Modern Aspects of Radiation Oncology for Rectal Cancer

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Introduction

Rectal cancer (RC) accounts for about 30% of all large bowel tumours and is effectively treated by radical surgery, which may also preserve anorectal func- tion when tumours are small, exophytic, mobile and located in the proximal rectum. As stated by the National Institutes of Health Consensus Conference in the United States in 1990 [1], combined treatments including radical surgery and radiation therapy with or without chemotherapy may improve both local control as well as survival when the disease is staged as locally advanced (stages II–III RC), is located to the distal rectum, has poor mobility or deep mucosal ulceration with circumferential bowel wall infiltra- tion and lymph node involvement. Recurrence rates after surgical treatment of RC range from less than 5% to more than 30% and they are probably related to the surgeon’s experience and skills, patient selection and different definitions of local failure. A modern concept for the surgical oncologist is the impor- tance of a sharp dissection of the entire mesorectum in patients with potentially curable middle to lower RC, as suggested by Heald [2], who has performed this kind of surgery without any adjuvant treatment in a series of 115 patients reporting, at a mean follow- up of 4.2 years, very low recurrences which were only detected in the pelvis (2.6%) and not at the anasto- mosis. Circumferential margin is an important factor determining recurrence during potentially curative surgery and it may be predicted by magnetic reso- nance imaging (MRI) findings while assessing the mesorectal fascia. According to these points, radiation therapy may probably be omitted when surgery without adjuvant treatments is performed by teams who report less than 5% local recurrence rates at five years. On the other hand, a meta-analysis of all randomised trials showed that neoadjuvant are more effective than adjuvant treatments for both reducing local failure rates as well as improving cancer-specif- ic survival [3]. The Dutch trial [4] randomised patients with clinically resectable RC to surgery alone by total mesorectal excision (TME), or short-course

radiation followed by TME. In this trial the TME procedures and the pathological analysis of the speci- mens were standardised to limit the bias due to surgical expertise. While there were no significant dif- ferences in overall survivals, local recurrence rates were decreased in the group who received neoadjuvant treatment (12% vs. 6% at five years) [5]. Based on the results of the recently completed German Trial [6], patients with T3 and/or N1–2 RC should receive pre-operative combined modality therapy and undergo TME with adequate nodal dissection. The potential advantages of neoadjuvant therapy include earlier onset, increased tumour radio sensibility, decreased radiation complications, decreased local recurrence rates due to tumour seeding during the surgical procedure, and, probably, increased feasibil- ity of performing sphincter-sparing surgery. The primary disadvantages of neoadjuvant therapy are the absence of a pretreatment pathological classification with a risk of overtreating small tumours as well as the risk of understaging lymph node status. Lymph node staging in patients who undergo pre-operative radiotherapy alone or in combination with chemotherapy should be interpreted with caution because the clinical relevance of the number of nodes involved and the pathologic stage are not completely evaluated by clinical studies. For example, a large study reported that T3N0 RC patients, who had undergone surgery combined with post-operative radio and/or chemotherapy, had a poor prognosis if few lymph nodes had been evaluated by the patholo- gist [7, 8]. MRI advances have improved the selection of patients with stage T2–T3 disease, thus reducing overtreatment of pre-operative radio- and chemotherapy. Advanced MRI with particular contrast medium will improve accuracy in staging the lymph node metastases as well as patient pre-operative selection for aggressive chemoradiotherapy regimens. As RC represents not a uniform entity but a wide spectrum of diseases, it is extremely important to classify and stage RC patients correctly because the application of radiotherapy principles requires information including concerning tumour biology,

Mario Romano, Antonio B. Porcaro

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surgical procedures and expertise, anatomy of the pelvis, and RC failure patterns. In conclusion, we think that the modern approach of radiation oncology is to select the best patient for the best treatment.

After this overview and as depicted in Fig. 1, we will briefly describe RC radiation therapy dealing with patient selection and protocols as performed at our institution.

Post-Operative Radiation Therapy

In our institution, we rarely perform post-operative radiation therapy, which is frequently associated with5-fluorouracil (5-FU)-based chemotherapy and is delivered when the surgical specimen of a good patient selected for exclusive surgery shows risks of local recurrence such as incomplete tumour resection as well as nodal disease involvement. Post-operative radiotherapy has shown the advantage of being selectively delivered in patients at high risk of local recurrence as well as the disadvantage of the increased risk of radiation damage of the small bowel loops which may be fixated to the pelvis as a result of the surgical procedure. The risk of small bowel injury has decreased with the advent of a 3D planning sys- tem, dietary care and not exceeding the limit dose of 50–54 Gy. Complications of pelvic radiation therapy are related to the radiation field volume, surgical procedure, overall treatment time, fraction size, radiation energy, total dose and technique [9]. Generally, successful treatment of RC depends on large irradiation fields whose arrangement depends on the loca-

tion of the primary tumour, surgical procedure (low anterior vs. abdominal perineal resection) and volume of the small bowel. Small bowel radiation induced complications are directly proportional to their volume and may be reduced by using contrast media in defining the radiation fields. Gallagher et al.

[10] determined the volume, distribution and mobility of small bowel in the pelvis by using different techniques. There was a significant average small bowel volume decrease when patients, compared with the supine position, were treated in the prone position with compression of the abdominal wall and distension of the bladder. At our institution we use the prone position and a custom-made belly board for selected patients undergoing post-operative radiation therapy [11]. The knowledge of both local and nodal failure patterns is important for planning radiation therapy fields which should include all potentially contaminated retroperitoneal soft tissue. The majority of local failures in cases of APR occur in the posterior pelvis, presacral space, primary tumour site and perineum. The reported risk areas include the internal iliac, presacral and obturator lymph nodes.

After an APR, a wire marker should be used to identify the perineal scar for defining the inferior limit of the beams. When the rectum is resected anteriorly, a Foley catheter is inserted into the rectum and retract- ed inferiorly in order to identify the anorectal junc- tion and define the inferior limit of the beams. The cranial limit of the field is usually L5-S1 interspace;

the lateral borders extend 1.5–2 cm lateral to the widest part of the pelvis bones. Posterior fields include the whole sacrum including a 1-cm posterior Fig. 1.RC radiation therapy and patient selection

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margin to allow dose to build up in the presacral area. The anterior border is defined to encompass the internal or internal plus external iliac nodes according to the pathological N stage. When boost doses of radiation are required, the fields are redesigned and 3D treatment planning are performed in order to spare the tissues which are considered not at risk. At present, intensity modulated radiation therapy (IMRT) does not have an established role in post- operative radiation therapy for RC including stages assessed as T3N0N+ and M0R0.

Pre-Operative Radiotherapy

In our department pre-operative radiotherapy is the standard treatment for stage 2–3 rectal RC and, as reported before, an increasing body of data suggests the superiority of pre-operative radiotherapy combined with chemotherapy in terms of local control, disease-free survival and reduction of bowel toxici- ties. There are two types of pre-operative radiotherapy: fractionated radiotherapy and short course.

Short-course pre-operative radiotherapy is delivered one week before surgery in 5 daily fractions of 5 Gy without any chemotherapy. Pre-operative frac- tioned radiotherapy is delivered in a period longer than5 weeks (daily doses of 1.8–2 Gy for total doses of 45–50 Gy), usually with a 5-FU schedule, and is followed by surgery which is performed 4–6 weeks after in order to restore the acute damage and as well as to reduce tumour volume. Probably the most important argument in favour of pre-operative radiation therapy is tumour regression, which may improve the likelihood of a successful resection with free margins. The possibilities of preserving the sphincter are increased for regressing tumours aris- ing in the distal rectum. From this point of view, short-course radiation offers low tumour reduction probabilities due to the surgery timing. The choice of treatment is fractionated radiotherapy because it offers a high probability of sphincter preservation.

After pre-operative chemo- and radiotherapy, a pathologic complete response rate of 10–25% has been reported as well as a tumour downstaging rate of 40–80% with both improved local control and survival [12, 13]. For this reason, different institu- tions, including our department, have routinely used some form of dose intensification and the addition of chemotherapeutical agents such as oxali- platin in order to increase the pathological complete response rate as well as local control and survival. By using a novel, custom-made, modified belly board, we investigated the effects of reduced radiations on the small bowel as well as their effects on volume and median dose. Using a four-field box technique,

the mean dose of the small bowel of patients treated on our belly board was significant lower than with the standard technique [14]. We have also investigated the possibility with this bowel device of an escalation of the radiation dose. Between October 1998 and December 2002, 109 patients with primary RC (T3–T4) underwent pre-operative radiochemotherapy plus hyperthermia with escalation of the radiation dose. The median total dose in this series was delivered and escalated as follows: 54 Gy in the first 21 patients, 56 Gy in the second group of 41 patients,62 Gy in the third group of 22 patients and 64 Gy in the fourth group of 25 patients. The treatment was well tolerated without any significant side effect. Six patients with a clinical complete response refused surgery and were submitted to an intensive surveillance protocol. The pathological complete response rate was 30% and the local recurrence rate was 2%, and also the survival was 76% after mean follow-up of 4 years. Of the 6 patients that refused surgery,1 patient died from metastatic disease without evidence of local recurrence, while the other 5 patients are still alive without disease. A multivariate analysis showed that radiation doses >60 Gy and tumour length less than 3 cm were related to a high- er rate of complete pathological responses. In this experience, dose escalation may have contributed to an increase of the pathological complete response rate and to a better outcome for patients refusing surgery [15]. A valid criticism of this kind of study is that we do not know how applicable the staging sys- tem is for patients who have undergone pre-operative radiochemotherapy. Probably, post-treatment pathologic findings represent a composite situation of stage of the tumour and its response to pre-operative therapy and pathological complete responders may simply represent the quota of patients with less aggressive disease and/or with a disease that strong- ly responds to the treatment. In the future, the use of more precise pre-operative staging systems will allow evaluation of how pre-operative radiochemo- downstaging may impact patient survival. Of much interest is the report of overall long-term results of stage 0 RC following neoadjuvant chemoradiation that compared operative and non-operative treatment [16]. In this report, after radiochemotherapy patients with incomplete clinical response treated by surgery resulting in stage pT0 were compared to patients with complete clinical response not treated with surgery: five-year overall and disease-free survival rates were 88 and 83%, respectively, in the resection group and 100 and 92% in the observation group. The Authors concluded that stage 0 RC disease after radiochemotherapy is associated with excellent long-term results irrespective of surgical resection.

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Treatment of Local Recurrences

Local recurrent RC represents a major problem to the surgical oncologist, occurs in 4–5% of patients after apparently curative resection and is resectable in only 15–20% of cases. This type of pelvic tumour causes significant morbidity and accounts for 90% of disease-related deaths within five years. Surgical resection is the initial choice of treatment. The objec- tive, if feasible, is removal of both the tumour and primary nodal drainage with as wide a margin around them as possible. If recurrence occurs in patients not previously treated with radiation therapy, pre-operative radiochemotherapy is highly rec- ommended and it is possible to complete the radiation treatment in case of suboptimal resection of the tumour with intraoperative radiation therapy boost (IORT). Patients who achieve a gross total resection at the time of IORT have a markedly better prognosis than those with residual gross disease. The major IORT-related post-operative complications are leak- age from anastomoses, deep pelvic abscesses and peripheral nerve injury causing lower extremity weakness. Other complications including perineal pain, hydronephrosis and bladder perforations are less common [17]. In previously heavily irradiated patients the treatment is mainly palliative with hypofractionated radiation therapy regimens and chemotherapy. The Dutch Hyperthermia group investigated with a randomised trial the effect of additional hyperthermia in recurrent inoperable tumours of the rectum. In this trial 50% of the patients were randomised to standard radiation alone and 50% to combined treatment. The complete response rate was 13% following radiotherapy alone and19% following combined treatment. This differ- ence was not significant so it did not lead to any definitive conclusion [18]. At our department we have also treated a consecutive series of 44 patients for RC local recurrences with regional hyperthermia plus radiochemotherapy with a good complete pathological response rate in patients not previously irradiated, and a good palliation of symptoms without any relevant toxicity in those previously irradiated for more advanced disease [19].

Conclusions

In conclusion, a wide spectrum of radiation treatment possibilities are available for all clinical presen- tations of RC natural history. We need to perform a global strategy of appropriate patient selection and combine the different treatment modalities including surgery, radiotherapy, chemotherapy, IORT, hyper-

thermia and (more recently) immunotherapy. These multimodality and integrated treatment pro- grammes will allow a more conservative treatment in limited disease, better survival and reduction of local recurrence in advanced disease, and good symptom palliation in recurrent or metastatic disease.

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