Journal of Radiation and Cancer Research

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 11  |  Issue : 3  |  Page : 81--89

A single-institution retrospective analysis of outcomes for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy


Kannan Venkatesan1, Vivek Anand1, Ranjeet Bajpai1, Rohit Santosh Kabre1, Asha Kapadia2, Sachin Almel2, Muzammil Shaikh2, Vinay Babu3, Ajay Kolse4, Ganesh Nagrajan5, Murad Lala5, Smruti krishna6, P Jagannath7, Sudesh Deshpande8,  
1 Department of Radiation Oncology, P. D. Hinduja National Hospital and Medical Research Center, Pune, Maharashtra, India
2 Department of Medical Oncology, P. D. Hinduja National Hospital and Medical Research Center, Pune, Maharashtra, India
3 Consultant Radiation Oncologist, Ruby Hall Clinic, Pune, Maharashtra, India
4 Consultant Radiation Oncologist, Holy Spirit Hospital, Mumbai, Maharashtra, India
5 Consultant Surgical Oncologist, P. D. Hinduja National Hospital and Medical Research Center, Mumbai, Maharashtra, India
6 Consultant Medical Oncologist, Lilavati Hospital, Mumbai, Maharashtra, India
7 Consultant Surgical Oncologist, Lilavati Hospital, Mumbai, Maharashtra, India
8 Chief Medical Physicist, P. D. Hinduja National Hospital and Medical Research Center, Mumbai, Maharashtra, India

Correspondence Address:
Dr. Rohit Santosh Kabre
Department of Radiation Oncology, P. D. Hinduja National Hospital and Medical Research Center, Pune, Maharashtra
India

Abstract

Background: Neoadjuvant chemoradiotherapy (NACTRT) is an established standard of care for the management of locally advanced rectal cancer (LARC). A retrospective analysis was conducted to assess the results of treatment and predictors of overall survival (OS) for patients treated in a tertiary care hospital in India from 2013 to 2019. Materials and Methods: Biopsy-proven 79 patients of LARC were included in the analysis. Clinical and treatment parameters were assessed. Prognostic factors associated with OS and pathologic response were studied. Treatment toxicities and sphincter preservation rates were documented. Results: There were 55(69.6%) patients with Stage III rectal cancer. Majority of the patients, i.e., 74 (93.7%), received long-course radiation therapy by intensity-modulated radiation therapy–volumetric modulated arc therapy technique after computed tomography + magnetic resonance imaging fusion-based simulation. Pathological complete response (pCR) was achieved in 20 (25.3%) while 45 (57%) showed tumor downstaging post-NACTRT. Time interval (TI) to surgery of ≤8 weeks was significantly associated with higher pCR and tumor downstaging. Actuarial 5-year OS rate was 64.4% and local recurrence-free survival (LRFS) rate of 72.2%. Both OS and LRFS were significantly higher in patients who showed pCR and tumor downstaging. Long-term gastrointestinal and genitourinary toxicities were seen in 11 (15%) and 15 (21.5%) patients, respectively. Conclusions: This study reaffirms the efficacy of preoperative NACTRT as an upfront standard of care in LARC in the Indian population. TI to surgery to the tune of ≤8 weeks yielded optimal pCR and tumor downstaging which translated into significantly better survival.



How to cite this article:
Venkatesan K, Anand V, Bajpai R, Kabre RS, Kapadia A, Almel S, Shaikh M, Babu V, Kolse A, Nagrajan G, Lala M, krishna S, Jagannath P, Deshpande S. A single-institution retrospective analysis of outcomes for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.J Radiat Cancer Res 2020;11:81-89


How to cite this URL:
Venkatesan K, Anand V, Bajpai R, Kabre RS, Kapadia A, Almel S, Shaikh M, Babu V, Kolse A, Nagrajan G, Lala M, krishna S, Jagannath P, Deshpande S. A single-institution retrospective analysis of outcomes for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. J Radiat Cancer Res [serial online] 2020 [cited 2020 Dec 2 ];11:81-89
Available from: https://www.journalrcr.org/text.asp?2020/11/3/81/296550


Full Text



 Introduction



Colorectal cancer (CRC) is a significant health problem at global level as it is ranked third in terms of incidence and second in terms of mortality.[1] The age-standardized rate for CRC in India is 7.2 per 100,000 population in males and 5.1 per 100,000 population in females.[2] As per the Indian Council of Medical Research data published in 2014, in India, the annual incidence rates for rectal cancer in men was 4.1 per 100000.[3]

Locally advanced rectal cancer (LARC) is defined as the presence of either T3–4 and/or node-positive disease in the absence of distant metastases. Neoadjuvant chemoradiotherapy (NACTRT) followed by total mesorectal excision-based radical surgery is a standard treatment for these patients. The estimated 5-year overall survival (OS) and local recurrence (LR) rates were 76% and 6%, respectively, with the distant recurrence rate at 36% in CAO/ARO/AIO-94 study.[4] Similar results were reported by the European Organization for Research and Treatment of Cancer Radiotherapy Group Trial 22921 with a 5-year cumulative incidence of LR at 7.6% and distant recurrence at 34.4%.[5]

Our study aims to analyze the results of treatment and toxicities and to identify the prognostic markers for survival in LARC patients after NACTRT and radical surgery in a tertiary care hospital in India.

 Materials and Methods



This was a retrospective observational study of biopsy-proven rectal cancer patients treated with NACTRT from January 2013 to February 2019. The clinical practice guideline is in accordance with the National Comprehensive Cancer Network Version 3.2019. This study was published as an abstract in the Journal of Cancer Research and Therapeutics in November 2019 as proceedings of the G. C. Pant Young Doctor Award.[6]

Patient's demographic profile, clinical parameters, details of treatment modalities, and toxicity profiles were assessed. Tumor staging was determined by physical examination, endoscopic evaluation, and imaging techniques including computed tomography (CT) scan abdomen-pelvis and/or positron emission tomography (PET) scan and/or magnetic resonance imaging (MRI) of the pelvis. The overall staging was determined according to the American Joint Committee on Cancer 7th Edition guidelines.

Radiation therapy

Radiation therapy (RT) planning was based on clinical target volumes contoured on planning CT/contrast-enhanced CT/CT+MRI/PET-CT fusion scans. RT plan was primarily long-course radiation therapy (LCRT) to the pelvis (45–50.4 Gy in 25–28 fractions) or short-course RT (SCRT) of 25 Gy in 5 fractions using either three-dimensional conformal radiotherapy, intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). All the patients received oral capecitabine concurrently to a dose of 850 mg/m2 in twice daily.

Surgery

The patients underwent a total mesorectal excision-based surgery at a median of 54 days post-NACRT. Type of surgery, time interval (TI) between RT completion-surgery, and colostomy rate were documented. Postoperative complications including wound infection, surgical site infection, anastomotic leak, and small bowel obstruction or ileus within the first 30 days of surgery were analyzed. They were determined by documentation as per the primary surgical team.

Pathological response

Pathological tumor response was graded as complete response, intermediate, or poor based on pathological staging.[7] Pathological complete response (pCR) was defined as the absence of viable adenocarcinoma cells in the surgical specimen (ypT0N0). Intermediate response was defined as an improvement in stage to ypT1-2 and ypN0. Patients with ypT3-4 or positive lymph nodes were classified as poor response. Inoperable disease status at time of surgery or disease progression during treatment was deemed as poor response to NACTRT.

Acute and chronic toxicity profile was documented as per the Common Terminology Criteria for Adverse Events (CTCAE v4.03). Postoperative follow-up consisted of routine history and physical examination with carcinoembryonic antigen measurements (CEA) along with CT scans.

Outcomes and analysis

OS was determined by the time from the date of diagnosis to death due to any cause or last follow-up for survived individuals considering worst-case scenario. Similarly, local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were also analyzed.

Gathered data were analyzed by SPSS (Version 21) software (IBM, Chicago, IL, USA). The categorical variables were described as frequency or percentages and compared with the Chi-square test, Fisher's exact test, or Kendall's tau test. Evaluation of the effects of clinical and treatment-related parameters for OS, LRFS, and DMFS was carried out with Kaplan-Meier curves and compared with the log-rank test. P < 0.05 was considered statistically significant.

 Results



A total of 79 patients were eligible for the analysis. Majority (45%) of the patients were from the age group of 41–60 years. Male preponderance (72.15%), long duration of symptom history (74.68% showing >12 weeks of symptoms), and 27.84% of the patients having family history of malignancy were salient features in demographic parameters. Bowel obstruction, either as a presenting symptom or during treatment, was seen in 8 (10.1%) patients. Comorbidity profile, performance status, and past history were documented [Table 1].{Table 1}

Disease characteristics

Craniocaudal length of disease >50 mm was seen in 58.2% of the patients, while ulceroinfiltrative disease (40%) dominated the characterization of tumor. In majority of the patients (57%), distance of disease from anal verge was at 50 mm. Lower third rectal cancer was seen in 23 (29.1%) patients. A total of 55 (69.6%) patients had clinical Stage III disease. Clinical node-positive status, either N1 or N2, was diagnosed in 56 (70.9%) patients. On biopsy confirmation, 50 (63.3%) had Grade II adenocarcinoma [Table 2].{Table 2}

Treatment parameters

Treatment plan were generated on CT + MRI fusion scans in 59 (74.7%) patients. LCRT protocol was utilized in 74 (93.7%) patients while 5 (6.3%) patients underwent SCRT. IMRT-VMAT treatment was executed in 68 (83.5%) patients. VMAT treatment was either with VMAT-sequential boost or simultaneous integrated boost (SIB). Of 79 patients, all completed treatment protocol except one patient developed distant metastases during treatment. Sixty-five (82.3%) patients completed treatment in ≤42 days. Oral capecitabine was given in 73 (92.4%) patients. Two patients completed total neoadjuvant therapy regimen while neoadjuvant chemotherapy before NACTRT was given in six patients for various reasons.

Of 79 patients, 3 patients declined surgical management, 3 defaulted for surgery, 66 patients underwent definitive surgery, while 7 patients had exploratory laparotomy and closure due to inoperable disease after NACTRT. Median TI from completion of RT to definitive surgical management was 54 days, with 38 (48.1%) patients undergoing surgery in ≤8 weeks from completion of RT.

Abdominoperineal resection (APR) was performed in 21 (26.5%) patients while low or ultra-low anterior resection (LAR) was possible in 41 (51.9%) patients. Robotic APR or LAR was possible in 6 patients [Table 3]. Permanent colostomy was mandated in 29 (36.7%) patients while temporary or no colostomy was achieved in 46 (56.2%) patients. Out of 30 patients having lower third rectal cancer, sphincter preservation rate was 30%. Distribution for type of colostomy with respect to site of disease is shown in [Table 4].{Table 3}{Table 4}

Histopathological evaluation records were available for 69 patients. Twenty (25.3%) patients showed complete response. Tumor downstaging was achieved 45 (65.21%) patients. Tumor response grade was reported in 44 patients. Lymph nodal dissection to the tune of ≥12 nodes which is considered standard was seen in 32 (40.5%) patients. All patients had R0 resection. Adjuvant chemotherapy after NACTRT and definitive surgery was given in 48 patients [Table 3].

On univariate analysis, both tumor downstaging and pathological response were significantly better in patients with TI of ≤8 weeks (P = 0.033, P = 0.026, respectively). Site of tumor, craniocaudal length of tumor, and grade of disease failed to show association with pathologic response and tumor downstaging. Early stage of disease correlated with better pathological response (P = 0.032) [Table 5] and [Table 6].{Table 5}{Table 6}

Survival analyses

Actuarial 5-year OS was 64.4%. LRFS and DMFS rates were 77.2% and 71.1%, respectively. Considering pathologic response, 5-year OS rates were 95%, 73.3%, and 33.8% among complete, intermediate, and poor responders (P = 0.005). Group of patients showing tumor downstaging showed significantly better OS (81.1% vs. 31.8%, P < 0.0001) [Figure 1]a, [Figure 1]b, [Figure 1]c.{Figure1}

Factors such as grade of disease, type of primary tumor, stage of the disease, and TI were not associated with better OS [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d.{Figure 2}

LRFS among complete, intermediate, and poor responders were 93.8%, 73.3%, and 64.5%, respectively (P = 0.031). Similarly, tumor downstaging predicted significantly better LRFS (87.2% vs. 55%, P = 0.001). DMFS rates were not significantly better in patient cohorts based on tumor response and tumor downstaging [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e, [Figure 3]f.{Figure 3}

Toxicity profile

Acute toxicity in the form of Grade III–V diarrhea was seen in 14% of the patients. Grade III proctitis was seen in 5 (6.3%) patients while 3 (3.8%) showed Grade II cystitis. Acute Grade III skin reaction was limited to 2 (2.5%) patients. Postoperative wound complication and anastomotic leakage were encountered in 7 (9%) patients. Long-term gastrointestinal (GI) complications such as bowel urgency, fistula, bowel stricture, and stoma complications were seen in 11 (15%) patients. Genitourinary complications such as renal dysfunction, hydronephrosis, stricture, and erectile dysfunction were present in 17 (21.5%) patients [Table 7].{Table 7}

 Discussion



Numerous retrospective studies and a single prospective study have shown significant improvement in pCR with TI ≥8 weeks.[8],[9],[10],[11],[12],[13] In their prospective study, Garcia-Aguilar et al. performed a nonrandomized study comparing 6- to 11-week TI, with those in the longer interval also receiving two additional cycles of FOLFOX. Whether the improved pCR (25% vs. 18%) in the 11-week cohort is due to the delayed interval or the additional chemotherapy cannot be conclusively determined by this study.[13]

In contrast, few studies did not advocate delayed surgery by finding no difference in pCR, OS, DFS, or LR.[14],[15],[16],[17],[18] The Lyon trial is the only reported randomized controlled trial to date to examine the impact of timing interval on OS. It did not show improved OS or LR with longer intervals.[19] Our results showed that TI interval of ≤8 weeks was associated with higher pCR rate and tumor downstaging (P = 0.033, P = 0.026, respectively).

In the current study, pCR was achieved in 25.3% of the patients which is higher than the pCR rate reported in the CAO/ARO/AIO-94 study (8%), the PAN-EX study (19%), ACCORD12/0405-Prodige 2 trial (14%–19%), and Tata Memorial Hospital retrospective analysis from India published in 2014 (14.8%).[4],[20],[21] Some studies have reported higher rates of pCR.[22],[23] It has been reported that patients who achieve pCR tend to have better long-term outcomes.[24],[25],[26],[27] Our study also highlighted better OS and LRFS in patients achieving pCR and pathological tumor downstaging.

Our study did not show differences in pCR rates and survival among groups based on grade of rectal cancer which was in accordance with previous retrospective analyses.[28],[29],[30] Similarly, stage of disease was predictor for pathological response but failed to show its association with tumor downstaging. Other factors such as site of primary tumor and craniocaudal extent of disease were not predictors for better pathological response or tumor downstaging.

Our study showed an actuarial 5-year OS rate of 64.4%. The estimated 5-year and 10-year OS was 76% and 59.6% in CAO/ARO/AIO-94.[31] The 5-year OS rate in the study by Bosset et al. was 64.8% in the two groups receiving preoperative radiotherapy.[5] With a median follow-up of 42 months, TMH study showed a 5-year OS of 77%.[32] As per CONCORD study, for patients diagnosed with rectal cancer during 2005–2009, age-standardized 5-year net survival was in the range 50%–59% while survival was very low for the Indian population (29%).[33]

All patients in this study who underwent definitive surgery had a R0 resection. The surgical complications were seen in 7 (9%) patients. This rate is lesser when compared with TMH study.[32] The results from this study revealed 15.2% of the patients with long-term GI toxicity such as obstruction, fistula, or stoma complications while literature showed anastomotic strictures rate of 12%[4] while the frequency of small bowel obstruction was 13% for the irradiated patients.[34]

Late urinary tract symptoms were rarely seen after rectal cancer surgery with or without RT.[4],[34],[35] In our study, late urinary tract toxicity in the form of hydronephrosis, urinary incontinence, stricture, erectile dysfunction, and renal dysfunction was seen in 21% of the patients. Metachronous second cancer was documented in 1 patient.

 Conclusions



Studies outlining outcomes in LARC patients managed as per globally accepted standard of care from the Indian subcontinent are scarce. As per our analysis, optimal TI from completion of RT to definitive surgery is ≤8 weeks. This study revealed 5-year OS rate of 64.4% and pCR rate of 25.3% with NACTRT. Patients who achieved pCR and tumor downstaging had significantly better OS and LRFS. Hence, this study consolidates the value of upfront NACTRT in LARC patients. Incorporating molecular markers and radiomics to predict prognosis and clinical complete response remains area of exploration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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