Carol J. Fabian

Exemestane for Breast-Cancer Prevention in Postmenopausal Women

BACKGROUND Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. METHODS In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. RESULTS A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. CONCLUSIONS Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).

Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy

BACKGROUND Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05). CONCLUSIONS Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.).

Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To update the 2009 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012 was completed using MEDLINE and Cochrane Collaboration Library. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. Guideline recommendations were revised based on an Update Committees review of the literature. RESULTS Nineteen articles met the selection criteria. Six chemoprevention agents were identified: tamoxifen, raloxifene, arzoxifene, lasofoxifene, exemestane, and anastrozole. RECOMMENDATIONS In women at increased risk of BC age ≥ 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of estrogen receptor (ER) -positive BC. In postmenopausal women, raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) should also be discussed as options for BC risk reduction. Those at increased BC risk are defined as individuals with a 5-year projected absolute risk of BC ≥ 1.66% (based on the National Cancer Institute BC Risk Assessment Tool or an equivalent measure) or women diagnosed with lobular carcinoma in situ. Use of other selective ER modulators or other aromatase inhibitors to lower BC risk is not recommended outside of a clinical trial. Health care providers are encouraged to discuss the option of chemoprevention among women at increased BC risk. The discussion should include the specific risks and benefits associated with each chemopreventive agent.

American Society of Clinical Oncology Position Statement on Obesity and Cancer

Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team--the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis--is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer.

Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). METHODS MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. RESULTS Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. CONCLUSION Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

Low-Dose Involved Field Radiation after Chemotherapy in Advanced Hodgkin Disease: A Southwest Oncology Group Randomized Study

Up to 40% of patients with stage III or IV Hodgkin disease relapse within 5 years of entering complete remission with current chemotherapy regimens [1-4]. Only 20% of patients who relapse enter a prolonged second complete remission after receiving chemotherapy, radiation, or bone marrow transplantation [5-14]. Thus, prevention of relapse remains an important issue. Factors associated with relapse after a complete response has occurred with chemotherapy include the following: nodular sclerosis histology, bulky disease, more than three cycles of chemotherapy required to achieve complete response, decreased chemotherapy doses, and B symptoms [15-22]. Eighty percent of relapses in patients with Hodgkin disease occur in sites of initial clinical involvement [22, 23]. Because Hodgkin disease is a radiosensitive tumor, a logical step is to use radiation in an attempt to eradicate subclinical disease after remission induction with chemotherapy. Kaplan [24] and others have shown that a radiation dose of 2000 to 2500 cGy is effective in preventing recurrence in all but 25% to 30% of patients with clinical disease when radiation is used as the sole treatment modality [24]. This relatively low dose of radiation might be even more effective if only subclinical disease was being treated. Further, using low-dose radiation after chemotherapy might decrease some of the morbidity associated with the combined use of both modalities at full doses. Early nonrandomized studies by Prosnitz and colleagues [25], in which the MVPP regimen (nitrogen mustard, vincristine, prednisone, and procarbazine) was administered with low-dose involved field radiation, showed only a 10% relapse rate when stage III or IV patients had achieved complete response with chemotherapy before receiving radiation. In 1978, we initiated a randomized trial for patients with stage III or IV Hodgkin disease that was designed to test the efficacy of low-dose involved field radiation after complete remission induction with chemotherapy. The MOP-BAP (nitrogen mustard, vincristine, procarbazine, bleomycin, doxorubicin, and prednisone) chemotherapy regimen was used as induction treatment because this regimen had been associated with a complete response rate of 77% [2]. Complete responders to six cycles of MOP-BAP were randomly assigned to a radiation dose of 2000 cGy to initially involved sites or to no further treatment. We determined the remission duration and relapse-free and overall survival rates for the entire group of patients with advanced Hodgkin disease as well as for several major subsets of patients. Methods Previously untreated patients (n = 564) with clinical or pathologic evidence (or both) of stage III or IV Hodgkin disease were registered for induction with MOP-BAP chemotherapy between June 1978 and September 1988. Pathology slides were reviewed by the Southwest Oncology Group Pathology Review Committee. A final review was made by the Lymphoma Central Repository. Patients who were known to be positive for human immunodeficiency virus or who had a clinical diagnosis of the acquired immunodeficiency syndrome were excluded from analysis. The pathology review is now complete for 95% of the patients who entered this study. Thirty-four patients (6%) were ineligible, primarily because they had non-Hodgkin lymphoma after pathology review. The Ann Arbor Staging Classification was used [26]. Staging requirements included bone marrow aspiration and biopsy; renal, heart, and lung function studies; and staging laparotomy or radiographic evaluation of the abdomen with either computerized tomography or lymphangiography or both. Patients with any mass 6 cm or more in size were designated as having bulky disease. Flow sheets, prestudy forms, and radiographic reports were reviewed on all patients who achieved complete response to make the assessment of bulky disease. Liver biopsy was required in patients with stage IIIB or IV disease unless the patient had clinical liver involvement or it was medically contraindicated. Clinical liver involvement was defined as an enlarged liver on physical examination or computed tomography together with increased levels of at least one liver enzyme other than alkaline phosphatase or lactate dehydrogenase. Clinical spleen involvement was defined as a palpable spleen on physical examination or an enlarged spleen on computed tomography with or without filling defects. Response Definitions A partial response was defined as a 50% or greater decrease in the sum of the products of the largest diameter and its perpendicular for 4 weeks or more. Patients with questionable residual disease were classified as partial responders. For patients with minimal residual disease detected by computerized tomography scanning after six cycles of chemotherapy, designation of partial or complete remission was left to the discretion of the individual investigator. In general, however, patients with minimal residual disease were classified as partial responders. If the residual mediastinal mass on the computerized tomographic scan was less than 3 cm or the residual peripheral nodal mass was 1.5 cm or less, partial responders were classified as having minimal residual disease. Complete response was defined as disappearance of all clinical evidence of disease for 4 or more weeks. Treatment Chemotherapy The MOP-BAP chemotherapeutic regimen consisted of nitrogen mustard (6 mg/m2) on day 1, bleomycin (2 mg/m2) and vincristine (1 mg/m2; maximum dose, 2 mg) on days 1 and 8, doxorubicin (30 mg/m2) on day 8, and prednisone (100 mg) and procarbazine (100 mg/m2) on days 2 to 7 and 9 to 12. Courses were repeated every 28 days if the absolute granulocyte count was 1500 cells/mm3 or more. A total of 6 cycles was administered. Prednisone was given only during the first and fourth cycles. Initial doses of MOP-BAP were 50% of those listed above if the patient was older than 65 years or had bone marrow involvement with leukopenia. Dose escalation in subsequent courses was encouraged. Initial doxorubicin doses were also decreased by 50% to 75% for serum bilirubin levels greater than 1.5 mg/dL or increases in liver enzyme levels of more than threefold the normal level or both. Subsequent drug doses were reduced for severe myelosuppression or delayed hematopoietic recovery as in previous Southwest Oncology Group studies [2] using this regimen. The ratio of actual/planned full-dose chemotherapy for each of the 5 drugs (nitrogen mustard, bleomycin, procarbazine, vincristine, and doxorubicin) was calculated for the 530 eligible patients. The average percentage was used to describe the amount of chemotherapy given. The average for the 5 drugs was 85%. The average number of courses was 5.6. The average actual/planned ratio for each drug was 86% for nitrogen mustard, 84% for doxorubicin, 82% for procarbazine, 91% for bleomycin, and 81% for vincristine. Sixty-six percent of patients achieving complete response received more than 85% of the planned induction chemotherapy. Radiation Therapy for Complete Responders All patients were seen in consultation by a radiation oncologist before induction chemotherapy was started, and all clinical and pathologic sites of disease were mapped. If the patient was later given radiation, all initially involved areas were included in the treatment ports with the exception of bone marrow. Patients with previously involved nodal sites received 2000 cGy in 150-cGy fractions, those with previously involved liver sites received 1500 cGy in 150-cGy fractions, those with previously involved spleen sites received 1500 cGy in 125-cGy fractions, and those with previously involved lung sites received 1000 cGy in 100-cGy fractions. Kidney blocks were used when necessary, and a spinal cord block was used when the dose to the cord had reached 2000 cGy. Patients only received radiation to those areas identified as being clinically or pathologically involved with Hodgkin disease. Radiation was started, 6 weeks after day 1 of the sixth MOP-BAP cycle, if the leukocyte count was more than 3000 cells/mm3 and if the platelet count was more than 100 000/mm3. A 3-week rest was recommended between radiation of large volumes or major lymph node areas. Supervoltage radiation of at least 2 MV or cobalt-60 was required. Port films, dose calculations, and treatment records were reviewed by the Quality Assurance Center, the Radiologic Physics Center, and the Medical and Radiation Oncology Coordinators. Failure to give any radiation to a previously involved site or concomitant administration of radiation and chemotherapy was considered a major radiation violation. Dose infractions and failure to complete radiation for any reason were considered minor radiation violations. Ninety-six percent of patients receiving radiation have had their records evaluated by the Radiologic Physics Center in Houston, Texas, and the Radiation and Medical Oncology Study Coordinators. All eligible patients who achieved complete response and were randomized were included in comparisons of remission duration, relapse-free survival, and survival regardless of whether a major or minor radiation violation had occurred. Patients randomized to no further treatment received no radiation or chemotherapy after six cycles of MOP-BAP until they relapsed. Planned follow-up intervals in patients randomized to receive low-dose radiation were identical to those for patients randomized to no further treatment. Treatment at the time of relapse was at the discretion of the individual investigator. Study Design When the study was initially opened, patients in complete response were randomized after six cycles of MOP-BAP and restaging to one of three possible groups: no further therapy, levamisole for 2 years, or low-dose radiation to previously involved sites of disease. The study design was changed in 1982 because of lower-than-anticipated patient accrual. The levamisole arm was eliminated, and patients were randomized before

Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

SummaryThe limiting toxicity of low dose continuous infusion 5-fluorouracil (200–300 mg/m2/day) is often palmarplantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42% –82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m2/day until toxicity or progressive disease forced discontinuation.The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42–92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6–61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups.Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.The five previously untreated patients who received pyridoxine for PPE continued 5-FU for a median of 6 months after development of the syndrome. The six previously untreated patients who did not receive pyridoxine when they developed PPE were able to continue 5-FU for a median of only 2.5 months after development of the syndrome. A similar number of clinical responders to 5-FU were present in both groups.Considering the high incidence of PPE and response in previously untreated colon cancer patients who receive protracted continuous 5-FU, prophylactic pyridoxine in conjunction with this treatment modality might be useful.

Can a Controlled-Release Oral Dose Form of Oxycodone Be Used as Readily as an Immediate-Release Form for the Purpose of Titrating to Stable Pain Control?

Two separate trials compared controlled-release (CR) oral oxycodone (administered every 12 hours) with immediate-release (IR) oxycodone (4 times a day) to determine whether patients with chronic pain could be titrated to stable pain control as readily with the CR as with the IR formulation. In one study, 48 patients with cancer pain were randomized to open-label titration with either CR or IR oxycodone (maximum dose, 400 mg/day) for a period of up to 21 days. In a study of similar design, 57 patients with low back pain were titrated with either CR or IR oxycodone (maximum dose, 80 mg/day) for a period of up to 10 days. The majority of patients in both studies were converted to oxycodone from other opioid analgesics. Results of both studies showed no difference between CR and IR oxycodone with respect to both the percentage of patients achieving stable pain control, the time to achieve stable pain control, and the degree of pain control achieved. Among cancer patients, 85% achieved stable analgesia, 92% with the CR formulation and 79% with the IR formulation. Among noncancer patients, 91% achieved stable pain control, 87% with the CR formulation and 96% with the IR formulation. The most commonly reported adverse effects in both studies were similar for the two formulations and were those anticipated with opioids: nausea, vomiting, constipation, somnolence, dizziness, and pruritus. Nausea and vomiting were the most frequently cited reasons for treatment discontinuations. These studies suggest that dose titration can be accomplished as readily with oral CR oxycodone as with IR oxycodone in patients with chronic, moderate to severe pain.

Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer

Selective estrogen receptor modulators (SERMs) impact a variety of biologic processes regulated by activated estrogen receptor (ER). Depending on the target tissue, physiologic conditions, and their structure, SERMs may exhibit either estrogen antagonist or estrogen agonist effects. SERMs have a long history in the treatment of breast cancer, based on estrogen antagonist activity in ER-positive breast cancer cells. Beginning with tamoxifen, SERMs have moved to the prevention arena, where their partial estrogen effects may provide other organ benefits, particularly for postmenopausal women. It is because of these partial estrogen agonist effects on organs such as the bone, vagina, CNS, and cardiovascular system that SERMs are likely to remain preferable to pure antiestrogens as primary breast cancer prevention agents in the context of total women’s health. The ideal SERM should function as an antiestrogen in the breast and uterus and a partial estrogen agonist in skeletal, cardiovascular, CNS, gastrointestinal tract, and vagina. Further, this ideal SERM should be devoid of procoagulant effects and should not be associated with an increase in perimenopausal symptoms. Although several generations of SERMs have been developed, the ideal SERM for prevention remains elusive. We will review progress to date for SERMs as single agents and potential for combination therapy in the future. BIOLOGY BEHIND THE MULTIFACETED ACTION OF SERMs

Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.