Adjuvant radiotherapy after local excision of rectal cancer

Abstract

Background: Local excision is now accepted as a standard treatment option for certain patients with early rectal cancer. However, there is a higher risk of local recurrence than after radical surgery with total mesorectal excision. Adjuvant radiotherapy after local excision may reduce this excess risk, and yet retain the benefits of local excision, with rectal preservation.

Methods: A review of the literature pertaining to the use of adjuvant radiotherapy after local excision of rectal cancer and a discussion of current practice.

Results: We first considered local excision as a treatment option for early rectal cancer, looking at technical developments and the risks and benefits of organ preservation, in particular, the advantages for quality of life and the risk of leaving residual disease which may result in local recurrence. We then looked at reported outcomes for studies using adjuvant radiotherapy after local excision. Few of the studies routinely used modern endoscopic methods of local excision and only the recent used chemoradiation. Local recurrence rates after adjuvant radiotherapy have improved over time, with rates of around 3.5% in the recent studies. Adverse effects of adjuvant radiotherapy are not commonly described, but generally, they are relatively mild when described. We then discussed current practice regarding adjuvant radiotherapy, including pathological criteria, discussion of local recurrence risk with the patient and the importance of a surveillance regime to detect any recurrence at an early stage.

Conclusion: We conclude that the current state of knowledge regarding adjuvant radiotherapy after local excision suggests a potential role in decreasing the risk of local recurrence but further studies are required to better define this effect, clarify which patients will gain the most benefit from this pathway, and identify those who should avoid exposure to the risks of radiotherapy.

Introduction

Radical surgery in the form of total mesorectal excision (TME) is the conventional treatment for rectal cancer, but in early rectal cancer local excision can provide definitive treatment in selected early-stage cases as defined in the recent ACPGBI guidelines published in 2017 [1], and indeed radical surgery may be considered as overtreatment.

The precise role of local excision is now becoming better delineated, and the use of adjuvant radiotherapy may potentially expand this role. Local excision carries lower operative risks than radical surgery with TME and allows organ preservation with evident advantages for subsequent quality of life. However, by not removing the mesorectum it precludes definitive determination of any nodal involvement by tumor and carries an increased risk of local recurrence. Such local recurrence may be due to undiagnosed nodal disease, vascular invasion by tumor or implantation of cancer cells at the time of local excision. Adjuvant radiotherapy allows retention of the benefits of local excision but, by ‘sterilizing’ the excision bed and mesorectum, has the potential to reduce the risk of local recurrence to what might be expected after TME. An alternative organ-preserving strategy using neo-adjuvant chemoradiation followed by surveillance if the tumor responds, is also becoming more common. This strategy is not so relevant to early rectal cancer, and cannot be used where a malignant diagnosis has not been confirmed prior to local excision.

In this paper, we review the literature on adjuvant radiotherapy after local excision and discuss the current practice of this strategy.

Background

Over recent decades technical developments have enabled ongoing refinement to local excisional procedures for rectal cancer [2,3]. Traditional transanal excision has been largely superseded by the use of an endoscopic platform providing clear visualization even to the upper rectum, such as transanal endoscopic microsurgery (TEM), transanal minimally invasive surgery (TAMIS) or transanal endoscopic operations (TEO). These techniques allow more precise dissection, both at the lateral and deep margins, achieving en bloc excision of the tumor, more effective marginal clearance, and reduced risk of local recurrence compared to traditional transanal excision [4,5].

The benefits of local excision compared to radical surgery are clear. Operative morbidity and mortality are lower, with shorter hospital stay and reduced healthcare costs. Preserving the rectum offers better subsequent bowel function, as radical surgery often involves a permanent stoma or can be followed by ‘anterior resection syndrome’ which many patients find distressing. Preservation of pelvic nerves also retains better urinary and sexual function. Allaix [6] followed 93 patients for 5 years after TEM with questionnaires and anorectal manometry, and found that the early urgency and reduced anal resting pressure were improving at 1 year and resolved by 5 years. A smaller study looking at anorectal function after TAMIS found no detrimental effect at six months [7].

These benefits can make local excision an attractive option for patients with early rectal cancer, but need to be weighed against the risks of leaving behind the mesorectal lymph nodes and the potential for recurrent disease which may necessitate further treatment. Despite the application of pre-operative staging using high-resolution MRI (magnetic resonance imaging) and endo-rectal ultrasound (ERUS), unexpectedly involved lymph nodes and more invasive spread is sometimes encountered during histopathological analysis of the surgically-resected TME specimen. A study comparing pre-operative high-resolution MRI with histopathological assessment of TME specimen found MRI to have an accuracy of 84% in determining the lymph node status and an accuracy of 89% in distinguishing T1 sm1 and sm2 stage cancers from more invasive cancers [8]. If these cancers had been removed by local excision, in those where the MRI was not accurate the involved lymph nodes would have remained undiagnosed in the mesorectum.

This is the essential concern with local excision – undiagnosed residual tumor cells left behind in the mesorectum resulting in a higher rate of local recurrence compared with TME [9]. This has been demonstrated in many studies. For example, a review of the US National Cancer Database [10] found a 5-year local recurrence rate of 12.5% after local excision for T1 tumors, nearly double the 6.9% rate observed after TME. Similarly, for T2 tumors, the local recurrence rate after local excision was 22.1% compared with 15.1% after TME. A smaller Dutch study [11] found a 5-year local recurrence rate of 24% after local excision compared with 0% after TME for T1 cancers.

One option for dealing with this recurrence risk after local excision, if the tumor is shown on histopathology to be more advanced or aggressive than expected or if the resection margin is not clear, is to proceed with completion surgery – undertaking the TME that the patient previously avoided. A second option is close surveillance, ensuring that the patient is aware of the risk of recurrence and the imperative of adhering to a surveillance regime, and also that a system is in place to facilitate this surveillance so any hint of recurrence can be addressed promptly with salvage surgery. The third option is adjuvant radiotherapy. A review of salvage surgery after local excision [12] noted relatively high post-operative morbidity and relatively low long-term survival, however, it is noteworthy that most of the recurrences were detected relatively late (the majority were pT3 at salvage surgery) in the absence of a clear surveillance regime.

Adjuvant radiotherapy

Radiotherapy has long been used in combination with radical surgery for rectal cancer in an effort to reduce the local recurrence rate. The Swedish rectal cancer trial [13] found that pre-operative radiotherapy before TME decreased the 5-year local recurrence rate from 27% to 11% for all tumor stages combined. The same rationale led to the use of radiotherapy following local excision when pathological features suggested that local excision may not have been an adequate treatment. Early results were not particularly promising. One example is a Canadian study of 73 patients who received radiotherapy after local excision; 20 developed local recurrence, with 5-year local recurrence rates of 39% for T1 tumors, 21% for T2 and 25% for T3 tumors [14]. The local excision technique in this study was transanal excision in 67%, electrocautery in 29% and posterior sacrectomy in 4%, and none of the patients received chemotherapy in combination with the radiotherapy. However, modern techniques of local excision utilizing endoscopic assistance are likely to result in better outcomes than traditional transanal approaches, as they have been shown to result in less tumor fragmentation and improved rates of clear margins [4]. In addition, evolution of radiotherapy techniques, particularly the use of chemosensitizing agents, has improved efficacy and at the same time reduced adverse events. For example, the EORTC radiotherapy group trial 22921 demonstrated improved local control of rectal cancer when fluoropyrimidines were added to a radiotherapy regime [15].

A systematic review looking at radiotherapy in combination with local excision for T1 and T2 rectal cancer [16] found 10 studies that met their inclusion criteria where postoperative radiotherapy was used. Two of these specifically considered transanal endoscopic surgery, but neither of these added chemotherapy to the regime [17,18]. The first, from Israel [17], reported on 21 patients with T2 cancer treated with TEM. Following TEM, 16 were advised to undergo adjuvant radiotherapy because of pathological features; 12 agreed. At a median follow-up of 3 years, no recurrence had occurred among these 12 patients whereas two of the four who declined developed recurrence. It is notable that two of the radiotherapy-treated patients eventually required proctectomy for complications of radiotherapy, suggesting a radical radiotherapy regime was used, although the paper does not give details. The second study, from Spain [18], reviewed 88 patients treated by TEM for rectal cancer 28 of whom underwent adjuvant radiotherapy (50.4 Gy in 28 fractions) because of histopathology findings. Mean follow-up was 6 years and three of the 28 (10.7%) developed local recurrence.

A more recent, Canadian study [19] reviewed 93 patients managed by local excision with adjuvant radiotherapy for T1-3 grade tumors. The operative technique was transanal excision in 86% and TEM in 14%; six patients had concomitant chemotherapy with the radiation. The estimated five-year local recurrence rate was 13.9% for the whole group and 7.5% in the T1 subgroup. In a smaller UK study [20] 28 patients were offered adjuvant chemoradiotherapy (CRT) following local excision because of adverse histopathological findings; 18 patients accepted. The operative technique was transanal excision in the majority, with TEM in the remainder. At a median follow-up of 4 years there had been no local recurrence in the radiotherapy group but four instances of local recurrence among the 10 patients who declined. Two of these were residual tumor diagnosed at first post-operative surveillance and the patients underwent salvage abdomino-perineal excisions within 3 months of the local excision. The other two were diagnosed at 6 and 7 months following local excision. It is not clear which operative technique for local excision preceded these recurrences.

Two more recent Asian studies used adjuvant CRT in a more structured regime for tumors with adverse histopathological features. A Korean study [21] looked at 83 patients after local excision; 70% had transanal excision and 30% underwent EMR or EMD. The standard adjuvant treatment was radiotherapy (50.4 Gy over 5 weeks) with concurrent chemotherapy. Two patients did not have the concurrent chemotherapy, and 14 received additional adjuvant chemotherapy following CRT. Three patients (3.6%) developed local recurrence, at a median follow-up of 5 years. A Japanese multi-center trial [22] enrolled 61 eligible patients who had a transanal excision with high-risk features being found on histopathological analysis. Of these, 57 agreed to CRT (45 Gy in 25 fractions), and four declined. The full course of CRT was completed in 86%. Median follow-up was over 7 years. Two of 57 (3.5%) developed local recurrence while one of the four who declined CRT also developed local recurrence. These more recent studies generally define the histopathological features that are considered to warrant adjuvant radiotherapy after local excision more clearly than earlier papers and appear to favor the use of concurrent chemotherapy with the adjuvant radiation. The most common operative technique reported remains transanal excision, rather than the newer endoscopically-assisted methods. In our unit, 33 patients received adjuvant radiotherapy after local excision by TEM for early rectal cancer over a 10-year period. The estimated 3-year local recurrence rate was 6.9% compared with 21.2% in a propensity-score matched group followed by surveillance alone [23]. The standard adjuvant regime was 45 Gy in 25 fractions with oral capecitabine, and, for patients where more limited treatment was indicated, 25 Gy in five fractions without chemotherapy was used.

Only a few of the studies mention adverse effects due to adjuvant radiotherapy. In the Spanish study [18] 13 of 28 patients developed complications of radiotherapy (8 grade I, 5 grade II) and all were managed conservatively. The Korean study [21] noted early proctitis (grade 2) in 11% of patients. The same number showed asymptomatic proctitis later at follow-up. In the Japanese study of 57 patients [22], 26 early adverse effects were noted although the number of patients affected is not given. Only three of these were classified as grade 3, and almost half the adverse effects were diarrhea or anal pain. No late adverse effects were noted. This relatively minor risk profile contrasts with adverse events reported following CRT as a neo-adjuvant treatment strategy. The Dutch CARTS study [24] which treated 55 patients with CRT (50 Gy in 25 fractions) prior to planned TEM recorded 39-grade 3–5 complications in 23 patients. The full CRT regime was completed by 89% of patients. There were two deaths during CRT, one due to sepsis and one attributed to arrhythmia. Furthermore, they noted a post-operative complication rate after TEM of 28% in patients who had neo-adjuvant radiotherapy, higher than generally reported after primary treatment with TEM.

Adjuvant radiotherapy in practice

The option of adjuvant radiotherapy for a particular patient comes under consideration once the histopathology results of the locally-excised cancer are available. These results are reviewed at a multi-disciplinary team (MDT) meeting. While the meeting may recommend one of the three follow-up pathways – completion surgery, surveillance or adjuvant radiotherapy – for any particular patient, the final decision will be made in consultation with the patient. Apart from co-morbidity and functional status, the patient’s perception of risk, both regarding tumor recurrence and the adverse effects of any further treatment need to be taken into account. Estimated risk of local recurrence of 15% may be considered high by the clinicians, but the patient may consider the analogous 85% risk of having no further recurrence and avoiding any further treatment to be a good choice. On the other hand, another patient may find even a 5% risk unacceptable and actively seek further treatment. The height and location of the tumor may also be a consideration for the patient, as if completion surgery would require an abdomino-perineal excision, the patient may be prepared to accept a different level of recurrence risk than if an anterior resection was contemplated. A further consideration is the patient’s ability and willingness to adhere to an effective follow-up regime. The decision regarding further treatment after local excision is therefore not prescribed based on rigid histopathological categories but is reached by a fully-informed discussion with the individual patient.

In general, adjuvant radiotherapy may best be reserved for patients in whom there is a ‘significant’ risk of local recurrence after the local excision and where completion TME surgery is not favored. At present, the risk of local recurrence after local excision is often assessed using a model based on tumor grade and size and the presence of lymphatic invasion [25]. Bosch [26] demonstrated that for T1 cancer lymph node involvement was associated with lymphatic invasion, submucosal invasion ≥1mm, tumor budding and poor differentiation. Several of the studies mentioned above use some of these as criteria for advocating adjuvant radiotherapy [19,21,22]. There is still much room for improvement in finding more sensitive and specific markers to predict the risk of recurrence in an individual patient, for example using digital pathology and molecular markers. This is an active area for research currently. The ability to predict whether or not a specific tumor is radiosensitive is also an important question yet to be resolved, as this would allow patients in whom radiotherapy would not be effective to avoid exposure to the risks of the adjuvant treatment.

When a decision has been made to undertake adjuvant radiotherapy, this generally commences around six weeks following the local excision. The aim is to sterilize the excision bed and mesorectum as soon as possible, but after ensuring that the local excision site has healed in order to prevent any further delay of healing. In the authors’ experience, an endoscopic examination to confirm healing of the local excision site is valuable before commencing radiotherapy.

Following radiotherapy patients remain under surveillance as it is important to detect any local recurrence at an early stage when effective salvage surgery is possible. A standard follow-up regime may review the patient at 4 monthly intervals following treatment for the first two years and then at 6-monthly intervals to a total of five years, evaluating the patient with clinical and endoscopic examinations as well as MRI scan and CEA measurements, and annual CT scans. Any abnormalities may be further assessed by CT-PET scan. Adjuvant radiotherapy may also serve to delay the time till local recurrence, although there is as yet insufficient data to fully understand its implications. This does nonetheless raise the possibility that surveillance may need to be continued for longer than it would be the patient managed by surveillance alone when five years is generally considered the end of surveillance.

Future prospects

The current state of knowledge regarding adjuvant radiotherapy after local excision of rectal cancer indicates that it does potentially have a role to play in decreasing the risk of local recurrence, and patients may enjoy the benefits of organ-preserving treatment without exposing themselves to an undue risk of local recurrence or excessive toxicity effects from radiation. However further knowledge is required to clarify the group of patients who will gain the most benefit from this pathway. Larger-scale assessments of long-term outcome and randomized clinical trials will help to provide this knowledge.

Disclosure statement

The authors report no conflicts of interest.