Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy does not alter anal sphincter preservation or postoperative complications compared with short-course radiotherapy alone in patients with clinical stage T3 or T4 resectable rectal cancer. The aim of this study was to compare survival, local control and late toxicity in the two treatment groups. METHODS: The study randomized 312 patients to receive either preoperative irradiation (25 Gy in five fractions of 5 Gy) and surgery within 7 days or chemoradiation (50.4 Gy in 28 fractions of 1.8 Gy, bolus 5-fluorouracil and leucovorin) and surgery 4-6 weeks later. The median follow-up of living patients was 48 (range 31-69) months. RESULTS: Early radiation toxicity was higher in the chemoradiation group (18.2 versus 3.2 per cent; P < 0.001). The actuarial 4-year overall survival was 67.2 per cent in the short-course group and 66.2 per cent in the chemoradiation group (P = 0.960). Disease-free survival was 58.4 versus 55.6 per cent (P = 0.820), crude incidence of local recurrence was 9.0 versus 14.2 per cent (P = 0.170) and severe late toxicity was 10.1 versus 7.1 per cent (P = 0.360) respectively. CONCLUSION: Neoadjuvant chemoradiation did not increase survival, local control or late toxicity compared with short-course radiotherapy alone.

Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs chemoradiation.

OBJECTIVE: The primary outcome was sphincter preservation. No benefit was found with chemoradiation. The aim of this report is to analyse postoperative complications, which were the secondary outcome. MATERIAL AND METHODS: Patients with resectable T3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation (50.4 Gy, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by TME after 4-6 weeks. RESULTS: Three hundred and five patients (153 in 5 x 5 Gy group and 152 in chemoradiation group) were analysed. The rates of patients with postoperative complications for the 5 x 5 Gy group and for the chemoradiation group were 27 vs 21%, respectively (P = 0.27). If the values were expressed in terms of number of complications, the rates were 31 vs 22%, respectively (P = 0.06). The corresponding values for severe complications were 10 vs 11% (P = 0.85) of patients with complications and 12 vs 11% (P = 0.85) of events. CONCLUSION: The study did not demonstrate a statistically significant difference in the rate of postoperative complications after short-course pre-operative radiotherapy compared with full course chemoradiation.

Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy.

BACKGROUND AND PURPOSE: The aim was to verify whether preoperative conventionally fractionated chemoradiation offers an advantage in sphincter preservation in comparison with preoperative short-term irradiation. PATIENTS AND METHODS: Patients with resectable T3-4 rectal carcinoma without sphincters' infiltration and with a lesion accessible to digital rectal examination were randomised into: preoperative 5x5Gy short-term irradiation with subsequent total mesorectal excision (TME) performed within 7 days or chemoradiation to a total dose of 50.4Gy (1.8Gy per fraction) concomitantly with two courses of bolus 5-fluorouracil and leucovorin followed by TME after 4-6 weeks. Surgeons were obliged to base the type of operation on the tumour status at the time of surgery. RESULTS: Between 1999 and 2002, 316 patients from 19 institutions were enrolled. The sphincter preservation rate was 61% in the 5x5Gy arm and 58% in the radiochemotherapy arm, P = 0.57. The tumour was on average 1.9 cm smaller (P < 0.001) among patients treated with chemoradiation compared with short-term schedule. For patients who underwent sphincter-preserving procedure, the surgeons generally followed the rule of tailoring the resection according to tumour downsizing; the median distal bowel margin was identical (2 cm) for both randomised groups. However, in the chemoradiation group, five patients underwent abdominoperineal resection despite clinical complete response. CONCLUSIONS: Despite significant downsizing, chemoradiation did not result in increased sphincter preservation rate in comparison with short-term preoperative radiotherapy. The surgeons' decisions were subjective and based on pre-treatment tumour volume at least in clinical complete responders.

Prognostic factors for the time of occurrence and dynamics of distant metastases and local recurrences after radical treatment in patients with rectal cancer.

BACKGROUND: A remarkable increase has been noted in the rate of incidence of rectal cancer. Post- or preoperative adjuvant treatment has significantly decreased the risk of local recurrence, but still only about 50% of all patients with rectal cancer treated radically can achieve a permanent cure. The majority of failures are due to distant metastases (DM) and/or local recurrences (LR). The risk and dynamics of failure after treatment of neoplasmtic disease has been analyzed on several occasions. MATERIAL AND METHODS: This retrospective study involved 161 consecutive patients with rectal cancer treated by radical surgery between 1972 and 1989. The mean age was 57 years. All patients underwent radical abdominoperineal rectum excision. The average follow-up was 10 years. In terms of the time elapsing to failure, the entire group of patients was divided into two subgroups: 'early' (occurring within 18 months after surgery) and 'late' (more than 18 months after surgery). RESULTS: The actuarial 5-year disease-free survival rate was 61.3%. Distant metastases occurred in 42 cases (26%), of whom 50% developed 'early' relapses, whereas local recurrences (29 cases - 18%) developed 'early' in 72% of the cases. Male gender was found to be an independent factor increasing the risk of 'early' relapses, particularly in the pN2 group. The stage of the disease is an indisputable risk factor for distant metastases and 'early' local recurrences. CONCLUSIONS: The time to failure varied significantly regarding local and distant relapses, suggesting different dynamics and origin. It seems that aggressive systemic and local treatment may decrease the incidence of relapses and improve long-term results. There is an urgent need to define new prognostic factors for identifying patients threatened by early dissemination.

Incidence and kinetics of distant metastases in patients with operable breast cancer.

The purpose of this paper is to evaluate the incidence and kinetics of distant metastases in operable breast cancer and to relate these estimates to various tumor and patient characteristics. The records of 309 consecutive patients with operable breast cancer in stage T1-4N0-1M0 were reviewed, and the incidence of distant metastases (DM) and death due to DM were evaluated. 195 patients had positive axillary nodes with the following distribution of the number of nodes: 45% had 1-2 node, 16% had 3-4 nodes, 14% and 25% had 5-7 and more nodes, respectively. All patients were treated with radical mastectomy with axillary nodes dissection (the only treatment in 39% of cases). In 198 cases radical mastectomy was combined with radiotherapy and/or chemotherapy given pre- or postoperatively. Hormonal treatment was given in 27% of cases. Minimum follow-up was 10 years. Distant metastases were found in 150 cases (49%) and in 78 cases (25%) they developed early, during the first 18 months follow-up. Average rate of DM in N0 cases was 25%. Number of involved nodes and extracapsular invasion were found significant and independent prognostic factors. High risk (50%) of DM and death due to DM correlate with age < 40 y, premenopausal status, tumor stage > or = T3, more than 2 axillary nodes and/or extracapsular invasion. The linearity of the curves for freedom from DM and for freedom from death due to the DM suggest uniform distribution of progression rates with a median value for halving time for freedom from early DM of about 8 months, and of about 40 months for freedom from the DM occurring later than 18 months, being for whole group an average of 20 months. High incidence of DM is a significant cause of poor long-term survival. Early appearance (< 18 month follow-up) of about half of the DM suggests that they are already present as subclinical micrometastases at the time of initial loco-regional treatment. The time of appearance of distant metastases is consistent with a wide range of metastatic cell burdens among patients. Systemic therapy, at least for selected group of patients, might decrease the incidence of DM and improve long-term results.

Influence of verapamil on central and peripheral effects of prostacyclin on circulatory system in rats.

The influence of verapamil on cardiovascular effects of prostacyclin (PGI2) in rats was examined. PGI2 administered into the lateral brain ventricle (i.c.v.) or intravenously (i.v.) in a dose of 2.7 x 10(-8)mol evoked hypotension and tachycardia. Pretreatment with verapamil in a dose of 2.0 x 10(-5)mol/kg given intraperitoneally (i.p.) diminished hypotensive effect of PGI2 i.c.v. as well as inhibiting the influence of PGI2 i.c.v. and i.v. upon the heart rate. Bolus injection of PGI2 in a dose of 2.7 x 10(-10), 2.7 x 10(-9) or 2.7 x 10(-8)mol evoked biphasic inotropic and chronotropic effects on isolated rat heart. Short-term increase of the contractile force together with bradycardia and afterwards long-lasting decrease of contractility with sustained, slight tachycardia were observed. Verapamil in a concentration of 1.0 x 10(-6)M blocked biphasic inotropic effect and bradycardia after PGI2 administration. Because some central and peripheral cardiovascular effects of PGI2 were inhibited by verapamil, it is concluded that PGI2 may participate in transmembrane calcium ions movements.