Prajnan Das

Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data

BACKGROUND Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15-27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR. METHODS In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test. FINDINGS 484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0-277). 5-year crude disease-free survival was 83.3% (95% CI 78.8-87.0) for patients with pCR (61/419 patients had disease recurrence) and 65.6% (63.6-68.0) for those without pCR (747/2263; HR 0.44, 95% CI 0.34-0.57; p<0.0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0.54 (95% CI 0.40-0.73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0.91 (95% CI 0.73-1.12). The effect of pCR on disease-free survival was not modified by other prognostic factors. INTERPRETATION Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival. FUNDING None.

Preoperative Gemcitabine and Cisplatin Followed by Gemcitabine-Based Chemoradiation for Resectable Adenocarcinoma of the Pancreatic Head

PURPOSE We conducted a phase II trial of preoperative gemcitabine and cisplatin chemotherapy in addition to chemoradiation (Gem-Cis-XRT) and pancreaticoduodenectomy (PD) for patients with stage I/II pancreatic adenocarcinoma. PATIENTS AND METHODS Chemotherapy consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given every 2 weeks for four doses. Chemoradiation consisted of four weekly infusions of gemcitabine (400 mg/m(2)) combined with radiation therapy (30 Gy in 10 fractions administered over 2 weeks) delivered 5 days per week. Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery. RESULTS The study enrolled 90 patients; 79 patients (88%) completed chemo-chemoradiation. Sixty-two (78%) of 79 patients were taken to surgery and 52 (66%) of 79 underwent PD. The median overall survival of all 90 patients was 17.4 months. Median survival for the 79 patients who completed chemo-chemoradiation was 18.7 months, with a median survival of 31 months for the 52 patients who underwent PD and 10.5 months for the 27 patients who did not undergo surgical resection of their primary tumor (P < .001). CONCLUSION Preoperative Gem-Cis-XRT did not improve survival beyond that achieved with preoperative gemcitabine-based chemoradiation (Gem-XRT) alone. The longer preoperative interval required more durable biliary decompression (metal stents) but was not associated with local tumor progression. The gemcitabine-based chemoradiation platform is a reasonable foundation on which to build future phase II multimodality trials for stage I/II pancreatic cancer incorporating emerging systemic therapies.

Elective clinical target volumes for conformal therapy in anorectal cancer: a radiation therapy oncology group consensus panel contouring atlas.

PURPOSE To develop a Radiation Therapy Oncology Group (RTOG) atlas of the elective clinical target volume (CTV) definitions to be used for planning pelvic intensity-modulated radiotherapy (IMRT) for anal and rectal cancers. METHODS AND MATERIALS The Gastrointestinal Committee of the RTOG established a task group (the nine physician co-authors) to develop this atlas. They responded to a questionnaire concerning three elective CTVs (CTVA: internal iliac, presacral, and perirectal nodal regions for both anal and rectal case planning; CTVB: external iliac nodal region for anal case planning and for selected rectal cases; CTVC: inguinal nodal region for anal case planning and for select rectal cases), and to outline these areas on individual computed tomographic images. The imaging files were shared via the Advanced Technology Consortium. A program developed by one of the co-authors (I.E.N.) used binomial maximum-likelihood estimates to generate a 95% group consensus contour. The computer-estimated consensus contours were then reviewed by the group and modified to provide a final contouring consensus atlas. RESULTS The panel achieved consensus CTV definitions to be used as guidelines for the adjuvant therapy of rectal cancer and definitive therapy for anal cancer. The most important difference from similar atlases for gynecologic or genitourinary cancer is mesorectal coverage. Detailed target volume contouring guidelines and images are discussed. CONCLUSION This report serves as a template for the definition of the elective CTVs to be used in IMRT planning for anal and rectal cancers, as part of prospective RTOG trials.

Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy

The current study was conducted to determine whether there were differences in outcome for patients with unresectable locally advanced pancreatic cancer (LAPC) who received treatment with chemoradiation therapy (CR) versus induction chemotherapy followed by CR (CCR).

Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer

The objective of this study was to identify predictive factors for pathologic complete response and tumor downstaging after preoperative chemoradiation for rectal cancer.

Phase II Trial of Cetuximab, Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally Advanced (T4) Pancreatic Adenocarcinoma: Correlation of Smad4(Dpc4) Immunostaining With Pattern of Disease Progression

PURPOSE This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression. RESULTS Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016). CONCLUSION This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

Neoadjuvant treatment response as an early response indicator for patients with rectal cancer

PURPOSE Neoadjuvant chemoradiotherapy for rectal cancer is associated with improved local control and may result in complete tumor response. Associations between tumor response and disease control following radical resection should be established before tumor response is used to evaluate treatment strategies. The purpose of this study was to assess and compare oncologic outcomes associated with the degree of pathologic response after chemoradiotherapy. PATIENTS AND METHODS All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasonography, computed tomography, or magnetic resonance imaging) rectal carcinoma diagnosed from 1993 to 2008 at our institution and treated with preoperative chemoradiotherapy and radical resection were identified, and their records were retrospectively reviewed. The median radiation dose was 50.4 Gy with concurrent chemotherapy. Recurrence-free survival (RFS), distant metastasis (DM), and local recurrence (LR) rates were compared among patients with complete (ypT0N0), intermediate (ypT1-2N0), or poor (ypT3-4 or N+) response by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression. RESULTS In all, 725 patients were classified by tumor response: complete (131; 18.1%), intermediate (210; 29.0%), and poor (384; 53.0%). Age, sex, cN stage, and tumor location were not related to tumor response. Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v 58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5-year LR only rates (0% v 1.4% v 4.4%; P = .002). CONCLUSION Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes. These data provide guidance with response-stratified oncologic benchmarks for comparisons of novel treatment strategies.

Phase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer

PURPOSE We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. METHODS Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m(2) orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. RESULTS Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. CONCLUSIONS The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.

Clinical and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer

Objectives:To identify predictive factors for locoregional recurrence (LR), distant metastasis (DM), and overall survival (OS) in patients treated with chemoradiation and surgery for rectal cancer. Methods:Between 1989 and 2001, 470 patients with rectal cancer were treated with preoperative (89%) or postoperative (11%) chemoradiation and mesorectal excision. Median radiation dose was 45 Gy; 97% received concurrent infusional 5-fluorouracil, and 65% received adjuvant chemotherapy. Median follow-up interval was 5.7 years. Results:The 5-year rates of freedom from LR, freedom from DM, and OS were 90%, 79%, and 80%, respectively. On univariate analysis, significant predictors of LR were female sex, clinical T stage, pathologic T and N stages, and positive radial margin. Significant univariate predictors of DM were circumferential extent of tumor, tumor immobility, lymphovascular invasion, perineural involvement, and pathologic T and N stages. Significant univariate predictors of lower OS were age, circumferential extent of tumor, shorter distance from anal verge, tumor size, tumor immobility, anal canal involvement, lymphovascular invasion, perineural involvement, positive radial margin, and pathologic T and N stages. On Cox multivariate analysis, female sex and pathologic T and N stages independently predicted for LR; pathologic T and N stages independently predicted for DM; and age, circumferential extent of tumor, positive radial margin, and pathologic T and N stages independently predicted for lower OS. Conclusions:Pathologic T and N stages significantly predicted for all 3 end points (LR, DM and OS) on multivariate analysis. Investigations of more aggressive adjuvant chemotherapy appear warranted for pathologic stage T3/T4 or N1/2 rectal cancer.

Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation

Although patients with locally advanced pancreatic cancer (LAPC) have an extremely poor prognosis, they are a heterogeneous group. Prognostic factors are inadequately defined for disease‐free survival and overall survival in patients with LAPC who are receiving chemoradiation, so more definitive prognostic factors would be very useful for designing clinical trials.