The ideal management of rectal cancer is often not performed, particularly in more rural areas. Management is based on the 'clinical' stage of disease. These guidelines are from the NCCN.
Early Disease (Stage I)
Early stage disease includes isolated T1 and T2 disease with no nodal metastases.
- For T1 tumours, local excision through a trans-anal approach is usually sufficient
- If there are positive margins, lymphovascular invasion or poorly differentiated features then abdominal resection is required
- If there are no high risk features then observation is sufficient
- For more advanced T1 or T2 tumours, abdominal resection of the rectum is required.
- If pathological tumour stage is confirmed to be T2 or less, then observation is sufficient
- If pathological staging shows T3 disease then further management is recommended; this usually involves chemotherapy and concurrent chemoradiotherapy (see locally advanced disease below).
Observation is every 3 months for 2 years, then every 6 months until 5 years have elapsed. See the Observation section below.
Locally advanced disease
Locally advanced disease includes patients with tumour extending through the muscular wall of the rectum (T3, T4 Stage II) and those with nodal disease (Tany N1-2 Stage III).
Most commonly in Australia, patients with rectal cancer and stage II or stage III disease are recommended to have neoadjuvant chemoradiotherapy followed by anterior resection with total mesorectal excision (TME). The reasons for this approach are:
- Adjuvant radiotherapy following anterior resection leads to improved local control (17 vs 28% recurrence, see CCCG trial below)
- Adjuvant radiotherapy has not proven survival benefit
- Adjuvant chemotherapy has a proven survival benefit
- Trials exploring the use of adjuvant chemotherapy used concurrent chemoradiotherapy in their treatment (GITSG trial)
- Neoadjuvant chemoradiotherapy is superior to adjuvant chemoradiotherapy in terms of local control and toxicity
- Neoadjuvant short course therapy (eg 25 Gy/5# in 1 week) is used in Europe but may have inferior results (particularly with regards to long term toxicity) when compared to conventional chemoradiotherapy; the results of TROG 01.04 trial are awaited
- Evidence supporting omitting adjuvant radiotherapy in the era of total mesorectal excision is limited
German Trial
The so-called "German trial" is the main study quoted for the superiority of neoadjuvant chemoradiotherapy in rectal cancer. Over 800 patients were randomised to 50.4 Gy in 28 fractions delivered either adjuvantly or neo-adjuvantly. It was published in 2004 and longer follow up was reported in 2012. Local recurrence was less common in the neoadjuvant group (6 vs 13% falling to 7 vs 10% with longer follow up), whereas disease free and overall survival were similar. Patient were also less likely to require abdomino-perineal resection.
Role of Chemotherapy
Chemotherapy involving 5-fluorouracil has an established role in the management of node positive colon cancer (Stage III). Chemotherapy in stage II disease is less established and is often controversial. This has led to discussion of the need for chemotherapy in conjuction with radiotherapy for rectal cancer, particularly patients with T3-4 N0 disease. The type of chemotherapy is firmly established as 5-fluorouracil; the ideal method of delivery appears to be continuous infusion rather than bolus 5-fluorouracil.
Concurrent Chemotherapy
Concurrent chemotherapy has been used for rectal cancer treatment since the 1990s where randomised evidence demonstrated improved survival. The ideal chemotherapy agent was found to be 5-fluorouracil; older agents (eg. semustine) were found to add no benefit. Further randomised trials of 5-fluorouracil confirmed improved outcomes with continuous infusion versus bolus infusion, and established no added benefit with leucovorin (used in adjuvant and primary chemotherapy for colon cancer). More recent studies have also shown no benefit from oxaliplatin with added toxicity.
For neoadjuvant chemoradiotherapy, there have been two trials evaluating the need for combined treatment. These have shown improvement in local control with combined treatment but no survival advantage; these trials have been criticised for not delivery adequate doses of adjuvant chemotherapy.
Adjuvant Chemotherapy
Randomised studies examining the role of chemotherapy have shown that local control is worse if it is omitted in the neoadjuvant setting although survival outcomes are similar. Pathological complete response is also much more common if chemoradiotherapy is given concurrently.
Role of Surgery
Surgery remains central to the outcomes achieved in rectal cancer therapy. There is a school of thought that some patients with complete response may not require surgery (ie. chemoradiotherapy is sufficient) but identification of these patients is not yet possible. Prospective studies should evaluate this problem further.
The more recent adoption of total mesorectal excision (TME) has led some to challenge the need for radiotherapy. Proponents cite articles showing recurrence rates of < 5% in patients receiving TME; opponents cite alternative data showing recurrences of > 10%. There is no randomised evidence and this approach is not undertaken in most cases.
Neoadjuvant Radiotherapy
In Europe, the trend is towards short course radiotherapy. This treatment is delivered in 1 week (25 Gy / 5#) with surgery performed the following week. In a randomised study, this was associated with improved local control and overall survival. The approach is criticised in the USA, who cite the inclusion of stage T1 patients might have influenced the excellent results seen. This was further explored in a Dutch trial where the Swedish protocol was compared against total mesorectal excision alone; this showed reduced local recurrence (5% vs 10%) but similar overall survival. Late toxicity was significant in the Dutch trial, prompting further concerns about this strategy.
In Australia, it is often difficult to find surgeons willing to treat patients with the Swedish/Dutch approach. An Australian TROG trial (01.05) will report outcomes in a randomised study of both techniques.
Adjuvant Therapy
Some patients may proceed directly to surgery without neoadjuvant radiotherapy. This may be due to the impression that the disease is only stage T2, or due to bias against neoadjuvant treatment. For this (hopefully minority) group of patients, adjuvant chemoradiotherapy has proven advantages in local control and is usually recommended.
Evidence for Radiotherapy Alone
Camma et al meta-analysis (2000)
A meta-analysis performed by Camma et al (here), published in 2000 in the Journal of the American Medical Association (JAMA), found a significant body of evidence supporting the use of pre-operative radiotherapy.
In summary:
- 14 trials were reviewed
- The trials were heterogenous in dose, fractionation and time between radiotherapy and surgery
- There was a statistically significant:
- Reduction in overall mortality in patients treated with radiotherapy (odds ratio 0.84 (0.72 - 0.98))
- Reduction in cause specific mortality (odds ratio 0.71 (0.61 - 0.82))
- Reduction in local recurrence (odds ratio 0.49 (0.38 - 0.62))
- There was also:
- No change in development of distant metastases (odds ratio 0.93 (0.73 - 1.18))
- Increased risk of perioperative sepsis (21% vs 15%, p <0.001)
- Increased risk of other complications (21% vs 18%, p = 0.03)
- No statistically significant change in perioperative mortality (odds ratio 1.38 (0.86 - 2.32))
The conclusions presented by Camma et al is:
- Neoadjuvant radiotherapy improves overall and cancer specific survival for rectal cancer
- Neoadjuvant radiotherapy improves local control of rectal cancer
- There is no significant effect on the development of distant metastases
- There is a statistically significant increase in complications
- There is no significant increase in perioperative mortality
Colorectal Cancer Collaborative Group (2001)
The CCCG performed an analysis (see here)of both neo-adjuvant and adjuvant radiotherapy trials in rectal cancer. Unlike the Camma study, there was minimal evidence for an overall survival advantage.
In summary:
- 14 neo-adjuvant and 8 adjuvant radiotherapy studies were investigated
- There was some difference in overall survival:
- 45% vs 42% of patients alive at 5 years (no p-value quoted)
- 26.9% vs 25.3% of patients alive at 10 years (p = 0.06)
- No significant difference between neo-adjuvant / adjuvant radiotherapy schedules
- Significant reduction in local recurrences
- Significant reduction in any recurrence - 46% (radiotherapy) vs 53% (no radiotherapy)
- Significant reduction in isolated local recurrence - 12.5% (radiotherapy) vs 22% (no radiotherapy)
- This effect was only significant for biologically effective doses of over 30 Gy
- The risk of local recurrence was greatest in the neo-adjuvant radiotherapy studies (57%) compared to adjuvant radiotherapy (37%).
- Increased non-rectal cancer mortality at 5 years
- 18% vs 14.5% for all groups
- This trend is most marked in the older age group (> 75 years)
- This trend is most significant for Dukes A, where the risk of death from rectal cancer is relatively lower
The conclusions from this study are:
- There is a small advantage in overall survival from both neo-adjuvant and adjuvant radiotherapy
- This is most pronounced for locally advanced disease (Dukes B/C)
- There is an increased rate of non-cancer deaths, which is most significant in the elderly and in those with Dukes A stage of disease
- The relative reduction in risk is similar for Dukes A, B and C cancers, but the absolute benefit is highest in Dukes C due to their higher risk of death from rectal cancer
- Short, neo-adjuvant radiotherapy courses seem to be at least as effective as long, post-operative adjuvant courses of radiotherapy
