|Year : 2012 | Volume
| Issue : 2 | Page : 209-214
Neo adjuvant chemo-radiotherapy and rectal cancer: Can India follow the West?
Vivek Bansal1, Ritu Bhutani1, Dinesh Doval2, Kapil Kumar3, Pankaj Pande3, Gaurav Kumar1
1 Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector V, Rohini, Delhi-110 085, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector V, Rohini, Delhi-110 085, India
3 Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector V, Rohini, Delhi-110 085, India
|Date of Web Publication||26-Jul-2012|
Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector V, Rohini, Delhi-110 085
Source of Support: None, Conflict of Interest: None
Aims: The management of locally advanced rectal cancer has changed over the years with an emphasis on neoadjuvant chemo radiation therapy (CT-RT) followed by surgery. This study is undertaken to evaluate the efficacy of this treatment in our set of patients with a special focus on the outcome in large circumferential tumors.
Materials and Methods: The study included patients who underwent neo adjuvant CT-RT between Jan 2006 and Oct 2009 in our institution. They received radical radiotherapy with conventional fractionation to a dose of 45-50Gy along with continuous two cycles of 5-FU infusion. All patients were assessed at four weeks clinically and by CT scan and underwent surgery if the tumor was resectable followed by adjuvant chemotherapy.
Results: A total of 52 patients received the neoadjuvant treatment in form of CT-RT out of which 13 patients had undergone defunctioning colostomy before commencing treatment for severe obstructive symptoms. Only 73% patients underwent surgery in form of AR (anterior resection) or APR (abdominoperineal resection) and adjuvant chemotherapy was delivered in 28 (53.8%) patients only. The patients who underwent diversion colostomy had worse disease-free survival (DFS) as compared to those who received definitive treatment (33% vs. 74.9%, P<0.009).
Conclusions: This study represents Indian experience with standard neoadjuvant chemo radiotherapy followed by surgery in rectal cancer. Large circumferential tumors in our set of patients lead to poor outcome leading to more APR. Also this study supported the need for an abbreviated protocol which can be economically suited and organ preservation protocols have a long way to go.
Keywords: Chemo radiotherapy, colostomy, neoadjuvant therapy, rectal cancer
|How to cite this article:|
Bansal V, Bhutani R, Doval D, Kumar K, Pande P, Kumar G. Neo adjuvant chemo-radiotherapy and rectal cancer: Can India follow the West?. J Can Res Ther 2012;8:209-14
|How to cite this URL:|
Bansal V, Bhutani R, Doval D, Kumar K, Pande P, Kumar G. Neo adjuvant chemo-radiotherapy and rectal cancer: Can India follow the West?. J Can Res Ther [serial online] 2012 [cited 2020 Aug 9];8:209-14. Available from: http://www.cancerjournal.net/text.asp?2012/8/2/209/98972
| > Introduction|| |
Colorectal cancer is the third commonly diagnosed cancer accounting for 9.4% of the world's new cancers.  However, the incidence rates in India are quite low ranging from 4 to 5 per 100,000 populations. ,, Despite the low incidence, the absolute number of cases is estimated to be high and majority of them present in locally advanced stage due to delayed referral, lack of awareness and no proper screening available in the country. Prior to the mid-1980s, patients with rectal cancer usually underwent surgery alone, resulting in high rates of pelvic failure with subsequent morbidity and death. Major trials from the 1980s to 1990s showed that postoperative chemo radiotherapy decreased pelvic failure rates and improved survival, leading to its incorporation into the routine management of patients with resected stage II/III disease. ,, Although surgery is still the main stay of treatment but the compliance is poor due to fear of living with permanent colostomy associated with APR (abdominoperineal resection). 
The large randomized trial from the Netherlands evaluated the benefit of preoperative radiation therapy leading to significantly lower rates of pelvic relapse.  Follow-up analyses of this trial further showed that node-positive patients undergoing total mesorectal resection (TME) alone experience pelvic failure rates exceeding 20%.  More recently, the German Rectal Cancer Study demonstrated that preoperative chemo radiotherapy (vs. postoperative therapy) leads to superior pelvic control and sphincter preservation, as well as lower rates of acute and chronic toxicity.  The results of this trial contributed to a paradigm shift and preoperative treatment has been widely adopted as the standard of care for locally advanced rectal cancer. Other European trials have recently established the value of concurrent chemotherapy with preoperative radiation therapy in optimizing local disease control. , It is important to remember that chemotherapy is used in radio sensitizing doses in this setting.
Although preoperative chemo-radiation followed by surgery is well established for over a decade, data from India is lacking. In 2006, we implemented neoadjuvant CT-RT as a uniform treatment for all the locally advanced rectal cancers that were not amenable to surgery and retrospectively evaluated this protocol with regard to feasibility, tolerance and their impact on disease-free survival (DFS) and overall survival.
| > Materials and Methods|| |
The study included patients who underwent preoperative concomitant chemo-radiotherapy at the institute from January 2006 to October 2009. Eligibility criteria included histologically confirmed adenocarcinoma (including mucinous type); patient age >18 years; Karnofsky performance status >70; Stage T2 or T3 or small T4 tumors without sacral invasion. In patients with severe obstructive symptoms, a defunctioning colostomy was done before commencing radiotherapy to avoid complete obstruction during therapy and the requirement of emergency laparotomy. Patients were excluded if distant metastasis was documented and if any concurrent malignancy was diagnosed in the previous five years. Female patients were also excluded if they were pregnant or breastfeeding. The extent of disease was assessed by clinical examination, colonoscopy, chest radiography and computed tomography (CT) of abdomen and pelvis or magnetic resonance imaging (MRI). Regional lymph nodes were considered involved if measuring > 5 mm and/or if they showed heterogeneous texture and irregular margin.
All the patients were irradiated with megavoltage beams to the whole pelvic field followed by boost to primary tumor with adequate margins. They were treated with conventional fractionation (180cGy per fraction, one fraction per day, five fractions per week) to a dose of 45 -50.4Gy in 25- 28 fractions. The concurrent chemotherapy was delivered in two courses during the first and fifth week of radiotherapy. 5-Fluorouracil was given at a dose of 350 mg/m 2 of body surface area per day as a continuous infusion for five days.
Surgery was scheduled to take place five to six weeks after the completion of chemo-radiotherapy depending upon the response and feasibility of surgery. Patients underwent either sphincter preservation operation (anterior resection/low anterior resection) or APR with permanent sigmoid colostomy. Resected samples were analyzed histologically to define the pathologic tumor size (ypT) and nodal stage (ypN) along with surgical stage (yp Stage). The specimen was also evaluated for radial margin, lymphovascular and perineural invasion. Post operative chemotherapy was scheduled to begin three to four weeks after surgery and delivered in 10 courses in every two weeks with 5FU Regimens along with Inj. Oxaliplatin and Leucovorin (FOLFOX-4). In the patients who had undergone anterior resection (AR), the colostomy closure were planned three to four months after the last cycle of chemotherapy.
All patients were reviewed weekly during neo adjuvant treatment for tolerance and compliance, skin and mucosal reactions, blood counts and need for symptomatic treatment. Toxicity was reported utilizing the common toxicity criteria (CTC) version 3.0.  They were evaluated at four weeks clinically and by CT scan for response assessment before undergoing surgery. Subsequent follow-up visits after adjuvant treatment were scheduled at six monthly intervals for the first two years and annually thereafter. All efforts were made to update the disease status of patients by the medical records department through reply-paid postcards or telephonic contact. Patients not responding to above measures were considered lost to follow-up and censored for statistical consideration.
DFS and overall survival (OS) were calculated using the Kaplan-Meier actuarial method. The analysis used standard log rank methods on an intention to treat basis. Univariate analysis was performed to identify the significance of various patient characteristics and pathological down staging for DFS and OS.
| > Results|| |
Fifty-two patients were treated with the neo adjuvant protocol. Patient characteristics are summarized in [Table 1]. The median age of presentation was 51 years and median follow up was 16.7 months (range 1.1 months--4.2 years). All the patients underwent CT scan or MRI before treatment to assess the nodal disease. On presentation 75% had T3 staging while the nodal involvement was seen in 33 patients. Thirteen patients (25%) had undergone defunctioning colostomy in view of large circumferential growth resulting in difficulty in passage of stools and requiring frequent laxatives.
All the patients completed the planned course of preoperative CT-RT. Radiotherapy was delivered according to the institutional protocol ranging from 45 to 50.4Gy. Minor violation of protocol was seen in four patients with three patients treated with oral form of fluorouracil and one patient had received combination of cisplatin and 5-FU. The treatment was very well tolerated. The acute toxicity is summarized in [Table 2]. Grade 3 hematological toxicity was seen in two patients with no grade 3 gastrointestinal and genitourinary side effects.
Radical surgery was performed in 38(73%) patients with AR done in 16 (30.7%) and abdominoperineal resection (APR) in 22 patients (42.3%). The median interval from completion of radiotherapy to surgery was six weeks. Eight patients (15.3%) refused surgery because of symptomatic relief and fear of permanent colostomy (in spite of psychological counseling). Rest three patients were found ineligible for surgery due to disease progression.
The postoperative TNM staging of the 38 patients is shown in [Table 3]. Complete pathological response (CR) was seen in only nine patients with radial margin being involved in six patients. Only 28 out of the 38 patients (68.28%) who had undergone radical surgery could complete the intended schedule of adjuvant chemotherapy without delay. In the remaining 10 patients, the planned FOLFOX regimen could not be delivered due to poor compliance of patients. There was no death from toxic effects. The late toxicity was seen in four patients as anastomotic stricture and small bowel complication.
|Table 3: Characteristics of treatment and post operative histopathological parameters in patients undergone radical surgery|
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Using the Kaplan-Meier actuarial method, OS and DFS at two years for all patients was 81.8 and 64.1% [Figure 1], respectively. The younger patients (≤ 45 years) did worse (P=0.02) in terms of DFS while there was no effect of sex (P=0.29) on survival [Table 4]. The patients who underwent diversion colostomy had poor DFS as compared to those who underwent afferent neoadjuvant CT-RT (33% vs. 74.9%; P=0.009) [Figure 2].
On subgroup analysis of patients who had undergone radical surgery, the patients undergoing anterior resection did better than those who underwent APR and this was statistically significant for DFS (P=0.02). The radial margin involvement had a worse DFS as compared to those patients where a clear resection was obtained (P=0.005) [Table 5].
| > Discussion|| |
Chemo radiotherapy before surgery is now a common approach in the treatment of locally advanced rectal cancer which has focused on the potential for down staging to enable a curative surgical resection or sphincter sparing procedure. In India, with approximately half of the incidence of rectal cancer compared to western data, there is paucity of data on the preoperative chemo radiation followed by surgery and adjuvant chemotherapy.
Rectal cancer in India is more common than colon cancer and trends show a high incidence among young Indians,  a finding that can neither be explained by heredity or traditional diet related. The mean duration of symptoms was seven months suggesting delayed primary presentation due to lack of awareness and screening protocols. These patients usually present in advanced stage with a large number of them requiring diversion colostomy prior to definitive treatment. However, our study is unique to suggest that patients undergoing this surgical intervention fare worse due to large circumferential growth and this can be an important prognostic factor affecting the outcome (33% vs 74.9%, P<0.009).
The effect of radiotherapy on pathological characteristics and consequently on the occurrence of down staging in rectal cancer depends on total dose, fractionation size and interval between the start of RT and the day of surgery, i.e. the overall treatment time (OTT). Marijnen et al analyzed 1805 patients who received preoperative radiotherapy followed by surgery within 10 days with no change in staging though better local control was seen.  Also Lyon R90-01 randomized trial reported lower tumor stage after long term interval from preoperative radiotherapy to surgery as compared to short interval (six to eight weeks vs less than two weeks, P=0.007).  This is because cancer cells damage after radiotherapy need time to undergo necrosis and non viable cells may look morphologically intact shortly after irradiation. Our patients were assessed and operated within seven weeks of completion of neoadjuvant therapy. It remains a matter of debate whether sphincter preservation is on the basis of response to the preoperative treatment or surgeon's expertise. Sphincter preservation with R0 resection had been seen in 69% in CAO trial and 52.4% in FFCD trial as compared to 30.8% in our set of patients. , However, no surgical difficulties were detected during rectal resection after radio chemotherapy suggesting that lower rectal tumors with large volume can be a negative factor.
Another aspect reflected in our study in contrast to other series is the high rate of refusal (15.3%) for surgery after neoadjuvant CT-RT due to symptomatic relief.  During this protocol, the patients were thoroughly counseled and well informed regarding the need for radical surgery. The stigma associated with colostomy, poor socioeconomic conditions with lower literacy rates and sense of wellbeing after neoadjuvant chemo radiation are possibly important reasons for this refusal. The high rate of only partial response in these patients suggests that the need of surgical intervention cannot be obviated in loco regionally advanced large volume disease.
M. D. Anderson evaluated this preoperative radio chemotherapy protocol in T3, N0-1 patients with complete pathological response seen in 27% as compared to 23.6% in our study.  The German intergroup trial showed that ypT, ypN and yp stage are significantly associated with DFS on univariate analysis.  Bujko et al and Kim et al showed that ypN was the independent prognostic factor for DFS and OS respectively. , The present study also showed that all the three parameters were independently affecting the DFS with statistically significant P value. The radial margin involvement is also recognized as a strong prognostic factor after preoperative therapy with better DFS for patients with uninvolved radial margins (86.1% vs. 50%, P=0.04). This is in consistent with Kennecke et al where radial margin positivity is seen more frequently in patients undergoing APR.  The European experience based on a pooled analysis of five European randomized trials has revealed that APR procedure is associated with increased risk of local recurrence and death due to cancer which is consistent with our results.  A better understanding of prognostic factors will help to design the risk adapted therapy for the rectal cancer patients.
The recently reported European Organization for Research and Treatment of Cancer (EORTC) 22921 trial evaluated the role of adjuvant chemotherapy in rectal cancer patients treated with preoperative radiotherapy.  Patients who received adjuvant chemotherapy appeared to show higher DFS than did those receiving no post surgery adjuvant chemotherapy (58.2% vs. 52.2%), but this difference did not attain statistical significance (P=0.13). In our study, adjuvant chemotherapy was recommended in all the patients who had undergone surgery but 22% patients could not complete adjuvant chemotherapy as per protocol due to financial constraints suggesting that these extensive regimen demand high treatment cost associated with substantial toxicity. In our country where the per capita income is low, these extended protocols have poor compliance. Thus, economic evaluations in area of rectal cancer of these fast-changing chemotherapy combinations should be conducted on a routine basis along with determination of clinical benefits and efficacy. 
| > Conclusion|| |
This study represents the first Indian experience with preoperative chemo radiotherapy for loco regionally advanced rectal cancer with higher percentage of them requiring diversion colostomy prior to starting any treatment and have poor outcome as compared to western literature. In our set of patients, the compliance to complete treatment has to be evaluated since the fear of permanent colostomy as well as symptomatic response lead to failure of protocol and thus affect outcome. More aggressive psychological counseling is needed for higher surgical conversion rate and completion of adjuvant chemotherapy. The findings presented in this study have opened the avenue for a more serious consideration of the use of preoperative management in a population where cost effectiveness and bulky tumors are a major issue. However, more experience is needed with better expertise and larger number of patients to establish neoadjuvant approach as standard of care.
| > References|| |
|1.||Greenlee RT, Hill-Hannon BM, Murray T, Thun M. Cancer statistics 2001. Cancer J Clin 2001;51:15-36. |
|2.||Rao DN, Ganesh B. Estimates of cancer incidence in India in 1991. Indian J Cancer 1998;35:10-8. |
|3.||Mohandas KM, Jagannath P. Epidemiology of digestive tract cancers in India. VI Projected burden in new millennium and the need for primary prevention. Indian J Gastroenterol 2000;19:74-8. |
|4.||Deo S, Kumar S, Shukla NK, Kar M, Mohanti BK, Sharma A, et al. Patient profile and treatment outcome of rectal cancer patients treated with multimodality therapy at a regional cancer center. Indian J Cancer 2004;41:120-4. |
|5.||Smalley SR, Benedetti JK, Williamson SK, Robertson JM, Estes NC, Maher T, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006;24:3542-7. |
|6.||Wolmark N, Weiand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project protocol R-02. J Natl Cancer Inst 2000;92:388-96. |
|7.||Fisher B, Wolmark N, Rockette H, Redmond C, Deutsch M, Wickerham DL, et al. Postoperative adjuvant chemotherapy and radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Natl Cancer Inst 1988;80:21-9. |
|8.||Pachler J, Wille-Jørgensen P. Quality of life after rectal resection for cancer, with or without permanent colostomy. Cochrane Database Syst Rev 2005;2:CD004323. |
|9.||Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46. |
|10.||Nagtegaal ID, Marijnen CA, Kranenbarg EK, van de Velde CJ, van Krieken JH, Pathology Review Committee, et al. Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: Not one millimeter but two millimeters is the limit. Am J Surg Pathol 2002;26:350-7. |
|11.||Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124-30. |
|12.||Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40. |
|13.||Collette L, Bosset JF, den Dulk M , Nguyen F, Mineur L, Maingon P, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radio chemotherapy: Does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organization for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007;25:4379-86. |
|14.||Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81. |
|15.||Marijnen CA, Kapiteijn E, van de Velde CJ, Martijn H, Steup WH, Wiggers T, et al. Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol 2002;20:817-25. |
|16.||Gerard JP, Chapet O, Nemoz C, Hartweig J, Romestaing P, Coquard R, et al. Improved sphincter preservation in low rectal cancer with high dose preoperative radiotherapy: The Lyon R 96-02 randomized trial. J Clin Oncol 2004;22:2404-9. |
|17.||Sauer R, Fietkau R, Wittekind C, Rödel C, Martus P, Hohenberger W, et al. Adjuvant vs. neoadjuvant radio chemotherapy for locally advanced rectal cancer: The German trial CAO/ARO/AIO-94. Colorectal Dis 2003;5:406-15. |
|18.||Gerard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent Fluorouracil and leucovorin T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 2006;24:4620-5. |
|19.||Kim CW, Kim JH, Yu CS, Shin US, Park JS, Jung KY, et al. Complications after sphincter-saving resection in rectal cancer patients according to whether chemo radiotherapy is performed before or after surgery. Int J Radiat Oncol Biol Phys 2010;78:156-63. |
|20.||Janjan NA, Khoo VS, Abbruzzese J, Pazdur R, Dubrow R, Cleary KR, et al. Tumor down staging and sphincter preservation with preoperative chemo radiation in locally advanced rectal cancer: The M.D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999;44:1027-38. |
|21.||Rodel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemo radiotherapy for rectal cancer. J Clin Oncol 2005;23:8688-96. |
|22.||Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemo radiation for rectal cancer. Br J Surg 2006;93:1215-23. |
|23.||Kim JS, Kim JS, Cho MJ, Song KS, Yoon WH. Preoperative chemo radiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2002;54:402-8. |
|24.||Kennecke H, McGahan CE, MacFarlane J, McGregor G, Hay J, Phang PT. Predictors of positive radial margin status in a population based cohort of patients with rectal cancer. Curr Oncol 2008;15:98-103. |
|25.||den Dulk M, Putter H, Collette L, Marijnen CA, Folkesson J, Bosset JF, et al. The abdomino perineal resection itself is associated with an adverse outcome: The European experience based on a pooled analysis of five European randomised clinical trials on rectal cancer. Eur J Cancer 2009;45:1175-83. |
|26.||Hisashige A, Yoshida S, Kodaira S. Cost-effectiveness of adjuvant chemotherapy with uracil-tegafur for curatively resected stage III rectal cancer. Br J Cancer 2008:99:1232-8. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]