Max Norvell

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.

Radiation Recall Pneumonitis During Systemic Treatment With Everolimus.

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.

Fulvestrant (F) and letrozole (L) combination in second-line or more for estrogen receptor (ER)-positive (+) metastatic breast cancer (MBC): Efficacy and predictive factors of response.

e11137 Background: Preclinical data show that complete estrogen blockade, by down regulating ER and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone. Combination of an aromatase inhibitor (AI) and F may be an optimal second-line therapy by preventing activation of growth factor pathways and possible cross talk with ER. One clinical study has shown no benefit of adding anastrozole (A) to F at first relapse. No clinical data on combination L and F in the second line or more MBC is available. METHODS ER+, progesterone receptor(PgR) + or negative (-) MBC patients (pts) with prior chemo and/or non-AI endocrine(E) therapy were treated with L and F. Pts with complete/partial response, or stable disease were considered to have clinical benefit (CR+PR+SD). The predictive effect of age, number of prior regimens, ER/PgR status, and lobular histology were examined using Chi-square test. RESULTS 32 pts received L (2.5 mg/d po) plus F (250 mg/month, im). Mean age was 70 (Range: 35-92), median number of prior treatments was 2 (range1-6). 25 pts had ER+/PgR+, 7 pts had ER+/PgR- tumors. 25 pts had prior non-AI E therapy. 8 pts had lobular histology. Overall clinical benefit rate was 71% (3 CR, 7 PR, 13 SD). Mean duration of the clinical benefit was 15 months (range 2-38). 8 pts progressed under therapy. Age > 65 vs younger (89% vs 46%, p=0.007), prior treatments< 4 vs more (87% vs 25%, p=0.0007) and ER+/PgR+ vs ER+/PgR- (84% vs 42%, p<0.05) were predictive of clinical benefit; lobular histology and prior E therapy did not have any effect on clinical benefit (p>0.05). CONCLUSIONS In pretreated MBC, combination of L and F can be effective with mean clinical benefit duration of 15 months. Older age, < 4 prior lines of therapy, and expression of both ER/PgR are predictive of clinical benefit while lobular histology and prior E therapy are not. L and F combination can be a reasonable option in selected group of MBC pts and should be further evaluated in larger studies using high dose F schedule.