Debashis Biswas and Thankamma Ajithkumar
Case history
A 47-year-old man presented with a 2-month history of increased frequency of loose bowel motions with intermittent passage of fresh rectal blood mixed with the stools. His weight had been steady, and he had a normal appetite. Digital rectal examination (DRE) revealed a low rectal mass which was tethered. The remainder of the clinical examination was unremarkable. A barium enema is shown in Fig. 13.1.
Fig. 13.1
Questions
1. What does the barium study show?
2. How would you investigate him further?
Answers
1. What does the barium study show?
The barium enema shows a large lesion in the lower rectum with mucosal ulceration suggesting a carcinoma.
2. How would you investigate him further?
Further investigations include FBC and biochemistry, colonoscopy to biopsy the mass and to exclude any synchronous tumours or polyps in the remainder of the colon, and a staging CT scan of the chest, abdomen, and pelvis. A MRI scan of the pelvis is useful for assessing the local spread of the cancer.
In patients with similar symptoms but without a palpable tumour on DRE the most appropriate initial investigation would be a procto-sigmoidoscopy.
Colonoscopy showed an ulcerative growth arising from the left lateral wall of the rectum and a pedunculated growth in the distal sigmoid colon. A biopsy confirmed a moderately differentiated adenocarcinoma of the rectum and a tubular adenoma of the sigmoid colon. There were no distant metastases. CT and MRI scans are shown in Fig. 13.2.
Fig. 13.2
Questions
3. What do the scans show?
4. What is the stage of his disease?
5. Outline your treatment approach.
Answers
3. What do the scans show?
The CT and MRI scans (A in Fig. 13.2) show a lesion in the rectum with extramural extension at the 4 o’clock position. The tumour is extending to involve the left lateral circumferential resection margin (CRM). Both scans (B in Fig. 13.2) show an enlarged mesorectal node at the 5 o’clock position. Other MRI images (not shown) show extension of the tumour up to the fascia of the left lateral pelvic side wall compartment posteriorly but without infiltration of the left lateral pelvic side wall.
4. What is the stage of his disease?
Radiologically the tumour extends into the left lateral CRM (T3) with an enlarged mesorectal node (N1) making the stage rT3N1M0 (rStage IIIB/Dukes C).
5. Outline your treatment approach.
Loco-regional recurrence is the predominant type of treatment failure in rectal cancer. Approximately 25% patients develop loco-regional recurrence after radical treatment. Microscopic involvement of the CRM (CRM+) is an independent predictor of local failure.
MRI scan, including a T2-weighted image, is an essential investigation in the local staging of rectal cancer. It is useful in defining the extent of the tumour and for identifying any invasion of the mesorectal fascia (MRF) by the tumour (as in this case). MRI can also detect vascular invasion, which is a predictor of systemic recurrence. The close proximity of tumour to the MRF (as defined by a distance of ≤ 1mm) increases the risk of a positive CRM.
Recent strategies have focused on reducing the risk of local recurrence in rectal cancer. One of the strategies is the use of pre-operative radiotherapy in patients with rectal cancer where MRI can assess the risk of CRM involvement. This helps to downstage tumours so as to enable a compete resection (R0). This patient’s imaging and clinical features suggest mesorectal fascial invasion and therefore pre-operative radiotherapy should be considered to improve the chance of an R0 resection.
Questions
6. Could the need for a pre-operative treatment have been foreseen at the time of his first consultation?
7. Describe the two regimens of pre-operative treatment for rectal cancer.
8. Which regimen would you choose for this patient and why?
Answers
6. Could the need for a pre-operative treatment have been foreseen at the time of his first consultation?
Yes. DRE is important in the staging process in rectal cancer. It helps to identity a number of tumour characteristics such as size, percentage of the circumference involved, radial position, tumour level, and the level of deep fixation. Occasionally large mesorectal nodes can also be palpated. In this patient, DRE revealed that the tumour was tethered, which suggest a deeper level of invasion, and therefore the possibility of the tumour extending to the CRM.
7. Describe the two regimens of pre-operative treatment for rectal cancer.
The two evidence-based regimens of pre-operative treatment for rectal cancer are short-course radiotherapy and long-course chemoradiotherapy.
Short-course radiotherapy involves five daily doses of 5Gy followed by resection within a week of completion, whereas long-course radiotherapy delivers 45–54Gy in 25–28 fractions (usually combined with chemotherapy) followed by surgery 6–8 weeks later. Short-course radiotherapy is proven to reduce the risk of local recurrence in operable rectal cancer. The MRC-CR07 trial compared pre-operative radiotherapy with selective post-operative chemoradiotherapy in operable rectal cancer (Sebag-Montefiore 2009). At a median follow-up of 4 years, pre-operative radiotherapy resulted in a significantly lower local recurrence (4.4% versus 11%), and a better 3-year DFS (78% versus 72%) compared with selective post-operative chemoradiotherapy.
The EORTC 22921 study compared concurrent chemoradiotherapy (using 5-FU and leucovorin for 5 days during the first and fifth weeks of radiotherapy) with pre-operative radiotherapy (45Gy in 25 fractions) alone (Bosset et al. 2005). Pre-operative chemoradiotherapy resulted in a higher pathological complete response rate (14% versus 5%), and better downstaging (tumour less than pT3, 42% versus 57%). A meta-analysis has shown that pre-operative chemoradiotherapy results in a higher complete pathological response rate (12% versus 3.5%) and local control rate (16.5% versus 9.4%) than pre-operative radiotherapy alone.
In patients with T3/T4 or node-positive rectal cancer, studies show that neoadjuvant chemoradiotherapy is associated with more favourable long-term toxicity and fewer local recurrences than post-operative treatment. The German Rectal Cancer Study (Sauer et al. 2012) compared a regimen of chemoradiotherapy (50.4Gy in 28 fractions alone with 5-FU for 5 days during the first week and fifth weeks of radiotherapy) given either pre- or post-operatively. Follow-up at 10 years showed a lower risk of pelvic recurrence (7% versus 10%) with pre-operative treatment but with no survival advantage compared with post-operative treatment. Patients who received pre-operative treatment were twice as likely to undergo sphincter-sparing surgery (39% versus 19%).
The NSABP trial R-04 reported a similar efficacy of 5-FU and capecitabine with regard to complete pathological response (22% versus 19%), surgical downstaging, and sphincter preservation, along with radiotherapy (Roh et al. 2011). Therefore 5-FU and capecitabine are accepted drugs of choice in the pre-operative chemoradiotherapy regimen.
8. Which regimen would you choose for this patient and why?
This patient has a T3N1M0 rectal cancer and the MRI scan showed tumour extension into the CRM. Therefore he was recommended to have long-course radiotherapy with concomitant capecitabine chemotherapy to maximize the chance of an R0 resection.
The patient received 45Gy in 25 fractions over 5 weeks with concomitant capecitabine chemotherapy followed by a restaging CT scan and MRI scan of the pelvis. There was regression of the rectal tumour and no metastatic disease. Therefore he underwent a low anterior resection with the formation of a loop ileostomy. Histopathology showed a moderately differentiated adenocarcinoma with mucous differentiation. The tumour extended beyond the muscularis propria into the subcutaneous fat. Margins were clear. There was no evidence of vascular invasion. None of the 16 lymph nodes retrieved showed metastasis.
Questions
9. What is the post-operative staging?
10. Would you recommend further treatment, and if so what?
Answers
9. What is the post-operative staging?
ypT3N0 (0/16 lymph nodes) V0 (vascular invasion negative) R0Mx—the prefix ‘y’ indicates that patient had pre-operative treatment.
10. Would you recommend further treatment, and if so what?
The issue of adjuvant chemotherapy after pre-operative chemoradiotherapy in rectal cancer is controversial, and there is an on-going debate as to which patient groups may benefit from adjuvant treatment. Two trials have addressed the role of post-operative chemotherapy following pre-operative chemoradiotherapy in rectal cancer. An unplanned subset analysis of the EORTC 22921 trial showed that post-operative chemotherapy improved survival in patients whose tumours were downstaged to ypT0–2 (10% absolute DFS benefit) but not in patients whose tumours were downstaged to ypT3–4(Collette et al. 2007). A second trial from Italy showed no benefit with post-operative 5-FU-based chemotherapy.
Two current trials (the GERCOR study and ECOG–E5204) are assessing the role of post-operative chemotherapy using irinotecan and oxaliplatin-based regimens after pre-operative chemoradiotherapy in rectal cancer.
In the above patient, there was minor downstaging seen on the surgical pathology and therefore the benefit from adjuvant chemotherapy was felt to be very small.
Treatment and follow-up
This patient did not undergo adjuvant chemotherapy and remains well under surgical follow-up at 1 year.
Further reading
Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results—EORTC 22921. Journal of Clinical Oncology 2005; 23: 5620–5627.
Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. Journal of Clinical Oncology 2007; 25: 4379–4386.
Glynne-Jones R, Hughes R. Critical appraisal of the ‘wait and see’ approach in rectal cancer for clinical complete responders after chemoradiation. British Journal of Surgery 2012; 99: 897–909.
Haustermans K, Debucquoy A, Malbrecht M. The ESTRO Breuer Lecture 2010: towards a tailored patient approach in rectal cancer. Radiotherapy and Oncology 2011; 100: 15–21.
Kosinski L, Habr-Gama A, Ludwig K, Perez R. Shifting concepts in rectal cancer management: a review of contemporary primary rectal cancer treatment strategies. CA: a Cancer Journal for Clinicians 2012; 62: 173–202.
Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. [Abstract] Journal of Clinical Oncology2011; 29 (Suppl 15): A-3503.
Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. Journal of Clinical Oncology 2012; 30: 1926–1933.
Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. The Lancet 2009; 373: 811–820.