Kiran Devisetty

Concurrent Chemotherapy and Intensity-Modulated Radiation Therapy for Anal Canal Cancer Patients: A Multicenter Experience

PURPOSE To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography-based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. RESULTS Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. CONCLUSION Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.

A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy

Using previous dosimetric analysis methods, we identified the volume of bowel receiving 30 Gy (V(30)) correlated with acute gastrointestinal (GI) toxicity in anal cancer patients treated with intensity-modulated radiation therapy and concurrent chemotherapy. For V(30)>450 cc and < or =450 cc, acute GI toxicity was 33% and 8%, respectively (p=0.003).

Cisplatin and Etoposide Versus Carboplatin and Paclitaxel With Concurrent Radiotherapy for Stage III Non–Small-Cell Lung Cancer: An Analysis of Veterans Health Administration Data

PURPOSE The optimal chemotherapy regimen to use with radiotherapy in stage III non-small-cell lung cancer is unknown. Here, we compare the outcome of patents treated within the Veterans Health Administration with either etoposide-cisplatin (EP) or carboplatin-paclitaxel (CP). METHODS We identified patients treated with EP and CP with concurrent radiotherapy from 2001 to 2010. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods and an instrumental variables analysis. Comorbidities and treatment complications were identified through administrative data. RESULTS A total of 1,842 patients were included; EP was used in 27% (n = 499). Treatment with EP was not associated with a survival advantage in a Cox proportional hazards model (hazard ratio [HR], 0.97; 95% CI, 0.85 to 1.10), a propensity score matched cohort (HR, 1.07; 95% CI, 0.91 to 1.24), or a propensity score adjusted model (HR, 0.97; 95% CI, 0.85 to 1.10). In an instrumental variables analysis, there was no survival advantage for patients treated in centers where EP was used more than 50% of the time as compared with centers where EP was used in less than 10% of the patients (HR, 1.07; 95% CI, 0.90 to 1.26). Patients treated with EP, compared with patients treated with CP, had more hospitalizations (2.4 v 1.7 hospitalizations, respectively; P < .001), outpatient visits (17.6 v 12.6 visits, respectively; P < .001), infectious complications (47.3% v 39.4%, respectively; P = .0022), acute kidney disease/dehydration (30.5% v 21.2%, respectively; P < .001), and mucositis/esophagitis (18.6% v 14.4%, respectively; P = .0246). CONCLUSION After accounting for prognostic variables, patients treated with EP versus CP had similar overall survival, but EP was associated with increased morbidity.

External Beam Radiation Therapy After Transurethral Resection of the Prostate: A Report on Acute and Late Genitourinary Toxicity

PURPOSE To describe genitourinary (GU) toxicity in men with a history of transurethral resection of the prostate (TURP) treated with external beam radiation therapy (EBRT) for prostate cancer. METHODS AND MATERIALS Seventy-one men with a history of TURP were treated with EBRT for prostate cancer. The median time from TURP to EBRT was 15 months. The median EBRT dose was 70 Gy, and 21 men (30%) received androgen deprivation therapy (ADT). Acute GU toxicity and late GU toxicity were scored by Radiation Therapy Oncology Group criteria and compared with a cohort of 538 men without prior TURP. The median follow-up for men with TURP and men without TURP was 40 months and 50 months, respectively (p = 0.7605). RESULTS The rate of acute Grade 2 GU toxicity or higher was 41%, and was increased with a history of more than 1 TURP (73% vs. 31%, p = 0.0036). The 4-year rate of freedom from late Grade 3 GU toxicity or higher was 84%, and was decreased with ADT (45% vs. 95% without ADT, p = 0.0024). By last follow-up, maximal GU toxicity tended to resolve (p < 0.0001) and there was no worsening of urinary symptom scores (p = 0.6911). Compared to men without a prior TURP, TURP patients had a lower rate of freedom from late Grade 3 toxicity or higher (84% vs. 96%, p = 0.0483). Multivariate analysis suggested a higher rate of late Grade 3 toxicity or higher with TURP (risk ratio, 2.87; p = 0.0612) and EBRT dose of 74 Gy or greater (risk ratio, 2.26; p = 0.0521). CONCLUSIONS Men treated for prostate cancer with EBRT after TURP have a higher risk of severe GU toxicity; however, the overall incidence is low, and toxicity tends not to persist.

Low-Dose Neoadjuvant External Beam Radiation Therapy for Soft Tissue Sarcoma

PURPOSE For soft tissue sarcoma, neoadjuvant external beam radiation therapy (EBRT) to 50 Gy has the same local control (LC) and overall survival as postoperative radiation therapy (PORT) to 60 Gy, but with increased wound complications. We examined whether low-dose neoadjuvant EBRT would decrease acute toxicity while maintaining LC. METHODS AND MATERIALS From 1971 to 2008, 1,765 patients with nonmetastatic soft tissue sarcoma were treated with radiation therapy at Massachusetts General Hospital. We identified 42 patients treated with low-dose neoadjuvant EBRT (median, 20 Gy; range, 16-26) followed by surgical resection and PORT. PORT included EBRT (25 patients; median, 40 Gy; range, 20-56.2), brachytherapy (13 patients; median, 42 Gy; range, 26-50), and intraoperative radiation therapy (IORT) (4 patients; median, 12.5 Gy; range, 8-20). The median total dose was 63.3 Gy (range, 28-78.4). RESULTS Median follow-up was 36 months (range, 4-318). Severe acute wound complications were reported in 15 patients (36%) and correlated to PORT technique (16% EBRT, 69% brachytherapy, 50% IORT, p = 0.004). The 5-year LC was 73% and correlated to PORT technique (68% EBRT, 100% brachytherapy, 50% IORT, p = 0.03) and histology (p = 0.05), with a trend to improvement if >60 Gy (p = 0.10). The 5-year overall survival was 65% and correlated to extent of resection (p < 0.001) and margin status (p < 0.001). CONCLUSIONS Despite using low-dose neoadjuvant EBRT, we report a high rate of severe acute wound complications that was strongly associated with brachytherapy. Modification of the brachytherapy technique may decrease acute toxicity while maintaining excellent local control. Further study must be conducted before recommending broader application.

Validation of Normal Tissue Complication Probability Predictions in Individual Patient: Late Rectal Toxicity

PURPOSE To perform validation of risk predictions for late rectal toxicity (LRT) in prostate cancer obtained using a new approach to synthesize published normal tissue complication data. METHODS AND MATERIALS A published study survey was performed to identify the dose-response relationships for LRT derived from nonoverlapping patient populations. To avoid mixing models based on different symptoms, the emphasis was placed on rectal bleeding. The selected models were used to compute the risk estimates of grade 2+ and grade 3+ LRT for an independent validation cohort composed of 269 prostate cancer patients with known toxicity outcomes. Risk estimates from single studies were combined to produce consolidated risk estimates. An agreement between the actuarial toxicity incidence 3 years after radiation therapy completion and single-study or consolidated risk estimates was evaluated using the concordance correlation coefficient. Goodness of fit for the consolidated risk estimates was assessed using the Hosmer-Lemeshow test. RESULTS A total of 16 studies of grade 2+ and 5 studies of grade 3+ LRT met the inclusion criteria. The consolidated risk estimates of grade 2+ and 3+ LRT were constructed using 3 studies each. For grade 2+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.537 compared with 0.431 for the best-fit single study. For grade 3+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.477 compared with 0.448 for the best-fit single study. No evidence was found for a lack of fit for the consolidated risk estimates using the Hosmer-Lemeshow test (P=.531 and P=.397 for grade 2+ and 3+ LRT, respectively). CONCLUSIONS In a large cohort of prostate cancer patients, selected sets of consolidated risk estimates were found to be more accurate predictors of LRT than risk estimates derived from any single study.

Consolidating Risk Estimates for Radiation-Induced Complications in Individual Patient: Late Rectal Toxicity

PURPOSE To test the feasibility of a new approach to synthesize published normal tissue complication data using late rectal toxicity in prostate cancer as an example. METHODS AND MATERIALS A data survey was performed to identify the published reports on the dose-response relationships for late rectal toxicity. The risk estimates for Grade 1 or greater, Grade 2 or greater, and Grade 3 or greater toxicity were obtained for a test cohort of patients treated at our institution. The influence of the potential factors that might have affected the reported toxicity levels was investigated. The studies that did not conform to the general data trends were excluded, and single, combined risk estimates were derived for each patient and toxicity level. RESULTS A total of 21 studies of nonoverlapping patient populations were identified. Three studies provided dose-response models for more than one level of toxicity. Of these 21 studies, 6, 14, and 5 were used to derive the initial risk estimates for Grade 1, 2, and 3 or greater toxicity, respectively. A comparison of risk estimates between the studies reporting rectal bleeding and rectal toxicity (bleeding plus other symptoms) or between studies with follow-up <36 months and ≥36 months did not reveal significant differences (p ≥ .29 for all comparisons). After excluding three reports that did not conform to the general data trends, the combined risk estimates were derived from 5 reports (647 patients), 11 reports (3,369 patients), and 5 reports (1,330 patients) for Grade 1, 2, and 3 or greater toxicity, respectively. CONCLUSIONS The proposed approach is feasible and allows for more systematic use of published dose-response data to estimate the complication risks for the individual patient.

Evolving use of radiotherapy and radiosurgery in the treatment of pituitary adenomas

Conventional external beam radiotherapy has been historically employed in the treatment of pituitary adenomas either as a single modality or following suboptimal surgical resection. However, with the widespread adoption of the trans-sphenoidal surgery, the role of radiation therapy has been limited to cases deemed resectable or in those with subtotal resections. Advances in radiotherapy have improved the dose distribution to the pituitary mass while minimizing the volume of normal tissues receiving doses of radiation near or exceeding their inherent tolerances, permitting radiation oncologists to migrate from simple 2D radiation planning to 3D planning. Fractionated radiosurgery, linear-accelerator/γ source-based radiosurgery, or image-guided/intensity-modulated radiotherapy is now commonly employed. Long-term follow-up data demonstrate excellent progression-free survival and local control along with few complications for all radiation treatment modalities whether employed as monotherapy or following subtotal resection.

Tumor Necrosis and Cavitation after Stereotactic Body Radiation Therapy

Two asymptomatic, elderly patients with a distant history of smoking presented with solitary lung masses on screening chest radiographs ordered by their primary care physicians. One was an 87-year-old man with a 3.7-cm left upper lobe mass and the other a 72-year-old woman with a 2.6-cm right upper lobe mass. Both had a significant history of cardiovascular disease, peripheral vascular disease, and type II diabetes mellitus. Because of clinical suspicion for a primary lung malignancy, positron emission tomography/ computed tomography (CT) scans were ordered and demonstrated increased hypermetabolic activity within the lung masses, but not within the mediastinum or outside the thorax. CT-guided biopsies revealed poorly differentiated, nonkeratinizing squamous cell carcinoma in both patients. Per standard guidelines, the patients were referred to a thoracic surgeon; however, both were deemed high-risk surgical candidates. 1 Therefore, both patients were referred for definitive radiotherapy of their stage I lung cancers. Using CT-based radiotherapy planning, both patients were treated with stereotactic body radiation therapy (SBRT) using three doses of 18 Gy delivered within 1 week and at least 72 hours between each fraction (Figures 1A, B). Per our standard practice, on each day of treatment, we performed cone beam CT scans on the treatment machine to ensure proper positioning before the delivery of each radiotherapy dose. In these two patients, the cone beam CT scans performed before the first and second radiation doses did not identify any tumor changes. However, the cone beam CT scan before the third radiation dose demonstrated a large, central cavitation within the tumors of both patients (Figures 2A, B). These findings represented a rapid and significant change from the second treatment cone beam CT that was just 3 days prior. A review of the literature and experienced practitioners (personal communications) failed to reveal any similar cases of rapid tumor cavitation during or after SBRT. The phenomenon of central tumor cavitation in nonsmall cell lung cancer has been observed in patients receiving the antivascular endothelial growth factor antibody, bevacizumab. In two randomized trials, central tumor cavitation with associated pulmonary hemorrhage was observed in patients receiving bevacizumab, carboplatin, and paclitaxel, but not in those receiving just carboplatin and paclitaxel. 2,3 A subsequent pooled matched analysis from these studies found that pretreatment tumor cavitation was the only significant factor predictive of pulmonary hemorrhage in the setting of bevacizumab. 4 This pretreatment cavitation could actually reflect already compromised vasculature. We speculate that SBRT-mediated damage acted similar to the antivascular effects of bevacizumab. 5 Both patients presented here had significant atherosclerotic disease in the setting of type II diabetes mellitus. SBRT may have been the tipping point for occluding the already compromised vasculature that lead to nutrient depletion and subsequent rapid central necrosis and cavitation. This is merely a hypothesis-generating observation; however, it should be followed carefully because central cavitation has been a harbinger for severe and lethal toxicity in patients with non-small cell lung cancer treated with systemic antivascular therapy. 2

Reply to D.A. Palma et al and A. Addeo et al

We thank Palma et al for their insightful comments on our study of carboplatin and paclitaxel (CP) versus etoposide and cisplatin (EP) using the Veterans’ Affairs Central Cancer Registry. In our initial analysis, we did not include International Classification of Diseases, 9th revision, code 508.0 as radiation pneumonitis because it is most often a clinical diagnosis with no definitive diagnostic test. Furthermore, in our clinical experience, it is infrequently coded and largely underreported. We have since performed an analysis using this International Classification of Diseases, 9th revision, code and found that this adverse event did not differ between treatment arms and was infrequent overall. Specifically, it was reported in 6.3% of CP treatments and 6.8% of EP treatments (P .001, Pearson ). We agree with Palma et al that the lack of difference in our study, when compared with the individual patient data meta-analysis and randomized clinical trial (RCT), could be because of the patient populations studied. In response to Addeo and Comins, we agree that in the absence of a large, well-powered, prospective RCT, there will be no definitive answer as to either inferiority or superiority of CP versus EP. However, as is often the case in oncology, we must use the best available evidence to guide clinical decision making. We believe that our work adds to this evidence base. In particular, using multiple approaches (multiple regression, propensity score, and instrumental variables) to analyze rich clinical data can increase the usefulness of observational data analyses. We acknowledge the concerns of Addeo and Comins regarding retrospective analysis of observational data. We believe that our analysis comparing the outcomes of CP versus EP in a relatively uniform patient population, along with the limited availability of informative RCTs, establishes sufficient equipoise to justify the conduct of RCTs to settle this important question. In the meantime, our data suggest that after controlling for important clinical variables, patients treated with these two regimens have equivalent survival.