Watch and Wait Approach After Neoadjuvant Chemoradiotherapy in Rectal Cancer: Initial Experience in the Indian subcontinent

Abstract

Patients with locally advanced rectal cancer (LARC) that have a complete clinico-radiological response after neoadjuvant chemoradiation (NACRT) can be offered nonoperative or watch and wait (W&W) management. This study assessed the compliance and outcomes of such patients at our institute. Thirty-six patients with locally advanced low-lying rectal cancers treated between December 2013 and November 2018 and had a near-complete clinical response (ncCR) or complete clinical response (cCR) after completing NACRT and were reluctant to undergo surgery were included. They were followed up at 3 monthly intervals with a combination of pelvic MRI, digital rectal examination, and sigmoidoscopy. Twelve weeks after chemoradiation, 24 (67%) patients had cCR and 12 (33%) had ncCR. All the 36 patients were kept on the W&W protocol. At a median follow-up of 35 (range 17–72) months, six (17%) patients developed local regrowth, one from the cCR group, while five were from the ncCR group. Four of the six patients underwent surgery for local disease (three had sphincter preserving resections and one had abdominoperineal resection), and one of these also had liver metastatectomy. Two of the six patients refused surgery, giving a compliance rate of 94.5%. Three of the 36 patients (8%) had distant metastasis, one had liver metastasis, one had leptomeningeal metastasis, and the third who refused surgery at regrowth developed lung metastasis. Thus, of the 36 patients on the W&W protocol, organ preservation rate was 80%. Local regrowth free DFS was 92.4%, and OAS was 96% at 3 years. W&W approach after cCR and ncCR to NACRT in LARC is acceptable with reasonable compliance and with good outcomes.

Introduction/Background

The standard management of locally advanced rectal cancer (stage II and stage III) is neoadjuvant chemoradiation (NACRT) and total mesorectal excision (TME) followed by adjuvant chemotherapy [1]. Approximately 15–30% of all the patients who receive NACRT achieve a complete clinico-radiological response. In the past decade, there have been emerging reports that surgery can be altogether avoided in these subgroups or performed only at the time of regrowth. Moreover, when regrowth occurs, there is a scope for local excision rather than TME. This strategy has been coined as the “watch and wait” approach. Habr-Gama A et al. were the first to report excellent outcomes in patients having a complete clinical response (cCR) in whom surgery was performed only at the time of tumor regrowth [2]. Subsequently, there have been many studies and meta-analyses from different parts of the world reporting excellent outcomes in those patients who achieved cCR. Identifying the complete responders clinico-radiologically and sparing them of major surgery to achieve organ preservation have been the focus of these reported studies [3–6].

Watch and wait (W&W) approach after complete response to NACRT in locally advanced rectal cancer (LARC) is the standard of care in medically inoperable patients [7]. The recent ESMO guidelines also recommend it for those patients who have cCR and refuse to undergo major surgery. In low- and middle-income countries (LMICs), there is frequent non-compliance with the strict follow-up protocol of the W&W approach, owing to factors such as geographical vastness, limited resources, ignorance, and poor socioeconomic status. In these developing countries, the presentation of the disease is at an earlier age (median age 47 years) and present with locally advanced stage [8]. The percentage of patients who default on treatment fearing a permanent stoma is as high as 18%, and W&W is an excellent tool to motivate them to finish chemoradiotherapy [9]. This study aimed to assess the compliance of patients to undergo strict W&W follow-up protocol and assess outcomes in patients who had cCR, or near-complete clinical response (ncCR) to NACRT and agreed to the W&W protocol and/or were reluctant to undergo surgery after NACRT.

Objective

To assess the outcome, feasibility, acceptance, and subsequent compliance to W&W approach after cCR and ncCR to NACRT in LARC.

Materials/Methods

Patients diagnosed with low-lying LARC and who completed NACRT between December 2013 and November 2018 and who had a good response after 6–12 weeks of NACRT and were reluctant to undergo surgery were included in the study. In this retrospective cohort, data were extracted from a prospectively maintained rectal cancer database at our institution. The institutional ethics committee approved the study. Radiotherapy was delivered with standard techniques using three-dimensional conformal radiotherapy technique (3DCRT) or intensity modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT). The radiotherapy doses were 50–54 Gy administered in 25–28 fractions. Concurrent chemotherapy using oral Capecitabine was given with a dose of 825 mg/m2 12 hourly on all the days of radiation including the weekends. All patients were initially assessed, at 6– 8 weeks following completion of Radiotherapy by the MDT (multi-disciplinary team). Those patients that were found to have a good response on digital rectal examination (DRE) and MRI (magnetic resonance imaging) and were reluctant to undergo surgery were assessed again after another 6 weeks (i.e., 12 weeks after finishing NACRT) with sigmoidoscopy and a repeat MRI of the pelvis. If there was cCR or ncCR, the patients were counseled and put on the W&W protocol after duly signing the consent. Based on the published literature, they were informed in detail about the 20–30% chance of regrowth and 8–12% risk of distant metastasis which is similar in the group undergoing surgery [10]. If patients agreed to take the associated risks of W&W and seemed likely to comply with treatment (social status and intelligence), they were put on the W&W protocol. This was discussed by 2 consultants, a surgeon and a radiation oncologist in a joint clinic and decision recorded to avoid medico-legal issues.

The cCR was defined as no palpable abnormality on DRE, white scar with telangiectasia on sigmoidoscopy, and absence of residual tumor on MRI (complete absence of tumor on the T2 W sequences and DWI MRI showing complete absence of restricted diffusion in the tumor bed). The ncCR was defined as superficial soft irregularity or small flat ulcer at DRE, small residual flat ulcer or irregular wall thickening on the sigmoidoscopy, and on MRI, significant downstaging with no visible intermediate signal intensity representing tumor and with either fibrotic residue/mucinous degeneration. These patients were then followed up 3 monthly for 2 years, with the digital rectal examination (DRE), magnetic resonance imaging (MRI) of the pelvis, and sigmoidoscopy and six monthly CT scan chest and abdomen to look for distant metastases. After 2 years they were followed up 6 monthly for 2 visits, and thereafter they were put on annual routine surveillance.

Statistical analysis

We estimated local regrowth rate (luminal regrowth only), local regrowth free disease-free survival (LRF-DFS), and overall survival (OS) with Kaplan–Meier curves. LRF-DFS was defined as the absence of local regrowth or pelvic and distant failure and was calculated from the time of completion of NACRT to the last follow-up. Kaplan–Meier method was used to determine the survival using SPSS version 25.0, Inc., Chicago, IL.

Results

Between December 2013 and November 2018, 39 patients who had a good response to NACRT were assessed. Patient characteristics are mentioned in Table 1. Four patients had mid rectal tumors and were put on this protocol due to reluctance, even for low anterior resection. There were six patients with T2 tumors, of these three had N2 disease, one was > 65 years and two had already commenced neoadjuvant treatment outside our institute. At six weeks’ response evaluation post-NACRT, 14 (39%) patients had cCR (Fig. 1). At 12 weeks another 10 (28%) achieved cCR. Therefore, at 12 weeks post-NACRT, there were 24 (67%) patients with cCR and 12 (33%) having ncCR (Fig. 2). All these 36 patients were kept on the W&W protocol. The median time to cCR was 12 weeks (range 6–60 weeks) post NACRT. Three patients who had a good response at 6 weeks but did not regress at 12 weeks (clinically partial response) underwent R0 surgical resection and thus 36 (92%) patients were kept on close follow up with the W&W protocol. The median follow-up of the 36 patients was 35 months (range 17–72 months). Of the 36 patients, 34 complied with wait and watch protocol. Two of the 36 patients refused surgery after being detected with local regrowth for the fear of permanent colostomy and continue to be on regular follow-up, giving a compliance rate of 94.5%. A total of six (17%) patients developed local regrowth at the median time of months (range 5–31 months). Of 24 patients with cCR, one developed local regrowth (4%) at 9 months and underwent surgery and is alive and well. Of 12 patients with ncCR, five developed local regrowth (42%) of which one had resectable liver metastases at 6 months, while one more developed leptomeningeal metastases and bilateral iliac nodes after 11 months of NACRT and was treated with palliative radiotherapy to the whole brain, and succumbed within one month of palliative RT. Hence, six out of 12 patients with ncCR had an event. Distant metastasis was seen in three (8%) patients.

Table 1.

Patients characteristics

		N (%)
Age		Median—50 years Range (18–73 years)
Sex	Male Female	27 (69) 12 (31)
T stage	T2 T3 (a-b) T3 (c-d) T4	6 (15) 16 (41) 13 (24) 4 (10)
N stage	N0 N1 N2	12 (31) 18 (46) 9 (23)
MRF	Free Threatened Involved Not known	18 (46) 5 (12.8) 14 (2) 2 (5)
Distance from anal verge	0–5 cm 5–10 cm	34 (87) 5 (13)
Histology	Well differentiated Moderately differentiated Poorly differentiated Mucinous/Signet ring Not known	3 (8) 25 (64) 8 (20) 2 (5) 1 (3)

Fig. 1.

Study flow diagram

Fig. 2.

Interval of completion chemoradiation and complete response

Of the six patients with regrowth, four patients underwent surgery (three had sphincter preserving resection with diversion ileostomy and closure at later date, and one had abdominoperineal resection); one of the four also had metastectomy. On histopathology, two patients had pT2 pN0 and the other two had pT3 pN0. Two patients refused surgery. Of these one had localized disease and the other has developed unresectable lung metastasis receiving palliative chemotherapy. In all of 36 patients, 35 patients are alive to date (two with the local tumor). Of the patients undergoing surgery, none had any additional postop morbidities like dense fibrosis or loss of normal planes. Thus, of the 36 patients on the W&W protocol, organ preservation rate is 80%, and the organ and sphincter preservation rate is 89%. Local regrowth free DFS was 92.4% (Fig. 3), and OAS was 96% at 3 years (Fig. 4).

Fig. 3.

Local regrowth free disease-free survival

Fig. 4.

Overall Survival

Discussion

For low-lying rectal cancers achieving a good or complete clinical response, organ preservation non-operative management or W&W policy is increasingly becoming acceptable to both the clinicians and the patients worldwide. The outcomes of W&W in the relatively young population with aggressive behavior have been reported by only a few centers in the Indian subcontinent [11]. Unlike in anal squamous cancers, where observation after the clinical complete response is the standard of care, for adenocarcinomas of the rectum, surgery after chemoradiation is a granted certainty for the surgeons. W&W policy is still evolving in India. The time to achieve cCR in anal squamous cancers has been studied extensively and now waiting for up to 9 months may not be considered unusual. However, for rectal adenocarcinomas, there is no consensus as yet on the timeline until when the surgery can be deferred and the patient continued to be monitored on the W&W approach [12, 13]. In the present study, we observed that 12/39 (31%) patients continued to respond beyond 12 weeks of completing chemo-radiation. The baseline T stage affects the outcomes in terms of time to cCR and regrowth rate [14]. Habr-Gama et al. observed that patients with earlier cT status (cT2/T3a) achieved a cCR significantly earlier than those patients with more advanced disease (cT3b-d/cT4) i.e. 19 vs 26 weeks; p = 0.03) [12]. In our study, the majority were staged as T3 (79%) and T4 (10%) with mesorectal fascia being threatened or involved in 15% of the cases and 30% of T3 + tumors achieved cCR after 12 weeks (Fig. 2).

The presence of mesorectal nodes before receiving NACRT has also been reported to lead to poorer outcomes contraindicating a W&W approach in such patients [15]. Habr-Gama A and colleagues compared 117 patients with node-positive and 218 patients with node-negative cancer at baseline [16]. They observed that both groups had similar rates of achieving cCR. In our study, the majority (69%) of the patients had node-positive disease on baseline MRI, and no nodal regrowth was observed. Though MRI nodal staging has its shortcomings, as yet it is the best available method for the assessment of mesorectal nodes [17]. Of the four patients who underwent TME post regrowth, all had pN0 disease. In a systematic review and meta-analysis, Dossa et al. reported a pooled regrowth rate of 15.7%, and following a regrowth, the pooled rate of salvage therapy was 95.4% [6]. For those patients undergoing salvage surgery, the rate of sphincter preservation was 49.8%. Similarly, Sammour et al. in a systematic review of 15 studies reported a pooled regrowth rate of 21.3% with a salvage rate of 91.3% [18]. Despite having patients with advanced T and N stage, the local regrowth rate of 17% in the present study is comparable to that in published literature and all the six local recurrences were surgically at a salvageable stage when detected. The rates of regrowth were higher in patients with ncCR, and caution is to be exercised when counseling such patients. Kong et al., in a systematic review on the outcomes of the W&W approach, reported the rate of distant recurrence was similar between patients in the W&W group and patients having immediate surgery [19].

In the long-term follow-up from the IWWD (International Watch and Wait Database) of 1009 patients, the distant metastasis rate was reported to be 8% [20]. In the present study, only 3 (8%) patients developed distant metastasis of which one had local regrowth as well, which was surgically salvaged. One patient had leptomeningeal metastasis and died of it. The third patient who refused surgery after developing regrowth also developed lung metastasis and is on palliative chemotherapy. There are few studies and meta-analysis comparing management with the W&W approach to the patients undergoing TME surgery. The randomized trial comparing surgery vs. nonoperative management has not been successful due to the non-compliance of the patients in the surgery arm or refusal to undergo surgery if they have complete response post NACRT. All have concluded that there is no difference between patients managed with W&W protocol after an cCR and patients with pathological complete response identified at resection concerning non-regrowth recurrence or cancer-specific mortality or survival and a better quality of life [10, 21–23]. In the present series, two patients who developed local regrowth refused surgery. It is a continuous challenge to convince such patients to undergo surgery, which entails a permanent stoma, a fact also observed by Yeom et al. [24]. Therefore, this approach is a personalized management achieved by the MDT which is coordinated and in close dialogue with the patient to achieve the best outcomes. To minimize the rejection of salvage treatment in the event of local regrowth, proper and timely counseling is a must.

Conclusion

In the Indian subcontinent where a relatively young population presents with rectal cancer, W&W policy is acceptable with a compliance rate of 94%. Outcomes of the cCR group support a W&W program. Caution should be exercised in offering a W&W approach for near-complete responders with a higher regrowth rate. The W&W approach after cCR and ncCR to NACRT in LARC is therefore acceptable with reasonable compliance, feasible in LMICs in well-selected patients, and the outcomes of this approach are similar to published literature. However, it should be implemented carefully in select cases after proper counseling.

Declarations

Ethics Approval

Institutional Review board number—3108.

Conflict of Interest

Nil.