group III) and metastatic (group IV) rhabdomyosarcoma. METHODS AND MATERIALS: Using the linear quadratic equation, and an alpha/beta ratio of 10 Gy for acute reacting tumor effect and 3 Gy for late reacting normal tissue effect, a HF XRT protocol was developed giving a total radiation dose of 59.4 Gy, in 1.10 Gy fractions, twice daily at 6-8 h intervals. All patients received chemotherapy in addition to irradiation. The radiation scheme was calculated to increase the biologically effective dose to the tumor by 10% without increasing late effects, when compared to a conventional schedule of 50.4 Gy in 1.8 Gy daily fractions. This protocol also was predicted to cause an increase in acute normal tissue effects. RESULTS: Four hundred forty-nine children age 21 years and younger were eligible for the hyperfractionated radiation study of whom 297 had Group III disease and 152 had Group IV disease. A total of 117 patients were excluded from the feasibility and toxicity analysis because of progressive disease or death prior to scheduled irradiation, surgical resection, major protocol violation, treatment with brachytherapy, or missing data. Thus, 332 children were evaluable for the HF XRT protocol. Twenty-eight of the 332 (8%) were given conventional radiation because of physician preference or young age. Twenty of the 332 (6%) were not irradiated because of young age, anesthesia, or transportation problems. All nonirradiated children were < or = 3 years of age. Thus, 284 children, 86% of the evaluable population, received HF XRT. The radiation dose, number of fractions, number of days, and interfractional interval were scored as appropriate in 93% of cases. Review of radiation portals revealed that in 230 of 284 cases (81%) the radiation fields were appropriate, as per protocol. Thus, the HF XRT was feasible treatment in a multiinstitutional study. Analysis of toxicity revealed that 152 of 204 (75%) of Group III and 52 of 80 (65%) of Group IV patients experienced severe or life-threatening toxicity, explained by the addition of chemotherapy with the radiation. The majority of this toxicity was hematopoietic. Observed organ toxicity, which was potentially explained by the radiation treatment, was greatest at the end of radiation, and improved at the 6-week and 3-month evaluation periods. There were no deaths attributed to radiation toxicity and no instance of toxicity that required alteration of the radiation protocol. Thus, the treatment was not associated with toxicity that was considered excessive or unusual. CONCLUSION: The IRS IV-P study confirms that HF XRT combined with chemotherapy is both feasible and tolerable in children with rhabdomyosarcoma. A prospective randomized trial is underway to test its efficacy as compared to conventional radiation among children also receiving concurrent chemotherapy for rhabdomyosarcoma.

Radiation therapy for rhabdomyosarcoma: local failure risk for Clinical Group III patients on Intergroup Rhabdomyosarcoma Study II.

PURPOSE: A subset of 362 pediatric patients with rhabdomyosarcoma was selected from a total of 532 eligible IRS-II patients in Clinical Group III to assess the local and regional failure rates following radiotherapy and to determine patient, tumor, and treatment factors contributing to the risk for local and regional failure. METHODS AND MATERIALS: The study population was selected from all eligible IRS-II Clinical Group III patients. Excluded patients were those with "special pelvic" primary sites whose protocol management restricted radiotherapy (n = 123), and those who were removed from the study before radiotherapy was to begin, or because it was omitted (n = 47). A binary recursive partitioning model was used to identify subgroups of the remaining 362 patients at risk of local or regional failure. RESULTS: The local (only) failure rate was 17% (95% confidence interval, 13-21%), and the local (all) failure rate was 20% (95% confidence interval, 16-24%). The 5-year actuarial risk of local (all) failure was 22% (95% confidence interval, 18-27%). The risk of regional (nodal) failure was between 2% and 23%. Increasing tumor size predicted an increased local failure risk. Primary tumors located above the clavicle had a reduced risk of local failure. The binary recursive partitioning model identified a subset of patients at high risk of local failure. Those patients had primary tumors in the chest, pelvic region, extremity, or trunk, or tumors > 10 cm in diameter. Their local failure rate was 35% (compared to 15% for the remaining patients). The subset of patients at high risk for regional (nodal) failure had node involvement at diagnosis and a primary tumor originating at a site other than orbit, parameningeal, or trunk. Compliance with radiation treatment guidelines approached but did not achieve statistical significance as a predictive factor for local failure. By univariate analysis, factors not influencing local failure risk were age, race, gender, adenopathy, and histology. CONCLUSION: Radiation therapy and chemotherapy administered to Clinical Group III patients entered into the IRS-II protocol produced sustained local control in most cases. Knowledge of the factors which predict an increased risk of local or regional failure will facilitate the design of new treatment strategies.

Clinical trials in cancer research.

This is a review paper which gives a discussion of various aspects of clinical trials in cancer research. Since the conduct of the first randomized controlled clinical trial in cancer patients in the mid-1950's, substantial progress has been made in the utilization of the clinical trial technique for the evaluation of therapeutic efficiacy. The important elements of a protocol are given with some discussion of items to be considered in designing a protocol. The types of clinical trial (phase I, II, III) are defined, and the place of each phase of study in the context of the search for new treatments is delineated. A comprehensive discussion is given of the elements in the comparative clinical trial (phase III), including objectives, consierations in planning (comparability of treatment groups stratification of patients, feasibility and size of study, and prospective versus retrospective studies). Brief descriptions are given of designs for comparative clinical trials and a trial in oat cell lung carcinoma is discussed in some detail. Finally, some comments and references are given concerning the analysis of clinical trials.