Factors influencing response to neoadjuvant chemoradiation and outcomes in rectal cancer patients: tertiary Indian cancer hospital experience

Introduction

Colorectal cancer accounts for third most commonly diagnosed cancer in the world. In India, rectal cancer accounts for 6^th most common digestive tract cancer as per cancer group projection from 2010 to 2020 (1).

Several randomized trials have demonstrated that neoadjuvant chemoradiotherapy (NACRT), as compared with postoperative CRT, downstaged tumours and improved local control, frequently permitting sphincter preservation in patients with low rectal tumours. Preoperative CRT was also associated with reduced toxicity (2-4). Though downstaging is achieved in majority of the tumours receiving long course NACRT the extent of downstaging and survival may vary from patient to patient. Many factors have been reported in literature that predicts response to (NACRT) of which advanced stage at presentation is the most important (5). Other factors such as mucinous and signet ring pathology also influence the outcomes and the data is scant. Therefore we studied the factors that can indicate the tumour response to preoperative CRT as well as the factors that influence disease free survival (DFS) and overall survival (OS) in our set of patients. In this study we present the results of a prospectively maintained data of rectal cancer patients who underwent NACRT and surgery at our centre.

Materials and methods

Patient selection

This study included 182 patients who underwent NACRT for biopsy proven rectal cancers at our institute between June 2006 and December 2010. The eligibility criteria included patient’s age more than 18 years, Karnofsky Performance Status (KPS) >70, resectable or unresectable rectal cancer who underwent chemoradiation as pre-operative treatment with different intent along with oral concurrent chemotherapy. The patients with distant metastasis at presentation, or who underwent short course of radiotherapy and those who did not receive concurrent chemotherapy or received altered fractionated RT were excluded from the study.

For initial staging evaluation all the patients underwent contrast enhanced computed tomography (CECT) abdomen and pelvis and chest X-ray. Additional MRI pelvis was done only in six patients. Multiplanar reformats were used to report T staging and involvement of mesorectal fascia (MRF) which was reported in most of the cases. The tumors were labelled as T3 if there was perirectal fat stranding and T4 if there was definite invasion of the surrounding organ. A thorough clinical examination including a careful per-rectal examination both by an onco-surgeon as well as radiation oncologist was performed. Distance from anal margin was assessed by digital rectal examination in majority of the patients. In addition colonoscopic evaluation and biopsy, serum carcino-embryonic antigen (CEA) estimation was also done.

Treatment protocol

Radiotherapy was given to a dose of 45-50.4 Gy in conventional fractionation (180-200 cGy per fraction, one fraction per day and five fractions per week) with treatment ranging between 5-5.5 weeks. All the patients received oral capecitabine concurrently to a dose of 850 mg/m² in twice daily. Post chemoradiation at 6 weeks, patients were assessed by per-rectal examination and pelvic imaging and surgery was planned if deemed resectable. All the eligible patients underwent complete total mesorectal excision with either low anterior resection or abdominoperineal resection (APR) with permanent colostomy. The post-operative specimen was analysed in detail for tumour size, nodal stage, pathological response, margin status including circumferential resection margin, tumour regression grade (TRG) score using Mendard’s scoring were assessed. Every attempt was made by the pathologist to retrieve maximum nodes possible. All patients were planned for adjuvant chemotherapy. If all the nodes were negative in the resected specimen they were planned for 6 cycles of adjuvant chemotherapy of capecitabine alone, and for node positive disease 6 cycles of CAPOX (capecitabine 1,000 mg/m² and injection oxaliplatin) was advised. Patient who had unresectable tumour post CRT were given further chemotherapy (preferably CAPOX) and were continued to assess for operability every 3 months or till disease progression and were taken up for surgery if deemed operable.

Follow up

All patients were reviewed weekly during CRT for treatment compliance, toxicities and need for symptomatic management. The toxicities were recorded as per common terminology criteria for adverse events (CTCAE) version 3 criteria. Weekly blood counts were done to monitor haematological parameters. Post-surgery the further follow up were scheduled 3 monthly for the first 2 years and then 6 monthly for 5 years. Complete blood count liver function tests and renal function tests with CEA were done at each follow up. Colono videoscope examinations were performed at 1-year postoperatively and then once every 3 years. Recurrence was diagnosed pathologically by surgical resection, biopsy or cytology and/or radiological findings showing an increase in tumour size over time.

Statistical analysis

DFS was calculated from the date of registration to the date of disease recurrence and OS till the date of last follow up. DFS and OS were calculated using Kaplan-Meir actuarial method. The analysis used standard log rank test with an intention to treat basis. Univariate and multivariate analysis were performed to find out factors affecting both DFS and OS. The patients who underwent surgical resection after chemo-radiation the factors influencing DFS and OS in both univariate and multivariate analysis were observed. All the statistical analysis was performed using SPSS version 18.

Results

Total 182 patients underwent NACRT. The patient and disease pre-treatment characteristics are being summarized in Table 1. The median age was 42 years and there were more males than females (70% vs. 30%) and 38% of the patients had MRF threatened or involved at presentation.

Table 1 Patient and disease characteristics on presentation (n=182)
Full table

Following the institutional protocol 178 patients completed NACRT, of these 131 (72%) of the patients underwent surgical resection. Twenty nine patients continued to have unresectable disease post chemo radiation were given palliative chemotherapy. Nine (5%) patients refused surgery due to fear of colostomy and 11 (6%) patients were found to have distant metastasis on imaging at 6 weeks so were given palliative chemotherapy. Two patients died of myocardial infarction post CRT. Capecitabine based adjuvant chemotherapy was received by 112 (85%) of the patients.

The major factors affecting tumour downsizing and subsequent R0 surgical resection were advanced T stage and signet ring cell pathology (Table 2).

Table 2 Factors affecting surgical resection (n=131)
Full table

Acute toxicity

During the chemo-radiation protocol most of the patients tolerated treatment well. The main acute side effects are being summarized in Table 3. The toxicity grading was done as per the CTCAE version 3. In gastrointestinal toxicity majority had grade 1 anorexia or diarrhoea. The skin toxicity was limited to perianal skin and groins. In haematological toxicity a large number had grade 1 anaemia which improved with regular haematinics.

Table 3 Acute toxicities of the treatment
Full table

The surgical complications were few and mostly due to wound infection in 10 patients, anastomotic leak in 2 patients and urinary leak from perineal wound in 1 patient respectively. The wound healing rate was mostly within time and only 10 (17.2%) patients had delayed wound healing.

Survival

The median follow up for all the patients was 43 [4-88] and 47 [8-88] months for the patients who underwent resection. Two patients died of acute myocardial infarction post CRT. The analysis of tumour control and survival has been restricted to the 131 patients who underwent R0 or R1 resection. Of the 131 patients, 91 (72%) are alive and disease free. At 5 years the DFS and OS was 60% and 77% (Figures 1,2). For the patients who did not undergo surgery their median survival was 13 [3-78] months since the disease progressed locally and distally and most of them died by 2 years.

Figure 1 DFS for all patients. DFS, disease free survival.

Figure 2 OS for operated vs. non operated patients. OS, overall survival.

Factors affecting local and distant failures

Of the 131 operated patients 9 (7%) failed locally and 4 (3%) failed locally and distally, while the majority 26 (20%) failed distally. The majority of distant failures were in lung (30%), liver (23%) and paraaortic nodes (20%). The details of patterns of failure and the factors influencing is being represented in (Table 4). Of the 16 patients whose circumferential resection margin was positive, 10 (62%) failed. Four locally and 3 distant metastasis and 2 failed both local and distant.

Table 4 Pattern of failures in patients with surgical resection
Full table

Of the 28 (20.3%) patients achieving complete pathological (pCR) response, only 1 failed locally while 3 patients had distant metastasis.

Factors affecting DFS and OS

Using Kaplan-Meier actuarial method both univariate and multivariate analyses were performed in terms of DFS and OS (Tables 4,5).

Table 5 Univariate analysis and multivariate analysis for factors affecting DFS
Full table

In univariate analysis DFS was inferior in pre RT CEA levels of ≥5 ng/mL, signet ring cell pathology, R1 resection, and lack of tumour downstaging represented by pathological T & N stage and higher TRG scores. On multivariate analysis the factors independently affecting inferior DFS were only the pathological node positivity.

OS was inferior in patients with young age of patients, pre RT CEA levels of ≥5 ng/mL, higher pathological T, N stage and TRG scores. In multivariate analysis the factors independently affecting OS were only signet ring cell pathology and a trend towards worse survival for the patients presenting with pre RT CEA levels of ≥5 ng/mL.

Multivariate analysis for DFS and OS being represented in Tables 5,6.

Table 6 Univariate and multivariate analysis of factors affecting OS
Full table

OS, overall survival; DRE, basis of clinical; CEA, carcino-embryonic antigen; MD, moderately differentiated; TRG, tumour regression score.

Discussion

The response to NACRT can vary in locally advanced rectal cancers and thus affect survival. Therefore it is very important to predict these factors before starting NACRT so as to deliver the appropriate treatments. In the present study the factors predicting poor OS were locally advanced tumours with signet ring cell pathology and baseline high CEA levels.

The most common histopathological type of rectal cancer being adenocarcinoma and in accordance to world data our study also had 2/3^rd patients with the same. Rectal cancers with signet ring cell morphology is reported as rare in most of the literature, the incidence ranging from 1-13% in most of the studies (6-8). In our study the signet ring cell carcinomas were seen in 17% patients and majority (19 patients) were in younger age group of <40 years. The three main concerns regarding signet ring cell carcinomas being younger age at presentation, locally advanced and unresectable to begin with and hence poor survival. Chang et al. in Stanford University studied these early onset sporadic rectal cancers and found that signet ring cell differentiation was the major factor leading to poor outcomes in these patients (8).

Patients having signet cell pathology only 17 (56%) underwent downstaging and subsequent surgical resection. Among the operated patients again 11 (65%) of them failed both locally and distally leading to a significantly poorer OS when compared to moderately differentiated (MD) adenocarcinoma. In multivariate analysis signet ring cell carcinoma stood out to be an independent poor prognostic factor for an inferior OS but not for DFS. This indicates that after recurrence the salvage therapy is more effective for prolonging survival in patients with non-signet ring cell tumours compared to the signet cell ones, therefore there is a need for more aggressive salvage strategies for signet ring cell cancers.

A report from National Cancer Database on 244,794 colorectal cases from America reported that signet ring cell histology was independently associated with higher risk of death (HR 1.42, 95% CI, 1.33-1.51) (9). The Korean National registry also reported their SEER database of signet ring cell carcinoma and found to have higher grade and worse DFS (10). In accordance to our series similar data were available regarding higher disease burden and primarily unresectable stage of rectal signet cell carcinoma (11). This was similar to a German series of 34 patients with 65% being primarily unresectable (12).

Another, rather contradictory study among Indian population stated signet ring cell carcinomas to be associated with better pCR rates and better survival (13). This prompts us to study prospectively with a larger population about actual behaviour of signet ring cell carcinomas and whether their histology per se or their late presentation is actually responsible for the worse outcome.

Several studies have proved the importance of serum CEA level as tumour marker for rectal cancers and its significant impact upon resectability, DFS and OS suggesting it could predict occult distant metastasis as well as predict CRT response and serves as an important marker in patient outcomes (14,15). It inhibits cell death by causing a loss of anchorage to the extracellular matrix. Tumour cells containing a high density of CEA are resistant to radiation (16). In the present study, pre-treatment CEA level of ≥5 ng/mL was associated with worse DFS and OS and was an independent factor predicting OS on multivariate analysis. Similarly in a study from Korea, the 5-year DFS rate was significantly higher in the CEA <5 ng/mL group than in the CEA ≥5 ng/mL group (73.2% vs. 60.9%, P=0.002) (17).

Pathological T and N stage are known to be important factors influencing DFS and OS (18). Pathological nodal staging was an independent prognostic marker in most of the studies analyzing the postoperative predictive factors for survival (4,19). In the present study patients with positive nodes in the pathological specimen had significantly higher rates of distant failures leading to poorer DFS which was also a significant factor in multivariate analysis.

Tumour regression is categorized on the basis of a semi quantitative assessment comparing the amount of viable tumour with the amount of fibrosis TRG and is a good indicator of tumour response (20). This was reflected in our patients where the lower TRG score was associated with better survival in the univariate analysis but was not a significant factor on the multivariate analysis.

Due to resource constraint most of the patients were staged on the basis of clinical (DRE) and CT scan imaging. Though preoperative staging with MRI is considered the standard of care there are studies in the literature which suggest that CECT can be used for initial staging in the resource constrained environment (21,22). Rectal cancer mostly present in younger age group in India, a factor which is neither hereditary nor diet related (1) (Table 1). In our study about 43% of the patients were below 40 years and the negative effect of age upon disease free and OS has recently been highlighted in few studies where the younger patients had statistically significant difference in survival and fared poorly (7,23). Similarly in our study patients with age less than 40 years had 5 years DFS and OS (61% and 68% vs. 68% and 88%) respectively and compared to the other group results were statistically significant (P=0.001 and 0.009). But in multivariate analysis this was not significant. This was in contrast to another study were advanced age was associated with worse OS (24).

Overall the survival outcomes of our patients are comparable with the data in the literature. Besides this the study highlights the fact that locally advanced tumors having CRM threatened margins with high CEA levels and signet ring cell morphology are independent good predictive markers for poorer survival pre NACTRT. Therefore more aggressive neoadjuvant treatment strategies both in terms of locoregional and systemic should be employed to treat these aggressive tumours.

Patients with positive nodes in the surgical specimens have a high chance of failures more so distally. Though most of the patients in this study received adjuvant chemotherapy still almost half of the node positive patients failed distally. Therefore pN stage serves as a good marker post neoadjuvant treatment, indicating a need for more aggressive adjuvant chemotherapy regimens to tackle distant metastasis (25,26).

Conclusions

The outcome of our patients were similar to World Literature and signet ring cell morphology, initial stage, pre-treatment CEA level, and pathological nodal staging all were influential in determining survival. Besides this the study also highlights the fact that locally advanced tumours with signet cell histology are aggressive and fare poorly in terms of achieving R0 resection and poorer survival compared to the other histologies, therefore more intensive chemo radiation strategies like neoadjuvant chemotherapy followed by chemo radiation and aggressive surgical resections can be attempted. The possibility of radiotherapy dose escalation and addition of newer biological agents in conjunction would be the future direction.

Acknowledgements

We would like to thank all the authors for their significant contribution towards the manuscript. We would also thank the authors whose articles were selected for reference and was a constant help while preparing the manuscript.

Disclosure: The authors declared no conflict of interest.

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