R.B. Jimenez

Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

PURPOSE To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). METHODS AND MATERIALS All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. RESULTS Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients had medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. CONCLUSIONS Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.

Outcomes after whole brain reirradiation in patients with brain metastases.

PURPOSE Patients with brain metastases are often treated with whole brain radiation therapy (WBRT) for purposes of palliation. The treatment of those who experience subsequent intracranial disease progression can include a second course of WBRT, although there is controversy surrounding its safety and efficacy. This study examines the outcomes in patients at Massachusetts General Hospital who underwent reirradiation. PATIENTS AND METHODS We examined the medical records of 17 patients at Massachusetts General Hospital with brain metastases who were initially treated with WBRT between 2002 and 2008 and were subsequently retreated with a second course of WBRT. The median dose for the first course of WBRT was 35 Gy (range, 28-40 Gy), with a fraction size of 2 to 3 Gy (median, 2.5 Gy). The median dose at reirradiation was 21.6 Gy (range, 14-30 Gy), with a fraction size of 1.5 to 2 Gy (median, 1.8 Gy). RESULTS The second course of WBRT was administered upon radiographic disease progression in all patients. Of 10 patients with complete follow-up data, 8 patients experienced complete or partial symptom resolution, and 2 did not show clinical improvement. The time to radiographic progression was 5.2 months. The median overall survival for all patients after diagnosis of metastases was 24.7 months. The median survival time after initiation of reirradiation was 5.2 months (95% CI, 1.3-8.7). In 6 patients with stable extracranial disease, the median survival time after retreatment was 19.8 months (95% CI, 2.7-∞), compared with 2.5 months (95% CI, 0.8-5.5) for those with extracranial disease progression (p = 0.05). Acute adverse reactions occurred in 70.5% of patients but were mild to moderate in severity. CONCLUSION In select patients and especially those with stable extracranial disease, reirradiation may be an appropriate and effective intervention to provide symptomatic relief and slow intracranial disease progression. Side effects were minimal and did not cause substantial changes in quality of life.

Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: A treatment planning study

BACKGROUND AND PURPOSE Delivery of post-mastectomy radiation (PMRT) in women with bilateral implants represents a technical challenge, particularly when attempting to cover regional lymph nodes. Intensity modulated proton therapy (IMPT) holds the potential to improve dose delivery and spare non-target tissues. The purpose of this study was to compare IMPT to three-dimensional (3D) conformal radiation following bilateral mastectomy and reconstruction. MATERIALS AND METHODS Ten IMPT, 3D conformal photon/electron (P/E), and 3D photon (wide tangent) plans were created for 5 patients with breast cancer, all of whom had bilateral breast implants. Using RTOG guidelines, a physician delineated contours for both target volumes and organs-at-risk. Plans were designed to achieve 95% coverage of all targets (chest wall, IMN, SCV, axilla) to a dose of 50.4 Gy or Gy (RBE) while maximally sparing organs-at-risk. RESULTS IMPT plans conferred similar target volume coverage with enhanced homogeneity. Both mean heart and lung doses using IMPT were significantly decreased compared to both P/E and wide tangent planning. CONCLUSIONS IMPT provides improved homogeneity to the chest wall and regional lymphatics in the post-mastectomy setting with improved sparing of surrounding normal structures for woman with reconstructed breasts. IMPT may enable women with mastectomy to undergo radiation therapy without the need for delay in breast reconstruction.

Clinical Trial Participation among Ethnic/Racial Minority and Majority Patients with Advanced Cancer: What Factors Most Influence Enrollment?

BACKGROUND Studies using administrative data report that racial/ethnic minority patients enroll in clinical trials less frequently than white patients. We studied a cohort of terminally ill cancer patients to determine a) if racial/ethnic minority patients have lower rates of drug trial enrollment than white patients once socioeconomic characteristics are accounted for and b) what factors most influence drug trial enrollment among patients with advanced canceroverall. METHODS Coping with Cancer (CwC) is a National Cancer Institute/National Institute of Mental Health (NCI/NIMH)-funded multisite, prospective, longitudinal study of patients with advanced cancer. Baseline interviews assessed drug trial enrollment as well as socioeconomic characteristics. Logistic regression models estimated associations between drug trial enrollment and baseline characteristics. Stepwise, backward, and subset model selection was applied to select the final model where characteristics significant at α=0.05 remained in the model. RESULTS At a median of 4.4 months prior to death, 35 of 358 patients (9.8%) were enrolled in a drug trial. In unadjusted analyses, race/ethnicity, health insurance, performance status, recruitment site, cancer type, preference for life-extending care, and lack of end-of-life care planning were associated (p<0.05) with enrollment. In multivariable analysis, patient race/ethnicity was not significantly associated with enrollment. Patients who reported not having an end-of-life discussion (adjusted odds ratio [AOR], 0.18; 95% confidence interval [CI] 0.04-0.83) and those not wanting to discuss life expectancy (AOR, 0.31; 95%CI 0.12-0.79) were more likely to be trial enrollees. CONCLUSION Patient race/ethnicity was not associated with clinical trial enrollment after adjustment for socioeconomic covariates. Patients with advanced cancer endorsing less engagement in end-of-life planning were more likely to be enrolled in a clinical trial.

Predictors of intensive end-of-life and hospice care in Latino and white advanced cancer patients.

BACKGROUND The role of end-of-life (EOL) care preferences and conversations in receipt of care near death for Latinos is unclear. OBJECTIVE This study examines rates and predictors of intensive EOL and hospice care among Latino and white advanced cancer patients. DESIGN Two-hundred-and-ninety-two self-reported Latino (n=58) and white (n=234) Stage IV cancer patients participated in a U.S. multisite, prospective, cohort study from September 2002 to August 2008. The Latino and white, non-Hispanic participants were interviewed and followed until death, a median of 118.5 days from baseline. MEASUREMENTS Patient-reported, baseline predictors of EOL care included EOL care preference; terminal illness acknowledgement; EOL discussion; completion of a DNR order; and religious coping. Caregiver postmortem interviews provided information regarding EOL care received. Intensive EOL care was defined as resuscitation and/or ventilation followed by death in an intensive care unit. Hospice was either in- or outpatient. RESULTS Latino and white patients received intensive EOL and hospice care at similar rates (5.2% and 3.4% for intensive care, p=0.88; 70.7% versus 73.4% for hospice, p=0.33). No white or Latino patient who reported a DNR order or EOL discussion at baseline received intensive EOL care. Religious coping and a preference for life-extending care predicted intensive EOL care for white patients (adjusted odds ratio [aOR] 6.69 [p=0.02] and aOR 6.63 [p=0.01], respectively), but not for Latinos. No predictors were associated with Latino hospice care. CONCLUSIONS EOL discussions and DNR orders may prevent intensive EOL care among Latino cancer patients. Efforts should continue to engage Latino patients and caregivers in these activities.

Establishing Cost-Effective Allocation of Proton Therapy for Breast Irradiation

PURPOSE Cardiac toxicity due to conventional breast radiation therapy (RT) has been extensively reported, and it affects both the life expectancy and quality of life of affected women. Given the favorable oncologic outcomes in most women irradiated for breast cancer, it is increasingly paramount to minimize treatment side effects and improve survivorship for these patients. Proton RT offers promise in limiting heart dose, but the modality is costly and access is limited. Using cost-effectiveness analysis, we provide a decision-making tool to help determine which breast cancer patients may benefit from proton RT referral. METHODS AND MATERIALS A Markov cohort model was constructed to compare the cost-effectiveness of proton versus photon RT for breast cancer management. The model was analyzed for different strata of women based on age (40 years, 50 years, and 60 years) and the presence or lack of cardiac risk factors (CRFs). Model entrants could have 1 of 3 health states: healthy, alive with coronary heart disease (CHD), or dead. Base-case analysis assumed CHD was managed medically. No difference in tumor control was assumed between arms. Probabilistic sensitivity analysis was performed to test model robustness and the influence of including catheterization as a downstream possibility within the health state of CHD. RESULTS Proton RT was not cost-effective in women without CRFs or a mean heart dose (MHD) <5 Gy. Base-case analysis noted cost-effectiveness for proton RT in women with ≥1 CRF at an approximate minimum MHD of 6 Gy with a willingness-to-pay threshold of

Postmastectomy radiation therapy technique and cardiopulmonary sparing: A dosimetric comparative analysis between photons and protons with free breathing versus deep inspiration breath hold

100,000/quality-adjusted life-year. For women with ≥1 CRF, probabilistic sensitivity analysis noted the preference of proton RT for an MHD ≥5 Gy with a similar willingness-to-pay threshold. CONCLUSIONS Despite the cost of treatment, scenarios do exist whereby proton therapy is cost-effective. Referral for proton therapy may be cost-effective for patients with ≥1 CRF in cases for which photon plans are unable to achieve an MHD <5 Gy.

United States Acculturation and Cancer Patients’ End-of-Life Care

PURPOSE Dosimetric studies have suggested greater cardiopulmonary sparing with protons over photons for left-sided postmastectomy radiation therapy (PMRT). Modern techniques such as deep inspiration breath hold (DIBH) can help spare the heart. This analysis compares photon and proton delivery with and without DIBH. METHODS AND MATERIALS Ten women with left breast cancer referred for PMRT on a prospective clinical trial with unfavorable cardiac anatomy underwent free breathing (FB) and DIBH computed tomography simulation. A partially wide tangent photon (PWTF) during DIBH, passively scattered proton during FB, pencil-beam scanning (PBS) proton during FB, and PBS proton during DIBH plan was completed for each patient. Plans were designed to achieve 95% prescription dose coverage to 95% of chest wall and regional lymphatics while maximally sparing heart and lungs. RESULTS All techniques resulted in similar target coverage, although protons improved homogeneity indices and cardiopulmonary sparing (omnibus P < .0001 for each metric). Heart/lung metrics for PWTF with DIBH, scattered protons with FB, PBS protons with FB, and PBS protons with DIBH, respectively, were as follows: mean heart dose (2.09, 0.39, 0.98, 0.71 Gy relative biological effectiveness [RBE]), mean left ventricle dose (3.72, 0.08, 0.19, 0.21 GyRBE), V20 left ventricle (2.73, 0.03, 0, 0%), maximum left anterior descending artery dose (46.14, 8.28, 4.58, 4.63 GyRBE), mean lung dose (13.30, 5.74, 7.63, 7.49 GyRBE), and V20 lung (26.04, 12.04, 15.18, 14.43 %). Pairwise testing confirmed an improvement in each metric with all proton plans compared with PWTF with DIBH; there were no differences in homogeneity indices or cardiopulmonary sparing between passively scattered and PBS protons, regardless of addition of DIBH. CONCLUSIONS For left-sided PMRT, passively scattered or PBS protons with or without DIBH improves homogeneity and cardiopulmonary sparing without compromise in target coverage compared with PWTF photons with DIBH. Furthermore, the addition of DIBH to proton therapy did not provide a significant dosimetric benefit.

Role of bone-modifying agents in metastatic breast cancer: An American Society of Clinical oncology-cancer Care Ontario focused guideline update

Background Culture shapes how people understand illness and death, but few studies examine whether acculturation influences patients’ end-of-life treatment preferences and medical care. Methods and Findings In this multi-site, prospective, longitudinal cohort study of terminally-ill cancer patients and their caregivers (n = 171 dyads), trained interviewers administered the United States Acculturation Scale (USAS). The USAS is a 19-item scale developed to assess the degree of “Americanization” in first generation or non-US born caregivers of terminally-ill cancer patients. We evaluated the internal consistency, concurrent, criterion, and content validity of the USAS. We also examined whether caregivers’ USAS scores predicted patients’ communication, treatment preferences, and end-of-life medical care in multivariable models that corrected for significant confounding influences (e.g. education, country of origin, English proficiency). The USAS measure was internally consistent (Cronbach α = 0.98); and significantly associated with US birthplace (r = 0.66, P<0.0001). USAS scores were predictive of patients’ preferences for prognostic information (AOR = 1.31, 95% CI:1.00–1.72), but not comfort asking physicians’ questions about care (AOR 1.23, 95% CI:0.87–1.73). They predicted patients’ preferences for feeding tubes (AOR = 0.68, 95% CI:0.49–0.99) and wish to avoid dying in an intensive care unit (AOR = 1.36, 95% CI:1.05–1.76). Scores indicating greater acculturation were also associated with increased odds of patient participation in clinical trials (AOR = 2.20, 95% CI:1.28–3.78), compared with lower USAS scores, and greater odds of patients receiving chemotherapy (AOR = 1.59, 95% CI:1.20–2.12). Conclusion The USAS is a reliable and valid measure of “Americanization” associated with advanced cancer patients’ end-of-life preferences and care. USAS scores indicating greater caregiver acculturation were associated with increased odds of patient participation in cancer treatment (chemotherapy, clinical trials) compared with lower scores. Future studies should examine the effects of acculturation on end-of-life care to identify patient and provider factors that explain these effects and targets for future interventions to improve care (e.g., by designing more culturally-competent health education materials).

The impact of different stereotactic radiation therapy regimens for brain metastases on local control and toxicity

Purpose To update, in collaboration with Cancer Care Ontario (CCO), key recommendations of the American Society of Clinical Oncology (ASCO) guideline on the role of bone-modifying agents (BMAs) in metastatic breast cancer. This focused update addressed the new data on intervals between dosing and the role of BMAs in control of bone pain. Methods A joint ASCO-CCO Update Committee conducted targeted systematic literature reviews to identify relevant studies. Results The Update Committee reviewed three phase III noninferiority trials of dosing intervals, one systematic review and meta-analysis of studies of de-escalation of BMAs, and two randomized trials of BMAs in control of pain secondary to bone metastases. Recommendations Patients with breast cancer who have evidence of bone metastases should be treated with BMAs. Options include denosumab, 120 mg subcutaneously, every 4 weeks; pamidronate, 90 mg intravenously, every 3 to 4 weeks; or zoledronic acid, 4 mg intravenously every 12 weeks or every 3 to 4 weeks. The analgesic effects of BMAs are modest, and they should not be used alone for bone pain. The Update Committee recommends that the current standard of care for supportive care and pain management-analgesia, adjunct therapies, radiotherapy, surgery, systemic anticancer therapy, and referral to supportive care and pain management-be applied. Evidence is insufficient to support the use of one BMA over another. Additional information is available at www.asco.org/breast-cancer-guidelines and www.asco.org/guidelineswiki .