Radiological and clinical findings following rectal contact X-ray brachytherapy (Papillon technique) - how to assess response

Purpose

Colorectal cancer is the 4th most common cancer in the UK [1]. Rectal cancer comprises 32% of these in men and 23% in women [2]. With the advent of the national bowel cancer screening program, it is predicted that more rectal cancers will be diagnosed at an earlier stage. At the same time, there is an increase in the aging population in the UK [3]. Older patients have a higher morbidity from surgery for rectal cancer, with elderly patients having a 10% higher risk of dying after surgery for distal colorectal cancer than those with proximal cancers [4]. Therefore, interest is increasing in techniques that preserve the rectum, and decrease the morbidity and mortality associated with major surgery. The use of external beam radiotherapy (EBRT) to attain a complete clinical response (cCR) is described with higher doses of radiation achieving higher rates of clinical response [5]. Rectal contact X-ray brachytherapy (CXB), also known as Papillon radiotherapy, has been shown to accomplish sphincter sparing in a greater number of patients than EBRT alone [6]. With combined Papillon, EBRT, and chemotherapy, initial cCR rates of 68% are achievable, with local regrowth rates of 12% and organ preservation rates of 79% [7].
According to National Institute for Health and Care Excellence (NICE), low energy CXB is recommended for patients with early rectal cancer who are not fit for surgical resection, as it is both safe and efficacious [8]. NICE recognizes that some patients who are suitable for a resection do not wish to have an operation, and state that whilst this approach is safe, its efficacy is not proven.
At our institution, a CXB “boost” is given in combination with EBRT with or without chemotherapy to patients with early rectal cancer (T1 to T3, node negative) for whom major surgery would be high-risk, or who do not wish to have a permanent stoma. All patients are discussed in a multidisciplinary team meeting. Informed consent involves detailed discussion around the evidence regarding the outcomes after CXB (combined with EBRT and chemotherapy) versus the outcomes and risks of surgical resection. Some high-risk patients wish to defer major surgery, and it is explained that if the watch-and-wait approach fails, or if tumor regrowth occurs, salvage surgery will be offered. This combined approach has been used with or without transanal excision; either to induce regression of a local tumor, or to irradiate the mesorectum and tumor bed following incomplete or high-risk local excision.
A so-called “watch-and-wait” approach is then assumed, in which a surgical resection is not undertaken unless tumor regrowth (i.e. local recurrence after non-operative treatment) is detected on surveillance [9]. Several authors have published conflicting guidelines for surveying rectal cancer patients following neoadjuvant chemotherapy with external beam radiotherapy. Initially, Habr-Gama et al. published guidelines on the standard findings of cCR on proctoscopy and at digital rectal examination [10]. Namely, signs of cCR were a whitened scar, telangiectasia, palpable stiffness of the scar, and a lack of visible tumor or palpable nodule. Incomplete clinical response was indicated by nodularity, ulceration or significant stenosis. These, it was proposed, should prompt transanal excision. However, Smith et al. demonstrated that 74% of patients with visible ulceration or mass in fact had no evidence of residual malignancy on proctectomy specimens, whilst 27% with cCR according to these guidelines demonstrated residual disease on histology. This highlighted the importance of alternative techniques, such as imaging, in assessing response to chemoradiotherapy [9]. The “magnetic resonance tumor regression grade” (mrTRG) has previously been described, based on the degrees of low signal intensity, intermediate signal intensity, and tumor signal intensity present on magnetic resonance imaging (MRI) following neoadjuvant treatment [11]. Bhoday et al. suggested that mrTRG was 10 times more likely to correctly diagnose complete clinical response than clinical assessment, therefore allowing a greater number of patients to avoid immediate surgery and instead undergo a watch-and-wait approach. In addition, MRI can identify extramural disease [12]. Another group have suggested the importance of “triple assessment”, in which the combination of T2-weighted and diffusion-weight MRI, endoscopy, and digital rectal examination were suggested to miss only 2% of patients with residual disease [13].
In light of the above, an intensive follow-up protocol is undertaken following CXB to ensure that tumor recurrence is detected at an early stage, when salvage surgery can be successfully undertaken. MR scanning, sigmoidoscopy, and digital rectal examination are recommended at three monthly intervals for the first two years and six monthly during the third year. If changes are stable at that point, then surveillance can revert to digital rectal examination and rigid sigmoidoscopy in outpatients, with MR scanning only if abnormalities are detected.
However, no authors have described the endoscopic or MR appearances following CXB and as such, no published guidance is available describing response assessment in this group of patients.
In this paper, seven cases are presented that demonstrate the changes seen following rectal CXB, in order to aid clinicians with interpretation of post-CXB MR scans and endoscopic appearances. Diffusion-weighted MRI is not discussed as experience with this modality is limited at our center.

Material and methods

A case series of 7 non-consecutive patients with T2 to 3C N0 rectal adenocarcinoma on MR staging is presented from a regional center for rectal CXB in the South of England, United Kingdom. These patients either expressed a preference for sphincter-sparing treatment/avoidance of stoma, or were considered high-risk for a major operation, and wished to defer surgical resection. Treatments included immediate or delayed transanal excision and adjuvant or neoadjuvant chemo/radiotherapy. All patients underwent Papillon radiotherapy. These cases were chosen to illustrate response assessment only, to a variety of treatment strategies. Each patient provided written informed consent for the case histories and accompanying images to be published.

Results

Case 1

Patient No 1 was a 57-year-old man, who had a one-year history of change in bowel habit with recent rectal bleeding. On endoscopic assessment, he was found to have a moderately differentiated adenocarcinoma of the rectum. On MRI it was benign appearing, 3.7 cm in length and arising 6.7 cm above the anal verge at the 2 o’clock position. He underwent a transanal endoscopic resection, which revealed a pT2 G2 N0 L0 V0 adenocarcinoma arising from a tubulovillous adenoma with low- and high-grade dysplasia. The tumor was focally infiltrating the muscularis propria. The tumor was excised with 5 mm clearance from the nearest peripheral margins and 7 mm from the deep margin. The patient was advised to have a surgical resection, but he wished to avoid the risk of a stoma, and therefore underwent CXB 90 Gy in 3 fractions to the excision scar with a 22 mm applicator, and then EBRT to the pelvis 45 Gy in 25 fractions, with concomitant capecitabine. At two years, the patient has no clinical evidence of disease. He had some loose stool and urgency, which resolved by increasing his fibre intake.

Case 2

Patient No 2 was an 83-year-old man, who presented with rectal bleeding. Imaging and biopsy determined that he had a T3C N0 moderately differentiated adenocarcinoma of the rectum. It was 4 cm in length, arising at 2.2 cm above the anal verge, between 9 and 2 o’clock, and infiltrating the superior aspect of the anal sphincter. No residual tumor bulk was present following EBRT 45 Gy in 25 fractions. Standard treatment would have been an abdominoperineal excision of rectum (APER) and permanent stoma formation. Watch-and-wait alone could have been offered at this stage, but it was felt appropriate to offer a CXB boost to increase the chances of sustained cCR. The patient underwent CXB 90 Gy in 3 fractions (with a 25 mm applicator), over 4 weeks after a 12-week interval (this longer interval to CXB boost was due to a new CXB machine being commissioned). He did not suffer from radiation toxicity, and at 30 months follow-up he has no evidence of tumor regrowth. The patient describes himself as “fit as a fiddle”.

Case 3

Patient No 3 was a 45-year-old woman, with a T3B N0 moderately differentiated adenocarcinoma of the rectum, 2.5 cm in length at 3 cm from the anal verge, extending from 11 to 1 o’clock, with possible encroachment onto the posterior vaginal wall anteriorly on MRI assessment. The patient wished to explore an approach that did not involve stoma formation and primary reconstructive surgery of the vagina. She underwent Papillon boost of 90 Gy in 3 fractions with a 25 mm applicator. During this time, the tumor shrank from 2.5 cm in length at the 1st fraction to 2.3 cm at the 2nd fraction, and 2 cm at the 3rd fraction. She then underwent EBRT 45 Gy in 25 fractions with concomitant capecitabine. Endoscopy 1 month following treatment showed a partial response to treatment with a residual polyp for which she underwent a transanal full thickness resection. Histology revealed a moderately differentiated adenocarcinoma with minimal tumor regression, pT2 G2 L0 V0. At 30 months follow-up, there was no evidence of tumor recurrence.

Case 4

Patient No 4 was a 67-year-old man, who presented via the bowel cancer screening programme with a positive fecal occult blood test. The patient was found to have a T2 N0 adenocarcinoma, 2.5 cm in length, arising 1.7 cm from the anal sphincter from 6 to 9 o’clock. He underwent a transanal excision, which demonstrated a high-risk tumor (pT2 G3 N0 L1 V0). He wished to avoid a permanent stoma, therefore he opted to have 45 Gy in 25 fractions EBRT with concomitant capecitabine, followed by 90 Gy in 3 fractions CXB boost with a 22 mm applicator. Initially surveillance demonstrated no evidence of recurrence; however, at 17 months post-treatment on repeat imaging, he had changes as demonstrated in Figures 4J and 4K, and mucosal abnormalities on his flexible sigmoidoscopy. Biopsy of these confirmed tumor recurrence with poorly differentiated adenocarcinoma. CT scanning showed no evidence of distant metastases. He underwent salvage surgery with APER and had a pT3b G3 N1 L1 V0 adenocarcinoma excised. The patient has just completed 12 cycles of adjuvant FOLFOX (5-flurouracil and oxaliplatin) chemotherapy.

Case 5

Patient No 5 was a 74-year-old man, with a long history of anal fissures and rectal bleeding, but when his bleeding became worse he underwent a colonoscopy. A mid-rectal polyp was found and removed. This showed high-grade dysplasia with an 11 mm focus of moderately differentiated adenocarcinoma. In January 2014, sigmoidoscopy demonstrated a recurrent, 3 cm tumor arising 5 cm from the anal verge, from 1 to 3 o’clock. MR imaging confirmed a T3C N0 rectal carcinoma, with no evidence of distant metastases. He wanted to explore a sphincter preserving approach if possible, and so he opted to have 45 Gy in 25 fractions EBRT with concomitant capecitabine and a subsequent CXB boost 90 Gy in 3 fractions. During the fractions, the tumor reduced from 2.5 cm to 1.5 cm in length and became palpably more fibrous. A 25 mm applicator was used for the first two fractions, with a 22 mm applicator used for the last. Although the local disease remained controlled, MR imaging demonstrated a nodal metastasis lateral to the L4 vertebra at 12 months post-treatment (above the previous EBRT field). The patient underwent chemotherapy with consideration of stereotactic radiotherapy to the node.

Case 6

Patient No 6, a 79-year-old man with multiple medical co-morbidities including atrial fibrillation, shortness of breath, and hypertension, presented with fresh rectal bleeding and occasional tenesmus. Sigmoidoscopy demonstrated a 4 cm polyp arising 3 cm from the anal verge and extending from 3 to 9 o’clock with a small polypoid projection in the center. Biopsies showed a tubulovillous adenoma with progression to adenocarcinoma. MR imaging staged this as a T2 N0 rectal cancer. Given his medical co-morbidities, he was deemed high-risk for major surgery. Therefore, the patient was given 45 Gy in 25 fractions EBRT followed by Papillon CXB 90 Gy in 3 fractions. The large tubular adenoma remained after treatment, therefore 6 months later, he underwent trans­anal endoscopic excision of the polyp, which revealed a tubular adenoma with focal superficial high-grade dysplasia, no residual carcinoma. He was well following this excision and had occasional rectal bleeding and occasional diarrhea.

Case 7

Patient No 7, a 70-year-old man, presented with rectal bleeding, with MR imaging demonstrating a T3C N0 adenocarcinoma of the low rectum. It was 4.7 cm in length and extended to less than 1 cm above the anorectal junction from 3 to 9 o’clock. He wished to avoid a permanent stoma if possible. The patient underwent EBRT to the pelvis 45 Gy in 25 fractions with concomitant capecitabine, and MR imaging demonstrated a significant reduction in soft tissue at the tumor site. Therefore, he then underwent a Papillon boost 90 Gy in 3 fractions. Following the treatment, he had a persistent ulcer at the boost site that bled occasionally; however, it was soft to palpation, benign on biopsy, and remained unchanged on follow-up. At 3.5 years post-Papillon treatment, it was noted that the ulcer now felt hard and craggy on rectal examination and bled freely on contact. The patient felt well with only small amounts of rectal mucus, otherwise he was regularly playing golf and enjoyed good health. Biopsy demonstrated recurrent adenocarcinoma and he proceeded to have an APER for a moderate to high-grade adenocarcinoma, staged pT2 G3 N0 L0 V0. Sadly, he died in the immediate post-operative period.

Discussion and conclusion

The use of rectal CXB to deliver a boost dose of radiotherapy is becoming more widespread. It has recently received NICE approval in the UK, with particular suitability for elderly patients who are unfit for surgical resection [8]. It may also be used in combination with EBRT and chemotherapy in patients who wish to avoid a stoma, or who are high-risk (although not entirely unfit) for major surgery. In these patients, the identification of clinical response or tumor regrowth that would necessitate salvage surgery is extremely important. Patients therefore undergo regular combined assessment with digital rectal examination, sigmoidoscopy to assess the rectal lumen and MR imaging to assess deeper within the wall and regionally for progression. Based on the presented case series, Table 1 provides a summary of the digital rectal examination, endoscopic and MR imaging findings that have been observed at our center during surveillance following CXB. In particular, the reassuring nature of maturing fibrosis is noted, the “black spider” sign, whilst the loss of low signal fibrosis or new soft tissue nodularity on MR imaging warrants biopsy to exclude tumor regrowth. This article presents a highly selective case series of patients with heterogeneous treatment strategies, chosen to illustrate only the assessment of response to CXB following a range of treatment approaches. High quality evidence regarding the efficacy of CXB is awaited from randomized control trials such as the OPERA trial [14]. Similarly, evidence is awaited regarding the best management of patients with abnormal findings on surveillance.

Disclosure

The authors report no conflict of interest.

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