Matthew D. Hall

Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy

Abstract Background: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision. Material and methods: A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000–2013 from the National Oncology Data Alliance™ (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR. Results: On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT. Conclusion: Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery.

Definitive chemotherapy and radiotherapy in patients with stage II non-small cell lung cancer: A population-based outcomes study

OBJECTIVES There is a paucity of data on non-surgical outcomes specific to stage II non-small cell lung cancer (NSCLC) patients receiving definitive chemotherapy and radiation therapy (CRT). This study reports population-based outcomes for this subgroup, and investigates a radiation dose-response for overall survival. MATERIALS AND METHODS The National Oncology Data Alliance (NODA), a merging of multiple tumor registries maintained by Elekta(®) medical systems, was queried for stage II patients and CRT. Only curative cases (RT doses ≥59 Gy) were included. Both sequential and concurrent CRT were allowed. Univariate and Cox multivariate techniques were used to assess factors significant for overall survival. These factors included: gender, age, race, radiation dose, radiation total treatment time, stage, histology, tumor size, and chemotherapy sequence. RESULTS A total of 568 patients were included in the analysis, with a median follow-up of 12.9 months for surviving patients. Patients were treated between 2004 and 2014. Median survival was 20.5 months (95% confidence interval (CI) 18-23 months), with 16% patients alive at 5 years. Only gender was found to be significantly associated with survival in the Cox model. Although median survival was higher in patients receiving greater than 60 Gy (21 months, 95% CI 18-24 moths) compared to 59-60 Gy (16.5 months 95% CI 10-23 months), this was not statistically significant (p=0.6). CONCLUSIONS This is the first report on outcomes for stage II NSCLC patients receiving CRT as definitive therapy. Survival approximates stage III CRT patients from historical phase III trials. As an increasing aging population may parallel a rise in medically inoperable stage II patients, this study can provide useful information when reviewing treatment options.

Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

PURPOSE/OBJECTIVE(S) To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). METHODS AND MATERIALS Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. RESULTS Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. CONCLUSIONS Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the combined data analyzed here. Although data were limited to articles with 5-year actuarial estimates, the development of radiation-induced cataracts extends beyond this time.

Treatment outcomes for patients with chloroma receiving radiation therapy.

This study aims to analyse treatment outcomes, disease control and toxicity in patients with chloromas referred for radiation therapy (RT).

Proton Therapy for Pediatric Malignancies

In 2005–2011, the 5-year overall survival rate for children diagnosed with cancer reached 83.4%. While an increasing number of children are cured, two-thirds of childhood cancer survivors will develop chronic health conditions and 20% will die from toxicities or secondary malignancies as a result of their curative treatment. Decreasing the late effects of treatment while maintaining high tumor control rates are fundamental to improving survivorship. The primary advantage of proton therapy in pediatric cancer lies in the potential to reduce the late toxicities of radiation therapy. Efforts to quantify the therapeutic value of proton therapy relative to photon radiation are underway but require systematic tracking of disease control and adverse events. The economic value of proton therapy may be justified if the costs of managing acute symptoms, hormone deficiencies, normal-tissue complications, loss of productivity and achievement, and secondary cancers are considered in long-term survivors. As proton therapy matures, however, it is important to recognize that, unlike recent technological advancements in photon radiation delivery, proton therapy involves an inherently different radiobiology and clinicians should monitor unexpected toxicities. The purpose of this chapter is to review the rationale for proton therapy in pediatric malignancies and to objectively critique the existing evidence for proton therapy in this population.

The use of dose-escalated radiation for locally advanced non-small cell lung cancer in the U.S., 2004-2013.

Purpose/ObjectivesThe clinical effects of radiation dose-intensification in locally advanced non-small cell lung (NSCLCa) and other cancers are challenging to predict and are ideally studied in randomized trials. The purpose of this study was to assess the use of dose-escalated radiation for locally advanced NSCLCa in the U.S., 2004–2013, a period in which there were no published level 1 studies on dose-escalation.Materials/MethodsWe performed analyses on two cancer registry databases with complementary strengths and weaknesses: the National Oncology Data Alliance (NODA) 2004–2013 and the National Cancer Database (NCDB) 2004–2012. We classified locally advanced patients according to the use of dose-escalation (>70 Gy). We used adjusted logistic regression to assess the association of year of treatment with dose-escalated radiation use in two periods representing time before and after the closure of a cooperative group trial (RTOG 0617) on dose-escalation: 2004–2010 and 2010–2013. To determine the year in which a significant change in dose could have been detected had dose been prospectively monitored within the NODA network, we compared the average annual radiation dose per year with the forecasted dose (average of the prior 3 years) adjusted for patient age and comorbidities.ResultsWithin both the NODA and NCDB, use of dose-escalation increased from 2004 to 2010 (p < 0.0001) and decreased from 2010 to 2013 (p = 0.0018), even after controlling for potential confounders. Had the NODA network been monitoring radiation dose in this cohort, significant changes in average annual dose would have been detected at the end of 2008 and 2012.ConclusionsPatterns of radiation dosing in locally advanced NSCLCa changed in the U.S. in the absence of level 1 evidence. Monitoring radiation dose is feasible using an existing national cancer registry data collection infrastructure.

Changing patterns of care for locally advanced non-small cell lung cancer (NSCLC): Implications for quality initiatives.

302 Background: Our purpose was to assess the utilization of dose escalated radiotherapy (RT) in Stage III NSCLC patients in the United States from 2004-2013, a period when no Level 1 evidence on dose escalation was published. METHODS Data on all NSCLC patients treated with RT were extracted from the National Oncology Data Alliance (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER, but also contains RT dose fields that are manually verified by trained staff. Search algorithms to identify patients with complete RT dose data and who met the RTOG 0617 eligibility criteria were developed and validated by manual chart review at two institutions. The search algorithm positive predictive values for RT dose and RTOG 0617 eligibility were 97% and 91%, respectively. The primary endpoint was utilization of dose escalated RT, defined as >70 Gy. Multivariate logistic regression (MVA) was used to measure the association of treatment year with dose escalated RT use in two predefined periods straddling the early closure of RTOG 0617 on 6/17/2011: Period 1 2004-2010 and Period 2 2010-2013. To address potential limitations in generalizability, we repeated the same analysis in the National Cancer Database (NCDB). RESULTS The percentage of patients treated with >70 Gy increased monotonically from 22% in 2004 to 37% in 2010 and then declined to 20% in 2012. On MVA, increasing utilization of doses >70 Gy was observed during Period 1 (p<0.001) followed by decreasing use during Period 2 (p=0.002), after adjusting for the effects of other significant patient and hospital level variables. A similar utilization pattern was observed in the NCDB. After adjusting for age and comorbidities, significant changes in the mean RT dose prescribed compared to the 3-year moving average could have been detected in 2008 and 2012, if dose had been prospectively monitored in the NODA. CONCLUSIONS Our study suggests that US radiation oncologists increasingly utilized RT doses >70 Gy in Stage III NSCLC patients treated from 2004-2010 followed by a decline after 2010. RT dose may be an important standardization metric in national quality initiatives.

Impact of total lymph node count on staging and survival after neoadjuvant chemoradiation therapy for rectal cancer.

736 Background: Neoadjuvant chemoradiation therapy (CRT) results in fewer retrieved lymph nodes at the time of surgery for rectal cancer. The extent of optimal regional nodal dissection is based on guidelines developed before neoadjuvant CRT was commonly used. The purpose of this study is to assess the impact of the number of dissected and positive lymph nodes on overall survival (OS) for rectal cancer patients treated with neoadjuvant CRT. Methods: Treatment data were obtained by structured query on all patients with rectal adenocarcinoma (2000-2013) in the National Oncology Data Alliance, a proprietary database of merged tumor registries. Eligible patients were treated with neoadjuvant CRT followed by surgery and had complete data on the number of positive and dissected lymph nodes and dates of treatment. The relationships between number of lymph nodes examined and OS were separately analyzed in patients with 0, exactly 1, or any number of positive nodes. Results: The median number of lymph nodes examin...