Martina Treiber, R. Krempien, H. P. Knaebel, J. Debus

Martina Treiber, R. Krempien, H. P. Knaebel, J. Debus

M. Treiber ( u)

Department of Radiotherapy, University of Heidelberg, INF 400, 69120 Heidelberg, Germany

e-mail: martina_treiber@med.uni-heidelberg.de

Introduction

One of the basic questions for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery. Can we achieve a better local con- trol? Is there a decrease in metastatic disease? Can we see an effect on overall survival? Although some questions remain to be answered, some general rec- ommendations for the treatment of rectal cancer can be given. Since the NIH recommendations in 1990, the majority of patients with rectal cancer are treated by a multimodality approach. Today surgery with total mesorectal excision (TME) is the standard therapy for cancers of the middle and low rectum in stages T1/2 N0. Radiochemotherapy (adjuvant or neoadjuvant) and short-term preoperative radiotherapy are both feasible approaches for the treatment of stage II and stage III rectal carcinomas. The superiority of any of these concepts is awaited clarifying by randomized trials. Patients with locally advanced rectal cancers (T4) should undergo long-term neoadjuvant radiochemotherapy with consecutive oncological resection.

Preoperative Versus Postoperative Radiotherapy or Radiochemotherapy

When both surgery and radiation are indicated in an adjuvant setting, different opinions exist regarding the preferred sequence of each modality. Potential advan- tages of preoperative irradiation and in long-term courses in combination with chemotherapy include the damaging effect on cells that may be spread locally or distantly at the time of resection and the downstaging of lesions in an attempt to improve the rate of sphincter preservation. The major advantage of postoperative radiotherapy or radiochemotherapy is that the staging is clear and there will be no over- or undertreatment. In this case, patients are treated with a high risk for local recurrence on the basis of pathological findings.

Recent Results in Cancer Research, Vol. 165

Springer-Verlag Berlin Heidelberg 2005 c

Preoperative Radiotherapy and Radiochemotherapy

Low-dose preoperative irradiation (less than 20 Gy in daily fractions from 1.8 to 2 Gy) showed no significant impact on either local or distant tumor control or survival. As best shown by the Medical Research Council trial (MRC) [15], which compared surgery alone with a preoperative irradiation with a total dose of 5 Gy in one fraction and 20 Gy in ten fractions. Although moderate-dose preoperative irradiation has shown improved local control in a randomized phase III European trial [5], improved survival was shown only in a subset analysis [10]. In both series, the dose delivered was 34.5 Gy (15 fractions, single dose 2.3 Gy, treatment time 19 days), which is equivalent to approximately 44 Gy in standard fractionation.

The Swedish phase III randomized trial showed that a significant improvement in local control could translate into improved survival as well [18]. The study randomized patients to surgery alone as a control arm (n=557), or to short-course high-dose preoperative irradiation with 25 Gy in five fractions (equivalent 45–

50 Gy in 2-Gy single doses) followed by resection within 1 week (n=553). After a follow-up of 5 years, the rate of local relapse was 27% with surgery alone versus 11% with preoperative irradiation (p <0.001). The 5-year overall survival was 48%

versus 58% (p=0.004), respectively. There was no impact on developing distant metastases with rates at 24% versus 23%.

Another Swedish randomized phase III trial [3] compared neoadjuvant, high- dose preoperative irradiation (25 Gy, five fractions, 1 week) to adjuvant postopera- tive irradiation (60 Gy, 30 fractions, 8 weeks, a split course with a break of 2 weeks).

In the group of preoperative irradiated patients, the local relapse was less than in the postoperative group (13% vs. 22%, p=0.02). There was no significant difference in survival or distant metastasis rates.

A clear dose–response relationship in the relative reduction in local failure rates was observed in trials using 4×5 Gy [2] or 5×5 Gy [6]. In the Imperial Cancer Research Fund Trial [6] using 3×5 Gy, the effect on the recurrence rate was found to be of less magnitude than the other four trials. A recent meta- analysis showed a highly significant effect on the risk of local recurrence for patients with surgery alone compared to the radiotherapy-plus-surgery group [1]. From the Dutch multicenter study (randomized trial with 1,861 patients) it can be concluded that short-term preoperative radiotherapy further reduced the risk of local recurrence, although total mesorectal excision alone with qual- ity control of the surgical technique can significantly decrease the risk of local recurrence [14].

The rationale for combining chemotherapy and radiotherapy is that chemother-

apy agents such as 5-FU may have a radiosensitizing effect, and thus enhance

the potential for locoregional control. In addition, by giving radiotherapy and

chemotherapy simultaneously, rectum cancer is treated systemically for occult

metastasis, and overall treatment time may also be decreased. Preoperative chemo-

therapy in combination with 5 Gy hyperfractionation for a short time such as in

the Swedish literature does not have the same radiosensitizing effect as chemother-

apy in combination with a radiation dose of 40–45 Gy in 5 weeks [3, 21]. Several

studies have reported that the use of radiochemotherapy in a preoperative setting

may increase the operability of T4-carcinomas and recurrent carcinomas and the prospects of preserving sphincter function in very low rectal cancer [4, 13, 17].

Postoperative Radiotherapy or Radiochemotherapy

Positive results are reported in randomized phase III adjuvant trials for resected high-risk rectal cancer [7, 8, 16, 20]. A decrease in local relapse and improvement in terms of both disease-free and overall survival with combined modality post- operative radiochemotherapy was shown. In the GTSG 7175 trial, patients were randomized to surgery alone and adjuvant therapy arms (postoperative irradiation, postoperative chemotherapy and postoperative combined radiochemotherapy) [7, 8]. Statistically significant advantages in disease-free and overall survival with the radiochemotherapy arm were achieved in a comparison with the surgery alone arm. Local relapse, an initial pattern of relapse, was significantly decreased with irradiation versus no irradiation. The best local control was achieved with com- bined radiochemotherapy (local relapse rate of 11% vs. 20% with irradiation alone).

No impact on local control was seen with adjuvant chemotherapy alone, although rates of distant metastasis were lower in the arms that contained chemotherapy.

In the two arms without chemotherapy, no single arm had a significant impact on the rate of distant metastasis.

In the GTSG 7180 and the O’Connell trial (NCCTG 864751) [9, 16], it was shown that a combination of 5-FU, methyl CCNU and radiotherapy did not produce a benefit. The NCCTG trial also tested the best method of giving 5-FU concomitant with irradiation. Interrupted bolus 5-FU (500 mg/m

, 3 days, week 1 and 5 of EBRT) was compared with protracted low-dose infusion 5-FU (225 mg/m

, 24 h, 7 days a week) in a randomized study (664 patients) [16]. In an interim analysis of disease control and time to relapse there was a significant advantage for patients who received protracted 5-FU chemotherapy during radiotherapy. Local relapse rates were 8% versus 12%, distant metastasis rates were 31% versus 40% and 4- year disease-free survival rates were 63% versus 53%. There was also a significant improvement in 4-year overall survival: 70% versus 60%.

The US Intergroup rectal adjuvant study tested various 5-FU bolus regimes in combination with radiotherapy. In the published final report [20], there was no difference in either overall survival or disease-free survival by drug regime.

After 5 years, the disease-free survival for the total group was 54% and the overall survival was 64%; there was no difference by drug regime.

Pooled Analysis

Gunderson [12] created a pooled analysis from three randomized North American

studies of adjuvant therapy in patients with rectal cancer. The study included 2,551

patients, all patients received postoperative radiotherapy, 96% were randomized to

receive concurrent and maintenance chemotherapy. Five years of follow-up were

available in 94% of patients and a 7-year follow-up in 84%. Overall survival and

disease-free survival were dependent on both T and TN stage. Although in cases in an N2 situation, the T stage influenced 5-year overall survival (T1–2 69%; T3 48%, T4 38%). Gunderson identified three risk groups: (1) intermediate (T3N0 and T1–2N1); (2) moderately high (T4N0, T1–2N2 and T3N1) and high (T3N2, T4N1–2). For group one, 5-year overall survival was 74% and 81% and disease-free survival was 66% and 74%. In group two, the 5-year overall survival ranged from 61% to 69% and for group 3 overall survival ranged from 33% to 48%. Cumulative incidence rates of local relapse and distant metastases revealed similar differences to those seen in the survival analysis. The conclusion of the first pooled analysis was that patients with a single high-risk factor of extended tumor (T3–4) or nodal involvement (T1–2N1) have improved overall survival, disease-free survival and disease control when compared with those with both high-risk factors. Based on this analysis, there may be different treatment strategies indicated for the group of patients with intermediate risk (T3N0 and T1–2N1).

Side Effects

An optimal therapeutic ratio between local control and complications is achieved only with close interaction between the surgeon and the radiation oncologist and the use of sophisticated radiation techniques. In series that used conformal ra- diotherapy based on three-dimensional planning of irradiation, the incidence of small bowel obstruction requiring operative intervention was the same in patients receiving adjuvant postoperative irradiation (also in combination with chemother- apy) and those with surgery alone (6% vs. 5%) [19]. The incidence of acute enteritis was higher in the patients with combined radiochemotherapy versus radiotherapy alone. This did not translate into increased chronic intolerance. The incidence of severe small bowel stenosis was less than 6% with either adjuvant radiotherapy or radiochemotherapy. In O’Connell’s study [16], acute gastrointestinal intolerance was higher with protracted venous infusion 5-FU than with bolus 5-FU during irradiation. Severe diarrhea occurred in 24% (protracted 5-FU) versus 14% (bo- lus 5-FU) of patients. Severe hematological problems were lower in the group of patients with protracted infusion (2% vs. 11%).

Another problem could be the unsatisfactory rectal function. The reasons could be decreased function of the nerve innovation of the sphincter (by operation or irradiation) or the increased frequency of bowel movements with resulting occa- sional stool incontinence and the need for antidiarrheal agents. It is not surprising that postoperative radiotherapy or radiochemotherapy may reduce compliance of the reconstructed stool reservoir and result in some dysfunction. The incidence of severe treatment-related dysfunction is low and the risk must be placed in proper perspective by considering the severe morbidity and dysfunction by pelvic relapse.

Prospective quality of life studies with a particular emphasis on these endpoints

need to be done.

Single-Modality Rectal Adjuvants

Neither radiotherapy nor chemotherapy as single adjuvant modalities achieve all suggested criteria of efficacy except for the Swedish preoperative irradiation trial [18]. Adjuvant irradiation reduces local recurrence in postoperative and preoper- ative trials, but this has no impact on overall survival in most series because of developing distant metastases. The only published trial in which single-modality adjuvant treatment improved both local control and survival was the large Swedish study with over 1,100 patients testing surgery alone versus preoperative radio- therapy [18]. No significant improvement in local control has been seen with single-modality adjuvant chemotherapy in any randomized study.

Combined-Modality Rectal Adjuvants

Only combined modality postoperative adjuvant treatments showed efficacy in all scientific endpoints [7, 8]. Bolus 5-FU was administered during irradiation and patients received additional chemotherapy after irradiation or in other trials before and after radiotherapy. In the US study, groups showed that MeCCNU does not provide additional benefit over bolus 5-FU [9, 16].

Systemic metastases, as an initial pattern of relapse, occurred in 26%–29% of patients despite combined radiochemotherapy [7]. It seems that metastases could be decreased with protracted infusion of 5-FU in combination with irradiation [16], but the magnitude of the problem is still significant. There is a need to evaluate the delivery of the most effective systemic therapy during as well as before and after irradiation to avoid delays of nearly 3 months between sequences of the most effective systemic therapy.

Conclusion

The standard of care for resectable rectal cancer patients who can tolerate a surgical

procedure is surgical resection. However, since both local and systemic relapses are

common after resection of rectal cancer, adjuvant treatment is indicated for many

TN stages (Table 1). Over the last few years, there has been a shift to the regimes

with preoperative radiotherapy or radiochemotherapy, especially in Europe. Before

that time, patients with mobile, resectable mid and upper rectal cancers usually

had surgical resection performed as the initial component of treatment, and con-

sultations were obtained with radiotherapists and medical oncologists if high-risk

features were found. Only patients with fixed T4N0–2 lesions were treated with

preoperative radiochemotherapy. In this extended tumor stage, a boost with intra-

operative radiotherapy with an electron irradiation (IOERT) was also used [11],

especially if there was the likelihood of positive resection margins. Patients with

a tumor very close to the sphincter also receive preoperative radiochemotherapy in

an attempt to improve the percentage of patients in whom sphincter preservation

could be accomplished.

Table 1. Treatment overview

Stage M0 Surgery Radiotherapy/radiochemotherapy

Possible treatment Our recommendation

T1–2 N0 Resection (TME) – –

Low anterior resection if possible Abdominoperineal resection and regional lymph nodes

Local excision of select lesions

T3 N0 Resection (TME) after/before RT/RCHT Postop RCHT Preop short-term RT (45 Gy + 5.4 Gy boost) (5×5 Gy, 1 week)

T4 N0 Resection after RCHT Preop RCHT

(45 Gy + 5-FU) Preop RCHT (41.1 Gy + 5-FU) + IORT (10 Gy) T1–2 N1 Resection after/before RT/RCHT Preop RCHT Preop short-term RT

Postop RCHT

T1–2 N2 Resection after/before RT/RCHT Preop RCHT Postop RCHT T3 N1 Resection after/before RT/RCHT Postop RCHT Preop short-term RT

IORT (10 Gy)+ Preop RCHT postop RCHT (45 Gy)

Preop RCHT + IORT

T3 N2 Resection after/before RCHT Postop RCHT Preop RCHT

IORT + postop RCHT Preop RCHT + IORT

T4 N1 Resection after RCHT Postop RCHT Preop RCHT

IORT + postop RCHT Preop RCHT + IORT

T4 N2 Resection after RCHT Postop RCHT Preop RCHT

IORT + postop RCHT Preop RCHT + IORT TME, total mesorectal excision; RT, radiotherapy; RCHT, radiochemotherapy; IORT, intraoperative radiotherapy.

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