Factors Associated With and Characteristics of Patients Receiving Proton Therapy at the End of Life.

Purpose: To identify the characteristics, indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at an academic medical center. Materials and Methods: A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010 to 2019. Patients were followed from the start of PBT until death or last follow-up. Acute (3 months) toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Imaging response was assessed using the Response Evaluation Criteria in Solid Tumors v1.1. The χ2 test was used to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with toxicity. Results: Bet299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Median age was 68 years (19-94 years), 58% male. The most common cancer was nonsmall cell lung cancer (27%). Patients were treated for symptom palliation alone (11%), durable control (57%), curative intent (16%), local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received reirradiation. Median treatment time was 32 days (1-189 days). Acute toxicity was noted in 85% of the patients (31% G1, 53% G2, 15% G3). Thirteen patients (4%) experienced chronic toxicity. Breast and hematologic malignancy were associated with palliative intent χ2 (1, N = 14) = 17, P = .013; (χ2 (1, N = 14) = 18, P = .009). Conclusion: The number of patients treated with PBT at the EOL was low compared to all comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Some patients spent a large portion of their remaining days on treatment. A prognostic indicator may better optimize patient selection for PBT at the EOL.

Is Detection of Relapse by Surveillance Imaging Associated With Longer Survival in Patients With Rhabdomyosarcoma?

BACKGROUND: We investigated whether surveillance imaging had an impact on post-relapse survival in patients with rhabdomyosarcoma (RMS). We hypothesized that relapse detected by imaging (group IM) would be associated with longer survival compared with relapse detected with a clinical sign or symptom (group SS). MATERIALS AND METHODS: We performed an observational multi-institutional study in 127 patients with relapsed RMS comparing overall survival (OS) after relapse using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Relapse was detected in 60 (47%) group IM and 67 (53%) SS patients. Median follow-up in survivors was 4 years (range 1.0 to 16.7 y). Four-year OS rates were similar between group IM (28%, 95% confidence interval [CI]: 14%-40%) and SS (21%, 95% CI: 11%-31%) ( P =0.14). In multivariable analyses accounting for institution, age at diagnosis, time to relapse, risk group at diagnosis, and primary site, not receiving chemotherapy (hazard ratio [HR]: 6.8, 95% CI: 2.8-16.6), radiation (HR: 3, 95% CI: 1.7-5.3), or surgery (HR: 2.8, 95% CI: 1.6-4.8) after relapse were independently associated with poor OS. CONCLUSION: These results on whether surveillance imaging provides survival benefit in patients with relapsed RMS are inconclusive. Larger studies are needed to justify current surveillance recommendations. Chemotherapy, radiotherapy and surgery to treat recurrence prolong OS.

Heterogeneity in Radiotherapeutic Parameter Assumptions in Cost-Effectiveness Analyses in Prostate Cancer: A Call for Uniformity.

OBJECTIVES: Cost-effectiveness analyses (CEAs) may provide useful data to inform management decisions depending on the robustness of a model's input parameters. We sought to determine the level of heterogeneity in health state utility values, transition probabilities, and cost estimates across published CEAs assessing primarily radiotherapeutic management strategies in prostate cancer. METHODS: We conducted a systematic review of prostate cancer CEAs indexed in MEDLINE between 2000 and 2018 comparing accepted treatment modalities across all cancer stages. Search terms included "cost effectiveness prostate," "prostate cancer cost model," "cost utility prostate," and "Markov AND prostate AND (cancer OR adenocarcinoma)." Included studies were agreed upon. A Markov model was designed using the parameter estimates from the systematic review to evaluate the effect of estimate heterogeneity on strategy cost acceptability. RESULTS: Of 199 abstracts identified, 47 publications were reviewed and 37 were included; 508 model estimates were compared. Estimates varied widely across variables, including gastrointestinal toxicity risk (0%-49.5%), utility of metastatic disease (0.25-0.855), intensity-modulated radiotherapy cost ($21 193-$61 996), and recurrence after external-beam radiotherapy (1.5%-59%). Multiple studies assumed that different radiotherapy modalities delivering the same dose yielded varying cancer control rates. When using base estimates for similar parameters from included studies, the designed model resulted in 3 separate acceptability determinations. CONCLUSIONS: Significant heterogeneity exists across parameter estimates used to perform CEAs evaluating treatment for prostate cancer. Heterogeneity across model inputs yields variable conclusions with respect to the favorability and cost-effectiveness of treatment options. Decision makers are cautioned to review estimates in CEAs to ensure they are up to date and relevant to setting and population.

Radiation Therapy for Plasma Cell Disease of the Brain and Skull: Poor Palliation and Survival After Treatment for Central Nervous System Involvement.

PURPOSE: Myeloma lesions of the head can present with central nervous system (CNS) involvement (leptomeningeal disease or brain metastasis), cranial neuropathy (CN), or impending neurologic involvement (INI). We analyzed response and survival after palliative radiation therapy (RT) to the brain and/or skull for myeloma lesions to determine whether CNS involvement fared worse than other RT indications. METHODS AND MATERIALS: We retrospectively analyzed 54 palliative RT courses administered at our institution from 2008 to 2019. Eleven courses were administered for CNS disease, 28 for CN, and 15 for INI. Demographic, disease, and RT variables were recorded as well as clinical response, radiographic response, and survival. Univariate analyses were performed for differences between groups, effects of clinical and RT treatment factors on response, as well as dose response. Survival was analyzed with the Kaplan-Meier method and compared by the log-rank test. RESULTS: This heavily pretreated cohort received a median of 20 to 24 Gy, most often to the base of skull, orbit(s), calvarium, or whole brain. Any clinical response (partial or complete vs no response or progressive disease) was significantly more likely for patients with CN and INI when collectively compared with patients with CNS disease (P < .001). Dose response was significant for doses ≥15 and 20 Gy for the whole cohort (P = .026 and .005, respectively) and patients with CN/INI (P = .023 and .002, respectively). Additionally, patients with high-risk cytogenetics were less likely to clinically respond (P = .009). Patients with CNS disease had worse survival (P = .005). CONCLUSIONS: Patients with leptomeningeal disease/brain metastasis have poor clinical response and survival after RT and their responses do not demonstrate a dose response. Given these poor outcomes, the potential benefit of RT may be limited for some patients who may be alternatively managed by supportive care or short RT courses. Patients with CN/INI have longer survival and better response rates and may benefit from RT courses ≥15 to 20 Gy.

Palliative Radiotherapy for Advanced Cancers: Indications and Outcomes.

Palliative radiotherapy (PRT) is well-tolerated, effective treatment for pain, bleeding, obstruction, and other symptoms/complications of advanced cancer. It is an important component of multidisciplinary management. It should be considered even for patients with poor prognosis, because it can offer rapid symptomatic relief. Furthermore, expanding indications for treatment of noncurable disease have shown that PRT can extend survival for select patients. For those with good prognosis, advanced PRT techniques may improve the therapeutic ratio, maximizing tumor control while limiting toxicity. PRT referral should be considered for any patient with symptomatic or asymptomatic sites of disease where local control is desired.

Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents.

PURPOSE: Metastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies. METHODS AND MATERIALS: A retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing. RESULTS: Eighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%). CONCLUSIONS: PRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.

Impact of Tumor-Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor-infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set. MATERIALS AND METHODS: A retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score-weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding. RESULTS: A total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602-0.933) and brisk (HR, 0.499; 95% CI, 0.338-0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550-0.944; Brisk: HR, 0.483; 95% CI, 0.286-0.814). CONCLUSION: The presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision-making with respect to treatment intensification in high-risk patients. IMPLICATIONS FOR PRACTICE: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor-infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision-making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node-negative patients, or offering closer follow-up.

A Retrospective Study of Rapid Symptom Response in Bleeding Gynecologic Malignancies With Short Course Palliative Radiation Therapy: Less is More.

CONTEXT: Advanced gynecologic malignancies can cause significant vaginal bleeding. Radiotherapy (RT) is often used to palliate symptoms, but limited data exist concerning the optimal dose and expected time to bleeding hemostasis in this population. OBJECTIVES: 1) To investigate the overall hemostasis response and kinetics of hemostasis in women with gynecologic malignancies receiving palliative RT. 2) To compare the efficacy of short-course RT (SCRT, less than or equal to five fractions, >3.5 Gy per fraction) vs. conventionally fractionated long-course regimens (greater than five fractions). METHODS: We identified women receiving palliative RT for bleeding gynecologic malignancies. Initial and maximal hemostasis responses (IHR and MHR) were recorded and categorized as progressive bleeding (PD), stable disease (SD), partial response (PR), or complete response (CR). Clinical variables were correlated with response or toxicity using binary logistic regression statistical methods. RESULTS: Thirty-three women (median age 63) were identified between 2010 and 2019. Median follow-up and survival after RT were 131 days. About 54.5% (18 of 33) received SCRT. Median time to IHR was five days (two-and-a-half days with SCRT) and 78.8% (26 of 33) responded during treatment. Median time to MHR was 13 days. About 100% achieved PR or CR at MHR. Rates of CR were similar between SCRT (83%) and conventionally fractionated schedules (87%). Average durability of hemostatic control was 5.4 months. Overall rate of rebleeding and Grade 3+ toxicity was 9.1% (3 of 33 each). CONCLUSION: Women receiving SCRT for bleeding gynecologic malignancies achieved rapid symptom control (often during treatment) with minimal rebleeding. In a population whose median survival is four months, SCRT effectively addresses symptomatic disease while minimizing patient burden and toxicity.

Making the Most of a Crisis: A Proposal for Network-Based Palliative Radiation Therapy to Reduce Travel Toxicity.

A multipronged model is proposed to improve the delivery of palliative radiotherapy by increasing access to care and reducing travel burden for patients.

Robust treatment planning in whole pelvis pencil beam scanning proton therapy for prostate cancer.

Whole-pelvis pencil beam scanning (PBS) proton therapy is utilized in both the intact and post-operative settings in patients with prostate cancer. As whole pelvis prostate radiotherapy has traditionally been delivered with standard photon beams, limited evidence and technical descriptions have been reported regarding the use of proton therapy. Here we present two robust three-field treatment planning approaches utilized to maximize target coverage in the presence of anatomic and delivery uncertainties. Both techniques, conventional optimization (CO) and robust optimization (RO), create treatment plans with acceptable target coverage and sparing of organs at risk (OAR). While the RO method is less time intensive and may theoretically allow for superior OAR sparing and improved robustness, the CO method can be implemented by institutions who do not have RO capabilities.

Advanced radiotherapy for metastatic disease-a major stride or a futile effort?

Radiation Oncologists are involved in patient care from cancer diagnosis to the end of life, and 30-40% of radiation courses are delivered with palliative intent. Recent data has supported the use of advanced technology in select metastatic settings with respect to improvements in symptom response, local control, and even survival. Practicing physicians must thus be aware of the appropriate uses of advanced radiation techniques, especially with the development of life-prolonging targeted therapy and immunotherapies for individuals with advanced disease. As patients live longer with metastatic burden clinicians may increasingly encounter complex clinical scenarios that strike a 'middle ground' between purely palliative or curative intent. That is, the situation in which aggressive palliation is warranted to provide durable local control and potentially improve progression free and overall survival. This article is intended to provide a framework that clinicians can utilize when considering treatment options in complex palliative settings. The review begins with an introduction to advanced radiation techniques, their relevance with respect to histology, and the importance of dosing and fractionation. It further explores the data supporting the use of advanced techniques in the setting of brain metastases, lung metastases, non-spine bone metastases, spinal bone metastases, spinal cord compression, and liver metastases. Each of the sections also discusses specific site-related factors to consider that may sway a practitioner toward or against the use of such techniques. Where applicable, outcomes of re-irradiation are also discussed.

Supportive cryotherapy: a review from head to toe.

CONTEXT: Conventional chemotherapy leads to multiple adverse mucocutaneous complications such as oral mucositis, alopecia, ocular toxicity, and onycholysis. Limited pharmacologic interventions are available for preventing these clinical problems. OBJECTIVES: This study aimed to critically review the role of cryotherapy (regional hypothermia) for alleviating these adverse symptoms. METHODS: A narrative review was performed, with an emphasis on randomized controlled trials. A comprehensive search using PubMed, Ovid, Embase, and MEDLINE(®) was completed. References of all cited articles also were reviewed. Data from the review were composed of articles published between 1970 and May 2013. RESULTS: Available evidence suggests that regional hypothermia decreases the burden of chemotherapy-related oral mucositis, alopecia, ocular toxicity, and onycholysis. The major limitations of studies include the absence of blinded control groups and variable clinical end points. CONCLUSION: Regional hypothermia decreases the burden of these four chemotherapy-induced complications and is well tolerated. More research is needed to determine what subgroups of cancer patients are most likely to respond to different types of regional hypothermia, the ideal duration of cooling needed, and further improve the ease of use of the cooling devices.