Chemoradiotherapy for Rectal Cancer

Dr A Sun Myint

Powerpoint File

There are over 10,000 new patients diagnosed with rectal cancer each year in the UK. Nearly half the patients will develop recurrences either locally or at distant sites within the first two years. Improved surgical training, increasing site specialisation and change in surgical technique to total mesorectal excision TME (Heald 1995)[1] has all helped to reduce local recurrences. There is now compelling evidence from several trials that radiotherapy reduces local recurrence in patients who have had radical curative surgery but so far, none of the trials has shown survival benefit.

Short course or Long course?
The long awaited results of NCRI CR07 trial was presented at last year ASCO (Atlanta) and ACPGBI (Gateshead). The results were also published as an abstract in JCO [2] and Colorectal disease. The results of UK CR07 confirmed the Swedish [3] and the Dutch [4] trial results that SCRT reduced local recurrence compared to surgery alone (6% vs. 11%). There were two unexpected results in that the benefit was seen in all levels of tumour location and there was also increased in DFS in favour of SCRT. However, the short course pre operative radiotherapy is only suitable for operable rectal tumour which is usually mobile (Clinical assessment) with no threatened CRM (radiological assessment). If the tumour is fixed or tethered or if the staging MRI scan showed threatened CRM (<1mm) then long course radiotherapy should be offered.
Conclusion- Pre operative assessment and staging (using MRI) is essential before MDT discussions as the recommendation made by the members of the MDT team can only rely on the accurate information that is presented to them. If there is MRI evidence of threatened CRM then long course CRT should be offered. Management of other operable rectal tumour needs careful discussion at MDT.

Radiotherapy alone or Chemo-radiotherapy?
Evidence from Post operative chemoradiotherapy trials
The initial data of chemo-radiotherapy came from two randomised trials which provide the evidence for the NIH (1990) consensus statement. These trials investigated the role of combined modality therapy following “curative” surgery for rectal cancer. The GITSG-7175 study [5] randomised 202 patients into 4 different treatment groups:-

1. Surgery alone
2. Post operative chemotherapy
3. post operative radiotherapy
4. post operative combined modality

There was a statistically non significant improvement in local control in those who were irradiated compared to those who were not (16%vs. 25% p=0.06) and a highly significant improvement in those patients who had combined therapy (6.5%). In addition, a significant improvement in survival was demonstrated in the combined group compared to control group. (53%vs 27% p= 0.01).There was no significant survival improvement when combined group was compared to the radiotherapy. However, in NCCTG trial [6] (n=204), local control, distant metastatic rate, cancer related death, and overall survival were all significantly improved when comparing post operative combined chemoradiotherapy to radiotherapy alone (p=0.036, p=0.011,p=0.0071,p=0.25 respectively). It is important to bear in mind that in both trials there were considerable increase in gastrointestinal (20%vs. 5%) and haematological (18% vs. 0%) toxicity. In the NCCTG trial despite using multiple fields, the second course of chemotherapy could not be given in 16% of patients due to persistent neutropenia. Delayed serious complications such as small bowel obstruction requiring surgery occurred in 6.7% of patients.
The mechanism by which the combination of chemotherapy and radiotherapy inter act and work is still not fully understood. It may be due to radio sensitisation or it may be due to systemic effect of the chemotherapy. Both NCCTG and GITSG trials suggest that the addition of 5-flurouracil to irradiation is crucial to improve local control and this suggests that this mechanism is through radio sensitisation. There also appear to be some effect on disseminated disease and it is possible that chemotherapy has some
cytotoxic effect on micro metastases.

Evidence from pre operative chemoradiotherapy trials
Because of the efficacy of post operative chemoradiotherapy as the adjuvant treatment for rectal cancer, there has been considerable interest in evaluating this approach pre operatively. The investigators have studied combination of radiotherapy 45-50.4Gy with 5 FU based chemotherapy for T3 and T4 tumours in the earlier trials. One such approach at M.D. Anderson Hospital [7] gave 45Gy of pre operative radiotherapy together with continuous 5FU and Cisplatin for 38 patients with locally advanced rectal cancer and this was followed by surgery 6-8 weeks later. Three year survival and local recurrence rates were 82% and 3% respectively. This was in contrast with 62% and 33% for similarly staged 36 patients who received radiotherapy only. In addition, 35% of the patients in chemoradiotherapy group had sphincter preservation surgery compared to 7% in radiotherapy only group. There was no difference in resectability rate or pathological downstaging between the two groups. Other investigators, however, reported higher resectability and pathological down staging rates with the use of preoperative chemo radiotherapy compared to radiotherapy alone. Swedish group[8]reported an enhanced resectability rate in patients with unresectable rectal cancer who received chemoradiotherapy compared with 38 patients who received radiotherapy alone (71%vs. 34%). Phase II studies of preoperative chemoradiation (45-50.4Gy) to pelvis delivering 1.8Gy per fraction, 5 days a week with 5 FU based chemotherapy have reported pathological complete response rates of 20-26%, compare to only 6-12% with radiation alone. Some investigators claimed that, using this preoperative chemoradiotherapy approach approximately 60-80% of patients with distal rectal cancer can achieve a sphincter-sparing resection with a coloanal anastomosis as an alternative to abdominoperineal resection (APER). Although the sphincter is disturbed by this surgery, most patients have acceptable ano-rectal function. This approach is obviously not suitable for elderly patients or those with poor ano-rectal function initially.

Whether the addition of chemotherapy to radiation is more efficacious than radiation alone in preoperative strategy was addressed in three large randomised trials in Europe. The long awaited results of EORTC -22921 [9]and the French (FFCD-9203) [10]were presented at the ASCO meeting in 2005. The European Organisation for Research and Treatment of Cancer trial 22921 included 1,011 patients. A significant tumour and nodal downstaging were reported with addition of 5FU chemotherapy to preoperative radiotherapy regime.
Local failure rates decreased in the 3 groups with chemotherapy: 8.8%, 9.6% and 8% with either pre-op, post-op or both respectively, compare to 17.1% with no chemotherapy (p=0.002). With 5 year follow-up, the data show no statistically significant effect on survival or on progression free survival. There was a late divergence of these two survival measures and a longer follow up is needed to evaluate the real effect of adjuvant chemotherapy. Similar results were found in the French (FFCD-9203) trial were 733 patients were randomly assigned to two arms of RT alone compared with RT and concurrent chemotherapy. All patients had surgery followed by adjuvant chemotherapy using bolus 5FU/folinic acid (which was the only difference with the EORTC trial). The local failure rate was reduced by half in chemoradiotherapy arm to 8% from 16.5% with radiotherapy alone arm. Similar to the EORTC trial, there was no difference in 5 year DFS or the overall survival.
Conclusion- Addition of chemotherapy to preoperative radiotherapy reduces local failure rate but so far there is no difference in survival.

Pre operative or post operative chemoradiotherapy?
Three randomised trials directly comparing preoperative and postoperative adjuvant chemoradiotherapy for clinically resectable T3 rectal cancers, to clarify the impact of either sequence on bowel function, as well as on the endpoints of local control and overall survival. The two trials from the USA (Intergroup 0147 and NSABP R-03) underwent early closures because of poor accruals. The German CAO/ARO/AIO-94 trial[11] completed its target accrual of 799 patients and reported its results at ASCO last year. With median follow-up of 4 years, there was no significant difference in overall survival. However, treatment compliance (92%vs 54%), the grade 3/ 4 toxicity (27%vs 40%), tumour downstaging, rates of sphincter preservation for low lying tumours (39%vs19%) and rates of pelvic recurrences (6%vs 13% p=0.006) were all in favour of pre operative chemoradiation.
Conclusion- Given the convincing German trial evidence, preoperative chemoradiotherapy should be considered a standard of care for patients with stage II and III rectal cancer not enrolled on investigative trials.

Prognostic factors after neoadjuvant chemoradiotherapy for rectal cancer.
An update of CAO/ARO/AIO-94 Phase III trial [12]was presented at the ASCO 2005.
Five year disease free survival (DFS) was 74% for patients after complete resection (RO). It was 86%,95%,81%,65%,42% for ypTO,ypT1,ypT2,ypT3,ypT4 tumours(p=<0.0001) and 85%,46% for NO, N+ disease (p=<0.0001) respectively. The tumour regression grade was significantly related to DFS in univariate analysis. However, in multivariate analysis, only the lymph node status was the most important prognostic factor (p=<0.001).
Conclusion- Positive pelvic lymph node after neoadjuvant chemoradiotherapy is associated with very unfavourable prognosis justifying more intense adjuvant chemotherapy. So far, there is no firm evidence of this and in the UK; CHRONICLE trial is evaluating the survival benefit for adjuvant chemotherapy in rectal cancer.

Which drugs to use for chemoradiotherapy?
Although 5FU based chemotherapy remains the standard for adjuvant chemoradiotherapy of rectal cancer, a number of novel chemotherapeutic and biological agents are currently undergoing phase II evaluation in combination with radiotherapy.
Novel radiosensitisers

• Oral 5FU prodrugs: Capecitabine (Thymidylate synthase inhibition)
• Irinotecan (Toposomerase I inhibitor)
• Oxaliplatin (damage DNA cross links)
• Anti epidermal growth factor receptor (EGFR)e.g. Cetuximab
• Anti vascular endothelial growth factor (VEGF) e.g. Bevacizumab

Conclusion- Phase II combination 2 drug (doublet) CRT studies have reported high rates of efficacy in terms of histopathological complete response (pCR) and acceptable toxicity with the addition of either Irinotecan or Oxaliplatin. A recent meta-analysis identified 52 phase II/III
trials of pre-op CRT with a total of 3157 patients. The overall pCR rate was 10% for fluoropyrimidine CRT (n=2524) and 19% for CRT using two drug combinations (n=633)

Toxicity of pelvic radiotherapy and chemoradiotherapy
Toxicity of combined modality therapy remains the obstacle to improving the outcomes of patients with rectal cancer. Although compliance for treatment is better for preoperative strategy, increase in toxicity was seen when chemotherapy was added to radiation in both EORTC and FFCD 9230 trials. Hematological and non hematological Grade 3/4 toxicity were 14% vs. 2% (p=0.001). It is well recognized that the complications of pelvic radiotherapy relate to the volume of the radiation field, overall treatment time, the fraction size, the total dose and technique used (two fields vs. multiple fields). In a study by Gallagher et. al., patients who had prior pelvic surgery showed a much higher incidence of diarrhoea requiring medication in 47% as opposed to 21% of those without prior surgery. This was confirmed in German CAO/ARO/AIO-94 trial where any acute toxicity was 27% for pre-operative group compared to 40% for post operative CRT. Like wise, any late grade 3/4 toxicity was 14% in preoperative group compared to 24% in postoperative CRT group.
Conclusion- Chemoradiotherapy is more toxic than radiotherapy alone. Every effort should be made to reduce the volume of small bowel in the irradiated field and patients should be treated preoperatively (if indicated) as the toxicity is much greater when treated postoperatively.

CONCLUSIONS

• All cases with rectal cancer should be discussed at the MDT
• MRI scan is essential for pre operative assessment
• Tumours with threatened CRM on MRI should have long course chemoradiotherapy.
• Preoperative chemoradiotherapy offers better local control than preoperative radiotherapy alone
• Preoperative chemoradiotherapy is more effective and less toxic than postoperative chemoradiotherapy
• Nearly half the patients with rectal cancer will develop recurrences; however, no DFS or overall survival benefit has been shown with adjuvant chemotherapy in any of the trials published so far.

References

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2. Sebag-Montefiore D, Steele R, Quirk P et al J Clin Oncol Proceedings of ASCO Vol 24, No 18 S, June 2006: Abst. 3511
3. Swedish Rectal cancer trial (1997) Improved survival with pre-operative radiotherapy in resectable rectal cancer. N Engl. J Med 336:980-987
4. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al for the Dutch Colorectal Cancer Group. preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N. Engl J Med 2001:345:638-646
5. Gastrointestinal Tumour Study Group. Radiation therapy and 5 FU with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. J Clin Oncol 1992;10:549-557
6. O’Connell MJ, Martenson JA,Wieand HS,et al.Improving adjuvant therapy for rectal cancer by combining protracted infusion 5FU with radiation therapy after curative surgery. N. Engl J Med 1994 ;331: 502-507
7. Weinstein GD, Rich TA, Shumate CR, et al. Preoperative infusional chemoradiation and surgery with or without electron beam intraoperative boost for advanced primary rectal cancer.Int J Radiat Oncol Biol Phys 1995;32:197-204
8. Prykolm G, Glimelius B,Pahlman L,Preoperative irradiation with or without chemotherapy (MFL) in the treatment of primary non resectable adenocarcinoma of the rectum. Results of two consecutive studies. Eur. J Cancer Clin Oncol 1989;25:1535-1541
9. Bosset JF,et al Pre-operative radiation in rectal cancer: Effect and timming of additional chemotherapy 5 year results of EORTC 22921 trial. J Clin Oncol,2005. 23(165) Annual Meeting Proceedings: Abstract 3505
10. Gerard JP et al., Preoperative radiotherapy + 5FU/folinic acid in T3-4 rectal cancers: Results of the FFCD 9203 trial. J Clin Oncol. 2005.23(165)Annual meeting Proceedings: Abstract 3504
11. Sauer R, Becker H, Hohenberger W, Rodel C, et al . Adjuvant versus neoadjuvant combination modality treatment for locally advanced rectal cancer. First results of the German rectal cancer study (CAO/ARO/AIO-94)Int J Radiat Oncol Biol Phys 2003;57:S124-S5
12. Rodel C, Martus P, Papadoupolos T et al. Postic significance of tumour regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005 23(34):8688-8696