Optimal staging and treatment of localised rectal cancer

DOI: 10.1093/annonc/mdf667

Optimal staging and treatment of localised rectal cancer L. Påhlman Department of Surgery, Colorectal Unit, Uppsala, Sweden

Introduction

Staging The first step in the management of patients with newly diagnosed rectal cancer is to evaluate whether the disease is local-

• grown through the rectal wall, i.e. muscularis propria, or • broken through the mesorectal fascia. Endo-rectal ultrasound is the best tool to evaluate the depth of tumour invasion into the rectal wall. There are numerous reports where tumour invasion into the bowel wall can be predicted with high sensitivity and specificity [4, 5]. It is of the

Table 1. Guidelines for staging rectal cancer Imaging technique

Tumour stage T1

T2

T3

T4

N1

M1

Standard X-ray

NA

NA

NA

NA

NA

Lung

Endorectal ultrasound

+++

+++

+

–

+

Abdominal ultrasound

NA

NA

NA

NA

NA

Liver

CT scan

–

+

+

++

–

Lung/liver

MRI scan

–

+

+++

+++

++

Lung/liver

PET scan

–

–

–

–

–

Recurrence

CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography. © 2002 European Society for Medical Oncology

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Although surgery is the most important part of treatment of patients with rectal cancer, the overall treatment policy has changed dramatically during the last three decades. Surgery has in one way become less aggressive, but in another way more precise, with specific attention to a locally more aggressive and meticulous technique. The value of concomitant radiotherapy given pre- or postoperatively has been studied extensively in many trials, which have shown the benefit of adding radiotherapy to surgery. Based on a modern treatment philosophy, that is a multimodal approach, it is important to offer the best and most appropriate treatment to every single patient. Before it is possible to decide on the optimal treatment, it is essential to carry out correct local staging as well as evaluating eventual spread of the disease to distant organs. After an appropriate local and distant staging process the next step is to decide how to use adjuvant radiotherapy and/or chemoradiotherapy, but also how to use different types of surgical approach, i.e. local excision or an abdominal procedure. This review will cover the staging process, how to choose the correct surgical procedure and the evidence of how to use adjuvant radiotherapy, chemoradiotherapy and chemotherapy.

ised or whether there are any signs of distant spread (Table 1). Approximately 20% of all patients with newly diagnosed rectal cancer already have distant metastases at diagnosis [1]. The common areas where metastases occur are the liver and lungs; both these areas have to be scanned before any decisions can be made regarding treatment options. Depending on the practice and routines at different hospitals, one can either choose pulmonary X-ray combined with ultrasound scans of the liver or a CT scan of both the abdomen and thorax. The main drawback in using ultrasound for liver metastases is that the sensitivity of the technique is dependent on the skill of the operator. In skilled hands, gross metastases (>0.5 cm3) can be diagnosed. If meticulous scanning of the liver is necessary, i.e. prior to surgery to detect liver deposits, either a magnetic resonance imaging (MRI) or a positron emission tomography (PET) scan is the best choice according to the data [2, 3], but during the decision-making process prior to the start of treatment, a computed tomography (CT) scan of the liver is probably sufficient. A more important evaluation is local staging (Table 1). The two main things that need to be evaluated are whether the tumour has:

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Surgery Gold standard An abdominal procedure is probably the safest and, at present, the most acceptable treatment for achieving cancer cure. There has been much debate on how such a procedure should be performed. With local recurrence rate as a specific endpoint rectal cancer surgery is one of the ideal procedures in terms of quality control. Twenty-five years ago most centres reported a local recurrence rate after standard surgery of approximately 30–40%. During the early 1980s there were specialised centres reporting local recurrence rates of <5–10% provided surgery was optimised. Professor Bill Heald (Basingstoke, UK) started the debate when he proposed total mesorectal excision (TME) in the treatment of rectal cancer. The local recurrence rate was decreased substantially using this technique [8] and it has become the ‘gold standard’ treatment in localised rectal cancer. He reported local recurrence rates much lower than the average local recurrence rate of 29% after surgery alone, shown in all trials performed during the 1980s and early 1990s comparing radiotherapy given pre- or post-

operatively [9]. After the introduction of TME surgery it was obvious that the local recurrence rate could be reduced to <10%, even in population-based series, which has been proven in several studies, although these were not randomised studies [10–12]. As a result, in Scandinavian countries (Denmark, Norway and Sweden) rectal cancer surgery is no longer within the domain of the general surgeon, but is the sole responsibility of surgeons specially trained in gastrointestinal or colorectal surgery [13]. Outcome has changed dramatically in these countries. This move towards using specially trained surgeons is ongoing in Holland and is also being discussed in the UK. Depending on the levels of tumour from the anal verge to the anal sphincter, either a sphincter saving procedure or an abdominal perineal excision with colostomy can be carried out. With modern knowledge about tumour growth and the introduction of stapling devices, rectal cancer surgery has also been changed dramatically in terms of sphincter preservation. Twenty years ago, approximately 75% of all patients with rectal cancer were offered an abdominal perineal excision with a definitive colostomy. During the last two decades a trend towards the preservation of sphincters has increased the quality of life for patients and currently only 15–20% of all patients will have a definitive colostomy following an abdominal procedure. Quality of life after a very low anterior resection is far from perfect but many patients do accept impaired bowel function in preference to colostomy. By adding a small colonic J-pouch when performing a coloanal anastomosis the immediate outcome for the patient is superior and the quality of life improved [14]. This has been evaluated in numerous randomised trials comparing J-pouch construction with straight anastomosis. It has been claimed that the addition of a J-pouch only results in an improvement during the first 1–2 years, but more recent reports have shown that even after long-term follow-up, bowel function is superior in those patients with a J-pouch rather than straight anastomosis [15]. However, it is important that the pouch is not too large, thus making it difficult for the patient to evacuate [16]. With modern TME techniques, where the dissection is done just outside the mesorectal fascial envelope, the hypogastric nerves as well as the nervii erigenti can be defined, and with this nerve sparing technique it is possible to reduce possible damage to sexual function, or problems with voiding postoperatively. This technique is done in an identical fashion both for low anterior resection and abdominal perineal excision.

Local treatment In patients with a T1 tumour and favourable grading a local excision can be considered. This is still not a technique that has gained wide acceptance, but it is used more frequently nowadays. In particular, this option has become more acceptable with the introduction of a new transanal endoscopic microsurgery technique (TEM surgery) [17]. With the TEM

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utmost importance to find out whether a tumour has only just penetrated into the subserosal layer (muscularis mucosae; uT1) or whether it has penetrated the bowel wall (muscularis propria; uT2). If the tumour is confined to the submucosal fat (pT1), a local excision can be considered, but if the tumour has penetrated the bowel wall (muscularis propria; pT2), there are no recommendations at present for local excision. Such a case should be operated upon with an abdominal procedure, but the value of additional radiotherapy is in question. If the tumour is growing through the bowel wall (uT3, pT3), there is no case for local excision and only an abdominal procedure should be considered, provided the patient can tolerate a major operation. In such a case, another important judgement is to evaluate the distance from the edge of the tumour, or the most lateral tumour deposit in the mesorectum, to the mesorectal fascia. For this purpose the best technique is MRI, although some authors have claimed that a CT scan can also be used. The main difference between CT scans and MRI is that CT cannot generally distinguish between tumour growth and fibrosis [6], whereas this distinction is often possible with MRI [7]. In all tumours where digital examination of the rectum has revealed a tethered or fixed cancer, MRI is advisable to evaluate the circumferential margin. This evaluation is essential in deciding how radiotherapy is to be used (see below). Besides the T-stage, it is also important to evaluate the N-stage. With endorectal ultrasound, specificity as well as sensitivity is <75% [3]. Therefore, this is not a reliable technique for the evaluation of whether lymph nodes are harbouring tumour deposits or not. It is also difficult to locate lymph nodes with CT scans [6]; consequently, MRI is the best technique [7].

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Adjuvant radiotherapy Radiotherapy has been used for more than 30 years with the purpose of reducing the local recurrence rate. The treatment has been given either preoperatively or postoperatively and there are rationales supporting both schedules (Table 2). Although different treatment volumes, doses and number of fractions have been used, overwhelming evidence from the literature indicates that preoperative radiotherapy reduces the local recurrence rate to a higher extent than postoperative radiotherapy [9, 21]. Moreover, in the only trial where preoperative radiotherapy was tested against postoperative radiotherapy, the Uppsala trial, preoperative treatment reduced the local recurrence rate more than postoperative radiotherapy [22]. An important observation is that most trials using adjuvant radiotherapy versus surgery alone have been performed during a period of time when surgery was not optimised, unlike in the case of the new TME technique. Therefore, there

Table 2. Advantages and disadvantages with pre- or postoperative radiotherapy Preoperative irradiation

Postoperative irradiation

Compliance

100%

85%

Tolerance to treatment

Good

Less good

Negative effect on surgery

Yes

No

Acute adverse effects

Similar

Late adverse effects

10%

20%

Effect on local recurrence rate

High

Moderate

Effect on survival

Slight

None

is still a big question mark over whether radiotherapy is superfluous or not, provided surgery is optimised. A recently published trial comparing TME surgery alone versus preoperative radiotherapy and TME surgery, where all surgeons were specifically trained in the TME technique, found that radiotherapy still reduces the local recurrence rate substantially from >8 to 2% [23]. The follow-up in this trial is still too short and the survival analyses are awaited. Those data support the findings from Sweden where TME surgery alone results in a recurrence rate of around 8–10%, but TME surgery and preoperative radiotherapy results in a recurrence rate of about 3% [10, 11]. The rationale with adjuvant radiotherapy is dependent on the aim of treatment. One aim is to sterilise the lymph node and tumour deposits outside the mesorectal fascia. This is the case among patients with a T3 tumour. Data from trials using 5 × 5 Gy over 1 week with surgery the following week do indicate that with such a schedule in resectable rectal cancer the reduction in local recurrence rate will also have an impact on survival [24]. Another option for using radiotherapy is on patients with a fixed or tethered tumour, which has been considered nonresectable (T4 tumour). The rationale for using radiotherapy in this group of patients is to give a prolonged treatment with conventional radiotherapy (25 × 2 Gy) over a 5 week period. After a waiting time of up to 5–6 weeks the tumour shrinkage will make it possible to do a curative procedure. Although no strong evidence-based data support the use of chemoradiotherapy in this setting, most radiotherapists and medical oncologists use this combined treatment to improve the effect of radiotherapy. There is only one small randomised trial indicating this [25], but there are ongoing trials which will hopefully answer the question whether chemoradiotherapy is superior to radiotherapy alone in this setting. A third option for radiotherapy or chemoradiotherapy is a prolonged treatment over a 5 week period in patients with resectable but very low rectal cancer, i.e. in the lower third, within 6 cm of the anal verge. After a delay of another 5 weeks surgery is performed. The rationale with this schedule is to achieve a downsizing of the tumour and by doing so more sphincters can be preserved. Numerous non-randomised trials have indicated that this is the direction to take, as there are no real evidence-based data supporting this effect. One recently published trial from Lyon indicates that more sphincters might be preserved but the recurrence rate was slightly increased in patients where the surgeons have changed their strategy from abdominal perineal excisions to anterior resections [26]. At least two ongoing trials, one in Germany and one in Poland, are exploring this issue and hopefully we will have new data in the near future supporting the fact that prolonged preoperative chemoradiotherapy will increase the number of patients where sphincter preservation is possible without increasing the local recurrence rate. Another option for local control is intraoperative radiotherapy. Again, no randomised trials have evaluated the use of

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technique it is possible with an endoscope to take a full thickness biopsy with a good margin around the tumour. By doing so, the pathologist is able to examine the whole specimen and give a good report regarding the local radicality. Provided the excision is radical and the tumour grading is not unfavourable, this option is as good as an abdominal procedure according to one small randomised trial [18]. For patients with a T2 tumour, local excision is still not an accepted technique, although this has been tested together with adjuvant chemoradiotherapy with excellent results [19]. Therefore, in very fragile patients and with concomitant diseases a local excision can be considered. Other local treatment techniques are fulguration, piecemeal shaving or local radiotherapy. All these techniques have shown excellent results if performed by experienced physicians; endo-cavitary radiotherapy especially has been used for many years [20]. The drawback, however, is the lack of a perfect specimen with a good pathological staging, which favours a local excision instead of other techniques. On the other hand, just comparing different reports, it looks like there is no difference in outcome, although there are no randomised trials comparing different local treatment techniques.

254 optimised. Hopefully these trials will give us more information about the value of adjuvant chemotherapy in rectal cancer patients.

Table 3. Guidelines for using preoperative radiotherapy Radiation technique

Tumour stage T1

T2

T3

T4

N1

Short-course (5 × 5 Gy)

NA

+

+++

–

+++

Conventional (25 × 2 Gy)

–

+

+++

+++

+++

Chemoradiation (25 × 2 Gy)

–

+

+

+++

+

Summary

To whom should radiotherapy be given?

References

The reason why many surgeons are reluctant to give radiotherapy is because of the reported toxicity. One cannot deny that this is something which must be discussed when adjuvant treatment is used; especially in the case of the short-course ‘Swedish’ schedule which has been criticised as being more toxic. In my opinion this is not correct, because it is only the Swedish trials which have reported toxicity in a more scientific way. Provided radiotherapy is given in an optimised way, the risk of toxicity is acceptable. For patients with a T1 lesion there is no rationale for giving radiotherapy, which is also the case for T2 tumours. Patients with a T3 tumour should be considered for radiotherapy if the tumour is growing very low, situated anteriorly or tethered, or in the case of narrow male pelvises. Whether this group should have a short-course treatment or conventional treatment over 5 weeks is not known. An ongoing Swedish trial is testing this hypothesis in a randomised trial. In T4 tumours prolonged radiotherapy with or without chemotherapy may be considered (Table 3).

Adjuvant chemotherapy Based on data from the early 1990s, adjuvant chemotherapy has been the standard treatment for patients with stage III colon cancer [27]. There are very little data which support the use of chemotherapy in patients with stage I or II rectal cancer, mainly due to the fact that the majority of patients with this stage of cancer will survive. The interesting observation from all trials where colon and rectal cancer have been involved is that the effect is only found in colon cancer but not in rectal cancer [28]. Logically, chemotherapy should have the same effect on the rectum as on the colon, since it is probably the same organ. One explanation why rectal cancer patients are not doing as well as colon cancer patients may be the fact that most trials have used old-fashioned surgery and not TME surgery. New trials are running where patients are randomised to postoperative chemotherapy or not provided surgery is

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