Combined chemo- and radiotherapy vs. radiotherapy alone in the treatment of primary, nonresectable adenocarcinoma of the rectum.

PURPOSE: In a randomized study in primarily inextirpable rectal cancer, conventional radiotherapy to reduce the tumor mass was compared with combined chemotherapy and radiotherapy. METHODS AND MATERIALS: The combined treatment (CRT) was given every other week, four times, during a 7-week period. The drugs used were methotrexate, 5-fluorouracil in bolus injection followed by continuous infusion and leucovorin rescue. Radiotherapy (RT) was given simultaneously with five 2-Gy fractions in 3 days to a dose of 10 Gy to a total dose in the four courses of 40 Gy. This regimen was compared with radiotherapy in 2-Gy fractions to a total dose of 46 Gy in the radiotherapy group. Surgery was performed 3-4 weeks after finished treatment. Seventy patients were included between November 1988 and August 1996; 36 patients were allocated to RT and 34 to CRT. RESULTS: Twenty-five (74%) of the patients in the CRT group underwent a locally radical resection with 20 (59%) patients without any known metastases. The corresponding figures in the RT group were 23 (64%) and 18 (50%), respectively. Among the patients who underwent any tumor resection, 5/29 (17%) in the CRT group and 12/27 (44%, p = 0.05) in the RT group have had a local recurrence. After a locally radical resection, the corresponding figures are 4% and 35% (p = 0.02), respectively. Local disease-free survival was significantly superior in the CRT group (66% at 5 years) compared with the RT group (38%, p = 0.03 log-rank test). Five-year survival was 29% (9 patients) in the CRT group and 18% (6 patients) in the RT group, a nonsignificant difference (p = 0.3). Five patients in the RT group did not complete planned treatment, mainly due to the appearance of metastatic disease. In this group toxicity was usually of Grade 0-1. In the experimental group, the toxicity usually was Grade 2 or higher, and 6 patients did not manage to fulfill the planned treatment due to toxicity. CONCLUSION: In this study, with fewer included patients than intended, resectability rates were high in both groups. The addition of chemotherapy to radiotherapy significantly improved local control rates, but no statistically significant difference was found in survival between the groups. The acute toxicity after CRT was higher than after RT alone, but manageable.

Preoperative radiotherapy in rectal carcinoma--aspects of acute adverse effects and radiation technique.

PURPOSE: To explain a possible association between treatment technique and postoperative mortality after preoperative radiotherapy of rectal carcinoma, the dose distributions were compared in model experiments. METHODS AND MATERIALS: Preoperative radiotherapy with a three-beam technique delivered in five fractions to 25 Gy (5 Gy/daily for 5 or 7 days) was given to patients with primary resectable rectal carcinoma. The adverse effects of this treatment, both acute and late, have been low. In a parallel trial using an identical fractionation schedule and total dose but with a two-beam technique, the postoperative mortality was higher. Two-, three-, and four-beam techniques were analyzed in 20 patients with computed tomography based, three-dimensional dose planning. Dose distributions and dose-volume histograms in the planning target volume (PTV) and in the organs at risk were considered. A numerical "biological" model was used to compare the techniques. RESULTS: The two-beam and the four-beam box techniques give the most homogeneous dose distributions in the PTV, although all techniques result in dose distributions that would be considered adequate, provided 16 MV or higher photon energies are used. Three- and four-beam techniques show advantages over the two-beam technique with respect to organs at risk, particularly the small bowel. With the two-beam technique and the upper beam limit at mid-L4, the volume of the bowel that receives > 95% of the prescribed dose, and hence, is included in the treated volume (TV), is more than twice as large as that with three- and four-beam techniques, and that of the total body between 1.5 and 2 times as large. The results of the analyses using the biological model indicate that the three- and four-beam techniques result in less small bowel complication rates than the two-beam technique. The integral energy to the total body is similar for all treatment modalities compared. CONCLUSIONS: The volume of bowel included in the TV, rather than the energy imparted to the body, influences postoperative mortality, and emphasizes the importance of precise radiotherapy planning to minimize normal tissue toxicity.

Acute lumbosacral plexopathy during and after preoperative radiotherapy of rectal adenocarcinoma.

The benefit of preoperative radiotherapy of adenocarcinoma of the rectum with respect to a reduced local recurrence rate and an improved survival should be weighed against adverse effects. For 14 years a three-beam, isocentric technique was employed at our hospital to deliver five fractions (5.0 or 5.1 Gy), over 5 or 7 days preoperatively, to patients with rectal cancer which was considered primarily resectable. The adverse effects of the radiotherapy were few, but acute pain and subacute neurological symptoms and signs did occur. An apparent increase in the frequency of these symptoms/signs was noted during 1993. The pain and neurological symptoms are described in case reports and the individual treatments are reviewed. The three-beam technique was analyzed in detail with individual, CT-based, three-dimensional dose-planning and dose distributions in the vicinity of the lumbar nerve plexus are presented. The major result of this analysis showed that technical errors could be excluded, that human errors were unlikely, and that the culprit probably was an unexpected sensitivity to marginal changes in the daily dose and unknown or unexpected radiosensitizing effects of concurrent diseases or medication.

Treatment of local recurrences of rectal carcinoma.

From 1978-1992, 159 patients were treated for local recurrences of rectal carcinoma. They could be subdivided into three groups according to the type of primary treatment given; 82 patients underwent primary surgery without irradiation, 37 patients had preoperative and 40 patients postoperative radiotherapy. The localizations of the recurrences and the curative and palliative potentials of surgery and radiotherapy in the treatment of local recurrences were studied. There was no difference in the localisation of the recurrences in the three groups. Median time between initial surgery and recurrence was also almost the same in the three groups and 75% of the recurrences appeared within 2 years. Twenty percent of the patients in the primary surgery alone group, compared with 49% and 38% in the preoperative and postoperative irradiation groups, respectively, had distant metastases at the time of the diagnosis of local recurrence. The predominant symptom from the local recurrence was pain and, after treatment of the recurrence, pain relief was registered in 63%. In 66%, 16% and 22%, respectively, of the patients in the three groups, the intention of the treatment was curative, with either radiotherapy alone, radiotherapy combined with surgery or surgery alone. The 5-years-survival after recurrence was 6% in the primary surgery alone group and 0% in the other 2 groups. Of the 69 patients treated with a curative intention, 32% were locally symptom-free at death or the last follow-up. Our conclusion is that a local recurrence must be avoided due to the morbidity associated with local failure and the potentially low likelihood of curative treatment of a local recurrence.

Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects.

From 1980 to 1985, 471 patients with resectable rectal and rectosigmoid cancer were randomly allocated to receive either preoperative short-term high-dose irradiation (25.5 Gy in one week) for all patients or prolonged postoperative radiotherapy (60 Gy in seven to eight weeks) only for patients with a Dukes B or C lesion. After a minimum follow-up of five years, the local recurrence rate was statistically significantly lower after preoperative than after postoperative radiotherapy (13 percent vs. 22 percent; P = 0.02). No difference in overall survival was noted (P = 0.5). To evaluate possible late side effects on the bowel, urinary bladder, or skin after surgery and additional preoperative or postoperative radiotherapy, all patients included in the randomized trial, together with 58 patients from a preceding pilot study with the same preoperative regimen, were studied in a prolonged follow-up program. The hospital files of all patients were re-examined. Of the patients who were carefully examined, 176 had a survival exceeding five years and 19 had a survival exceeding 10 years. Overall, 7 percent (33/464) either were operated upon or have had a radiologic diagnosis of small bowel obstruction: 14/255 (5 percent) after preoperative irradiation, 14/127 (11 percent) after postoperative irradiation, and 5/82 (6 percent) after surgery alone. The cumulative risk of developing a bowel obstruction was significantly increased after postoperative radiotherapy. Among the 98 patients alive after preoperative irradiation, significant morbidity from the bowel was noted in 11 patients, from the urinary bladder in two, and from the skin in six. In the postoperatively treated group of 34 patients, the bowel, urinary bladder, and skin morbidity were significant in five, two, and five patients, respectively. Corresponding morbidity in 44 nonirradiated patients was seen in five, one, and two patients, respectively. It is concluded that preoperative, short-term, high-dose radiotherapy decreases the local recurrence rate relative to postoperative radiotherapy, with no indications of increased late morbidity after a follow-up of 5 to 10 years.