Ethical issues in clinical trials.
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Clinical Trials as Topic↗
Biomedical subjects
E A Gehan
Publications and source records attributed to E A Gehan.
Methodological issues in cancer clinical trials: the comparison of therapies.
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Biometry↗
Paratesticular sarcoma in childhood and adolescence. A report from the Intergroup Rhabdomyosarcoma Studies I and II, 1973-1983.
This article reports on the diagnostic features, radiographic findings, staging, operative management, treatments, and treatment results for 95 children (mean age, 10 years) with paratesticular sarcoma; they were treated on the Intergroup Rhabdomyosarcoma Study (IRS) I and II protocols. Embryonal rhabdomyosarcoma (RMS) was the most common histologic subtype (97% of cases). Patients were randomly assigned to receive various therapeutic regimens according to IRS protocols. Among 81 patients (85%) with localized disease, most (57) were in Clinical Group I (localized, completely excised tumors), and 20 were in Group II (gross excision with tumor-involved, regional retroperitoneal lymph nodes or microscopic residual). Only four were in Group III (gross residual disease in the primary site or retroperitoneal lymph nodes). Three of them achieved a complete response (CR) after induction therapy and two then relapsed. The relapse-free survival (RFS) estimates at 3 years from diagnosis were 93% in Group I and 90% in Group II. Distant metastases were present at diagnosis in only 14 patients. Twelve of them achieved CR, but four subsequently relapsed; their 3-year RFS estimate was 67%. Overall, survival rates among the 95 children were excellent (89% at 3 years) compared to the entire IRS series (63%). Treatment with radical orchidectomy and chemotherapy was sufficient for Group I patients. Orchidectomy, chemotherapy, and radiation therapy were highly effective in Group II patients and in a large proportion of those with more advanced tumors. Recommendations for the diagnostic examinations and management of future patients with paratesticular sarcoma are given.
Adolescent↗
Improved prognosis with intensive treatment of children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites. A report from the Intergroup Rhabdomyosarcoma Study.
In the first Intergroup Rhabdomyosarcoma Study (IRS-I), it was found that, of 57 patients with nonorbital cranial parameningeal sarcoma treated from 1972 to 1976, 20 patients (35%) developed meningeal sarcoma and 90% (18/20) died of this complication. Since about half of these 20 patients had received inadequate radiation therapy and all had radiation therapy delayed until week 6, the treatment program was modified in December 1977 to begin radiation therapy on day 0 to the entire neuraxis and the primary tumor for all patients presenting with one or more risk factors indicating a high risk of meningeal involvement, and to administer periodic intrathecal medications to the same patients. The risk factors were intracranial extension of tumor, bony erosion at the cranial base, and cranial nerve palsy. In this report, the prognoses of two groups of patients with nonorbital cranial parameningeal sarcoma are compared: 95 patients treated before modification of the protocol in December 1977 with chemotherapy and nonintensive meningeal radiotherapy (preintensive group) and 68 patients treated subsequently with intensive meningeal radiotherapy and chemotherapy (intensive group). All patients received vincristine and actinomycin D (dactinomycin) with or without cyclophosphamide and Adriamycin (doxorubicin), according to the protocol. Radiation therapy consisted of 4000 to 5500 rad to the primary tumor in 5 to 6 weeks for most patients. The intensively treated patients also received intrathecal drugs via lumbar puncture and whole cranial or craniospinal radiation when one or more meningeal risk factors were present. In the preintensive group, the complete remission rate was 68% (65/95); the percentages of patients tumor free or alive at 3 years were 33% and 41%, respectively. In intensively treated patients, the complete remission rate was 76% (52/68); the percentages of patients tumor free or alive at 3 years were 57% and 68%, respectively. The improvements in the percentages of intensively treated patients tumor free or surviving were highly statistically significant (P less than 0.01 for both comparisons). Within the intensive treatment group, meningeal involvement at diagnosis was an unfavorable prognostic sign, since patients with no meningeal involvement had much better tumor-free survival at 3 years (81% vs. 51%) and survival (90% vs. 57%) than patients with evidence of meningeal involvement; the differences were highly statistically significant (P = 0.01).
Antineoplastic Combined Chemotherapy Protocols↗
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.
Child↗
Reporting outcomes in Hodgkin's disease and lymphoma.
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Clinical Trials as Topic↗
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.
Acute Disease↗
A pilot clinical trial of the toxicity and immunorestorative effects of T cell reconstituting factor (SR 270258) in immunosuppressed cancer patients.
The in vivo immunorestorative effects of a highly purified protein fraction from human serum--designated SR 270258, prealbumin, or T cell reconstituting factor--was examined in cancer patients following radiation therapy. Sixteen patients with either Stage III head and neck cancer, nonoat cell lung cancer, or esophageal cancer were randomized to either receive (11 patients) or not receive (five patients) subcutaneous injections or SR 270258 at a dose of 2 mg/m2 three times per week for a total duration of 1 month. Treated patients were observed frequently for signs of toxicity. Blood was drawn initially and at weekly intervals for measurement of immunologic tests, which included percentage and absolute number of T cells, B cells, and other lymphocyte subpopulations; lymphocyte blastogenic responses to the mitogens phytohemagglutinin, concanavalin A, and pokeweed; and one-way mixed lymphocyte responses. Delayed type hypersensitivity responses to seven recall antigens were also tested. Mean lymphocyte blastogenic responses were significantly suppressed in patients relative to normal (p less than 0.05). There were no consistent changes in lymphocyte blastogenic responses, the percentage of lymphocyte subpopulations, or skin test responses in patients receiving SR 270258 versus untreated patients. However, the absolute number of OKT11 positive (E rosette receptor positive) T lymphocytes increased a mean of 52% (406 +/- 356 to 617 +/- 344/mm3; p = 0.03) in treated patients whereas no change was observed in untreated patients (366 +/- 226 to 446 +/- 327). Significant increases in the absolute number of OKT4 positive helper cells (158 +/- 109 to 221 +/- 112; p less than 0.05), OKT8 positive suppressor cells (179 +/- 186 to 279 +/- 184; p less than 0.05), and surface immunoglobulin-bearing B cells (49 +/- 47 to 155 +/- 268; p less than 0.05) also occurred. Prealbumin can induce a significant lymphocytosis in heavily irradiated, lymphopenic cancer patients. Lymphocyte blastogenesis and skin tests, however, were not improved at this dose and schedule.
Antigens, Surface↗
Postsplenectomy sepsis and other complications following staging laparotomy for Hodgkin's disease in childhood.
This is a survey of 234 pediatric patients in whom staging laparotomy/splenectomy was carried out (1975 to 1981) in the course of the Intergroup Hodgkin's Disease in Childhood Study (IHDCS). Relapse has occurred in 44 of these patients, and 12 have died, 7 secondary to extension of lymphoma, 2 with herpes or pneumocystis infections, 2 with leukemia, and 1 from an unrelated accident. During the period of surveillance (mean 5.5 yr), five episodes of bacterial sepsis (positive blood cultures) have occurred, including two due to Streptococcus pneumoniae; and three, to Hemophilus influenzae. The former occurred in the small group of patients in this series who had not received the prescribed pneumococcal vaccination. No fatalities were associated with these septic episodes. Intestinal obstruction secondary to adhesions (benign) occurred in eight patients and was managed without intestinal resection or mortality. One patient required operative release of an obstructed ureter following laparotomy, and one, oophorectomy for an infarcted (transposed) ovary.
Adolescent↗
Randomized or historical control groups in cancer clinical trials: are historical controls valid?
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Clinical Trials as Topic↗
Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery: a Southwest Oncology Group Study.
Between 1977 and 1981, the Southwest Oncology Group entered 278 patients on a randomized study (SWOG 7703) to compare the effect of three different chemotherapeutic agents given in combination with radiotherapy (6000 rads over 7 weeks) following surgery for malignant gliomas. The chemotherapy regimens were: carmustine (BCNU)--80 mg/m2 iv daily X 3 every 6 weeks; procarbazine (PCB)--100 mg/m2 orally; or dacarbazine (DTIC)--175 mg/m2 iv daily X 5 every 4 weeks. Patients were stratified according to age, and degree of resection, with no differences identified between groups. The response rates (complete plus partial) for BCNU and DTIC were significantly better than for PCB [BCNU, 39%; PCB, 13%; and DTIC, 38% (P less than 0.01)]. The response duration and survival were somewhat better in patients treated with BCNU and DTIC, but compared to patients treated with PCB, the difference was not statistically significant. Median survival times were: BCNU, 45 weeks; PCB, 31 weeks; and DTIC, 49 weeks (P greater than 0.3). There were six toxic deaths with BCNU and four with PCB, most of which were due to infection associated with leukopenia. The high toxicity and minimal benefit of chemotherapy added to radiotherapy compared to historical results with radiotherapy alone suggest that combined treatment may not be indicated for some patients.
Brain Neoplasms↗
Results of adjuvant chemotherapy trials in breast cancer at M. D. Anderson Hospital and Tumor Institute.
Between 1974 and 1982, 796 patients with operable breast cancer following local therapy were treated with 3 consecutive doxorubicin-containing adjuvant therapy trials. The median follow-up of patients entered on the first trial was 102 months; the second trial, 71 months; and for the third trial, 41 months. The treatment program consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). We altered the study designs to determine the role of nonspecific immunotherapy with BCG and postoperative irradiation in the second trial and the impact of additional chemotherapy with alternate drugs after completion of FAC in the third trial. In the first study, an overall 39% reduction in mortality was observed, and, in stage II disease, reductions of 54% and 37% in mortality were observed for patients less than 50 and greater than or equal to 50 years of age, respectively, in comparison to the historical control group. The data of the second trial illustrated that BCG and postoperative irradiation had no significant impact on the disease-free and overall survival. In the third trial, patients with estrogen receptor-positive tumor treated with additional chemotherapy with alternate drugs following completion of FAC had significantly superior disease-free survival compared with patients who did not receive additional chemotherapy. The results of 3 studies show that intensive combination chemotherapy significantly reduced the risk of recurrence and death in patients with breast cancer.
Adult↗
Update on planning of phase II clinical trials.
A review is given of the statistical aspects of plans for phase II cancer clinical trials. The following plans were reviewed: a minimum number of patients plan proposed by Gehan in 1961, such that if no responses are observed, further study of the agent can be discontinued; a two-stage decision theory approach proposed by Sylvester and Staquet in 1977; a limited patient accrual plan proposed by Lee et al. in 1979, which assumes the number of patients available to be fixed, a false negative error to be more serious than a false positive error, and the possibility that the ultimate result will be inconclusive; a predictive probability plan of Herson, which permits early stopping when the initial results are poor; and a one-sample multiple testing procedure of Fleming, which assumes the trial to be carried out in k stages (usually k = 1, 2 or 3), with a test performed at each stage that permits early stopping when results are either very favourable or unfavourable. When the true response rate (p) is either very low (p less than p0) or in an area of definite interest (p greater than pa), the plans proposed by Gehan, Lee and Fleming perform reasonably well and an investigator should choose the plan that best fits the circumstances. None of these plans work very well when the response rate is intermediate (p0 less than p less than pa). The plans of Sylvester and Staquet require much more prior information, including data on expected utilities, but their plans can be optimal when such information is available.(ABSTRACT TRUNCATED AT 250 WORDS)
Antineoplastic Agents↗
Improved survival of patients with metastatic breast cancer receiving combination chemotherapy.
Groups of patients with newly diagnosed metastatic breast cancer who were consecutively registered into a breast cancer clinic beginning January 1956 (210 patients), January 1966 (210 patients), and January 1975 (251 patients), were analyzed to determine the impact on survival of the various treatment modalities utilized in each decade. Comparisons of survival were made among subgroups of patients with similar prognostic features. Except for patients with very poor performance status, all subgroups showed a significantly improved survival in the 1970s compared with the earlier decades. Combination chemotherapy was considered to be the major factor in the survival improvement.
Age Factors↗
Dose-response relationship in clinical oncology.
The relationship of dose (and dose rate) to response and toxicity in clinical oncology is reviewed. The concepts expressed by some authors in dose-response studies in animal and human systems are reviewed briefly. Dose rate and tactics of conducting clinical studies are reviewed for both radiotherapy and various types of chemotherapeutic treatment. Examples are given from clinical studies in Hodgkin's disease, acute leukemia, and breast cancer that may prove useful in planning future clinical studies.
Animals↗
Dose-response and dose-survival advantage for high versus low-dose cisplatin combined with vinblastine and bleomycin in disseminated testicular cancer. A Southwest Oncology Group study.
One-hundred fourteen patients with advanced testicular cancer were randomized to treatment consisting of either high-dose (120 mg/m2, monthly) or low-dose (15 mg/m2, daily X 5 monthly) cisplatin, both combined with vinblastine and bleomycin. There were 60 (53%) complete remissions and 42 partial remissions for an overall response rate of 90%. An additional 11 patients, 4 with carcinoma and 7 with mature teratoma, following surgical cytoreduction, were rendered free of disease. There was a significantly higher complete response rate for high dose induction chemotherapy, 63%, when compared with low dose, 43% (P = 0.03). A survival advantage was also observed for patients receiving high-dose therapy (P = 0.009). For the subgroup of patients with maximal disease and embryonal +/- teratoma +/- seminoma histology there was a clear advantage in favor of high-dose over low-dose therapy both in complete response rate and survival (P = 0.03). There have been only four relapses, all occurring within 1 year of study entry. While there has been a higher frequency of leukopenia, renal, neuromuscular, and mucosal toxicity with high-dose therapy, thus far no irreversible toxicity leading to functional impairment has been seen. The authors have demonstrated a clear-cut relationship for dose of therapy, not only with response and survival, but with the increased potential for cure as well.
Adolescent↗
Management of adult acute leukemia. A Southwest Oncology Group study.
Five hundred forty three adult patients with acute leukemia were entered on the study designed to: (1) test efficacy of vincristine and prednisone used as primary drug therapy in patients with good prognosis as judged by a circulating blast cell count less than 30,000 cm2; (2) investigate the use of either simultaneously or sequentially administered Adriamycin plus cytosine arabinoside plus vincristine and prednisone; and (3) to assess the use of bacillus Calmette-Guerin (BCG) in the maintenance phase on both the response and duration of response. Complete remissions were seen in 21% of patients with the vincristine and prednisone arm. Complete remission rates were similar in both the simultaneously and sequentially administered chemotherapy with overall complete remission rates of 55%. Median durations of complete remission and survival were 35 and 62 weeks, respectively, for patients with AML; and 47 and 75, respectively, for patients with ALL. Toxicity was within acceptable limits. BCG administered during the maintenance phase of therapy caused no differences in duration of complete remission and survival. These results demonstrate an improved response and duration of response over previous studies done by this group.
Acute Disease↗
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.
Bone Marrow↗