|Year : 2018 | Volume
| Issue : 2 | Page : 218-224
Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in locally advanced rectal carcinoma
Nawal M El-Kholy, Eman A Abdallah, Eman A Tosson, Ola M El-Nady
Clinical Oncology and Nuclear Medicine Department, Mansoura University, Mansoura, Egypt
|Date of Submission||18-Aug-2017|
|Date of Acceptance||18-Sep-2017|
|Date of Web Publication||17-Aug-2018|
Dr. Ola M El-Nady
Mansoura City, Dakahlia
Source of Support: None, Conflict of Interest: None
Background Evaluation of the safety and efficacy of neoadjuvant chemoradiation containing oxaliplatin in locally advanced cancer rectum.
Patients and methods A prospective, single-arm, phase-II study, carried out on 40 patients with locally advanced (T3, T4, N+) rectum cancer from June 2013 to June 2015. Patients received 2 months induction FOLFOX4 chemotherapy, followed by concomitant chemoradiotherapy (CRT) consisted of oxaliplatin 100 mg/m2 D1, 29 of radiotherapy (RT), folinic acid 20 mg/m2 D1: 29, and 5-FU 300 mg/m2 D1: 5, 29: 33 continuous infusion (during the first and fifth week of RT), with three-dimensional conformal pelvic RT 45 Gy by conventional fractionation. Surgery was done 4–6 weeks after end of the CRT course. Adjuvant treatment consisted of 2 months FOLFOX4 chemotherapy. A booster dose of RT 9 Gy/5 fractions was added in cases with positive margin or persistent T4 tumors after surgery.
Results In all, 95% of the patients ended neoadjuvant CRT course with 75% receiving full treatment doses. Overall response occurred in 86% of patients; 16% of them showed pathological complete response; initial failure occurred in only 5% of patients; sphincter sparing surgery was done in 43% of patients. CRT course passed with tolerable and reversible toxicity; grade III toxicity occurred in only 10% of patients, and no grade IV toxicity was reported.
Conclusion Adding oxaliplatin to neoadjuvant CRT in locally advanced cancer rectum cases was feasible, tolerable, with satisfactory response rates, thus encouraging more studies with larger number of patients and longer follow-up periods.
Keywords: concomitant chemoradiotherapy, neoadjuvant treatment, pathological complete response, rectal cancer
|How to cite this article:|
El-Kholy NM, Abdallah EA, Tosson EA, El-Nady OM. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in locally advanced rectal carcinoma. Benha Med J 2018;35:218-24
|How to cite this URL:|
El-Kholy NM, Abdallah EA, Tosson EA, El-Nady OM. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in locally advanced rectal carcinoma. Benha Med J [serial online] 2018 [cited 2019 Jan 20];35:218-24. Available from: http://www.bmfj.eg.net/text.asp?2018/35/2/218/239188
| Introduction|| |
Colorectal cancer (CRC) is one of the most common cancers worldwide; it is considered the third most common leading cause of death in both sexes. Rectal cancers make up approximately one-third of CRC . Approximately 80% of rectal cancer patients present with locoregional disease and 20% with metastatic disease. About 45% of rectal tumors are diagnosed as locally advanced rectal adenocarcinoma (LARA). According to TNM classification, these are stage II and III tumors defined as cT3 or cT4, and/or cN1 or cN2 .
LARA is more likely, compared with colon cancer, to relapse locally after surgical treatment, metastasize to liver or lungs . Over the last three decades, there is a remarkable improvement in outcomes of patients with rectal cancer after the advent of multimodality treatment  mostly by the application of neoadjuvant chemoradiotherapy (CRT), followed by surgical treatment and, eventually, adjuvant chemotherapy .
Neoadjuvant CRT became the standard treatment of advanced stage rectal cancer as it is associated with tumor downstaging, significantly higher rate of pathological complete response (pCR), and fewer cases with venous, perineural, or lymphatic invasion, increased tumor resectability, and therefore increasing the chance of sphincter sparing surgery (SSS) . Moreover, neoadjuvant CRT has the advantages of less acute and late toxicities, and higher rates of compliance enabling full systemic doses of chemotherapy as compared with adjuvant CRT .
Induction FOLFOX4 chemotherapy may allow for early treatment of micrometastatic disease and initial downstaging of the primary tumor. In addition, by following this immediately with infusional 5-FU based chemoradiation, optimal local control may be attained .
The rationale of adding oxaliplatin to 5-FU as a concomitant treatment with neoadjuvant radiotherapy (RT) was based on the known effect of oxaliplatin in the treatment of advanced CRC. There are two distinct philosophical approaches for integrating oxaliplatin; the first is its radiosensitizing effect, the second is reduction of micrometastasis outside the pelvis. This is proved by many recent trials in which pCR and disease-free survival (DFS) increased after oxaliplatin addition to 5-FU and RT in stage II and III rectal cancer ,,.
| Patients and methods|| |
Patients admitted to the Clinical Oncology and Nuclear Medicine Department, Mansoura University Hospital with histologically confirmed LARA, stage II, III, nonmetastatic clinical stage (according to AJCC’s seventh classification), ECOG performance status of 0–2, with no previous pelvic RT nor chemotherapy were included in our study. Other eligibility criteria included adequate baseline organ function with average normal hepatic, renal, and bone marrow functions.
Staging and follow-up
Clinical staging included full physical examination, routine laboratory evaluation with tumor markers (CEA, CA19-9), plain chest radiography, postcontrast computed tomography (CT) scan or MRI of the abdomen and pelvis, endoscopic examination, and biopsy for definitive diagnosis. Presurgical restaging was done 4–6 weeks after end of neoadjuvant CRT by CT scan or MRI and endoscopic examination.
Patients were reviewed 4 weeks after surgery, for completion of adjuvant chemotherapy and booster dose radiation in some cases, then reevaluated by another radiological examination 2 months after ending the whole course, then followed up every 3–6 months.
From June 2013 to June 2015, 40 patients received two full cycles of induction FOLFOX4 chemotherapy (after having a written consent) as follows: oxaliplatin 85 mg/m2 on D1 over 2 h infusion, folinic acid 200 mg/m2 on D1, 2 over 2 h infusion, and 5-FU 400 mg/m2, intravenous, bolus, followed by 5-FU 600 mg/m2, intravenous, continuous infusion over 22 h on D1, 2, repeated every 2 weeks for 2 months.
After 2 weeks from the end of induction chemotherapy, patients started concurrent chemoradiotherapy course which is composed of 2 cycles of modified FOLFOX concomitant with 3D Conformal pelvic radiotherapy.
Three-dimensional conformal pelvic RT was given with high-energy photon beams (6–15 MV) from a linear accelerator for a total dose of 45 Gy over 5 weeks in conventional daily fractions. All patients were simulated supine by CT-based simulation, after 50 ml, intravenous, contrast injection, with comfortably full bladder, with an anal radiopaque mark below the tumor. CT cuts every 3 mm were taken from upper lumbar vertebrae till below the anus.
The target volumes and organs at risk (OARs) were drawn according to the RTOG anorectal contouring Atlas More Details. Plans used either box technique (with weighting of the posterior field) or three-field arrangement (two laterals or lateral oblique and a posterior open field) which allow some sparing of the anterior pelvic structures. Wedges as beam modifiers were used on the lateral beams to improve dose homogeneity.
Patients were referred for surgical consultation within 4–6 weeks from CRT end. The aim was performing total mesorectal excision (TME) with trial of sphincter preservation if possible. Histopathological examination of the resected specimen, with comment on the size of the tumor, circumferential resection margin, distal and proximal cut margin status, degree of downstaging (yT, yN), and tumor grade was performed.
Patients were allowed to receive adjuvant chemotherapy FOLFOX4 regimen for 2 months to complete total 6 months of chemotherapy as recommended by NCCN guidelines. Moreover, nonresponder patients with persistent T4 tumors during surgery, and patients with microscopically positive margins, received a postoperative RT booster dose on tumor bed 9 Gy/1 week for a total RT dose of 54 Gy by conventional fractionation.
Toxicities were assessed according to the National Cancer Institute/Common Terminology Criteria of adverse events (CTCAE/NCI), version 4.0. Patients were followed up weekly during the treatment course for recording acute toxicities.
The primary endpoint was assessment of pathological response after resection, while secondary endpoints were assessing the tolerability and feasibility of this regimen, and the possibility of sphincter preservation.
Data entry and analyses were performed using IBM SPSS, version 24 (United States) in the whole study. Overall and DFSs were calculated using the Kaplan–Meier method. The overall survival (OS) rate was calculated from the date of starting treatment till date of death from any reason or date of last follow-up. While the DFS rate was calculated from the date of end of treatment (to all patients underwent R0, R1 resection) till occurrence of locoregional recurrence or distant metastasis, and all patients who were alive and free or died before the event were censored in the analyses of DFS.
| Results|| |
Patients and tumors characteristics
From the start of June 2013 till the start of June 2015, 40 patients were enrolled into the study. The median age was 51 years (range: 26–70 years), 27 (68%) patients were presented with radiologically significant pelvic lymph node metastasis, and 28 (70%) patients were presented with lower third tumors.
Thirty-five patients were assessed after induction chemotherapy by postcontrast CT scan, from them two patients only developed near-complete radiological response, 27 (77%) patients showed partial response, while six (17%) patients showed stable disease. Out of 40 patients, 38 have ended all neoadjuvant CRT course, all of them were assessed with MRI abdomen and pelvis after end of treatment by 1 month, which revealed that six (16%) patients developed complete radiological response, 30 (79%) developed partial response, and only two patients showed stable disease. No patients showed progression ([Table 1]).
Out of 38 patients who ended whole neoadjuvant CRT course, only 37 patients were referred for surgical consultation, one patient refused surgery, and was lost to follow-up. Twenty patients underwent abdominoperineal resection, and 12 patients underwent LAR, while only two patients underwent trans-anal proctoscopic localized excision of the rectum and mesorectum carrying the tumor.
One patient showed complete radiological and pathological response proved by exploration and multiple open biopsies from the pelvis, multiple endoscopic rectal biopsies, so the patient was closed, no surgical excision was done. Such patient completed her adjuvant chemotherapy, and was followed up clinically, radiologically, and by endoscopic examination every 6–12 months, and all were free.
On the other hand, two patients discovered to be metastatic in the form of hepatic and peritoneal nodules intraoperatively (initial failure), later received second-line chemotherapy ([Table 2]).
Out of 37 patients that proceeded to surgical interference, six (16%) patients showed pathological complete response (pCR or yT0, yN0); tumor regression grade 4 (TRG4) by the Mandard classification; no residual tumor cells are detected after precise pathological examination of the specimen .
Twenty-six (71%) patients showed partial pathological response, from them seven (19%) patients showed good regression (TRG3), with few tumor cells in fibrotic mass. And 11 (30%) patients showed moderate regression (TRG2); with abundant fibrosis and small residual groups of tumor cells, while the remaining eight (22%) patients showed minimal regression (TRG1), with residual tumor masses.
On the other hand, only three (8%) patients showed stable disease or no regression (TRG0), with resistant T4 tumors who received adjuvant RT boost on tumor bed after surgery 9 Gy/5 treatments or fractions (ttts) for total 54 Gy. Finally, only two (5%) patients showed initial treatment failure, discovered to be metastatic during laparotomy (as mentioned before).
Tumors were excised in all patients with free circumferential resection margin, upper, lower surgical margins except only two patients being with positive lower margin, so both received adjuvant RT boost on tumor bed, lower margin 9 Gy/5 ttts for total 54 Gy ([Table 3]).
Out of 37 patients completed the study, eight (21%) patients died; three patients from postoperative complications (two of them from anastomotic leak and septic shock, the third was diabetic, developed severe wound infection). The fourth patient was hepatitis C-virus positive, suffered from hepatic decompensation after induction chemotherapy, while the last four patients died after locoregional or distant failure during follow-up. So, there were no CRT toxicity-related deaths.
During the follow-up of 32 patients survived after surgery and/or achieved response, six (18%) patients only developed locoregional recurrence within 2–20 months after the end of adjuvant course, while three (9%) patients developed distant metastasis within 12 months after completion of treatment ([Table 4]).
Toxicities during the induction phase of chemotherapy
Eight (21%) patients developed grade I–II hematological toxicities in the form of anemia, leucopenia, and only one patient developed grade III thrombocytopenia. The major nonhematological toxicities were gastrointestinal tract (GIT) toxicities in the form of abdominal and anal pain, diarrhea, nausea, and vomiting. Seven (18%) patients suffered from grade I toxicity, while five (13%) patients suffered from grade II toxicity. Only three (7%) patients suffered from grade I hepatic toxicity in the form of elevation of transaminases.
Toxicities during chemoradiotherapy course
GIT toxicities were the major complications; 20 patients out of 38 suffered from it, six (16%) patients suffered from grade I toxicity, while 14 (36%) patients suffered from grade II toxicity, only four (10%) patients suffered from grade III toxicity. Hematological toxicities were mild; only two (5%) patients suffered from grade I toxicity, while four (11%) patients suffered from grade II toxicity. Furthermore, five patients developed peripheral sensory neuropathy; two (5%) patients suffered from grade I, three (7%) patients suffered from grade II toxicity. In addition, skin dermatitis was noticed in four patients only; two (5%) patients suffered from grade I, two (5%) patients suffered from grade II toxicity.
Toxicities during adjuvant chemotherapy phase
Out of 30 patients received adjuvant FOLFOX4 chemotherapy, 10 (33%) patients suffered from grade I–II GIT toxicity, only one (3%) patient suffered from grade III toxicity. Five (17%) patients developed grade I stomal ulcer. The same five patients suffered from grade I–II peripheral sensory neuropathy continued to suffer from it during and after adjuvant chemotherapy. In addition, grade I–II hematological toxicities were noticed in eight (27%) patients during adjuvant chemotherapy ([Table 5]).
The mean follow-up duration was 20 months (range: 12–28 months). The median survival of all patients was not reached at the time of analysis. Using the Kaplan–Meier method, the 2 years OS was 78.5% ([Figure 1]), while the 1 year DFS was 77.3% ([Figure 2]).
By using SPSS (IBM SPSS, version 24, United States) Pearson’s correlation analysis in the whole study, there was a significant negative correlation between tumor stage and pathological response; r=−0.418, P=0.01, while there was no significant correlation between tumor grade and pathological response, P=0.2 ([Figure 3],[Figure 4],[Figure 5]).
|Figure 3 MRI of male patient with stage III rectal cancer prior to treatment.|
Click here to view
| Discussion|| |
All studied patients were suffering from advanced stage rectal cancer with 88% of tumors reaching the lower rectum. Of these, 95% of patients ended neoadjuvant CRT course with 75% receiving full treatment doses; 92.5% were able to proceed to surgery. Overall response occurred in 87% of them; 16% of them showed pCR after receiving neoadjuvant CRT course; SSS was done in 43% of patients ([Table 4]).
Our study response rates (16% pCR, 87% overall response) are nearly matching the response rate of CAO/ARO/AIO-04 German randomized phase-III trial (which was a double-armed study on 1236 patients who received 50.4 Gy pelvic RT with concomitant infusional 5-FU with or without weekly oxaliplatin 50 mg/m2), as pCR occurred in 17% of the oxaliplatin arm patients versus 13% only in the second arm (P=0.038)  and the results of STAR-01 double-armed study (performed on 747 patients received 50.4 Gy RT with 5-FU with or without weekly oxaliplatin 60 mg/m2) in which pCR occurred in 16% of patients of both arms .
The response rate in our study was better than the response of the Korean phase-II study (which studied 31 patients who received concomitant CRT by using the same modified FOLFOX regimen with RT as our study) showing 77% overall response with 13% pCR. However, they succeeded to perform SSS in 93% of their patients . This success depends on the advances in surgical procedures which differ from center to center.
The RadiOxCape study also showed lower response rates than our study [single-armed study on 40 patients who received 45 Gy conventional pelvic RT with concomitant CAPOX chemotherapy; oxaliplatin (50 mg/m2), intravenous, weekly, and capecitabine (825 mg/m2 twice day) orally on each day of RT] as pCR was found in 14% patients only .
On the other hand, ACCORD12/0405-PRODIGE2 study showed higher response rates than ours (double-armed study on 598 patients who received 50.4 Gy RT with concomitant capecitabine with or without weekly oxaliplatin 50 mg/m2), pCR was obtained in 19% of the oxaliplatin arm patients versus 14% only of second arm patients, and R0 resection obtained in 90% of oxaliplatin arm versus 81% only of the other arm patients .
NSAPB-R-04 study is another double-armed study showing higher response rates than ours using the same regimen as the previous ACCORD12/0405-Prodige2 study but on 1608 patients, 21% of patients of the oxaliplatin arm showed pCR versus 19% in the second arm . Different treatment-related factors are probably responsible for this difference in outcomes between our study and others (either chemotherapy schedules or RT doses), beside the difference in patient and tumor factors, and randomization.
As regards treatment toxicity, our CRT course passed with tolerable and reversible toxicity; grade III diarrhea occurred in only 10% of patients ([Table 5]), while other studies showed higher toxicity levels as grade III–IV toxicities were recorded in 23% of the oxaliplatin arm patients versus 20% only of the second arm patients in CAO/ARO/AIO-04 German study . Moreover, the ACCORD12/0405-PRODIGE2 study recorded grade III, IV toxicities in 25% of oxaliplatin arm patients versus 11% only of the second arm patients .
The Korean study also showed higher toxicity levels as grade III diarrhea occurred in 19% of patients but no deaths secondary to the toxicity occurred . Additionally, in the RadiOxCape study the most frequent grade III, IV adverse event was diarrhea, occurring in 30% of patients . This increase in toxicity levels can be attributed to the difference in cumulative doses and application modes of oxaliplatin (weekly oxaliplatin with RT was less tolerable, showing more side effects than that given in the first and last weeks) especially with pelvic RT doses higher than 45 Gy.
Initial and follow-up failures are also important issues to be investigated to conclude the efficacy of this protocol in the treatment of locally advanced cancer rectum. The initial failure is known as surgical failure while follow-up failure may be in the form of local recurrence (tumor bed, pelvic, or nodal) and distant failure (distant metastasis).
In our study, initial failure occurred in only 5% of patients who completed whole CRT course, while locoregional recurrence occurred in 18% of patients, and distant failure occurred in only 9% of our patients. In a median follow-up period of 20 months, 1 year DFS rate was 77.3% and 2 years OS rate was 78.5%.
Many other double-armed studies showed a gain in DFS, and a lower proportion of perioperative distant metastasis in oxaliplatin arm; as in CAO/ARO/AIO German study: the initial failure was 4% in oxaliplatin arm versus 6% in the other arm. Median follow-up period was 50 months and 3 years DFS was 76% in oxaliplatin arm versus 71% only in the other arm (i.e. 5% gain in DFS), and 3.9% gain in local recurrence rate in oxaliplatin arm .
The STAR-01 study reported that initial surgical failure occurred in only 0.5% of oxaliplatin arm versus 2.9% in the other arm . ACCORD12/0405-PRODIGE2 study reported that only 2.8% of oxaliplatin arm patients had initial failure versus 4.2% of the other patients, while 3 years DFS increased from 68 to 73% in oxaliplatin arm; local recurrence rate decreased from 6 to 4.5%; and OS rate increased from 87.5 to 88.5% in oxaliplatin arm . Finally, in the Korean study, the median follow-up period was 12 months and 1 year DFS was 82%; 9% suffered from distant failure, and no cases of local recurrence recorded .
| Conclusion|| |
Adding oxaliplatin to 5-FU based neoadjuvant CRT was feasible, tolerable, led to satisfactory results in cases of locally advanced rectal cancer, thus encouraging new well-randomized, wide clinical trials.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]