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British Journal of Radiology (2007) 80, e257-e259
© 2007 British Institute of Radiology
doi: 10.1259/bjr/38988181
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Case report

Omission of concurrent chemoradiation after a response to neoadjuvant chemotherapy in locally advanced rectal cancer with a synchronous liver metastasis: a note of caution

I Craven, MRCS 1 J Haselden, MSc, MRCP, FRCR 2 K E Miller, MRCPath 2 G V Miller, MD, FRCS(Gen) 2 I Bradford, MBBCh, FRCS 2 and D Sebag-Montefiore, FRCP, FRCR 1

1 Cookridge Hospital, Hospital Lane, Leeds LS16 6QB, 2 York District Hospital, Wigginton Road, York YO31 8HE, UK

Correspondence: Dr David Sebag-Montefiore, Cookridge Hospital, Hospital Lane, Leeds LS16 6QB, UK. E-mail: David.sebag-montefiore{at}leedsth.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Case report
 Discussion
 References
 
There is clear evidence to support the use of pre-operative concurrent chemo-radiotherapy (CRT) in locally advanced rectal cancer. In the UK, most patients are selected for treatment if the resection margin is predicted to be involved. The selection criteria used includes primary tumours that threaten the resection margins on high-resolution pelvic MRI and low tumours requiring abdominoperineal excision. There is no consensus, however, to guide the treatment of patients who present with advanced rectal disease and synchronous, potentially resectable, metastatic disease. This case illustrates the potential risk of omitting radiation following a good response to neoadjuvant systemic chemotherapy.


   Introduction
Top
 Abstract
 Introduction
Case report
 Discussion
 References
 
There is clear evidence to support the use of pre-operative concurrent chemoradiotherapy (CRT) in locally advanced rectal cancer. In the UK, most patients are selected for treatment if the resection margin is predicted to be involved. The selection criteria used include primary tumours that threaten the resection margins on high-resolution pelvic MRI and low tumours requiring abdominoperineal excision.

There is no consensus, however, to guide the treatment of patients who present with advanced rectal disease and synchronous, potentially resectable, metastatic disease. This case illustrates the potential risk of omitting radiation following a good response to neoadjuvant systemic chemotherapy.


   Case report
Top
 Abstract
 Introduction
 Case report
Discussion
 References
 
A previously fit 46-year-old man presented with a 3-month history of altered bowel habit, rectal bleeding and buttock discomfort. He had no significant past medical history and his only regular medication was co-codamol.

Clinical examination demonstrated a mobile rectal tumour at 7 cm from the anal verge. Rectal biopsy confirmed an invasive adenocarcinoma of the rectum. The full blood count and hepatic and renal function were normal. Serum carcinoembryonic antigen (CEA) was 4.5 ng ml–1.

High-resolution pelvic MRI demonstrated a mid/upper T3 rectal tumour breaching the muscularis propria and extending to within 2 mm of the mesorectal fascia (Figure 1Go). A left internal iliac lymph node measuring 8 mm, of indeterminate significance, was noted. Thoracoabdominal CT scans identified a solitary liver metastasis in segment 7 with no other evidence of distal disease.


Figure 1
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  		Figure 1. Pre-treatment pelvic MRI showing rectal tumour threatening the mesorectal fascia.

 
In view of the presence of a locally advanced rectal tumour with synchronous liver metastasis, the initial treatment consisted of combination chemotherapy for 3 months with a planned repeat CT scan to determine subsequent treatment. Six cycles of the oxaliplatin modified de Gramont (OxMdG) regime were given at 2-weekly intervals via a Hickman line (oxaliplatin 85 mg m–2 day 1, leucovorin 350 mg day 1, 5-fluorouracil 400 mg m–2 bolus day 1 and infusional 5-fluorouracil 2400 mg m–2 46 hour infusion commenced on day 1). The treatment was well tolerated with no Grade 3 or 4 toxicity.

A repeat MRI after the six cycles of OxMdG showed a good response of the primary tumour in terms of the volume of mesorectal disease. There were areas of diffuse involvement on the initial MR scan. There remained residual focal areas of low intensity but, on balance, this was felt to be more likely to be reactionary fibrosis than active disease. The margin was assessed to be clear by 2 mm (Figure 2Go). Repeat CT scan demonstrated shrinkage of the hepatic deposit, although a second suspicious area in segment 4b was noted. This was reassessed by an ultrasound scan, which failed to find any abnormality.


Figure 2
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  		Figure 2. Pelvic MRI showing tumour response following adjuvant chemotherapy. The mesorectal fascia no longer appears to be threatened.

 
Careful discussion at the colorectal multidisciplinary team meeting considered the options of pre-operative CRT or proceeding straight to surgical excision. The decision was made to proceed with surgical resection in view of the marked tumour regression and the fact that initially the margins were threatened rather than involved.

The patient underwent a low anterior resection with total mesorectal excision and covering ileostomy. An intraoperative liver ultrasound scan confirmed that the 4b lesion was a simple cyst and a synchronous hepatic metastectomy was performed. There were no major surgical complications and the patient recovered well. Histopathological examination demonstrated a moderately differentiated adenocarcinoma, ypT3 ypN2, with 12 out of 15 lymph nodes involved. Tumour was identified involving a lymph node within 1 mm of the circumferential resection margin and microscopic foci of tumour were found within the mesorectal fat of the distal donut. The liver metastasis was completely excised.

The patient went on to receive post-operative pelvic chemoradiation for a period of 5 weeks. The dose of radiation received was 45 Gy in 25 fractions over 38 days to a planned pelvic volume (posteroanterior field size, 15.8 cm length by 17.4 cm wide; lateral field size, 15.8 cm length by 12.4 cm anteroposterior). Treatment was interrupted for 4 days during week 3 because of severe Grade 3 diarrhoea, abdominal cramps and abdominal tenderness on examination.

2 weeks after CRT was completed, a repeat CT scan showed no evidence of recurrent disease and the serum CEA was 0.8 ng ml–1. A contrast enema showed a healed anastomosis with no radiological leak, and the ileostomy was reversed 5 months after anterior resection. The patient recovered well and routine follow up continued until 3 months later when a CT scan identified a further metastasis in segment 7 of the liver and small-volume para-aortic lymph node enlargement. A positron emission tomography (PET) scan was requested to confirm or refute the presence of extrahepatic disease. This confirmed increased uptake in the demonstrated liver metastasis as well as extensive lymph node involvement (left para-aortic as described on the CT scan with additional increased uptake in the right hilar nodes, left perihilar nodes, subcarinal nodes, right lower paratracheal nodes and the aortopulmonary window).

Palliative chemotherapy was commenced with oxaliplatin combined with fluoropyrimidine (initially with capecitabine and subsequently infusional 5-fluorouracil). Following disease progression the patient is currently receiving second-line irinotecan-based chemotherapy. In view of an allergic reaction to oxaliplatin, treatment continues with irinotecan MdG.


   Discussion
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 Abstract
 Introduction
 Case report
 Discussion
References
 
This case illustrates the danger of omitting adjuvant pre-operative radiotherapy after a response to neoadjuvant chemotherapy. Even when a significant response to combination neoadjuvant chemotherapy is seen and the potential margins of resection do not appear threatened, there may be microscopic foci of malignancy that are inadequately treated by chemotherapy alone.

The presence of synchronous resectable metastases in locally advanced rectal cancer, which requires pre-operative concurrent CRT by MRI criteria, presents a difficult challenge to the oncologist. Usually, to treat the primary tumour, concurrent CRT is given over 5 weeks followed by a 6–8 week interval before surgical resection is performed. This approach is unsatisfactory in the presence of synchronous metastases. First, concurrent CRT is based on single-agent fluoropyrimidine given at a dose that is below that considered to be systemically active and, second, the duration of treatment is only 5 weeks. Therefore, for these reasons there is a real risk that the metastatic disease or undetected micrometastatic disease may progress during the period of up to 3 months before surgery is performed.

There is a convincingly strong evidence base which demonstrates that adjuvant radiotherapy significantly reduces the risk of local recurrence. Two meta-analyses have been performed. The first evaluated 8790 patients in 28 clinical trials, comparing the benefit of either pre-operative or post-operative radiotherapy with surgery alone [1]. The local recurrence rates at 5 years were significantly lower in the groups receiving radiotherapy, whether it was pre-operative (12.5% vs 22.2%, p<0.00001) or post-operative radiotherapy (15.3% vs 22.9%, p<0.0002). There was a trend suggesting that pre-operative therapy conferred a slight advantage.

The second study evaluated 6426 patients in 14 randomized controlled trials, comparing pre-operative radiotherapy and surgery with surgery alone [2]. The group receiving radiotherapy had a significantly improved 5 year overall survival rate (odds ratio (OR) = 0.84, p = 0.03), cancer-specific survival rate (OR = 0.79%, p<0.001) and local recurrence rate (OR = 0.49%, p<0.001).

Recent clinical trials have shown that pre-operative CRT is superior to post-operative CRT, with a significant reduction in local recurrence as well as acute and late toxicity [3]. Concurrent CRT is also superior to long-course radiotherapy alone, with two recent trials showing a significant reduction in local recurrence [4, 5].

In contrast, there is a lack of evidence supporting the use of neoadjuvant chemotherapy prior to rectal cancer resection. Future trials may address this question. A recent Phase II study of 79 patients from the Royal Marsden Hospital [6] evaluated a 12-week schedule of oxaliplatin and capecitabine at systemic doses followed by concurrent CRT using capecitabine and 54 Gy of irradiation. The authors report a radiological response rate of 88% prior to CRT. This excluded 11 patients (14%) who either were not fit for adjuvant chemotherapy (two patients) or did not complete the full course of neoadjuvant chemotherapy because of toxicities (four patients), bowel perforation (one patient) or death (four patients). In addition, two patients chose not to receive CRT because of the good radiological response to the neoadjuvant chemotherapy.

Although the overall results for this study are very encouraging, there is a danger that the high response rate to the neoadjuvant chemotherapy component may lead clinicians to consider whether the CRT component of treatment could be omitted.

We recognize that we are reporting an individual case in which CRT was omitted within a different clinical setting, i.e. the presence of synchronous metastatic disease. In our defence, the tumour was 2 mm from the mesorectal margin, which for some clinicians would be considered adequate to proceed directly to surgery. Our case has developed early metastatic relapse and, to date, there is no evidence of local recurrence.

However, we wish to sound a note of caution to clinicians who may consider omitting adjuvant CRT for a patient when there is no evidence of metastatic disease and when neoadjuvant chemotherapy has been delivered with significant tumour regression. This would appear to be unwise.

Received for publication June 19, 2006. Revision received August 4, 2006. Accepted for publication August 16, 2006.


   References
Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 

  1. Colorectal Cancer Collaborative G. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. [See comment.] Lancet 2001;358:1291–304.[CrossRef][Medline]
  2. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000;284:1008–15.[Abstract/Free Full Text]
  3. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40.[Abstract/Free Full Text]
  4. Bosset J-F, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, et al. Preoperative radiation (Preop RT) in rectal cancer: effect and timing of additional chemotherapy (CT) 5-year results of the EORTC 22921 trial. J Clin Oncol 2005;23(16Suppl):3505
  5. Gerard JP, Bonnetain F, Conroy T, Chapet O, Bouche O, Closon-Dejardin MT, et al. Preoperative (preop) radiotherapy (RT) ± 5 FU/folinic acid (FA) in T3–4 rectal cancers: results of the FFCD 9203 randomized trial. J Clin Oncol 2005;23(16Suppl):3504
  6. Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A, Norman AR, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006;24:668–74.[Abstract/Free Full Text]




This Article
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