Mary J. Brames

Fluoxetine Versus Placebo in Advanced Cancer Outpatients: A Double-Blinded Trial of the Hoosier Oncology Group

PURPOSE To determine whether fluoxetine improves overall quality of life (QOL) in advanced cancer patients with symptoms of depression revealed by a simple survey. PATIENTS AND METHODS One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were randomly assigned in a double-blinded fashion to receive either fluoxetine (20 mg daily) or placebo for 12 weeks. Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression. Patients with recent exposure to antidepressants were excluded. RESULTS The groups were comparable at baseline in terms of age, sex, disease distribution, performance status, and level of depressive symptoms. One hundred twenty-nine patients (79%) completed at least one follow-up assessment. Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General, compared with patients given placebo (P =.01). Specifically, the level of depressive symptoms expressed was lower in patients treated with fluoxetine (P =.0005), and the subgroup of patients showing higher levels of depressive symptoms on the two-question screening survey were the most likely to benefit from treatment. CONCLUSION In this mix of patients with advanced cancer who had symptoms of depression as determined by a two-question bedside survey, use of fluoxetine was well tolerated, overall QOL was improved, and depressive symptoms were reduced.

Psychosocial care for patients and their families is integral to supportive care in cancer: MASCC position statement

This position paper, written on behalf of the MASCC Psychosocial Study Group, reviews the most common psychosocial concerns and needs of cancer patients during all phases of the cancer continuum, from diagnosis to death or survivorship. Developments in psychosocial care at both individual and systems levels are surveyed and summarized, along with gaps in knowledge and research and needed improvements in the dissemination and application of acquired knowledge and expertise. The roles of culture, spirituality, and religion as part of psychosocial care are reviewed, along with families’ and caregivers’ specific psychosocial concerns and needs, and areas of needed psychosocial interventions in supportive cancer care. Deficits in recognizing and meeting patients’ psychosocial needs at the system level are examined, and international guidelines and models of psychosocial care are reviewed, including their potential applications to local contexts. The paper calls for a shift to a new paradigm of care through adoption of an integrated approach to identify and meet the psychosocial needs of cancer patients and survivors as part of supportive care worldwide.

Phase II Study of Paclitaxel Plus Gemcitabine Salvage Chemotherapy for Germ Cell Tumors After Progression Following High-Dose Chemotherapy With Tandem Transplant

PURPOSE To determine long-term survival and potential cure with salvage chemotherapy with paclitaxel plus gemcitabine after progression after both cisplatin combination chemotherapy and subsequent high-dose chemotherapy with tandem transplantation. PATIENTS AND METHODS One hundred eighty-four patients received salvage high-dose chemotherapy at Indiana University (Indianapolis, IN) from February 1996 to December 2004. After further evidence of progressive disease, 32 patients were subsequently treated with paclitaxel 100 mg/n2 over 1 hour plus gemcitabine 1,000 mg/m2 over 30 minutes, days 1, 8, and 15 every 4 weeks for a maximum of six courses. This is a retrospective review of this patient population. Patients were evaluated for response, duration of response, and survival. Patients were ineligible if they received prior paclitaxel or gemcitabine. RESULTS Ten (31%) of 32 patients achieved objective response, including four partial remissions (2- to 6-month duration) and six complete responses (CRs). Four of these six CRs (12.5% of total patient population) are continuously disease free (NED) with paclitaxel plus gemcitabine alone (no postchemotherapy surgery) at more than 20, 40, 44, and 57 months from start of paclitaxel plus gemcitabine, respectively. One additional CR is currently NED more than 63 months after paclitaxel plus gemcitabine with two subsequent resections of carcinoma. CONCLUSION Long-term disease-free survival is possible with paclitaxel plus gemcitabine in this patient population that progressed after high-dose chemotherapy, and had not received prior paclitaxel or gemcitabine.

Review of Cannabinoids and their Antiemetic Effectiveness

SummaryMarijuana has been used for over 2 centuries. Its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) was isolated in 1964 and first used to control nausea and vomiting during chemotherapy in the 1970s.THC has cardiovascular, pulmonary and endocrinological effects as well as actions on the central nervous system. Alterations in mood, memory, motor coordination, cognitive ability, sensorium, spatial- and self-perception are commonly experienced. The precise antiemetic mechanism is unknown. THC and nabilone act at a number of sites within the central nervous system. Cannabinoids have also been shown to inhibit prostaglandin synthesis in vitro.In controlled clinical trials, THC is superior to placebo and prochlorperazine in antiemetic effectiveness. Effectiveness of THC correlates to a ‘high’ experienced by the patient. A variety of chemotherapy regimens respond to THC including high-dose methotrexate and the doxorubicin, cyclophosphamide, fluorouracil combination. Cisplatin is more resistant. Side effects are generally well tolerated but may limit THC use in the elderly or when high doses are administered.Nabilone, a synthetic cannabinoid, is also an effective antiemetic which is more active than prochlorperazine in preventing chemotherapy-induced emesis, including cisplatin-containing regimens. Side effects are similar to THC and may be dose-limiting.Levonantradol, another synthetic cannabinoid, is an effective antiemetic. It may provide more flexibility in the outpatient setting since it can be administered orally or intramuscularly. Most side effects are mild except for dysphoria which may be dose-limiting.

Randomized, Double-Blind, Placebo-Controlled, Phase III Cross-Over Study Evaluating the Oral Neurokinin-1 Antagonist Aprepitant in Combination With a 5HT3 Receptor Antagonist and Dexamethasone in Patients With Germ Cell Tumors Receiving 5-Day Cisplatin Combination Chemotherapy Regimens: A Hoosier Oncology Group Study

PURPOSE Aprepitant, a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone are standard antiemetic therapy for prevention of single-day, cisplatin-induced nausea and vomiting. We conducted a double-blind, placebo-controlled phase III cross-over study that compared aprepitant to placebo combined with standard antiemetic prophylaxis (a 5HT3-RA and dexamethasone) in patients receiving 5 days of cisplatin combination chemotherapy for testicular cancer. PATIENTS AND METHODS Patients receiving two consecutive identical courses of a 5-day cisplatin-based chemotherapy were randomly assigned to aprepitant 125 mg on day 3 and 80 mg per day on days 4 through 7 or to placebo with the initial course and crossover to the opposite treatment with the second course. The primary objective was complete response (CR). Secondary end points were emetic episodes (acute and delayed), nausea measurement based on a visual analog scale (VAS), and patient-stated preference after the second study cycle. RESULTS In all, 71 patients were screened for the study and 69 were evaluable. Thirty-five patients were randomly assigned to receive aprepitant and 34 to receive placebo for the first course. Forty-two percent achieved CR with aprepitant compared with 13% with placebo (P < .001). Eleven patients (16.2%) had at least one emetic episode during the aprepitant cycle versus 32 patients (47.1%) with placebo. Thirty-eight patients preferred the aprepitant cycle whereas 11 preferred placebo (P < .001). There was no statistical difference in VAS for nausea, but it was numerically superior with aprepitant. There was no toxicity with aprepitant compared with placebo. CONCLUSION There was a significant improvement in CR rate with aprepitant combined with a 5HT3-RA and dexamethasone. Patient preference strongly favored the aprepitant cycle.

Phase ii study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors

PURPOSE Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer. This phase II clinical trial evaluated the combination of CIS plus epirubicin (CIS-EPI) in patients with metastatic germ cell tumors (GCT) not amenable to cure with standard salvage therapy. PATIENTS AND METHODS Between March 2001 and August 2005, 30 patients with GCT, who had received at least one previous CIS-based regimen, were enrolled. All patients were males, with median age 36 (range, 24 to 45 years). Twenty-one patients (70%) had experienced late relapses (> 2 years). Patients received EPI 90 mg/m2 on day 1 and CIS 20 mg/m2 on days 1 to 5 every 3 weeks for maximum of four cycles. RESULTS Nineteen (63%) of 30 patients received all four cycles. Toxicity was primarily hematologic: grade 3/4 neutropenia, four patients (one neutropenic fever); two patients had grade 3 thrombocytopenia, and five patients had grade 3/4 anemia. Nonhematologic toxicity was grade 3 acute renal failure in two patients; grade 3 electrolyte wasting in two patients; grade 3 nausea/vomiting in eight patients; grade 3 elevation of aminotransferases in one patient; and grade 3 diarrhea in one patient. There were no occurrences of severe mucositis, cardiotoxicity, or treatment-related deaths. Nine patients achieved a complete remission; seven of these patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. One patient remains alive with stable pulmonary nodules at 28+ months. CONCLUSION CIS-EPI is an active regimen in metastatic GCT, with an acceptable toxicity profile. This regimen offers potential for long-term disease-free survival in this population.

Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor

BACKGROUND The emergence of a primitive neuroectodermal tumor (PNET) within a germ-cell tumor (GCT) is rare. We assess the prognosis and response to treatment. PATIENTS AND METHODS Eighty-one patients were identified. Selected patients were treated with cyclophosphamide 1200 mg/m(2), doxorubicin 75 mg/m(2), and vincristine 2 mg i.v. alternating with ifosfamide 1.8 g/m(2) x 5 days plus etoposide 100 mg/m(2) x 5 days (CAV/IE). Ewings sarcoma (EWS) translocation was assessed using a FISH-based method. RESULTS Median follow-up was 41 months. Seventy-six patients had PNET in the primary tumor or in initial metastasis. Five harbored PNET only at relapse. Twenty-six of 76 underwent primary retroperitoneal lymph node dissection, 13 of whom had retroperitoneal PNET and four are dead of disease (DOD). Fifty of 76 were initially treated with GCT chemotherapy (n = 49) or CAV/IE (n = 1). Twenty-seven of these 50 underwent complete postchemotherapy resection of residual PNET and 17 are DOD. Ten patients received CAV/IE. Eight achieved an objective response, and five are currently alive. One of the 14 specimens examined carried the EWS translocation. CONCLUSIONS PNET of GCT origin is associated with an adverse outcome. For low-volume disease, surgery is the optimal initial therapy. CAV/IE may have a role in patients with unresectable disease.

Salvage chemotherapy with high-dose carboplatin and etoposide with peripheral blood stem cell transplant in patients with relapsed pure seminoma

Purpose: To evaluate rates of complete remission and overall survival for patients with relapsed pure seminoma treated with high-dose carboplatin and etoposide followed by peripheral blood stem cell transplant. Patients and Methods: Forty-eight consecutive patients with relapsed pure seminoma who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant between May 1996 and June 2006 were retrospectively reviewed. Upon relapse (first, second, or third relapse) patients were given HDCT with carboplatin 700 mg/m2 and etoposide 750 mg/m2 for 3 consecutive days followed by infusion of peripheral blood stem cells. Here, we review both response and survival. Results: Thirty-eight (79%) of 48 patients obtained a complete response (CR) with overall survival of 75%. Median follow-up of all patients was 45.6 months. Twenty-two (92%) of 24 patients in first relapse achieved CR and are still alive and continuously disease-free. Sixteen (67%) of 24 patients had HDCT as third- or fourth-line therapy with 67% CR and overall survival of 64%. There were 3 treatment-related deaths, all of which occurred as third- or fourth-line therapy. Conclusion: HDCT results in high rates of both CR and overall survival in patients with first or later relapsed pure seminoma germ cell tumors.

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014

BACKGROUND Based on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease. PATIENTS AND METHODS We conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin-etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis. RESULTS We identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03-24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic β-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25-9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74-6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01-1.06; P = 0.02). CONCLUSIONS Patients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990-2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975-1990).

Long-term Survival with Paclitaxel and Gemcitabine for Germ Cell Tumors after Progression Following High-Dose Chemotherapy with Tandem Transplant

Objectives:Germ cell tumor patients progressing after high-dose chemotherapy (HDCT) have a dismal prognosis. A prior retrospective study of paclitaxel and gemcitabine enrolled 32 patients. All failed first-line chemotherapy and salvage therapy with HDCT. We now present long-term results. Methods:Eligible patients received BEP or similar first-line chemotherapy and subsequent HDCT. They were treated with paclitaxel (100 mg/m2) on days 1, 8, and 15 and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks for a maximum of 6 cycles. Results:Ten of 32 (31%) had an objective response (4 partial remissions and 6 complete responses). Four patients (12.5% of total) have enjoyed long-term survival; 3 are continuously disease free for 64, 94, and 122 months. None of these 3 received subsequent chemotherapy or surgery. A fourth patient relapsed after 72 months, and has now reachieved remission for 36+ months after treatment with the same regimen. These patients had 2, 2, 2, and 4 prior therapies, respectively, and a rising serum human chorionic gonadotropin (69 and 138 mIU/mL), &agr;-fetoprotein (525 ng/mL), or increasing intrathoracic metastases. Longest prior response ranged from 5 to 24 months. Conclusions:Paclitaxel and gemcitabine salvage chemotherapy can offer long-term survival and probable cure in relapsed/refractory germ cell tumor patients after HDCT. This is an appropriate regimen in a taxane-naive and gemcitabine-naive patient population. This is the first example of a nonplatinum curative chemotherapy regimen in patients progressing after HDCT.