Still, the severe morbidity associated with local recurrence demands additional efforts to guarantee local control. Moreover, it may be hoped that a reduction of local recurrence translates into improved overall survival.

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

Introduction

Local recurrence following curative resection of rectal carcinoma is still a major problem. Recurrence rates of more than 30% have been reported in the past, but total mesorectal excision has reduced the incidence to considerably less than 10%.

Still, the severe morbidity associated with local recurrence demands additional efforts to guarantee local control. Moreover, it may be hoped that a reduction of local recurrence translates into improved overall survival.

Postoperative adjuvant radiotherapy allows treatment after precise pathological staging, thus preventing over-therapy. The target area, however, includes radiosen- sitive tissues such as urinary bladder, ureters and intestines as well as a hypoxic postsurgical tumor bed with potentially reduced radiosensitivity. Neoadjuvant therapy can render resectability in locally advanced tumors and often facilitates sphincter preservation in low rectal cancer [19, 22]. It also reduces the spread of viable tumor cells and seems to decrease side effects concerning the small bowel.

Finally radiosensitivity is expected to be better, because tumor cell oxygenation is not compromised preoperatively.

Many randomized trials have confirmed that adjuvant as well as neoadjuvant radiotherapy can reduce the incidence of local recurrence in UICC stage II and III rectal carcinoma by half [13] and neoadjuvant accelerated 5×5-Gy radiotherapy was associated with improved survival [20, 11].

Concept of Intraoperative Radiotherapy

To decrease acute and late toxicity of radiotherapy and to improve local con- trol, institutes in the US, Europe, Russia and Japan have combined fractionated three-dimensional planned external beam radiotherapy (EBRT) with intraopera- tive radiotherapy (IORT) as a local boost technique. External beam radiotherapy is limited to 40–45 Gy in the pelvic area (only a small boost volume without ir- radiating small bowl can be treated up to a total dose of 50 Gy), because of the Recent Results in Cancer Research, Vol. 165

Springer-Verlag Berlin Heidelberg 2005 c

Figure 1. Overview of all patients treated with IORT in our department since 1991 (June 1991–June 2003), n=1,203

normal tissue tolerance. Tolerance of gastrointestinal tissues to fractionated EBRT is limited and depends on treated organ volume and irradiation dose. Tolerance dose for the small bowel is 40–45 Gy and for the colon 45–50 Gy [5]. Higher doses can be applied by IORT in order to reach the recommended 60 Gy. A single high dose irradiation such as IORT (dose range, 10–15 Gy) results in a higher biological effectiveness (2.5 times greater) compared to fractionated radiotherapy (1.8–2 Gy daily in five fractions per week). Higher doses can be given for microscopically or macroscopically incompletely resected tumors by IORT [15]. Besides potentially better local control rates, IORT patients save 2 weeks time compared to patients who are treated with an additional percutaneous conventional boost therapy with low daily single dose fractionation.

The target volume IORT for rectal carcinoma is determined by observations in patients who had re-operation after resection of primary rectal carcinoma.

Recurrent carcinoma was most frequently found at the anastomosis and in the presacral area [6]. As a result, the presacral area and the lymphatic drainage up to the sacral promontory should be included in the IORT target volume.

Patients with rectal cancer who are candidates for IORT constitute a heteroge- neous group. IORT can be integrated at different points in the treatment schedule.

For locally advanced or recurrent carcinoma IORT is preferably used as an adju- vant treatment. It can also be applied in preirradiated patients. Figure 1 gives an overview of all patients (n=1,203) treated with IORT in our department since 1991.

Techniques and Dosage

In Heidelberg we use a dedicated operating unit equipped with a linear accelerator

(electron beam) for intraoperative radiotherapy (Fig. 2). IORT is administered

using special sterile chrome-plated brass applicators of different shapes, 5–12 cm

in diameter, which are held fixed to the operation table. IORT is then delivered

using a laser-guided air-docking system with electron energies of 8–18 MeV cor-

responding to a depth of 24–54 mm. The IORT dose is prescribed to the 90%

Figure 2. Dedicated IORT unit (linear accelerator Siemens Mevatron ME), University of Heidelberg

isodose and is delivered by a dose rate of 900 cGy per minute (Fig. 3). Surgical clips to identify the IORT volume facilitate 3D computed tomography planning of postoperative EBRT. EBRT is delivered at 1–4 weeks pre- or postoperatively in single fractions of 1.8 Gy (in combination with chemotherapy 5-FU/leucovorin) or with the new preoperative concept recommending 25 Gy in 1 week (5×5 Gy) by a linear accelerator with at least 6–23 MeV photons.

For patients who have not been preirradiated with 10 Gy, in case of residual or recurrent disease, up to 15 Gy are applied. The complete IORT procedure (position- ing of the applicator, transportation to the accelerator, air-docking and irradiation) requires about 20 min, with a well-organized team of surgeons, radiation therapists and anesthesiologists.

Figure 3. Rectal carcinoma: typical IORT situation

Morbidity and Toxicity

The most important dose-limiting factors to be considered in IORT are periph- eral neuropathy and ureter stenosis. The frequency of complications depends on radiation doses and on the indication for IORT. Higher IORT-related complica- tion rates (soft tissue or sacral damage and 10% pelvic neuropathy) were reported for patients with recurrent disease compared to those with primary disease (2%

sacral injury) [23]. In the RTOG 8508 trial, 2-year actuarial risk of significant complications with primary or recurrent rectal carcinoma was 16%. There was no significant difference in complications in the IORT group compared with a non- randomized group who had surgery without IORT [12, 16]. In our experience with recurrent rectal cancer, morbidity was not significantly increased when IORT was added to EBRCT (external beam radiotherapy and additional chemotherapy) [21].

The risk of chronic gastrointestinal damage could be reduced from 7% to 0% in patients who were treated by combined radiotherapy (EBRCT plus IORT) [4, 21]

due to dose reduction in the intestines. Still, only a randomized study will provide a reliable estimate of IORT-related complication rates, particularly in patients with recurrent disease.

Survival

Primary Advanced and Unresectable Rectal Cancer

A comparison of patients with completely resected tumors showed a reduction of local failure rates from 18% without IORT (n=66) to 11% when IORT was used (n=45). Patients with incomplete resection had a reduction of local failure from 83% without IORT to 35% with IORT. The 5-year overall survival rate for primary advanced rectal cancer patients within the IORT group was 63% for patients with negative margins and 32% for patients with positive margins [14]. Similar observations were made by other investigators [8, 9].

In our series of stage II and III primary rectal carcinoma, the 5-year overall survival was 64% and 41%, respectively. Local failure rates were inversely related to radiation doses: 32%, 40–48 Gy; 25%, 49–56 Gy; 5.2%, 66.4 Gy (41.4 + IORT 10 Gy;

biological effective dose IORT 25 Gy). The 2-year and 3-year overall survival rates were significantly improved after IORT plus EBRCT in both primary and recurrent disease [3]. This results were confirmed by the IORT group in Rome, Italy [2].

Recurrent Rectal Cancer

Patients with local recurrence of rectal cancer represent a rather heterogeneous

group with regard to tumor burden and prior treatment. Patients who already

have had pelvic irradiation and chemotherapy receive IORT only (often at a re-

duced dose) during resection of recurrent tumor, while others, who were not

preirradiated, can be treated with a full course of preoperative external beam ra-

vival of 21% for completely resected patients, but only 7% for those whose tumors were incompletely resected [23].

The poor outcome for incompletely resected tumors was confirmed by a group from Eindhoven, the Netherlands [17]. They found that patients with gross residual disease had a significantly lower rate of 3-year local control (21% vs. 79%), disease- free survival (11% vs. 54%) and overall survival (35% vs. 74%) compared to those with negative or microscopically involved margins.

Our data showed a 5-year local control rate of 78% in patients with complete resection and 58% in patients with microscopic residues. In the group of incom- pletely resected tumors (R2), a marked increase in local failures was observed and the local control rate was reduced to 29%. The 5-year overall survival rate was low (39%) because of the high distant metastasis rate [21]. The IORT group in Münster, Germany, presented comparable results [10]. These days preoperative ra- diochemotherapy followed by radical surgical resection plus IORT is the preferred sequence of treatment in our institution.

Randomized Trials

A prospective multicenter trial in France includes UICC stage II and III rectal cancers. Following preoperative radiotherapy of 40 Gy, patients were randomized to either no further radiotherapy or intraoperative radiotherapy of 18 Gy ( >10 MeV).

Until 1996, 57 of 288 planned patients were entered. Postoperative morbidity was not significantly different between groups, but long-term results await completion of the trial [1]. Another randomized trial was performed in Russia, where 42 patients were randomized after preoperative radiotherapy to receive additional 20 Gy intraoperative boost irradiation (8–15 MeV) or not. At a median follow-up of 7 months (range, 1–15 months), two patients in the control group, but no patient in the treatment group had locoregional recurrence [18]. Again, long-term results have not yet been reported.

Outlook

Intraoperative radiotherapy represents an important component of multimodal

therapy in rectal carcinoma. IORT makes it possible to give high irradiation doses

to the tumor bed, resulting in better local control rates without an increase in side

effects. Unfortunately, the potential therapeutic benefit of intraoperative electron

beam radiotherapy has never been tested in large prospective, randomized and

controlled trials. There were two main reasons for this: too few institutions were

equipped with a dedicated unit for intraoperative radiotherapy and patients ex- plicitly referred to receive IORT could hardly be randomized. Technical advances have made available a new generation of mobile accelerators such as the Novac 7 (Elektra) and others, which do not require special shielding of the operating room.

This allows a more flexible use in different operating rooms. In our department, we have used a flexible mobile operation table (Maquet) to facilitate patient posi- tioning to apply IORT over the last year. All these developments will allow a wider use of IORT in the future.

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