Dron Gauchan

What Is the Optimal Dose and Schedule for Dasatinib in Chronic Myeloid Leukemia: Two Case Reports and Review of the Literature.

Efficacy and safety of dasatinib in chronic phase (CP) chronic myelogenous leukemia (CML) patients has been well established. Initially approved dose and schedule of 70 mg twice daily has been changed to 100 mg once daily after demonstration of the same efficacy with less toxicity. Some patients require significant dose reductions to enable continued treatment with dasatinib. Even at a dose of 80 mg once daily, several patients may require further dose reductions due to substantial toxicity while maintaining good control of their disease. We report two CP-CML patients achieving and maintaining major molecular responses while on very low doses of dasatinib, ultimately achieving undetectable levels of BCR-ABL fusion transcript in their peripheral blood. Observations of several CP-CML cases responding remarkably well to dasatinib despite very low dose and frequent dose interruptions challenge our current understanding and the accuracy of the data regarding the optimum dose and schedule of this drug. In selected intolerant patients, low-dose dasatinib therapy may be a safe and effective alternative treatment option before a treatment discontinuation or change considered.

Is It Time to Reconsider Prophylactic Cranial Radiation in Non-Small-Cell Lung Cancer?

TO THE EDITOR: In their recent article in Journal of Clinical Oncology, Johung et al report prolonged survival in patients with brain metastasis from ALK-rearranged non–small-cell lung cancer (NSCLC) when treated with radiotherapy (RT; stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), along with tyrosine kinase inhibitor (TKI) therapy. The authors highlight the critical importance of the interventions for controlling intracranial disease in this particular subtype of patients with NSCLC. Although 30% of patients had brain metastases at the time of initial diagnosis and no prior TKI therapy, 49% of patients in the study had started ALK-targeted TKIs before the development of their brain metastases. However, it is not clearly stated if, when, for how long, and in what fraction of these patients the TKIs were interrupted, continued, or restarted during or after the RT. This piece of information may have therapeutic implications in the control of not only extracranial disease but also of CNS disease. Blood-brain barrier (BBB) disruption can be induced by irradiation. RTwith doses of 20 to 30Gywith fraction size of 2Gymay increase the permeability of the BBB to enhance the effect of systemic anticancer therapy. Poor penetration of TKIs through the BBB hinders the anticancer efficacy of these drugs in metastatic brain tumors. Alternative dosing schemes and/or increased doses have been suggested for patients who have systemic disease control but CNS progression while they are receiving crizotinib. An analysis of the first-line RT delivery (SRS v WBRT) in the study by Johung et al shows no difference in survival, but there is a trend toward increased failure of brain therapy for those patients who received first-line SRS as opposed toWBRT. Could this suggest a lesser disruption of the BBB with SRS and lesser penetration of systemic anticancer therapy to the rest of the brain? Prior randomized controlled trials and several prospective and retrospective studies have evaluated the role of prophylactic cranial radiation (PCI) in the general population of patients with locally advanced NSCLC. All of these studies have consistently shown a decrease and/or delay in brain metastases with PCI without major differences in global cognitive function or quality of life. The lack of overall survival benefit, however, has been partly attributed to poor extracranial disease control and/or poor performance status of the general population of patients with NSCLC. The population of patients with ALK-rearranged NSCLC in the study mostly presented with stage IV disease but only 30% of them had brain metastases at the time of diagnosis. The patients’ median overall survival time was more than 4 years. A majority of patients (74%) presented with multiple brain metastases but excellent performance status (80%). We commend the authors of the study for their hypothesisgenerating work. Although we agree with the authors, that interventions to control intracranial disease are critical, on the basis of all this information, we cannot help but wonder about and reconsider the possible utility of PCI in this particular patient population. PCI might help not only by having a direct effect on micrometastatic CNS disease but also by increasing the permeability of the BBB to the antitumor effects of TKIs. Future studies that evaluate the role of PCI with or without TKIs in this particular setting can be informative and helpful.

ReCAP: Impact of the National Cancer Institute Community Cancer Centers Program on Clinical Trial and Related Activities at a Community Cancer Center in Rural Nebraska

PURPOSE Although 85% of patients with cancer are diagnosed and treated in the community setting, only 3% are enrolled onto clinical trials. Lack of adequate time, infrastructure, resources, incentives, and reimbursement adversely affect clinical trial participation. In July 2007, Saint Francis Cancer Treatment Center (SFCTC) in Grand Island, Nebraska, was selected as one of the initial 16 sites for the National Cancer Institute Community Cancer Centers Program (NCCCP). METHODS Clinical trial and related activities data at SFCTC 5 years before and 5 years during the NCCCP were gathered and compared. Data included information on patients in clinical trials, number and type of trials, ratio of underserved patients, staffing, collection and storage of tissue samples, availability of new cancer services, and organizational infrastructure and linkage to National Cancer Institute-designated cancer centers. RESULTS The number and percentage of patients enrolled onto clinical trials increased from 89 (3.2%) to 640 (23%; P<.001). All enrollees were rural Nebraskans, with 70%age > 65 years. Available treatment and nontreatment (eg, prevention, biospecimen,cancer control) trials increased from eight and three per year to 28 and 12 per year (P=.012), respectively. Staffing increased from 1.2 to 3.9 full-time equivalents (P=.012). A genetic counselor, smoking cessation counselor, and outreach project coordinator and two nurse navigators were hired. The number of tissue samples collected and/or stored increased from 26 (19%) to 320 (52%; P<.001). CONCLUSION NCCCP participation had a direct and positive impact on all activities, with enhanced access to expanded types of trials and cancer care services. Our data demonstrate the feasibility of successful implementation of an expanded spectrum of clinical trials and programs in a rural community.

Germline BRCA1/2 Mutations: Are They Good Enough to Determine Who Will Respond to Poly(ADP-Ribose) Polymerase Inhibitor Therapy in Advanced Cancer?

monotherapy in advanced cancer patients with a germline BRCA1/2 mutation. Among other cancers, the study includes an ovarian cancer cohort of 193 patients with platinum-resistant or platinum-unsuitable ovarian cancer and a cohort of 62 patients with breast cancer. Patients with ovarian cancer were eligible if they were platinum resistant, or if they were not suitable for further platinum therapy due to hypersensitivity or toxicity as deemed by their primary oncologist. Percentage of patients fitting this unsuitability criterion has not been prospectively collected and reported. Data regarding if or what percentage of ovarian cancer patients had a high-grade serous histology have not been provided. Also, data on the percentage of patients with breast cancer with triple-negative disease is not available. The primary end point of the study was tumor response rate by RECIST criteria for all patients. CA-125 levels have not been provided to correlate for response in ovarian cancer cohort. Among patients with platinum-sensitive relapsed ovarian cancer, olaparib therapy has been shown to improve progression-free survival regardless of the BRCA mutational status. 2 The efficacy of olaparib may depend on platinum sensitivity even among patients with BRCAmutated ovarian cancer suggesting that platinum sensitivity may be more relevant to predict response to poly(ADP–ribose) polymerase (PARP) inhibitors than the mutational status of BRCA1 and BRCA2. 3 Many genes other than BRCA are involved in platinum-induced DNA damage repair and are related to platinum sensitivity. 4-5 Not knowing exactly what percentage of patients in Kaufman et al study were platinum resistant versus platinum unsuitable makes it less clear if more than 30% response rate for ovarian cohort were due to BRCA mutation or platinum sensitivity. In other tumor types response rates according to prior platinum therapy also favored no prior platinum exposure even though it did not reach statistical significance. However, the sample sizes were small and, as stated by Kaufman et al, 1 the CIs overlapped. In the Cancer Genome Atlas project 6 approximately 22% of tumors had a BRCA mutation, which is associated with homologous recombination deficiency (HRD), the hallmark for response to PARP inhibitors. The high grade serous ovarian cancers and triple negative breast cancers may represent histologically and phenotypically defined subgroups associated with HRD. The data regarding the percentage of these patients in these two subgroups in ovarian and breast cancer cohorts would be helpful if available. It remains to be shown what exactly determines the response to PARP inhibitor therapy; Is it germline BRCA1/2 mutations? Is it platinum sensitivity? Is it HRD? Or is it a combination of all? Currently, identification of germline BRCA mutations through a blood test seems to be the only US Food and Drug Administration–approved surrogate marker for HRD. However testing tumor tissue for somatic BRCA mutations as well as for genes associated with HRD may better define the subgroup of patients with cancer who would benefit from a number of PARP inhibitors yet to come into clinical practice. The recent US Food and Drug Administration approval of olaparib for ovarian cancer along with a companion diagnostic blood test of BRACAnalysis CDx (Myriad Genetics Laboratories, Salt Lake City, UT) seems to be just the beginning.

Cost-Effectiveness of Molecular Profiling for Early Breast Cancer

TO THE EDITOR: In their recent article, Bonastre et al reported a cost-effectiveness analysis of molecular profiling in adjuvant therapy for node-negative early breast cancer. They concluded that optimizing adjuvant chemotherapy decision making on the basis of the 70-gene signature is unlikely to be cost-effective compared with the use of Adjuvant! Online for decision making, or use of chemotherapy in place of adjuvant chemotherapy. First, it is important to understand that this analysis was conducted in France, which has a socialized health care system. The economic evaluation was conducted from the perspective of the French National Insurance Scheme, taking into account the medical costs, sick leave compensation, and an estimated cost of chemotherapy of €7,486, which was based on current unit costs for hospital stays and drugs in France. In the United States, the average cost of chemotherapy ranges from

Radiation Recall Pneumonitis During Systemic Treatment With Everolimus.

27,000 to

Potential cost savings by dose down-rounding of monoclonal antibodies in a community cancer center:

33,000, not including the other costs. That equates to €21,197 to €25,908. The cost of MammaPrint was €2,675 in the study by Bonastre et al and is

Normalization of Elevated Tumor Marker CA27-29 after Bilateral Lung Transplantation in a patient with Breast Cancer and Idiopathic Pulmonary Fibrosis

4,200 in the United States. Cost-effectiveness may be different in different health care systems. There have been several studies indicating that the use of a gene molecular profiling tool in early breast cancer is cost-effective, at least in the health care landscape of the United States. Second, granulocyte colony-stimulating factor was only used in 22% of the patients in the study. In addition, only three injections of pegfilgrastim were given to each patient, whereas in the United States, granulocyte colony-stimulating factor is frequently used after each adjuvant treatment in breast cancer. At present, this can translate into higher costs for chemotherapy use. Therefore, gene molecular profiling could still be a cost-effective approach in US health care. Last, the authors also mention the fact that chemotherapy cost has decreased as a result of the availability of generic docetaxel, which highlights the point that the same may apply to molecular profiling testing. In time, these tests will improve and become less expensive, similar to what has happened in BRCA testing. Ultimately, progress in conquering cancer will depend on coordinated, innovative efforts among all stakeholders—physicians, scientists, pharmaceutical companies, and governments—working with patience and dedication to accomplish the common goal of curing cancer.

Neoadjuvant Chemotherapy or Primary Debulking Surgery for Stage IIIC Ovarian Cancer.

Radiation recall syndrome is an acute inflammatory reaction developing at anatomical sites of previously irradiated tissue, weeks to months after the completion of radiation therapy. The distribution pattern of inflammation typically involves, and remains limited to, the boundaries of prior radiation treatment fields. Several classical chemotherapy drugs have been reported to have the potential for causing radiation recall syndrome. With the increasing availability and expanding use of novel biologic and targeted therapy anticancer drugs, isolated reports of radiation recall syndrome secondary to this class of agents are starting to appear in the literature. We describe a case of everolimus-induced radiation recall pneumonitis in a patient with metastatic renal cell cancer.

Impact of National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) and NCI Community Oncology Research Program (NCORP) on clinical trial (CT) activities in a community cancer center.

Purpose Increasing new cancer cases and approval of effective but expensive new drugs extending survival have led to unsustainable cancer care costs. Potential cost savings by a hypothetical dose down-rounding project of monoclonal antibodies at a community-based cancer center is presented. Methods From October 2014 through October 2015, metastatic cancer patients receiving monoclonal antibodies at CHI-Health St Francis Cancer Treatment Center in Grand Island, Nebraska, were identified through electronic health records. A total of 11 different types of monoclonal antibodies that were administered during the study period were identified. Trastuzumab, ofatumumab, and obinutuzumab did not require dose-rounding; thus, they were excluded from the analyses. Available vial size(s) and costs per milligram per average wholesale price for each monoclonal antibody were recorded. Costs of actual amounts prescribed were compared to the costs of theoretically reduced ≤5% and ≤10% doses rounded to the nearest vial sizes. Reduced doses resulting in a decreased number of opened vials qualified for meaningful dose down-rounding and were included in the analysis. Average actual dose reduction percentage resulting in cost savings for both groups was also calculated. Results A total of 728 doses of eight monoclonal antibodies suitable for dose down-rounding were identified. Vial sizes of pembrolizumab and ipilimumab did not allow for a meaningful dose down-rounding. At the ≤5% dose down-rounding, 255 of 728 doses (35%) qualified with a potential annual cost savings of