Cooperative Group Protocols Research Articles

Definition of standardized nutritional assessment and interventional pathways in oncology.

Weight loss and nutritional deterioration are associated with adverse outcomes in terms of cancer prognosis (response rate and survival) as well as increased complications, prolonged hospitalizations, increased risk of unplanned hospitalization, increased disability, and increased overall cost of care. The nutritional oncology service at Fox Chase Cancer Center defined a proactive, standardized assessment and interventional approach from 1987-1994. In 186 consecutive patients referred to the nutrition clinic and managed solely by oral intervention and aggressive symptom management, the team demonstrated a 50%-80% success rate in getting patients to maintain or gain weight during therapy, with a similar success in maintaining or improving visceral protein status as determined by serum transferrin and/or albumin. Evaluation of the home parenteral nutrition program (n = 65, from 1987-1993) demonstrated similar success when appropriate triaging was carried out, with 58% of patients able to be tapered off parenteral nutrition (PN) entirely or with transition to enteral tube feeding. The assessment of success for a nutritional intervention (e.g., a disease-specific nutritional supplement) requires the standardization of definitions, assessment tools, criteria for nutritional intervention, and appropriate end points for the assessment of outcomes. The Patient-Generated Subjective Global Assessment of nutritional status is used in conjunction with the nutritional risk of planned cancer therapy to define a standardized interventional approach in oncology patients, which can be used in clinical practice, cooperative oncology group protocols, and clinical trials of nutritional intervention regimens.

Relation of tumor-cell ploidy to survival in children with medulloblastoma.

To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

Late Effects of Treatment for Childhood Cancer

<b>Cancer Risk After Medical Treatment</b>, edited by Michel P. Coleman, 184 pp, $45, ISBN 0-19-26181-8, New York, NY, Oxford University Press, 1991. One in 1000 adults turning 20 years old is a cancer survivor, and every practicing physician will soon have survivors as patients. The iatrogenic diseases of successful cancer therapy are crippling our patients. Pediatric oncology has transformed pediatric malignancy from a hopeless to a hopeful outlook. Now pediatric oncologists ask, how can we cure without such serious sequelae? Monitoring late effects is now incorporated into the cooperative group protocols, and some institutions have established clinics to assist long-term survivors with complications. We need to optimize these lives so hard fought for. This monograph is part of the<i>Current Clinical Oncology</i>series. It catalogs problems by organ system, and thus duplication is minimized. It also makes it easy for the reader to review a specific problem of interest, eg,

Using a population-based registry to identify patterns of care in childhood cancer in Florida

Unlike cancers occurring in adults, childhood cancers are distinguished by being primarily nonepithelial in origin and by their relative rarity. Even with the availability of registries such as the Surveillance, Epidemiology and End Results program of the National Cancer Institute or the Florida Cancer Data System for the State of Florida, there are potential biases that may affect the estimates of pediatric cancer incidence, studies related to elucidating patterns of care, and other epidemiologic studies. To evaluate the magnitude of these potential biases and elucidate the settings (pediatric cancer center versus non-cancer center) in which childhood cancers are treated, the authors performed a retrospective study of childhood cancer in Florida. Approximately 19% of childhood cancer cases (in patients 0-19 years of age) in Florida diagnosed from 1981 to 1986 were treated outside of identified pediatric cancer centers in the state. Children with Hodgkin disease and brain tumors represented 43% of these cases. Among those cases treated in pediatric cancer centers, 23% were treated by physicians other than pediatric oncologists. Children with brain tumors represented 28% of these cases. Of those treated by pediatric oncologists, 65% were eligible for a cooperative group protocol and 55% of these were enrolled. Population-based registries are necessary for describing the full extent of childhood cancer, but they have limitations in demonstrating patterns of care. Consequently, generalization from the experience of pediatric cancer centers is questionable, and the opportunity to test and achieve advances in diagnosis and treatment may be subject to selection bias.

Radiation-induced brachial plexopathy: Neurological follow-up in 161 recurrence-free breast cancer patients

Purpose : The purpose was to assess the incidence and clinical manifestations of radiation-induced brachial plexopathy in breast cancer patients, treated according to the Danish Breast Cancer Cooperative Group protocols. Methods and Materials : One hundred and sixty-one recurrence-free breast cancer patients were examined for radiation-induced brachial plexopathy after a median follow-up period of 50 months (13–99 months). After total mastectomy and axillary node sampling, high-risk patients were randomized to adjuvant therapy. One hundred twenty-eight patients were treated with postoperative radiotherapy with 50 Gy in 25 daily fractions over 5 weeks. In addition, 82 of these patients received cytotoxic therapy (cyclophosphamide, methotrexate, and 5-fluorouracil) and 46 received tamoxifen. Results : Five percent and 9% of the patients receiving radiotherapy had disabling and mild radiation-induced brachial plexopathy, respectively. Radiation-induced brachial plexopathy was more frequent in patients receiving cytotoxic therapy ( p = 0.04) and in younger patients ( p = 0.04). The clinical manifestations were paraesthesia (100%), hypaesthesia (74%), weakness (58%), decreased muscle stretch reflexes (47%), and pain (47%). Conclusion : The brachial plexus is more vulnerable to large fraction size. Fractions of 2 Gy or less are advisable. Cytotoxic therapy adds to the damaging effect of radiotherapy. Peripheral nerves in younger patients seems more vulnerable. Radiation-induced brachial plexopathy occurs mainly as diffuse damage to the brachial plexus

Phase III Comparison of Doxorubicin and Dacarbazine Given by Bolus Versus Infusion in Patients With Soft-Tissue Sarcomas: A Southwest Oncology Group Study

Disseminated soft-tissue sarcomas are a group of uncommon malignancies generally treated in a uniform manner. This study questioned the impact of schedule on response rate and toxicity in patients with metastatic soft-tissue sarcoma treated with the two-drug combination doxorubicin and dacarbazine. Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients). Chemotherapy was to be repeated every 3 weeks. A unique feature of this cooperative group protocol was a provision for surgical resection of residual disease in patients with a partial response or with stable disease following chemotherapy. Similar overall response rates (17% in both treatment arms) and complete response rates (5% in both treatment arms) were observed. For patients receiving bolus therapy, the median response duration was 19.6 months for those in complete remission and 6.6 months for those in partial remission. For patients receiving infusional therapy, the median response duration was 12.6 months for those in complete remission and 9.3 months for those in partial remission. Examination of dose intensity received when combining treatment arms revealed a weak doxorubicin dose-response relationship. There was no difference in median survival times between the two treatment arms (bolus therapy, 10.6 months; infusional therapy, 10.5 months; logrank P = .97). Analysis of toxic effects favored infusional therapy. Significant reductions in cardiac toxicity (all events, P = .04; clinical events, P = .01) and nausea and emesis (P = .04) were seen in infusional therapy. Of 47 patients eligible for cytoreductive surgery following chemotherapy, 12 received surgery, and of those 12, eight were rendered disease free. The use of a 96-hour continuous intravenous infusion of doxorubicin-dacarbazine was comparable therapeutically with bolus dosing of these two agents and was better tolerated by the patients.

Evaluation of radiotherapy in high-risk breast cancer patients: Report from the Danish Breast Cancer Cooperative Group (DBCG 82) trial

The role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients included in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82. As of June 1989, a total of 1473 pre- and menopausal patients were randomized to postmastectomy irradiation + CMF versus CMF alone (protocol 82-b). A total of 1202 postmenopausal patients were randomized to postmastectomy irradiation + Tamoxifen versus Tamoxifen alone (protocol 82-c). At 5 years the actuarial loco-regional recurrence rate was significantly lower in the irradiated patients (82-b: 9% vs 28%, 82-c: 6% vs 36%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment (82-b: 54% vs 47%, 82-c: 52% vs 38%). At present, overall survival is significantly different in 82-b patients (68% vs 63%) but not in post-menopausal 82-c patients (62% vs 61 %). Thus, adjuvant systemic treatment alone (chemotherapy or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumor control in high-risk breast cancer patients with respect to overall survival.

Colorectal cancer. Are adjuvant therapies beneficial?

The American Cancer Society's recommendations for screening the population at normal risk for colorectal cancer have been promoted since 1983. Additional study of the effectiveness of these recommendations is in progress, but the medical community has generally endorsed them and urges their implementation in office practice. To date, chemotherapy is not clearly indicated as adjuvant therapy, but enrollment of patients in cooperative group protocols is recommended. Use of second-look surgery to resect selected recurrent tumors has increased in recent years, in part because of the contribution of the computed tomographic scan and carcinoembryonic antigen assay to follow-up of postoperative patients. For advanced disease, technologic advances have improved the technique of hepatic artery perfusion with chemotherapeutic agents, but evidence of a survival advantage afforded by this method is still lacking. Single-agent chemotherapy with fluorouracil remains the best choice for palliating advanced disease, but hepatic artery perfusion with floxuridine also may relieve liver-dominant disease.

A logistic model based on enzyme activities for the prediction of response of breast cancer patients to chemotherapy.

A logistic regression model, utilizing the activities of certain selected glycolytic enzymes and ER status measured on primary or recurrent lesions, has been applied to predict for response to combination chemotherapy regimens administered to women with advanced breast cancer. The clinical outcome of response or no response was evaluated retrospectively using criteria employed by cooperative group protocols. In 93 cases, 58/61 patients classified as nonresponders and 22/32 patients demonstrating objective responses would have been correctly designated, based on the 50% estimated probability as the level for separation of responders from nonresponders. The overall predictive accuracy of this model was 86%, with apparently greater accuracy for prediction of lack of response. Addition of estrogen receptor status to the model imparted no gain in accuracy of prediction. Application of this model to a prospective study is warranted.

A clinical trial of procarbazine plus vincristine plus bis-chloroethyl-nitrosourea plus imidazole carboxamide dimethyl triazeno in metastatic malignant melanoma.

Only a limited percentage of patients with metastatic malignant melanoma respond to single-agent chemotherapy. Vincristine, procarbazine, imidazole carboxamide dimethyl triazeno (DTIC) and bis-chloroethyl-nitrosourea (BCNU) have been used as single agents by various investigators. A response rate of +/- 20% was seen with vincristine (1-3) and BCNU (3, 4), and a response rate of 20-30% has been observed with DTIC (3, 5-8) and procarbazine (3, 9, 10). Newer agents such as triazeno imidazole carboxamide mustard (TIC mustard) (11), chloroethyl cyclohexyl nitrosourea (CCNU) (12), and chloroethyl methylcyclohexyl nitrosourea (methyl-CCNU) (13) have not so far proved superior. During the last years various drug combinations have been tried in an effort to improve the results of treatment in patients with metastatic malignant melanoma. In 1959 Moon reported objective response in 9 out of 20 patients who received a minimum of two courses of a combination of BCNU and vincristine (14). In a randomized trial performed by Acute Leukemia Group B (15), only 24% responded to this combination as compared to 32% and 29% for two different DTIC schedules. There were 120 patients who entered onto this protocol. A combination of DTIC plus cyclophosphamide plus vincristine was reported to give a 25% response (16). Workers at the Mayo Clinic reported objective response in 4 out of 18 patients treated with a combination of DTIC plus vincristine as compared to 1 out of 19 using CCNU (12). Costanza and co-workers (Eastern Co-Operative Oncology Group study) reported that 12 out of 61 patients responded to treatment with DTIC plus BCNU as compared to 9 out of 51 on DTIC alone (17); while Cohen (18) and co-workers reported that 10 out of 16 patients treated with the triple combination of vincristine plus BCNU plus DTIC showed significant response and concluded that this combined approach in the treatment of disseminated malignant melanoma warranted further study. Preliminary analysis of an Eastern Co-Operative Oncology Group protocol showed no statistical advantage of DTIC plus methyl-CCNU over each drug on its own (19). The present study was undertaken to investigate the possible advantage of combining DTIC plus vincristine plus BCNU plus procarbazine in courses of treatment. All of these agents are of some value on their own and all four have possible different mechanisms of action.