Richard A. Gams

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

PURPOSE To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy.

PURPOSE To assess whether dexrazoxane (DZR) given after a cumulative doxorubicin dose of 300 mg/m2 confers cardioprotection in patients with advanced breast cancer treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC). PATIENTS AND METHODS In two multicenter studies (088001 and 088006), patients were randomized to receive FAC and placebo (PLA) versus FAC and DZR. After a protocol amendment, all patients received open-label DZR after they had reached a cumulative doxorubicin dose of 300 mg/m2. Two groups were compared: 99 patients randomized to the PLA arms before the amendment who received FAC and PLA for at least seven courses (PLA group), and 102 patients randomized to the PLA arms after the amendment who received FAC and PLA for six courses followed by open-label DZR (PLA/DZR group). RESULTS The hazards ratio of PLA to PLA/DZR was 3.5 (95% confidence interval [CI], 2.2 to 5.7; P < .001, logrank and generalized Wilcoxon tests) for the doxorubicin dose at any cardiac event, ejection fraction changes, or congestive heart failure (CHF). The hazards ratio of PLA to PLA/DZR was 13.1 (95% CI, 3.7 to 46.0; P < .001, logrank and generalized Wilcoxon tests) for the doxorubicin dose at the development of CHF. The overall incidence of CHF in the PLA/DZR group was 3%, compared with 22% in the PLA group (P < .001, Fishers exact test). Twenty-six percent of PLA/DZR patients received at least 15 courses of therapy, compared with 5% of patients in the PLA group. These results do not appear to be attributable to a time trend. CONCLUSION DZR is a highly effective cardioprotective agent when used in patients with advanced breast cancer who continue to receive doxorubicin-based chemotherapy after a cumulative doxorubicin dose of 300 mg/m2 has been reached.

Do information systems improve the quality of clinical research? Results of a randomized trial in a cooperative multi-institutional cancer group☆

Abstract A facsimile communications network was established to serve eight randomly selected medical centers belonging to the Southeastern Cancer Study Group (SEG) to test whether clinical algorithms could augment protocol compliance and patient safety. An SEG protocol (75HD0103) for testing alternative chemotherapy regimens in Advanced Hodgkins Disease was rewritten as a clinical algorithm. The algorithm generates treatment advice rules, emulating how the clinical researcher would accurately and appropriately apply the general protocol to an individual patients specific visit, considering his prior response to therapy. The visit-specific advice rules were typed onto general encounter forms and sent to the oncologists over the facsimile equipment prior to each therapy visit. A facsimile of the completed form was transmitted back. Protocol compliance, as judged by explicit criteria on a visit-by-visit basis, was 94% in the algorithm user group and 64% in the nonuser group (p

Phase III study of BCOP v CHOP in unfavorable categories of malignant lymphoma: a Southeastern Cancer Study Group trial.

A total of 296 evaluable patients with unfavorable categories of malignant lymphoma were randomly assigned treatment with cyclophosphamide, vincristine, and prednisone plus BCNU (BCOP) or doxorubicin (CHOP). In diffuse histiocytic (DH) lymphoma, CHOP produced superior complete (54% v 34%) and total (70% v 46%) response rates. Among the responders to either therapy, no differences were seen in duration of response or survival times. Median duration of response has not been reached with follow-up in excess of 50 months. In categories of lymphoma other than DH (including small-cell, mixed, and nodular histiocytic lymphomas), complete (27% v 29%) and total (48% v 54%) responses were similar for BCOP and CHOP, as were durations of response and survival. These data suggest that BCOP and CHOP are equivalent regimens for other categories of malignant lymphomas. CHOP appears preferable for diffuse large-cell categories, since it resulted in greater overall survival in patients with DH lymphoma; this was due to a significantly greater response rate, since patients with DH lymphoma who did respond to BCOP maintained their response and survived as long as did the CHOP responders.

BCNU, velban, cyclophosphamide, procarbazine, and prednisone (BVCPP) in advanced Hodgkin's disease.

Three hundred twenty‐four evaluable patients with advanced or recurrent Hodgkins disease were treated with BVCPP. After stratification according to amount of prior therapy, patients who achieved complete remission were randomized to no additional therapy, 6 monthly cycles of MOPP or 6 additional monthly cycles of BVCPP. Complete remission rates were comparable to other studies: 68–73% for those who had not received prior chemotherapy and 28% for those who had. Although curves of disease‐free survival suggested that BVCPP maintenance therapy significantly prolonged a complete remission in previously untreated patients, multivariate analysis did not demonstrate such therapy to be a significant prognostic factor. Rather, favorable prognostic indicators were shown to be related to host factors. Subsequent analysis demonstrated that the maintenance and no‐maintenance groups of previously untreated patients were not strictly comparable in that the maintained group had more patients with favorable histologies who were less than 40 years of age. Herpes Varicella Zoster was not found to affect prognosis adversely. It is concluded that maintenance chemotherapy with BVCPP or MOPP does not significantly improve duration of complete remission or survival and that further comparative or sequential studies should include stratification of the important factors influencing duration of response and survival. Further, even though second remissions may be induced in the previously treated, their subsequent prognosis is poorer. For all patient groups female sex and an initial lymphocyte count > 1,372 were favorable factors. For those with little or no prior therapy, age <40, Caucasian race, and having lymphocyte predominance or nodular sclerosis favorably influenced the outcome as well. For those with major prior therapy not having had prior chemotherapy, having IIIA disease, and not having nodular sclerosis were important additional determinants of remission or survival. Cancer 42:2101–2110, 1978.

An HPLC Method for the Quantitative Determination of 1,4-Dihydroxy-5,8 Bis [[2-[(2-Hydroxyethyl) Amino] Ethyl] Amino] 9,10 - Anthracenedione (DHAQ, Lederle Labs CL232 315, NCS 301739) in Serum

Abstract An HPLC method using reverse phase chromatography is presented for the quantitative determination of 1,4-Dihydroxy-5,8 Bis [[2-[(2-Hydroxyethyl) amino] ethyl] amino] 9,10 - anthracenedione in serum and urine at levels which are expected to be found in clinical trials of this drug.

Acute myelogenous leukemia as a second malignant neoplasm following the successful treatment of advanced Hodgkin's disease.

For the Southeastern Cancer Study Group Of 209 Hodgkins disease patients treated at least 6 months with a five‐drug combination of induction chemotherapy and having a complete remission, four patients developed acute myelogenous leukemia (AML) as a second malignant neoplasm. The overall relative risk for development of AML is 185.0 (P < 0.05) and the mean time to occurrence of AML is 5.3 years (median, 5.25 years). When examining patient subgroups, the highest relative risk noted was 338.5 (P < 0.05) for that group of patients receiving an additional 6 months of postinduction MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone). Patients receiving only 6 months of induction BVCPP (BCNU, vinblastine, cyclophosphamide, procarbazine, and prednisone) had a relative risk of 166.2 (P < 0.05). These data results are consistent with previous reports that patients treated for Hodgkins disease are at high risk for development of AML. However, to date, no patients in this series have developed second malignancies other than AML. Cancer 52:2209‐2213, 1983.

Results of a uniform histopathologic review system of lymphoma cases a ten‐year study from the southeastern cancer study group

To determine the usefulness of a consulting panel for histopathologic review in lymphoma cases, a comparative study of the histopathologic diagnosis of the local pathologist was done and compared with the final diagnosis by an expert pathologist in 1088 cases of lymphoma studied by the Southeastern Cancer Study Group (SECSG) during the implementation of five protocols during the last ten years. The following conclusions were reached: (1) In 44 cases (4%), the material sent for review was judged inadequate to make a diagnosis; (2) In 82 cases (8%), the local pathologists diagnosis was judged incorrect; (3) In Hodgkins Disease (HD), the diagnosis was confirmed in 545 of 595 cases (92%). However, using the Lukes and Butler classification by subtype of HD, the expert pathologist judged only 289 of 595 cases as correct (49%). The least agreement was found in the lymphocytic predominance (LP) subtype, in which only six of 34 (18%) cases were correct. The best correlation was found in the nodular sclerosis (NS) type of HD where agreement occurred in 161 of 186 (87%) cases; and (4) In the non‐Hodgkins lymphomas (NHL) the diagnosis was confirmed in 428 of the 493 cases studied (87%). Subclassification using the Rappaport system revealed agreement in 274 of 493 (56%) cases. Subtypes associated with good prognosis were judged correct by the expert pathologist in 105 of 139 instances (76%). Likewise, agreement in subtypes of poor prognosis occurred in 254 of 351 cases (72%). These data again confirm the need for an uniform consulting panel system especially for cases involved in cooperative group trials. This has even become more important now with the increasing complexity of the different classifications currently in use.

Subcategories of histiocytic lymphoma: Associations with survival and reproducibility of classification. The southeastern cancer study group experience

Five pathologists reviewed histologic slides from 134 cases of histiocytic lymphoma and subclassified these cases using the Lukes‐Collins classification system. Of 98 morphologically subclassifiable cases, 85 were distributed among three categories, each presumed to represent a lymphoma of follicular center cell origin. The remaining 12 cases were classified among three additional categories. The cases within the three follicular center cell categories, considered collectively, had a significantly better survival than did the cases within the other three categories considered as a whole. The pathologists classified cases generally as being of a follicular center cell type with a high degree of reproducibility, but their individual classifications varied significantly with respect to more specific morphologic categories. Suboptimal quality of histologic sections was a significant factor contributing to problems in morphologic classification. Ancillary immunologic techniques may be required for definitive subclassification of large cell lymphomas.

A randomized multicenter trial of cyclophosphamide, Novantrone and 5-fluorouracil (CNF) versus cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) in patients with metastatic breast cancer

SummaryAs of August 1984, 115 women with advanced breast cancer have been randomized to receive a combination of either cyclophosphamide, Novantrone (mitoxantrone) and 5-fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil (CAF). Seventy-one percent of all patients were postmenopausal and 44% of CNF patients and 57% of CAF patients were estrogen receptor (ER) negative. Slightly over 30% of all patients had received hormonal therapy or chemotherapy in an adjuvant setting.Hematologic toxicity was similar in regard to platelet counts but slightly lower nadirs were experienced with CNF therapy than with CAF. However, there were fewer dosage decreases with CNF. Significantly less nausea and vomiting were observed with the CNF regimen compared to CAF. Moreover, alopecia was reduced appreciably in patients who received CNF.The response rate to CNF for the first 38 eligible and evaluable patients was 42%, and for 53 eligible and evaluable patients who received CAF the response rate was 45%, a non-significant difference. Median response durations were similar also, 140 days for CNF and 168 days for the CAF regimen. Time to treatment failure was similar for both regimens.CNF is an effective regimen for patients with advanced breast cancer, with less toxicity than CAF.