Can Radiotherapy Alone Be Effective for Treating Anastomotic Recurrence of Rectal Cancer? When the Patient Decides?

Introduction

In the past, local recurrence of rectal cancer following radical surgery occurred in 20%–35% of patients ^{1 –4} ; however, its incidence over the last 20 years has dropped to below 10% because of routine use of total mesorectal excision (TME ⁵ ) and to below 5% since TME has been combined with neoadjuvant radiochemotherapy. ^{6 –11}

It is not always clear in the literature what is meant by “recurrence” of a surgically treated rectal cancer. Although “pelvic recurrence” has been defined as the “regrowth of tumor in and around the tumor bed including the perirectal fat and lymph nodes,” ¹² on the other hand, “local recurrence” has been generally defined “as disease at the anastomosis or in the adjacent mesentery, peritoneum, retroperitoneum, or carcinomatosis” ¹³ or as “histologic, radiologic, or postmortem evidence of recurrent disease at or local to the anastomosis.” ¹⁴ In contrast, “anastomotic recurrence” (AR) has been defined more strictly as a recurrence “within 2 cm of the suture line and with no extramural spread” ¹⁰ or even more extensively as a “tumor that was located on the anastomotic suture line and mainly located in the intraluminal space.” ¹⁵

In the era of TME, there have been few reports focusing on AR after anterior resection of rectal cancer. ¹⁵ The authors report the case of a patient with AR treated only with radiotherapy.

Case Report

A 54-year-old man presented with a 10-month history of rectal bleeding. A colonoscopy revealed the presence of a pedunculated polypoid neoformation of the rectum (1.5 × 1 cm) at 12 cm from the anal verge. Endoscopic polypectomy was performed with histological diagnosis of moderately differentiated adenocarcinoma with peduncular infiltration, and for this reason, a rectal resection was decided. Using abdominal computed tomography (CT) scan and rectal endoscopic ultrasound (EUS), the neoplasia was preoperatively staged as N0 and no distant repetitive processes were seen. After informed consent was obtained, the patient underwent open anterior resection of the rectum with colorectal mechanical Knight-Griffen anastomosis. TME was performed according to the Heald's technique. ⁵ An intraoperative histological examination, as usually done, ruled out neoplastic infiltration of the distal resection margin.

The final histological evaluation showed no evidence of neoplastic cells in the resected rectum and reactive lymphadenitis in the 21 lymph nodes evaluated (T1 N0 M0; G2). The patient accepted the authors' tailored follow-up, ¹⁶ which in early stages provides medical and instrumental examination every 6 months during the first 3 years and then yearly until 10 years after surgery. However, after 12 months, colonoscopy showed some granulomas at 8 cm from the anal verge, at the site of the colorectal anastomosis, with diagnosis of moderately differentiated adenocarcinoma foci. Abdominal and pelvic CT scan revealed, behind the seminal vesicles at the site of metal suture, a 2-cm-diameter hypodensity lesion projecting posteriorly, suggestive of AR. No images of enlarged lymph nodes were present along the iliac axes or the internal obturator muscles. The EUS showed increased rectal wall thickness (maximum of 17 mm) at 7 cm from the pectineal line, with irregular appearance and mainly exophytic development, and confirmed the absence of enlarged perivisceral lymph nodes.

The patient refused reoperation, as the risk of a definitive colostomy was referred to him, and with his consent only radiotherapy treatment was started. The patient was treated on external beam radiotherapy by LINAC with three fields of irradiation (one posterior and two latero-lateral). The target volume involved the whole pelvis up to a dose of 45 Gy. Concomitant boost radiotherapy allowed irradiation of a further reduced volume, which included, in accordance with the recommendations of the International Commission on Radiation Unit and Measurements 60, the macroscopic extension of the lesion in addition to a 2 cm safety margin. A total dose of 54 Gy was delivered to the lesion. No adverse reactions or side effects were reported. The patient was again enrolled in the follow-up of colorectal cancer patients, which is personally done by one of the authors (G.L.D.), who reports electronically every datum in the patient registry. As the patient refused radical surgery, he underwent a more intensive follow-up. Rectoscopy, EUS, and CT scan were performed at 6 months after treatment, which showed complete disappearance of the neoplastic lesion. Endoscopic examinations were repeated every 6 months during the first 3 years of follow-up and then once a year. A CT scan was also repeated on an annual basis. Eight years after the diagnosis of AR, the patient was found to be free of any further distant or local recurrence and in good health.

Discussion

True AR is relatively rare ¹⁵ and its actual incidence is not completely known as it is difficult to differentiate between a recurrence that originates from the suture line and a recurrence that develops outside the anastomosis and then spreads to the mucosa ⁶ involving the suture line, which should be considered as a “local recurrence.”

The literature reports an incidence of AR between 2.4% and 12% of all patients who underwent colorectal anastomosis ^{6,15,17 –19} and between 10% and 22% when considering the incidence of AR as percentage of local recurrences. ^10,12,17

The pathogenesis of an AR after curative surgery for rectal cancer is not completely clear. When it is not caused by a positive margin of resection, ^6,18,19 the recurrence may be due, as suggested by experimental models, ¹² to the “cancer infection,” which is defined by Ryall ²⁰ as the implantation of exfoliated neoplastic cells along the anastomotic line particularly exposed maybe because of the suture material. ^6,12,18,19 AR has also been associated with stapled anastomosis ^8,21 even though recent comparative studies have shown no difference between stapled and handsewn anastomoses in terms of AR. ¹⁹ Other authors, on the contrary, suggest that laparoscopy may be more likely to cause this type of implantation because of the “spillage” occurring when using this technique. ²² In consideration of this theory, a cytocidal rectal washout has been recommended prior to performing the colorectal anastomosis, because it has been demonstrated both in vitro and in vivo that free malignant cells can be effectively destroyed by these agents. ^6,8,18,21 However, a true reduction of anastomotic implantations after washout has not been proved. ^12,15,21 In consideration of this pathogenetic theory, the risk of developing AR is lower in the group of patients who received preoperative radiotherapy, ²² as it might reduce the number and the viability of exfoliated cells.

Another pathogenetic cause may be associated, perhaps, as in the present case, with the grading of the tumor, which could be responsible for the cell proliferative instability in the mucosa at the anastomosis site, maybe caused by the suture materials, or in the mucosa near the tumor, as the simultaneous presence of polyposis may suggest. ^12,18,19

Finally, not always the development of an AR is associated with an advanced stage of the primary tumor. ^6,12 The importance of grading could be a key factor in the present case, wherein the AR developed in a patient treated for an early rectal cancer (T1 N0 M0), and further, an intraoperative histological examination of the distal resection margin revealed no evidence of neoplastic cells.

Because of the low incidence of clinical symptoms ^12,15,18 and the absence of elevated carcinoembryonic antigen levels, ¹⁵ an early diagnosis of AR can be made with digital rectal examination and especially sigmoidoscopy, ^12,15,18,21 which should be planned on a regular basis especially in the first 2 years of follow-up (80% of recurrences occur within this period ^12,15,21 ). So was the case of the present study's patient, who was asymptomatic and presented no elevated carcinoembryonic antigen levels, wherein the diagnosis of AR was made following a routine follow-up colonoscopy at 12 months after surgery.

Although few data are present in the literature on the treatment of an operable AR, ¹⁹ surgical R0 reresection is certainly the “best therapeutic option” ²¹ with a higher survival rate and better prognosis compared with local recurrence, which presents lower resectability rates (87% vs. 46%). ^9,15,21

With regard to the radiotherapy treatment, several studies have reported excellent results, especially in the preoperative and also in the intraoperative treatment of a “local recurrence.” ^{23 –27} At this point it should be stressed that the local control achieved with radiotherapy alone is due to low alpha/beta ratio of the neoplastic cells of the rectum, ²⁸ which allows to use single fractions of 5 Gy compared with an estimated value of 10–12 Gy used for most other cancers. According to these data and because of the absence of reports in the literature, AR could also benefit from this treatment, and in the authors' opinion, the results could be also more relevant because radiotherapy would be used to treat a smaller field. Further, as there are no precise guidelines for resectable AR, surgery or radiotherapy or both, the most appropriate treatment strategy has been chosen by the authors.

In the present case, the authors had proposed to the patient what they consider “the best therapeutic option,” ²¹ that is, the surgical reresection and the option to administer radiotherapy postoperatively if necessary. The patient, because of the probable option of colostomy, refused surgery and decided to undergo radiation therapy only. It should be taken into account that these patients often receive radiotherapy preoperatively and that, to avoid pelvic complication, low radiation doses are delivered with definitely poorer results, or other different techniques are used, such as hyperfractionated radiation therapy, intraoperative radiotherapy (IORT), or radiation therapy in combination with chemotherapy. ⁹ In the present study's case, as radiotherapy was not administered preoperatively, it has been given with maximum dose delivery and has proved to be effective in the long term. After 8 years, examinations have not shown any recurrence or distant metastases. So it can be believed that the patient “without knowing” took the right decision because he was cured of the recurrence by undergoing a less-invasive treatment.

In a recent European consensus conference, ²⁹ it has been underlined that in patients who refuse any surgical treatment for an early rectal cancer, the external radiotherapy alone might be a feasible alternative even though “the evidence is limited and definitive recommendation requires further studies.” At that moment the authors did not know the prognosis of this patient treated by radiotherapy only. However, based on their experience, the authors were confident because they knew that in 67% of the rectal cancer-treated patients who had undergone preoperative radiotherapy treatment, a pathological complete response was obtained by endoscopy, EUS, and biopsy and no neoplastic cells were present in the operatory specimen.

Conclusions

Finally, although at present radiation therapy alone may not be considered as an alternative to surgical reresection of early-diagnosed AR, the authors believe that, in a selected number of cases, maximal radiotherapy treatment can not only be an additional palliative treatment but also an excellent effective option. This therapeutic option is already recommended in a selected number of cases by other authors ⁶ in case of infiltrated distal resection margins following rectal cancer resection. Only time and evidence will tell what will be the effect of neoadjuvant or adjuvant radiotherapy on an AR of rectal cancer.