[Early evaluation using PET-FDG of the efficiency of neoadjuvant radiochemotherapy treatment in locally advanced neoplasia of the lower rectum]. / Valutazione precoce con PET-FDG della efficacia del trattamento radiochemioterapico neoadiuvante nelle neoplasie del retto inferiore localmente avanzate.

BACKGROUND AND PURPOSE: Preoperative chemoradiation allows downstaging of locally advanced rectal cancer and in selected patients also a sufficient downsizing to ensure sphincter preservation. Selection of patients warranting a preoperative approach is improved by magnetic resonance imaging (MRI) which is able to define the involvement of mesorectal circumferential margin. Similarly it would be crucial to define the response to chemoradiation during the treatment but traditional morphologic imaging techniques may fail in differentiating neoplastic tissue from scarring. PET-FDG has been successfully used in the detection of metastatic colorectal cancer allowing imaging of deposits as small as 0.5 cm and may have a role in evaluating early response to chemoradiation. METHODS: In the present study, in patients with T3-T4 rectal cancer undergoing preoperative chemoradiation PET-FDG and flow cytometry analysis on endoscopic biopsy specimen have been performed before, during and after preoperative chemoradiation. RESULTS: Chemoradiation treatment has been successful in terms of downsizing and downstaging of the tumor. PET-FDG was able to demonstrate local response at only ten-fifteen days after the beginning of neoadjuvant therapy, also identifying non responding patients. CONCLUSIONS: FDG-PET may have a role in defining the response to chemoradiation and modulate the treatments strategy in patients with advanced rectal cancer.

Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: a dose-finding study in patients with advanced gastrointestinal malignancies.

BACKGROUND: Oxaliplatin (OXA) and irinotecan (IRI) are active drugs in first-line as well as second-line treatment of advanced colorectal cancer patients, their toxicity profiles are not overlapping, and both drugs have shown synergism with folinic acid-modulated 5-fluorouracil (5-FU). We planned this phase I study to define the dose-limiting toxicities (DLTs), the maximum tolerated doses (MTDs), and the recommended doses (RDs) for a triplet regimen including OXA plus IRI on day 1, and 6S-folinic acid (LFA) plus 5-FU on day 2, every 2 weeks. PATIENTS AND METHODS: At least three patients had to be treated at each dose level, and the trial proceeded if no more than 33% of patients showed a DLT after the first cycle. Starting from OXA 85 mg/m(2) (over 2 h) and IRI 150 mg/m(2) (over 1 h), an alternated escalation was planned up to 110 mg/m(2) and 200 mg/m(2), respectively. Thereafter, a fixed dose of LFA, 250 mg/m(2) (as 2-h infusion), plus an escalating dose of 5-FU (from 650 to 800 mg/m(2) as an intravenous bolus) was added on day 2 to the previous dose level of OXA and IRI. RESULTS: Forty-six patients, all but four affected by advanced colorectal primaries, entered this study. The MTDs for OXA and IRI given on the same day were 110 and 200 mg/m(2): these doses caused a DLT in three of six patients. The previous dose level (110 and 175 mg/m(2), respectively) on day 1 was safely followed on day 2 by LFA plus 5-FU up to 800 mg/m(2). Indeed, only one of three patients treated at this last level had a DLT. This cohort was then expanded including a total of 14 patients, and on the whole series five cases of DLT occurred: WHO grade 4 neutropenia (two patients), grade 3 or 4 diarrhoea (three patients). Cumulative toxicity was analysed in 43 patients for a total of 347 cycles: grade 4 neutropenia was detected in 13 patients (30%); it was not dose-related, nor was it exacerbated by the addition of modulated 5-FU. Febrile neutropenia occurred in four patients. Grade 3 or 4 diarrhoea was suffered by nine (21%) and five (12%) patients, respectively. Two complete and nine partial responses were reported on 40 evaluable patients (six patients were disease-free at study entry), giving a response rate of 27.5% (95% confidence interval 15% to 44%); nine of 18 (50%) assessable patients of the two last cohorts treated with the triplet regimen achieved a complete response (two patients) or a partial response (seven patients). CONCLUSIONS: The RDs for this biweekly regimen were: OXA 110 mg/m(2) plus IRI 175 mg/m(2) on day 1, and LFA 250 mg/m(2) plus 5-FU 800 mg/m(2) on day 2. This regimen appeared active in pretreated gastrointestinal malignancies, and it is worthy of being evaluated in advanced colorectal carcinoma after failure of 5-FU-based adjuvant or palliative treatment.

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients.

The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg x m(-2) (2 h i.v. infusion) and raltitrexed 3.0 mg x m(-2) (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg x m(-2) (2 h i.v. infusion) and 5-fluorouracil 1050 mg x m(-2) i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43-79) years; ECOG performance status was 0 in 26 patients, > or =1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1-12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13-38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10-30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was > or =1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients.

Irinotecan and mitomycin C in 5-fluorouracil-refractory colorectal cancer patients. A phase I/II study of the Southern Italy Cooperative Oncology Group.

PURPOSE: To define the maximum tolerated dose (MTD) of irinotecan (CPT-11) given on days 1 and 8 with mitomycin C (MMC) given on day 1 in a monthly cycle, and to assess the toxicity and activity of this regimen in patients with previously treated colorectal carcinoma. METHODS: Fifty-two patients, all pretreated with adjuvant 5-fluorouracil (20 patients) and/or one (35 patients) or two (8 patients) lines of chemotherapy, were entered in this study. Escalating doses of CPT-11 (starting from 150 mg/m2) were administered on days 1 and 8, with escalating doses of MMC (starting from 8 mg/m2) given on day 1, recycling every 28 days. At least 3 patients were treated at each dose level. Escalation proceeded unless 2 out of 3 or 4 out of 6 patients experienced a dose-limiting toxicity (DLT) after the first cycle. RESULTS: Twelve patients were entered in the phase I study, and 4 consecutive dose levels were tested. At the last dose level (CPT-11 200 mg/m2 plus MMC 10 mg/m2) 4 of 6 patients experienced a DLT (i.e., grade 4 neutropenia in 2 patients and grade 3 diarrhea in 2 patients). Therefore, this dose level was considered as the MTD. Forty patients were treated at the previous dose level (CPT-11, 175 mg/m2 plus MMC 10 mg/m2). One complete, 4 partial, 3 minor responses and 11 cases of stable disease were registered, giving a response rate of 12% [95% confidence interval (CI), 4-27%] and an overall control of tumor growth in 47% (95% CI, 31-64%) of patients. The median time to treatment failure was 6 months (range 1-19+). The median survival time was 14.5 months, and the 1-year and 2-year probability of survival were 56 and 43%. Neutropenia and diarrhea affected 62 and 58% of patients, grade 3 or 4 being registered in 26 and 23% of them, respectively. One episode of neutropenic fever was reported. Other acute toxicities were usually mild and manageable. CONCLUSIONS: CPT-11 175 mg/m2 on days 1 and 8 associated with MMC 10 mg/m2 on day 1, every 4 weeks, is a safe and moderately active regimen in heavily pretreated patients with advanced colorectal carcinoma. The role of MMC in this combination is doubtful, and further attempts with other new agents should be made to improve the outcome in these patients.

Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial.

PURPOSE: The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex) (TOM + LFA-5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU). PATIENTS AND METHODS: One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 850 mg/m2 s i.v. bolus (arm A); TOM, 3 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 1050 mg/m2 i.v. bolus (arm B); or MTX, 750 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 800 mg/m2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more. RESULTS: The RRs were: 34% (95% confidence interval (95%, CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs, in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA 5-FU. Median relative dose intensity over eight cycles (DI8) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA-5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI8 was 93% for TOM, and 82% for 5-FU. CONCLUSIONS: CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.

Concurrent irinotecan and 5-fluorouracil plus levo-folinic acid given every other week in the first-line management of advanced colorectal carcinoma: a phase I study of the Southern Italy Cooperative Oncology Group.

OBJECTIVES: To determine the maximum tolerable doses (MTDs) of irinotecan (CPT-11) and 5-fluorouracil (5-FU) plus levofolinic acid (LFA) administered together every two weeks, to define the toxicity profile of this regimen, and to have a preliminary evidence of its activity in the first-line management of advanced colorectal cancer patients. PATIENTS AND METHODS: Patients with histologically proven colorectal carcinoma, no prior chemotherapy for their advanced disease, and with at least one measurable or evaluable indicator lesion, were admitted to this study. The starting dose of CPT-11 was 150 mg/m2 given i.v. (90 min infusion) on day 1, followed on day 2 by a fixed dose of LFA (250 mg/m2) as a two-hour i.v. infusion plus a starting dose of 5-FU 600 mg/m2 as i.v. bolus. No intra-patient dose escalation was allowed. If no dose limiting toxicity (DLT) was observed among three patients of each cohort, CPT-11 and 5-FU were alternately escalated in the subsequent cohort. Otherwise, three more patients were enrolled at the same dose level. DLT was defined as: WHO grade 3 non-haematological toxicity (except for vomiting or alopecia), grade 3 febrile neutropenia, grade 4 neutro- or thombocytopenia, or a > 2-week delay in recycling. The MTDs were defined as the doses at which two of three, or four of six, patients showed the same DLT. RESULTS: Thirty-one patients (five pretreated in adjuvant setting) were enrolled in this study, and a total number of 293 cycles (median 6/patient) were administered. Dose escalation safely proceeded to 210/950/250 mg/m2 of CPT-11/5-FU/LFA. These dosages were considered as MTDs, since four of six patients showed grade 4 neutropenia, in one case associated with grade 3 stomatitis. A mild decrease of both the CPT-11 and 5-FU doses to 200 and 850 mg/m2, respectively, caused different DLTs (neutropenia and diarrhoea) in two out of seven patients. At these dosages, transient grades 3 or 4 neutropenia affected two patients each during their treatment, while only one patient suffered from a severe delayed diarrhoea. Other non-haematological toxicities were mild and manageable. Therefore, we recommend this latter dose level for further study. Major responses (3 complete and 11 partial) were reported in 14 patients, for an overall response rate of 45% (95% CI: 27%-64%) according to an intent-to-treat analysis. Responses were observed from first dose level, and in four of five previously treated patients. Median failure-free and overall survivals, after a median follow-up of 39 weeks, were 42 and 55 weeks, respectively. CONCLUSIONS: The concurrent administration of CPT-11 and modulated 5-FU every two weeks is feasible at the recommended dosages. This regimen demonstrated interesting activity in the management of advanced colorectal cancer patients, and it probably better exploits the synergism between CPT-11 and 5-FU than recently tested alternating schedules. A phase II study is ongoing to more precisely define its activity and toxicity.