Navesh K. Sharma

SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer

PURPOSE SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

Intensity-Modulated Radiotherapy Reduces Gastrointestinal Toxicity in Patients Treated With Androgen Deprivation Therapy for Prostate Cancer

PURPOSE Androgen deprivation therapy (AD) has been shown to increase late Grade 2 or greater rectal toxicity when used concurrently with three-dimensional conformal radiotherapy (3D-CRT). Intensity-modulated radiotherapy (IMRT) has the potential to reduce toxicity by limiting the radiation dose received by the bowel and bladder. The present study compared the genitourinary and gastrointestinal (GI) toxicity in men treated with 3D-CRT+AD vs. IMRT+AD. METHODS AND MATERIALS Between July 1992 and July 2004, 293 men underwent 3D-CRT (n = 170) or IMRT (n = 123) with concurrent AD (<6 months, n = 123; ≥6 months, n = 170). The median radiation dose was 76 Gy for 3D-CRT (International Commission on Radiation Units and Measurements) and 76 Gy for IMRT (95% to the planning target volume). Toxicity was assessed by a patient symptom questionnaire that was completed at each visit and recorded using a Fox Chase Modified Late Effects Normal Tissue Task radiation morbidity scale. RESULTS The mean follow-up was 86 months (standard deviation, 29.3) for the 3D-CRT group and 40 months (standard deviation, 9.7) for the IMRT group. Acute GI toxicity (odds ratio, 4; 95% confidence interval, 1.6-11.7; p = .005) was significantly greater with 3D-CRT than with IMRT and was independent of the AD duration (i.e., <6 vs. ≥6 months). The interval to the development of late GI toxicity was significantly longer in the IMRT group. The 5-year Kaplan-Meier estimate for Grade 2 or greater GI toxicity was 20% for 3D-CRT and 8% for IMRT (p = .01). On multivariate analysis, Grade 2 or greater late GI toxicity (hazard ratio, 2.1; 95% confidence interval, 1.1-4.3; p = .04) was more prevalent in the 3D-CRT patients. CONCLUSION Compared with 3D-CRT, IMRT significantly decreased the acute and late GI toxicity in patients treated with AD.

Postmastectomy chest wall radiation to a temporary tissue expander or permanent breast implant--is there a difference in complication rates?

PURPOSE The purpose of this study was to evaluate the likelihood of complications and cosmetic results among breast cancer patients who underwent modified radical mastectomy (MRM) and breast reconstruction followed by radiation therapy (RT) to either a temporary tissue expander (TTE) or permanent breast implant (PI). METHODS AND MATERIALS Records were reviewed of 74 patients with breast cancer who underwent MRM followed by breast reconstruction and RT. Reconstruction consisted of a TTE usually followed by exchange to a PI. RT was delivered to the TTE in 62 patients and to the PI in 12 patients. Dose to the reconstructed chest wall was 50 Gy. Median follow-up was 48 months. The primary end point was the incidence of complications involving the reconstruction. RESULTS There was no significant difference in the rate of major complications in the PI group (0%) vs. 4.8% in the TTE group. No patients lost the reconstruction in the PI group. Three patients lost the reconstruction in the TTE group. There were excellent/good cosmetic scores in 90% of the TTE group and 80% of the PI group (p = 0.22). On multivariate regression models, the type of reconstruction irradiated had no statistically significant impact on complication rates. CONCLUSIONS Patients treated with breast reconstruction and RT can experience low rates of major complications. We demonstrate no significant difference in the overall rate of major or minor complications between the TTE and PI groups. Postmastectomy RT to either the TTE or the PI should be considered as acceptable treatment options in all eligible patients.

Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for (90)Y resin microspheres.

BACKGROUND Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-((90)Y)-labeled resin microspheres. METHODS Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fishers exact test and Kaplan-Meier estimates, respectively. RESULTS Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade ≥3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2(nd)-line, 3(rd)-line, or 4(th)-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. ≥1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy. CONCLUSIONS Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received ≥3 prior lines of chemotherapy.

Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer

PURPOSE To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. METHODS AND MATERIALS A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. RESULTS Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) CONCLUSION: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.

Increased recurrences using intensity-modulated radiation therapy in the postoperative setting

Purpose:To determine the pattern of failures following intensity modulated radiation therapy for head and neck cancer. Material and Methods:A retrospective single institution study. Between May 2001 and June 2008, 176 patients with head and neck cancer were treated with intensity modulated radiation therapy at Fox Chase Cancer Center. Ninety-five (54%) were squamous cell carcinoma treated with curative intent. Tumor and nodal stage, tobacco history, definitive versus postoperative therapy (PORT), addition of chemotherapy and RT duration were analyzed for association with patterns of failure. In patients treated with definitive radiation, high-risk PTV (PTV1) was prescribed to 70 Gy and low-risk PTV (PTV2) to 56 Gy. In the PORT setting, PTV1 was prescribed to 60 to 66 Gy and PTV2 to 54 Gy. Patterns of failure were assessed. Local failure (LF) was defined as the persistence of disease or recurrence within PTV1, marginal failure as recurrence at the region of high-dose falloff, and regional failure as nodal recurrence within PTV2. Results:Median follow-up was 20 months (range: 1–117). Median age was 60 years (range: 28–88), with 80% smokers and 81% stage III or IV. PORT was given to 29% and 71% were treated definitively, with concurrent Cisplatin used in the majority. Three-year local and locoregional (LR) failure rates were 9% and 16%, respectively. Failures occurred in 14 patients: 8 local, 3 regional, 1 LR, and 2 distant. Five of the 8 LF and all 3 marginal failures were observed in PORT cohort. On univariate analysis, the only predictor of LF was the use of PORT (P = 0.06). LR control was 66% for PORT versus 87%, 97% for definitive RT and chemoRT. Conclusions:Local, regional failures were more common following PORT related to an increased risk of marginal failures.

Hepatic imaging response to radioembolization with yttrium-90-labeled resin microspheres for tumor progression during systemic chemotherapy in patients with colorectal liver metastases

BACKGROUND To assess response and the impact of imaging artifacts following radioembolization with yttrium-90-labeled resin microspheres ((90)Y-RE) based on the findings from a central independent review of patients with liver-dominant metastatic colorectal cancer (mCRC). METHODS Patients with mCRC who received (90)Y-RE (SIR-Spheres(®); Sirtex Medical, Sydney, Australia) at nine US institutions between July 2002 and December 2011 were included in the analysis. Tumor response was assessed at baseline and 3 months using either the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1. For each lesion, known artifacts affecting the interpretation of response (peri-tumoral edema and necrosis) were documented. Survivals (Kaplan-Meier analyses) were compared in responders [partial response (PR)] and non-responders [stable (SD) or progressive disease (PD)]. RESULTS Overall, 195 patients (mean age 62 years) received (90)Y-RE after a median of 2 (range, 1-6) lines of prior chemotherapy. Using RECIST 1.0 and RECIST 1.1, 7.6% and 6.9% of patients were partial responders, 47.3% and 48.1% had SD, and 55.0% and 55.0% PD, respectively. RECIST 1.0 and RECIST 1.1 showed excellent agreement {Kappa =0.915 [95% confidence interval (CI): 0.856-0.975]}. Peri-tumoral edema was documented in 32.8%, necrosis in 48.1% and both in 57.3% of cases (using RECIST 1.0). Although baseline characteristics were similar in responders and non-responders (P>0.05), responders survived significantly longer in an analysis according to RECIST 1.0: PR median (95% CI) 25.2 (range, 9.2-49.4) months vs. SD 15.8 (range, 9.3-21.1) months vs. PD 7.1 (range, 6.0-9.5) months (P<0.0001). CONCLUSIONS RECIST 1.0 and RECIST 1.1 imaging responses provide equivalent interpretations in the assessment of hepatic tumors following (90)Y-RE. Radiologic lesion responses at 3 months must be interpreted with caution due to the significant proportion of patients with peri-tumoral edema and necrosis, which may lead to an under-estimation of PR/SD. Nevertheless, 3-month radiologic responses were predictive of prolonged survival.

Prognostic significance of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients treated with selective internal radiation therapy.

BACKGROUND Elevated neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types across different treatment modalities, including radiation therapy. Limited data suggest that NLR may predict for survival and disease control in patients receiving selective internal radiation therapy (SIRT). The correlation between clinical outcomes and change in NLR and PLR after SIRT has not been evaluated. METHODS We retrospectively reviewed 339 consecutive patients with primary (n=37) or metastatic (n=79) liver cancer treated with SIRT from 2006 to 2014. Complete blood counts with differential were available for 116 patients both before and after (median, 29 and 20 days, respectively) SIRT. Survival and progression were calculated from date of initial SIRT. Patient and tumor characteristics evaluated for ability to predict overall survival (OS) and progression free survival (PFS) included pre- and post-treatment neutrophil, platelet, and lymphocyte counts (LCs), as well as NLR, PLR, and relative change in NLR and PLR. Cutoff values were determined for variables that were significant on multivariate analysis (MVA) for OS and/or PFS. RESULTS Median follow-up of surviving patients was 12 months. Median OS was 8 months from SIRT and 20 months from date of liver metastasis diagnosis. Significant factors on univariate analysis (UVA) for both lower OS and PFS included higher post-treatment neutrophil count (NC), higher post-treatment NLR, higher liver tumor volume, higher percentage liver tumor burden, and worse Eastern Cooperative Oncology Group (ECOG) performance status. Significant factors on MVA for lower OS and PFS were ECOG performance status ≥2, higher liver tumor volume, higher pretreatment PLR, and increase in PLR after SIRT. Post-treatment increase in PLR >3-fold was the most predictive early marker for increased risk of death when compared with those whose PLR did not increase or increased <3-fold. Pretreatment PLR >78 was the most predictive serum marker associated with improved OS prior to therapy. CONCLUSIONS This is the largest study to evaluate the association between NLR and PLR with clinical outcomes in patients receiving SIRT, with results that confirm that pre- and/or post-treatment NLR and/or PLR are predictive of clinical outcomes. The largest increase in risk of death as well as local and extrahepatic disease progression was related to change in PLR, a datum not well reported in the literature. The impact of SIRT on blood count changes and the underlying implications of these ratios should be further characterized in a prospective study.

Biochemical and clinical experience with real-time intraoperatively planned permanent prostate brachytherapy

PURPOSE To evaluate patient characteristics and dosimetric parameters that predict biochemical failure (BCF) after real-time planned low-dose-rate prostate brachytherapy. METHODS From 1998 to 2008, a low-risk cohort by National Comprehensive Cancer Network criteria of 341 men with a median followup of 41.6 months was analyzed. This cohort had a median age of 65.1 years, prostate volume of 35.8cc, and pretreatment prostate-specific antigen of 5.6ng/mL. Patients had predominately Gleason 6 (95.9%) and T1c (81.3%) disease. About 3.6% of the patients received androgen deprivation therapy. Kaplan-Meier and Cox proportional hazards survival analysis methods were used to analyze predictors of BCF (Phoenix definition). RESULTS At 72 months, freedom from BCF was 91.1% (95% confidence interval=85.0-94.8). The median D(90) was 145.9Gy, and the median V(100) was 90.3%. Because of infrequent BCF, the following prostate volume groups were examined: 15-<25, 25-<35, 35-<45, and 45+cc. Of all possible predictors, only small prostate volume (15-<25cc group) was significantly associated with BCF (hazard ratio=8.44, 95% confidence interval=1.82-39.14, p=0.007). Using Kaplan-Meier analysis, time to BCF was also significantly increased in the lowest prostate volume 15-<25cc group with 24.1% failing at 48 months compared with 1.6-5.1% among the other groups. CONCLUSIONS Real-time planned low-dose-rate prostate brachytherapy provides excellent biochemical control as a single-agent treatment for low-risk prostate cancer with 91.1% freedom from BCF at 72 months. Only prostate volume less than 25cc was an independent predictor of BCF.

An intraoperative real-time sleeved seed technique for permanent prostate brachytherapy.

PURPOSE To describe a novel technique that integrates customized sleeved seed production to reduce seed migration using preloaded needles with real-time intraoperative dosimetric planning for patients treated with iodine-125 (I-125) permanent prostate seed implants. METHODS AND MATERIALS Customized seed-spacer sequences were calculated for patients in real time based on an intraoperative transrectal ultrasound-guided volume study. Using a Fox Chase Cancer Center modified Best Iodine-125 seed loader (Best Medical, Springfield, VA), the seeds and spacers were inserted into a hollow suture material (sleeve) and then loaded into the implant needles. Needles were placed sequentially under transrectal ultrasound guidance with sagittal plane visualization of the dropped sleeved seeds. RESULTS This technique was successfully implemented allowing intraoperative planning to be combined with real-time sleeved seed production. CONCLUSIONS The use of sleeves for seeds combined with real-time intraoperative planning allowed for the intraoperative customization of implants with the practical advantages of linked seeds.