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P-0286 Role of Pretreatment Cea Level in Patients With Rectal Cancer Receiving Preoperative Chemoradiotherapy
posters
Annals of Oncology
strategies into focus. Study aim: to assess the efficacy and tolerability of neoadjuvant chemotherapy followed by chemo-radiotherapy in patients with LARC over 75 years of age. Methods: We undertook a retrospective review of patients with locally advanced rectal cancer who received this treatment within the Sussex Cancer Network (UK) between 2006 and 2011. For patients over 75 with T3 (with threatened circumferential resection margin on pre-operative MRI) or T4, N0-2 M0 rectal cancer we collected data on treatment, toxicities and responses on MRI assessment and surgico-pathological outcomes. Neoadjuvant chemotherapy comprised 12 weeks of capecitabine and oxaliplatin followed immediately by long-course chemo-radiotherapy with 50.4Gy in 28 fractions of radiotherapy and concurrent capecitabine. Results: Seventeen patients were identified, with a mean age of 79 years. Patients were WHO performance status (PS) 0 or 1 with no comorbidities. Neoadjuvant chemotherapy was completed in 82% (14/17) of patients with two patients stopping due to infection (CTC grade 3/4) and one due to thrombocytopenia (CTC grade 3). All completed at least six weeks of treatment. Chemo-radiotherapy was given as planned in 76% (13/17) of patients. Of the remaining four patients, three completed radiotherapy without chemotherapy due to the accumulated toxicity of neoadjuvant chemotherapy, and in one patient treatment was stopped due to the unmasking of CTC grade 3 cognitive impairment. The overall response rate was 88% (15/17) with the other two patients demonstrating stable disease. Twelve patients (71%) proceeded to surgery with curative intent. The remaining five patients had no curative surgery as a result of: patient choice (2), discovery of second primary cancer at laparotomy (1) and being surgically unfit (2) (due to cognitive impairment and incidental finding of significant abdominal aortic aneurysm, respectively). Of the patients who had surgery, all had a pathologically complete excision; 81% were down-staged and two had a pathological complete response. Conclusion: Neoadjuvant chemotherapy followed by long-course chemo-radiotherapy for LARC is deliverable with manageable toxicity in patients over 75 who have a good performance status and no comorbidities. Response rates are consistent with those seen in younger patients and surgical outcomes are good. We conclude that decisions to use an intensive pre-operative strategy should not be based on age alone. However, better methods are needed to screen for biological fitness and predict for treatment toxicity in this age-group. P 0286
ROLE OF PRETREATMENT CEA LEVEL IN PATIENTS WITH RECTAL CANCER RECEIVING PREOPERATIVE CHEMORADIOTHERAPY
Seung-Gu Yeo1 and Dae Yong Kim2 1 Department of Radiation Oncology, Soonchunhyang University Cheonan Hospital, Cheonan, Chungnam, 2Center for Colorectal Cancer, National Cancer Center, Goyang-si, Gyeonggi-do Introduction: The pretreatment serum carcinoembryonic antigen (CEA) level is an independent prognostic factor in colorectal cancer. However, few studies have evaluated its prognostic significance after preoperative chemoradiotherapy (CRT), which has become widely adopted in patients with rectal cancer. Here, the significance of the CEA as a prognostic or predictive factor was investigated. Methods: In total, 609 patients with locally advanced (cStage II–III) mid to distal rectal cancer who underwent preoperative CRT and radical surgery between 2001 and 2008 were analyzed retrospectively. A prognostic factor analysis was performed using the log-rank test and Cox proportional hazards regression. Predictive factors for pathologic CRT response were determined using multivariate logistic regression. Results: Elevated CEA levels (> 5 ng/mL) were observed in 201 (33.0%) patients at diagnosis. Following preoperative CRT, a downstaging (ypStage 0–I) occurred in 255 (41.9%) patients, of whom 88 had pathologic complete tumor regression. The median follow-up period was 60 months, and the 5-year disease-free and overall survival rates were 76.2% and 84.6%, respectively. Prognostic factors independently associated with recurrence or survival included ypStage, circumferential resection margin, and histologic grade. Pretreatment CEA lost its significance in multivariate prognostic factor analysis. Pretreatment CEA was significantly associated with pathologic CRT response, in terms of downstaging and tumor regression grade, and was the most relevant predictive factor. Conclusion: In patients with rectal cancer who receive preoperative CRT, the pretreatment CEA level was a significant and independent predictor of pathologic CRT response. P 0287
PROSPECTIVE TRIAL OF SYNCHRONOUS CAPECITABINE, RADIOTHERAPY AND BEVACIZUMAB FOR LOCALLY ADVANCED RECTAL CANCER (CRAB)
Vaneja Velenik1, Janja Ocvirk2, Maja Mušicˇ 1, Bracˇ ko Matej3, Franc Anderluh4, Irena Oblak1, Ibrahim Edhemovic´1, Erik Brecelj1, Mateja Kropivnik1 and Mirko Omejc4 1 Institute of Oncology, Ljubljana, Slovenia, 2Institute of Oncology, Ljubljana, Ljubljana, 3University Medical Centre, Ljubljana, Slovenia, 4University Medical Centre, Ljubljana, Slovenia
Volume 23 | Supplement 4 | June 2012
Introduction: Neoadjuvant capecitabine based chemoradiotherapy and radical surgery are considered to be optimal treatment approach to locally-advanced rectal cancer. We assessed the efficacy and safety of adding targeting agent bevacizumab to this standard treatment to increase the pathological complete remission rate of locally advanced rectal cancer as primary end point. Secondary end points were survival parameters and quality of life. Methods: Enrolled patients ( pts) with MRI-confirmed stage II/III rectal cancer were treated with an infusion of Bev (5 mg/kg) 2 weeks prior to neoadjuvant CRT, followed by Bev 5mg/m2 on week 3, 5, 7 and capecitabine 825 mg/m2 bid including weekends during RT. RT was administered at 50.4 Gy (25×1.8 Gy with boost 3×1.8 Gy, 3D conformal technique), starting on week 3. Total mesorectal excision was scheduled 6-8 weeks after completion of CRT. Surgery was conducted 6-8 weeks following CRT, with post-operative chemotherapy with capecitabine (1250 mg/m2 twice daily for 14 days every 21 days). Results: Results A total of 60 pts were eligible for analysis: median age was 60 years (range: 31–79) years, 64% of pts were male. The most frequent MRI stage was T3 (87%) and N+(80%). The median tumor distance from anal verge was 6 (range: 0– 11) cm. The grade 3 toxic effects were leukopenia (n=3), diarrhea (n=1), dermatitis (n=6), proteinuria (n=4) and hypertension (n=1). and one grade 4 vascular toxicity. Radical resection was achieved in 58 pts (96.7%) TRG 4 ( pCR) was recorded in 8 pts (13.3%) and TRG 3 in 9 pts (15%). Fifty pts received capecitabine postoperatively. (83.3%). Perioperative adverse events (within 30 days after surgery) were recorded in thirty-eight pts (62.3%): delayed wound healing (n=18, 30%), infection/abscess (n=12, 20%) and anastomotic leak (n=7, 11.7%). Six pts required surgical reintervention for leak (n=3), abdominal abscess (N=2) and pneumothorax (n=1). With longer follow-up, the rate of adverse events was 40% (n=24) and most commonly due to delayed wound healing (n=9, 15%), followed by rectovaginal or uretero perineal fistula (n=4, 6.7%), anastomotic leak (n=2, 3.3%) and intestinal necrosis (n=1, 1.7%). Five pts (8.3%) required re-operation. Median follow-up was 24 months (7-35 months). No pts were lost during follow-up. The 2-year overall survival, disease-free survival, recurrence-free survival and local control rates were 91.4%, 76.2%, 84.9% and 96%, respectively. Conclusion: The addition of bevacizumab to conventional capecitabine-based preoperative CRT is tolerable treatment for LARC. Results of our study indicate the potential long-term therapeutic benefit in LARC, although longer follow-up is needed to fully assess survival parameters in this setting. On the other hand, it is associated with high rate of perioperative and postoperative complications. The open question in regard to efficacy, early and late toxicity of this combined modality treatment should be evaluated in large, phase III trial. P 0288
SAFETY AND EFFICACY OF METRONOMIC CAPECITABINE IN PRE-OPERATIVE CHEMORADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CANCER (LARC)
Francesco Sponziello1, Antonella Marino1, Margherita Cinefra2, Angelo Nacci2, Annamaria Quaranta2, Pietro Rizzo2, Nicola Calvani2, Laura Orlando2, Paola Schiavone2, Palma Fedele2, Chiara Caliolo2, Maria D’Amico2, Francesco Tramacere3, Maurizio Portaluri3 and Saverio Cinieri2 1 Medical Oncology & Breast Unit, P.O. “A. Perrino” Hospital, Brindisi, 2Medical Oncology & Breast Unit, P.O. “A. Perrino” Hospital, Brindisi, 3Radiotherapy Unit, P.O. “A. Perrino” Hospital, Brindisi Introduction: Preoperative radiotherapy (RT) combined with capecitabine is often the treatment of choice in patients with locally advanced rectal cancer (LARC). We would assess the safety and efficacy of a metronomic schedule of capecitabine combined with preoperative radiotherapy. Methods: From January 2009 to January 2012, 22 patients (19 males and 3 females with a median age of 71 years range 44-82) with locally advanced rectal cancer (LARC) (cT4N2 22.7%, cT4N0 9.1%, cT3N2 22.7%, cT3N1 18.2%, cT3N0 22.7% and cT3Nx 4.6%) were enrolled. In all patients histology was adenocarcinoma. Only 11 patients (50.0%) had a PS 0 whereas 10 (45.5%) had PS 1 and 1 patient (4.5%) PS 2. One group (16 patients) received pelvic RT (45Gy, 5 days/week, for 5 weeks) and another group (6 patients) received pelvic RT plus boost on rectum (45 Gy+boost 5.4 Gy, 5 days/week, for 5 weeks). All patients received preoperative chemotherapy with metronomic capecitabine 1500 mg/die, in a single dose within half an hour lunch, for 5 weeks for all the course of radiotherapy. Fourteen patients underwent surgery in 6-8 weeks after completion of the chemoradiotherapy, four patients after 8 weeks, two patients did not underwent surgery (too early) and two patients were lost to follow-up. Results: At the time of analysis 18 patients were evaluable for response. Downstaging was ypT4N1 5.60%, ypT3N2 11.1%, ypT3N1 5.60%, ypT3N0 33.3%, ypT2N1 5.60% and ypT2N0 38.8%. Only 8 patients achieved a downsizing between 0-1 cm whereas 10 patients between 2-3 cm. Grade 1 of WHO haematological toxicities (leucopenia) occurred in 1 patient (4.5%) and grade 1 of not-neutropenic fever occurred in 1 patient (4.5%). We also observed grade 3-4 of WHO gastrointestinal toxicities (diarrhea) only in 1 patient (4.5%) whereas grade 1-2 occurred in 7 patients (31.8%). Grade 2 of lack of appetite and asthenia occurred in 3 patients (13.6%). Overall, we did not observe any hand-foot syndrome, nausea and vomiting. Conclusion: Our data show that a schedule of metronomic capecitabine combined with preoperative radiotherapy may be beneficial in terms of downstaging of disease and tolerability in patients with locally advanced rectal cancer (LARC).
doi:10.1093/annonc/mds153 | iv
Annals of Oncology
strategies into focus. Study aim: to assess the efficacy and tolerability of neoadjuvant chemotherapy followed by chemo-radiotherapy in patients with LARC over 75 years of age. Methods: We undertook a retrospective review of patients with locally advanced rectal cancer who received this treatment within the Sussex Cancer Network (UK) between 2006 and 2011. For patients over 75 with T3 (with threatened circumferential resection margin on pre-operative MRI) or T4, N0-2 M0 rectal cancer we collected data on treatment, toxicities and responses on MRI assessment and surgico-pathological outcomes. Neoadjuvant chemotherapy comprised 12 weeks of capecitabine and oxaliplatin followed immediately by long-course chemo-radiotherapy with 50.4Gy in 28 fractions of radiotherapy and concurrent capecitabine. Results: Seventeen patients were identified, with a mean age of 79 years. Patients were WHO performance status (PS) 0 or 1 with no comorbidities. Neoadjuvant chemotherapy was completed in 82% (14/17) of patients with two patients stopping due to infection (CTC grade 3/4) and one due to thrombocytopenia (CTC grade 3). All completed at least six weeks of treatment. Chemo-radiotherapy was given as planned in 76% (13/17) of patients. Of the remaining four patients, three completed radiotherapy without chemotherapy due to the accumulated toxicity of neoadjuvant chemotherapy, and in one patient treatment was stopped due to the unmasking of CTC grade 3 cognitive impairment. The overall response rate was 88% (15/17) with the other two patients demonstrating stable disease. Twelve patients (71%) proceeded to surgery with curative intent. The remaining five patients had no curative surgery as a result of: patient choice (2), discovery of second primary cancer at laparotomy (1) and being surgically unfit (2) (due to cognitive impairment and incidental finding of significant abdominal aortic aneurysm, respectively). Of the patients who had surgery, all had a pathologically complete excision; 81% were down-staged and two had a pathological complete response. Conclusion: Neoadjuvant chemotherapy followed by long-course chemo-radiotherapy for LARC is deliverable with manageable toxicity in patients over 75 who have a good performance status and no comorbidities. Response rates are consistent with those seen in younger patients and surgical outcomes are good. We conclude that decisions to use an intensive pre-operative strategy should not be based on age alone. However, better methods are needed to screen for biological fitness and predict for treatment toxicity in this age-group. P 0286
ROLE OF PRETREATMENT CEA LEVEL IN PATIENTS WITH RECTAL CANCER RECEIVING PREOPERATIVE CHEMORADIOTHERAPY
Seung-Gu Yeo1 and Dae Yong Kim2 1 Department of Radiation Oncology, Soonchunhyang University Cheonan Hospital, Cheonan, Chungnam, 2Center for Colorectal Cancer, National Cancer Center, Goyang-si, Gyeonggi-do Introduction: The pretreatment serum carcinoembryonic antigen (CEA) level is an independent prognostic factor in colorectal cancer. However, few studies have evaluated its prognostic significance after preoperative chemoradiotherapy (CRT), which has become widely adopted in patients with rectal cancer. Here, the significance of the CEA as a prognostic or predictive factor was investigated. Methods: In total, 609 patients with locally advanced (cStage II–III) mid to distal rectal cancer who underwent preoperative CRT and radical surgery between 2001 and 2008 were analyzed retrospectively. A prognostic factor analysis was performed using the log-rank test and Cox proportional hazards regression. Predictive factors for pathologic CRT response were determined using multivariate logistic regression. Results: Elevated CEA levels (> 5 ng/mL) were observed in 201 (33.0%) patients at diagnosis. Following preoperative CRT, a downstaging (ypStage 0–I) occurred in 255 (41.9%) patients, of whom 88 had pathologic complete tumor regression. The median follow-up period was 60 months, and the 5-year disease-free and overall survival rates were 76.2% and 84.6%, respectively. Prognostic factors independently associated with recurrence or survival included ypStage, circumferential resection margin, and histologic grade. Pretreatment CEA lost its significance in multivariate prognostic factor analysis. Pretreatment CEA was significantly associated with pathologic CRT response, in terms of downstaging and tumor regression grade, and was the most relevant predictive factor. Conclusion: In patients with rectal cancer who receive preoperative CRT, the pretreatment CEA level was a significant and independent predictor of pathologic CRT response. P 0287
PROSPECTIVE TRIAL OF SYNCHRONOUS CAPECITABINE, RADIOTHERAPY AND BEVACIZUMAB FOR LOCALLY ADVANCED RECTAL CANCER (CRAB)
Vaneja Velenik1, Janja Ocvirk2, Maja Mušicˇ 1, Bracˇ ko Matej3, Franc Anderluh4, Irena Oblak1, Ibrahim Edhemovic´1, Erik Brecelj1, Mateja Kropivnik1 and Mirko Omejc4 1 Institute of Oncology, Ljubljana, Slovenia, 2Institute of Oncology, Ljubljana, Ljubljana, 3University Medical Centre, Ljubljana, Slovenia, 4University Medical Centre, Ljubljana, Slovenia
Volume 23 | Supplement 4 | June 2012
Introduction: Neoadjuvant capecitabine based chemoradiotherapy and radical surgery are considered to be optimal treatment approach to locally-advanced rectal cancer. We assessed the efficacy and safety of adding targeting agent bevacizumab to this standard treatment to increase the pathological complete remission rate of locally advanced rectal cancer as primary end point. Secondary end points were survival parameters and quality of life. Methods: Enrolled patients ( pts) with MRI-confirmed stage II/III rectal cancer were treated with an infusion of Bev (5 mg/kg) 2 weeks prior to neoadjuvant CRT, followed by Bev 5mg/m2 on week 3, 5, 7 and capecitabine 825 mg/m2 bid including weekends during RT. RT was administered at 50.4 Gy (25×1.8 Gy with boost 3×1.8 Gy, 3D conformal technique), starting on week 3. Total mesorectal excision was scheduled 6-8 weeks after completion of CRT. Surgery was conducted 6-8 weeks following CRT, with post-operative chemotherapy with capecitabine (1250 mg/m2 twice daily for 14 days every 21 days). Results: Results A total of 60 pts were eligible for analysis: median age was 60 years (range: 31–79) years, 64% of pts were male. The most frequent MRI stage was T3 (87%) and N+(80%). The median tumor distance from anal verge was 6 (range: 0– 11) cm. The grade 3 toxic effects were leukopenia (n=3), diarrhea (n=1), dermatitis (n=6), proteinuria (n=4) and hypertension (n=1). and one grade 4 vascular toxicity. Radical resection was achieved in 58 pts (96.7%) TRG 4 ( pCR) was recorded in 8 pts (13.3%) and TRG 3 in 9 pts (15%). Fifty pts received capecitabine postoperatively. (83.3%). Perioperative adverse events (within 30 days after surgery) were recorded in thirty-eight pts (62.3%): delayed wound healing (n=18, 30%), infection/abscess (n=12, 20%) and anastomotic leak (n=7, 11.7%). Six pts required surgical reintervention for leak (n=3), abdominal abscess (N=2) and pneumothorax (n=1). With longer follow-up, the rate of adverse events was 40% (n=24) and most commonly due to delayed wound healing (n=9, 15%), followed by rectovaginal or uretero perineal fistula (n=4, 6.7%), anastomotic leak (n=2, 3.3%) and intestinal necrosis (n=1, 1.7%). Five pts (8.3%) required re-operation. Median follow-up was 24 months (7-35 months). No pts were lost during follow-up. The 2-year overall survival, disease-free survival, recurrence-free survival and local control rates were 91.4%, 76.2%, 84.9% and 96%, respectively. Conclusion: The addition of bevacizumab to conventional capecitabine-based preoperative CRT is tolerable treatment for LARC. Results of our study indicate the potential long-term therapeutic benefit in LARC, although longer follow-up is needed to fully assess survival parameters in this setting. On the other hand, it is associated with high rate of perioperative and postoperative complications. The open question in regard to efficacy, early and late toxicity of this combined modality treatment should be evaluated in large, phase III trial. P 0288
SAFETY AND EFFICACY OF METRONOMIC CAPECITABINE IN PRE-OPERATIVE CHEMORADIOTHERAPY FOR LOCALLY ADVANCED RECTAL CANCER (LARC)
Francesco Sponziello1, Antonella Marino1, Margherita Cinefra2, Angelo Nacci2, Annamaria Quaranta2, Pietro Rizzo2, Nicola Calvani2, Laura Orlando2, Paola Schiavone2, Palma Fedele2, Chiara Caliolo2, Maria D’Amico2, Francesco Tramacere3, Maurizio Portaluri3 and Saverio Cinieri2 1 Medical Oncology & Breast Unit, P.O. “A. Perrino” Hospital, Brindisi, 2Medical Oncology & Breast Unit, P.O. “A. Perrino” Hospital, Brindisi, 3Radiotherapy Unit, P.O. “A. Perrino” Hospital, Brindisi Introduction: Preoperative radiotherapy (RT) combined with capecitabine is often the treatment of choice in patients with locally advanced rectal cancer (LARC). We would assess the safety and efficacy of a metronomic schedule of capecitabine combined with preoperative radiotherapy. Methods: From January 2009 to January 2012, 22 patients (19 males and 3 females with a median age of 71 years range 44-82) with locally advanced rectal cancer (LARC) (cT4N2 22.7%, cT4N0 9.1%, cT3N2 22.7%, cT3N1 18.2%, cT3N0 22.7% and cT3Nx 4.6%) were enrolled. In all patients histology was adenocarcinoma. Only 11 patients (50.0%) had a PS 0 whereas 10 (45.5%) had PS 1 and 1 patient (4.5%) PS 2. One group (16 patients) received pelvic RT (45Gy, 5 days/week, for 5 weeks) and another group (6 patients) received pelvic RT plus boost on rectum (45 Gy+boost 5.4 Gy, 5 days/week, for 5 weeks). All patients received preoperative chemotherapy with metronomic capecitabine 1500 mg/die, in a single dose within half an hour lunch, for 5 weeks for all the course of radiotherapy. Fourteen patients underwent surgery in 6-8 weeks after completion of the chemoradiotherapy, four patients after 8 weeks, two patients did not underwent surgery (too early) and two patients were lost to follow-up. Results: At the time of analysis 18 patients were evaluable for response. Downstaging was ypT4N1 5.60%, ypT3N2 11.1%, ypT3N1 5.60%, ypT3N0 33.3%, ypT2N1 5.60% and ypT2N0 38.8%. Only 8 patients achieved a downsizing between 0-1 cm whereas 10 patients between 2-3 cm. Grade 1 of WHO haematological toxicities (leucopenia) occurred in 1 patient (4.5%) and grade 1 of not-neutropenic fever occurred in 1 patient (4.5%). We also observed grade 3-4 of WHO gastrointestinal toxicities (diarrhea) only in 1 patient (4.5%) whereas grade 1-2 occurred in 7 patients (31.8%). Grade 2 of lack of appetite and asthenia occurred in 3 patients (13.6%). Overall, we did not observe any hand-foot syndrome, nausea and vomiting. Conclusion: Our data show that a schedule of metronomic capecitabine combined with preoperative radiotherapy may be beneficial in terms of downstaging of disease and tolerability in patients with locally advanced rectal cancer (LARC).
doi:10.1093/annonc/mds153 | iv