Background:Standard adjuvant chemoradiotherapy of rectal cancer still consists of 5-fluorouracil (5-FU) only. Its cytotoxicity is enhanced by folinic acid (FA) and interferon-α (INFα). In this trial, the effects of FA and IFNα on adjuvant 5-FU chemoradiotherapy in locally advanced rectal cancer were investigated.Methods:Patients with R0-resected rectal cancer (UICC stage II and III) were stratified and randomised to a 12-month adjuvant chemoradiotherapy with 5-FU, 5-FU+FA, or 5-FU+IFNα. All patients received levamisol and local irradiation with 50.4 Gy.Results:Median follow-up was 4.9 years (n=796). Toxicities (WHO III+IV) were observed in 32, 28, and 58% of patients receiving 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. No differences between the groups were observed for local or distant recurrence. Five-year overall survival (OS) rates were 60.3% (95% confidence interval (CI): 54.3–65.8), 60.4% (54.4–65.8), and 59.9% (53.0–66.1) for 5-FU, 5-FU+FA, and 5-FU+IFNα, respectively. A subgroup analysis in stage II (pT3/4pN0) disease (n=271) revealed that the addition of FA tended to reduce the 5-year local recurrence (LR) rate by 55% and increase recurrence-free survival and OS rates by 12 and 13%, respectively, relative to 5-FU alone.Conclusions:Interferon-α cannot be recommended for adjuvant chemoradiotherapy of rectal cancer. In UICC stage II disease, the addition of FA tended to lower LR and increased survival. The addition of FA to 5-FU may be an effective option for adjuvant chemoradiotherapy of UICC stage II rectal cancer.
In order to evaluate the protective efficacy of an agonist of luteinizing hormone releasing hormone (LHRHA) on spermatogenic stem cells, we undertook a prospective study in patients with germ cell tumors. Following orchiectomy and unilateral lymph node dissection all patients received adjuvant chemotherapy consisting of 2 courses of PVB regimen (cisplatin, vinblastine and bleomycin). Six men were treated with LHRHA (d-Ser-(TBU)6 LHRH ethylamide) before, during and after PVB chemotherapy. Eight patients without LHRHA protection served as controls, receiving the identical chemotherapy. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were within normal limits before therapy in all patients. In 6/6 protected patients, serum levels of FSH, LH and testosterone were effectively suppressed during pre-chemotherapeutic LHRHA administration. All protected patients showed elevated serum FSH levels and azoospermia after cessation of chemotherapy and LHRHA treatment due to germ and stem cell loss. Median FSH level and sperm density of the protected group normalized within 24 months after chemotherapy. In all unprotected patients elevated FSH values and azoospermia also occurred after chemotherapy. Likewise, median FSH level and sperm density normalized spontaneously in this group within 24 months after chemotherapy. Our results suggest completely reversible reproductive toxicity two years after 2 courses of adjuvant chemotherapy in all patients. Administration of LHRHA during chemotherapy seems to have no protective effects on germ cells since both groups developed reproductive toxicity. Furthermore, recovery time was identical in the protected and unprotected patients. FSH and LH could be used as diagnostic markers to assess the degree and duration of reproductive and endocrine gonadal toxicity after chemotherapy.
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