Ellen R. Gaynor

Prospective Multicenter Study of the Impact of the 21-Gene Recurrence Score Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection

PURPOSE The 21-gene Recurrence Score (RS) assay has been validated to quantify the risk of distant recurrence in tamoxifen-treated patients with lymph node-negative, estrogen receptor-positive breast cancer and predict magnitude of chemotherapy benefit. This multicenter study was designed to prospectively examine whether RS affects physician and patient adjuvant treatment selection and satisfaction. PATIENTS AND METHODS Before and after obtaining the 21-gene RS assay, medical oncologists stated their adjuvant treatment recommendation and confidence in it. Patients also indicated their treatment choice pre- and post-RS assay. Patients completed measures for decisional conflict, anxiety, and quality of life. RESULTS Seventeen medical oncologists at one community and three academic practices consecutively enrolled 89 assessable patients. The medical oncologist treatment recommendation changed for 28 patients (31.%). Twenty-four patients (27%) changed their treatment decision. The largest change after the RS results was conversion from the medical oncologists pretest recommendation for chemotherapy plus hormonal therapy (CHT) to post-test recommendation for hormone therapy (HT) in 20 cases (22.5%). Nine patients (10.1%) changed their treatment decision from CHT to HT. RS results increased medical oncologist confidence in their treatment recommendation in 68 cases (76%). Patient anxiety and decisional conflict were significantly lower after RS results. CONCLUSION The results of this study indicate that the RS assay impacts medical oncologist adjuvant treatment recommendations, patient treatment choice, and patient anxiety.

Phase III Randomized Intergroup Trial of Subtotal Lymphoid Irradiation Versus Doxorubicin, Vinblastine, and Subtotal Lymphoid Irradiation for Stage IA to IIA Hodgkin’s Disease

PURPOSE The management of early-stage Hodgkins disease in the United States is controversial. To evaluate whether staging laparotomy could be safely avoided in early-stage Hodgkins disease and whether chemotherapy should be a part of the treatment of nonlaparotomy staged patients, a phase III intergroup trial was performed. PATIENTS AND METHODS Three hundred forty-eight patients with clinical stage IA to IIA supradiaphragmatic Hodgkins disease were randomized without staging laparotomy to treatment with either subtotal lymphoid irradiation (STLI) or combined-modality therapy (CMT) consisting of three cycles of doxorubicin and vinblastine followed by STLI. RESULTS The study was closed at the second, planned, interim analysis because of a markedly superior failure-free survival (FFS) rate for patients on the CMT arm (94%) compared with the STLI arm (81%). With a median follow-up of 3.3 years, 10 patients have experienced relapse or died on the chemoradiotherapy arm, compared with 34 on the radiotherapy arm (P <.001). Few deaths have occurred on either arm (three deaths on CMT and seven deaths on STLI). Treatment was well tolerated, with only one death on each arm attributed to treatment. CONCLUSION These results demonstrate that it is possible to obtain a high FFS rate in a large group of stage IA to IIA patients without performing staging laparotomy and that three cycles of chemotherapy plus STLI provide a superior FFS compared with STLI alone. Extended follow-up is necessary to assess freedom from second relapse, overall survival, late toxicities, patterns of treatment failure, and quality of life.

Long-Term Survival of Patients With Localized Diffuse Histiocytic Lymphoma

From January 1970 to March 1981, localized diffuse histiocytic lymphoma (DHL) was identified in 31 patients by exploratory laparotomy and splenectomy (pathologic stage I, 17 patients; pathologic stage II, 14 patients) at the University of Chicago. The median follow-up time was 72 months. All patients were previously untreated and received radiation therapy as their primary treatment modality. Chemotherapy was administered only at the time of relapse. All but two patients achieved a complete remission (CR) with radiation therapy. The actuarial disease-free survival for patients with stage I disease is 94% at 5 years and 72% at 10 years. For stage II disease, the disease-free survival is 56% at 5 years and 31% at 10 years. The difference in the disease-free survival between stage I and II is statistically significant (P = .02). The survival at 10 years is 70% for stage I disease and 46% for stage II disease. Five patients had documented relapses (four had stage II disease). Only two of those who relapsed achieved a second CR with salvage chemotherapy. Our data show an excellent outcome in patients with pathologic stage I disease, indicating that a high percentage of these cases can be cured with radiotherapy alone. Patients with clinical stage II disease might be served better with chemotherapy.

Low‐dose cytosine arabinoside (Ara‐C) therapy in the myelodysplastic syndromes and acute leukemia

Twenty‐two patients with either a myelodysplastic syndrome or acute nonlymphocytic leukemia were treated with 10–21 days of subcutaneous cytosine arabinoside (Ara‐C) (5–10 mg/m2 every 12 hours). There were two complete remissions and ten partial responses. Clinically significant improvements in peripheral blood counts persisted for periods of 8 weeks to greater than 21 weeks. Responses were seen even in patients who had previously proven refractory to conventional induction regimens or high‐dose Ara‐C. The toxicity, however, was considerable. Nearly all patients developed significant thrombocytopenia. Platelet and red cell transfusion support was required in many cases. The response to low‐dose Ara‐C therapy seen in patients with the leukemic and myelodysplastic disorders may be mediated by the induction of cell differentiation or a direct cytotoxic effect on a sensitive population of cells. Low‐dose Ara‐C may provide an alternative therapy in the selected patient with acute nonlymphocytic leukemia or a myelodysplastic syndrome.

Treatment of diffuse histiocytic lymphoma (DHL) with COMLA (cyclophosphamide, oncovin, methotrexate, leucovorin, cytosine arabinoside): a 10-year experience in a single institution.

Between March 1974 and December 1983, 83 patients with diffuse histiocytic lymphoma (DHL) were treated with COMLA (cyclophosphamide 1.5 g/m2 day 1; Oncovin (Lilly, Indianapolis) 1.4 mg/m2 days 1, 8, and 15; and cytosine arabinoside 300 mg/m2 and methotrexate 120 mg/m2 days 22, 29, 36, 43, 50, 57, 64, and 71; and leucovorin 25 mg/m2 every six hours X 4, beginning 24 hours after methotrexate). For the purpose of analysis, patients were divided into two groups. Group 1 (n = 54) included patients age 65 or under who had received no prior curative radiotherapy or chemotherapy. Group 2 (n = 29) included all patients over age 65 and patients who had received prior curative radiation therapy or prior minimal chemotherapy. The median time of follow-up for all patients was 28 months. Group 1 included 11 stage II, ten stage III, and 33 stage IV patients. Of 48 evaluable patients in this group, 21 (44%) achieved a complete remission (CR), eight (17%) achieved a partial remission (PR), and 19 (40%) showed no response (NR). Median survival of CR patients was 114+ months, PR patients, 42 months, and NR patients, 13 months. Six CR patients relapsed. The median disease-free survival of CR patients was 108+ months. Group 2 included nine stage II, seven stage III, and 13 stage IV patients. Of 24 patients evaluable for response, eight (33%) achieved a CR, six (25%) achieved a PR, and ten (42%) showed no response. The median survival of CR patients was 114+ months, that of PR patients was 17 months, and that of NR patients, 9 months. Two CR patients relapsed. The median disease-free survival of CR patients had not been reached at 102 months. The regimen was well tolerated in most patients and toxicity was acceptable. We conclude that COMLA is a well tolerated outpatient chemotherapy regimen capable of inducing durable CRs in some patients with DHL. Results achieved with COMLA, however, are inferior to those of more aggressive treatment programs; thus, the use of COMLA as first-line therapy in DHL should be limited to those patients unable to tolerate a more aggressive treatment program.

Infusional CHOP Chemotherapy (CVAD) With or Without Chemosensitizers Offers No Advantage Over Standard CHOP Therapy in the Treatment of Lymphoma: A Southwest Oncology Group Study

PURPOSE Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkins lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516). PATIENTS AND METHODS All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m(2) by intravenous bolus day 1, doxorubicin 12.5 mg/m(2)/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days. RESULTS Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516). CONCLUSION CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.

Comparison of the intermediate risk 21-gene recurrence score (RS) with the 70-gene signature (GS) as a continuous variable, Magee equations, and Adjuvant! Online (AOL).

47 Background: Multigene assays and risk-prediction models are used to provide prognostic information in the management of patients with estrogen receptor positive (ER+) lymph node negative (LN-) breast cancer (BC). Some have predictive utility in determining the value of chemotherapy added to endocrine therapy. We previously reported a mix of high and low risk 70-GS within the intermediate risk 21-gene RS. The Magee equations provide an estimate of the 21-gene RS using standard pathological findings. AOL provides a 10-year risk of BC recurrence or death. The objective of this study is to evaluate correlations between the 70-GS as a nondichotomous continuous variable, the Magee equations, and AOL within patients (pts) with 21-gene intermediate RS. METHODS The 70-GS as a continuous variable (highest risk of -1 to lowest risk of +1) was obtained on all consecutive ER+LN- BC cases with an intermediate 21-gene RS at Loyola U Med Ctr from 1/2005 to 9/2012. AOL recurrence risk and the Magee equations were calculated from clinical-pathologic findings. Pearson pairwise correlations among all four recurrence measures were generated. RESULTS Results of the 70-GS as a continuous variable and the 21-gene RS were available in 89 cases. A higher risk 70-GS correlates with a higher 21-gene RS (r = -0.31; p = 0.003). A higher risk of recurrence as estimated by AOL is associated with a higher 21-gene RS (r = 0.22; p = 0.036), higher Magee equation 1 (r = 0.36; p = 0.001) and 2 (r = 0.32; p = 0.004), and a higher risk 70-GS (r = -0.40; p < 0.001). Magee equations 1 and 2 are statistically correlated to the 21-gene RS (r = 0.24; p = 0.028 and r = 0.23; p = 0.036 respectively), but not to the 70-GS (p = 0.064 and p = 0.057 respectively). Magee equation 3 is not statistically correlated with 70-GS, 21-gene RS or AOL. CONCLUSIONS There is a continuum of highest to lowest risk 70-GS among LN- ER+ BC within intermediate risk RS. The prospective PROMIS study will assess if the 70-GS adds clinical utility regarding adjuvant therapy choice for these pts.

An Overview of the Current Understanding and Management of the Non-Hodgkin’s Lymphomas

The hematologic malignancies have always provided the model tumor system tor the oncologist. These tumors traditionally have been among the most responsive to chemotherapy and hence chemotherapeutic developments stemmed largely from knowledge gained from the management of these diseases. What has been lacking is an understanding of the malignant process itself and so while we have been able to control and often cure these diseases, a void has existed in our understanding of basic pathophysiology. The past several years have brought tremendous developments in the fields of cytogenetics, immunology, molecular biology, and virology. Whereas previously we have been able to speak of these diseases in merely descriptive terms, we are now quickly gaining an understanding of the events leading to the phenomenon of malignant transformation. It is apparent that once the process is understood, it will be merely a matter of time before we are better able to control the process. While the gap between basic pathophysiology information and therapeutic application is a reality, it probably will not be an insurmountable hurdle.