Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST).

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.

Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study.

BACKGROUND: Data are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC. PATIENTS AND METHODS: This retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes. RESULTS: Most patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P=0.009) and produced a trend toward improved overall survival versus no zoledronic acid. CONCLUSION: This study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting.

Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study.

PURPOSE: To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued. PATIENTS AND METHODS: Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years. RESULTS: At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm. CONCLUSION: Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

[Clinical evaluation of the tolerability of imipenem in the treatment of postoperative infections in oncologic surgery]. / Valutazione clinica della tollerabilità dell'imipenem nel trattamento delle infezioni post-operatorie in oncologia chirurgica.

Fifteen neoplastic patients were examined in a pilot study to evaluate side effects and efficacy of imipenem (three doses of 500 mg/die, e.v.) as monochemotherapy of post-operative septic complications. These infections included: two wound infections, nine lung infections, one case of mixed infection (spread purulent peritonitis associated with lung infection), one case of urinary tract infection, one chronic suppurative malleolar ulcer in a patient with Kaposi's sarcoma, and one case of mediastinitis due to oesophageal perforation during endoscopic dilatation. Antibiotic treatment was successful in 14 patients, apyrexia being reached within 2nd to 13th day of treatment (median: 4th day) with negative microbiologic and radiologic assessment; only in the patient with chronic suppurative malleolar ulcer, notwithstanding apyrexia, microbiologic culture indicated the persistence of a pre-treatment pathogen (P. mirabilis). Side effects included only a slight and transient increase of serum transaminases in one patient.

Severe fluoropyrimidine-related toxicity: clinical implications of DPYD analysis and UH2/U ratio evaluation.

The fluoropyrimidines are commonly used in chemotherapeutic cancer medicine, but many patients still experience severe adverse side effects from these drugs. We observed a severe toxicity in a 50-year-old woman treated with capecitabine and docetaxel for a metastatic breast cancer. Since dihydropyrimidine dehydrogenase (DPD) is the main candidate for pharmacogenetic studies on 5-FU toxicity, the entire coding sequence and exon-flanking intronic regions of the DPYD gene were sequenced in the patient. None of the previously described deleterious variants were detected. Also, the haplotype-based analysis failed to reveal DPYD variations associated with 5-FU toxicity. We also evaluated the UH2/U ratio in plasma as an index of 5-FU pharmacokinetics. The UH2/U value did not demonstrate low DPD activity in the patient. We discuss the advantages and limitations of this approach, particularly concerning the clinical applications of 5-FU pharmacogenetics in the family setting.

Phase II study of mitoxantrone, 5-fluorouracil, and levo-leucovorin (MLF) in elderly advanced breast cancer patients.

We have carried out a phase II trial to evaluate the efficacy and toxicity of a combination therapy consisting of mitoxantrone 10 mg/sqm i.v. on day 1, levo-leucovorin 250 mg/sqm administered over 2 hours and 5-fluorouracil 500 mg/sqm i.v. push after the first hour of levo-leucovorin infusion, on days 15-16 (MFL) in patients aged more than 65 years. 24 patients with advanced breast cancer entered the study: 16 aged 65-70 yrs, 4 patients 70-75 yrs, and 4 > 75 yrs. Median PS was 1 (range 0-2); sites of metastases were: bone 14 patients, viscera 14 patients, soft tissue 11 patients, and CNS 1 patient. A median number of 6 cycles (range 3-9) was administered. All patients were evaluable for response and toxicity; partial response was obtained in 12 (50%) patients (95% C.I 30-70), stable disease was observed in 9 patients (37.5%), while 3 patients (12.5%) progressed. Median progression-free survival and survival were 9 months (range 2-14) and 14 months (range 5-36), respectively. Toxicity was generally mild and the most frequently observed side-effects were WHO gr. 1-2 leukopenia in 6/24 (25%) patients and gr. 1-2 emesis in 10/24 (41.6%) pts. 1 patient pretreated with doxorubicin cumulative dose of 240 mg/sqm showed clinical signs of congestive heart failure (NYHA grade 1) after the fifth cycle of treatment. MFL is a well tolerated regimen and could represent a safe and effective treatment in older advanced breast cancer patients.

The role of surgery in the combined treatment of locally advanced breast cancer.

Sixty patients with stage IIIA and IIIB breast cancer have been treated with a combined modality approach including induction chemotherapy, surgery and adjuvant chemotherapy: 74.5% of patients achieved an objective response after 3 cycles of induction chemotherapy, and 98.3% of patients were rendered disease-free after induction chemotherapy and surgery or radiotherapy; at 4 years, actuarial survival and disease-free survival are 71.5% and 43%, respectively. These results are significantly better than our historical control, and locally advanced breast cancer must now be considered a curable disease when treated with an aggressive multimodal approach.

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a multicentric phase II study.

We have recently reported high clinical activity against advanced colorectal cancer of a regimen-alternating bolus FUra, modulated by methotrexate (MTX), and continuous infusion FUra, modulated by 6-s-leucovorin (6-s-LV). Considering the low toxicity of the bolus part of this regimen and our recent in vitro finding of a strong synergism between bolus FUra and natural-beta-IFN (n-beta-IFN), this cytokine was incorporated in the bolus part of our treatment programme. Fifty-six patients with untreated, advanced, measurable colorectal cancer were treated with two biweekly cycles of FUra bolus (600 mg m(-2)), modulated by MTX (24 h earlier, 200 mg m(-2)), and n-beta-IFN (3 x 10(6) IU i.m. every 12 h, starting at the time of FUra administration for four doses), alternating with a 3-week continuous infusion of FUra (200 mg m(-2) daily), modulated by 6-s-LV (20 mg m(-2) weekly bolus). After a 1-week rest, the whole cycle (8 weeks) was repeated if indicated. A total of 5 complete and 17 partial responses were obtained (response rate, 41%; 95% confidence limits, 28-55%) in 54 assessable patients. After a median follow-up time of 36 months, five patients are still alive. Overall, the median time to treatment failure was 6.4 months. The median duration of survival was 15.0 months. There was one treatment-related death after a course of MTX --> bolus FUra/n-beta-IFN and grade III-IV toxicity occurred in 18% of the patients. As the addition of n-beta-IFN results in high toxicity, whereas the efficacy seems to be similar to that of the same regimen without the cytokine, our groups are currently randomizing the original regimen, without IFN, against standard modulated bolus FUra.

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer.

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.

Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a randomized study. GISCAD, IOR and collaborating centers.

BACKGROUND: We have recently suggested that bolus 5-fluorouracil (5-FU) may work via a RNA directed mechanism while continuous infusion 5-FU may kill cells via a thymidylate synthase related pathway. It may thus be possible to selectively modulate each schedule biochemically. We have compared an alternating regimen of bolus and continuous infusion 5-FU, selectively modulated for the schedule of administration, with modulated bolus 5-FU in advanced colorectal cancer patients. PATIENTS AND METHODS: Two hundred fourteen patients from nineteen Italian centers were randomized to the control arm consisting of biweekly cycles of MTX, 200 mg/m2 on day 1, followed by bolus 5-FU 600 mg/m2 on day 2 and 6-S-leucovorin rescue, or to the experimental arm consisting of two biweekly cycles of the same regimen as in the control arm alternated to three weeks of continuous infusion 5-FU (200 mg/m2 day) + weekly bolus 6-S-leucovorin, 20 mg/m2. RESULTS: Nine CR and twenty-seven PR were obtained on one hundred eleven evaluable patients treated in experimental arm (RR = 32%, 95% confidence interval (95% CI): 24%-42%), while two CR and eleven PR were observed among one hundred three evaluable patients in control arm (RR = 13%, 95% CI: 7%-21%). WHO grade 3-4 toxicity occurred in 13% of cycles of experimental arm and in 8% of cycles in control arm. The PFS was significantly longer in experimental arm (6.2 vs. 4.3 months, odds ratio 0.66, P = 0.003), while the overall survival was similar in both arms (14.8 months in experimental arm vs. 14.1 months in control arm); quality of life was similar as well. Eighty percent of patients receiving second-line chemotherapy in control arm were treated with continuous infusion 5-FU. CONCLUSIONS: Alternating, schedule-specific biochemical modulation of FU is more active than MTX --> 5-FU as first-line treatment of advanced colorectal cancer. However, the overall survival was similar suggesting that alternating bolus and infusional 5-FU upfront may be as effective as giving them in sequence as first- and second-line treatment.