A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma.

BACKGROUND: Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS: Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS: From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION: Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV: NCT02409472.

Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer.

PURPOSE: A multiinstitutional trial was performed to confirm the clinical activity, in terms of response rate and toxicity (primary objectives) and duration of responses and survival (secondary objectives), of an intensive weekly regimen in advanced gastric cancer. PATIENTS AND METHODS: Patients with measurable unresectable and/or metastatic gastric carcinoma received 1-day per week administration of cisplatin (CDDP) 40 mg/m2, fluorouracil (5FU) 500 mg/m2, epi-doxorubicin (epi-ADR) 35 mg/m2, 6S-stereoisomer of leucovorin 250 mg/m2, and glutathione 1.5 g/m2. On the other days, filgrastim was administered by subcutaneous injection at a dose of 5 mg/kg. One cycle of therapy consisted of eight 1-week treatments. Patients who showed a response or stable disease received a further 6 weeks of therapy. RESULTS: Of 105 enrolled patients, 11 had locally advanced unresectable disease only; 33 had primary nonresected and metastatic disease; 48 had metastatic disease and primary tumor resected; 10 had locoregional recurrence and metastatic disease; and three had locoregional recurrence only. After one cycle, 18 complete responses (CRs) and 47 partial responses (PRs) were achieved, for an overall response rate of 62% (95% confidence interval [CI], 53% to 71%). Twenty patients had stable disease and 20 progressed on therapy. The median survival duration of all 105 patients was 11 months, with 1- and 2-year survival rates of 42% and 5%, respectively. World Health Organization (WHO) grade III to IV toxicity, in terms of anemia, neutropenia, thrombocytopenia, and mucositis, was experienced by 40 patients (38%). There were no treatment-related deaths. CONCLUSION: These data support the results of the pilot study and confirmed the high activity of the regimen, with acceptable toxicity. This schedule deserves evaluation in the adjuvant setting.

Double modulation of 5-fluorouracil in advanced colorectal cancer with low-dose interferon-alpha 2b and folinic acid. The "GISCAD" experience. Italian Group for the Study of Digestive Tract Cancer.

In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-alpha (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m2 i.v. bolus) + 5FU (400 mg/m2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 x 10(6) U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13-35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction.

Phase II trial of 5-fluorouracil and the natural l isomer of folinic acid in the treatment of advanced colorectal carcinoma.

Between February 1991 and July 1992, 79 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study of combined 5-fluorouracil (5-FU) and l-folinic acid (FA). 5-FU 370 mg/m2/day was administered for 5 consecutive days as an intravenous (i.v.) bolus injection preceded by l-FA 100 mg/m2/day with the same administration modality. Treatment was given every 4 weeks until progression. 79 patients were evaluable for toxicity and 64 for response. 2 patients (3%) achieved a complete remission and 8 (12.5%) a partial remission, 33 (52%) had stable disease and 21 patients (33%) had progressive disease. Median duration of remission was 32.5 weeks and median survival for all evaluable patients was 64.5 weeks. Substantial to severe side-effects occurred in 39% of patients. Dose-limiting toxicity (grade 3-4) was mainly diarrhoea (18%) and mucositis (15%). Nausea/vomiting, cutaneous toxicity, leucopenia, alopecia and conjunctivitis of grade 3-4 occurred respectively in 6, 4, 2.5, 1 and 1% of cases. Toxicity appeared to be substantially similar to that characteristic of combined 5-FU and the chiral mixture of d,l-FA. Efficacy was within the range of that observed with the 5-FU/d,l-FA combination, although at the lower level.

Oral etoposide as second-line chemotherapy for colorectal cancer: a GISCAD study. Gruppo Italiano Studio Carcinomi Apparato Digerente.

Twenty-one patients with advanced colorectal cancer, all previously pretreated with a fluoropyrimidine-based regimen, received oral etoposide: 100 mg/die for 21 consecutive days, every three weeks. No objective response was achieved; 6 pts had a short-lasting stabilization of their disease. Toxicity was substantial and mainly represented by myelosuppression and alopecia. Protracted administration of etoposide is inactive as second-line treatment of colorectal cancer.

High dose alpha-2b interferon + folinic acid in the modulation of 5-fluorouracil. A phase II study in advanced colorectal cancer with evidence of an unfavourable cost/benefit ratio.

The combination of folinic acid (FA) and 5-fluorouracil (5FU) is the most active systemic chemotherapy against advanced colorectal cancer. Experimental and clinical studies have suggested that the activity of 5FU can be improved by the addition of alpha-interferon (IFN). To evaluate the possibility of a double modulation of 5FU, a pilot study was conducted in the period July 1989-December 1989 with the following regimen: FA (200 mg/m2 i.v. bolus x 5 days) + 5FU (400 mg/m2 i.v. in 15 min x 5 days) + alpha-2b IFN (10 x 10(6) IU subcutaneously on alternate days). FA and 5FU administrations were repeated every 28 days; IFN was administered every week. In the 16 treated patients, 4 partial responses, 4 no changes, and 8 with progression of disease were observed, with an objective response rate of 25% (95% CI, 7.8%-55.1%). Median duration of response was 9.5 months, as was overall survival. Toxicity (fever, fatigue, neurotoxicity, stomatitis and diarrhea) was considerable and led to a reduction in IFN doses in 10/16 patients. Due to the unfavorable cost/benefit ratio, the study was closed and a new trial, with different doses and schedule of IFN, was started within the GISCAD (Italian Group for the Study of Digestive Tract Cancer).

The value of oxaliplatin in combination with continuous infusion +/- bolus 5-fluorouracil and levo-folinic acid in metastatic colorectal cancer progressing after 5FU-based chemotherapy: a GISCAD (Italian Group for the Study of Digestive Tract) cancer phase II trial.

AIMS AND BACKGROUND: The phase II trial was designed to evaluate the activity of combined oxaliplatin (L-OHP), continuous infusion (CI) +/- bolus 5-fluorouracil (5FU) and levo-folinic acid (I-FA) in patients with metastatic colorectal cancer progressing after one or more lines of 5FU-based chemotherapy. PATIENTS AND METHODS: We designed two contemporary studies: in the former we enrolled patients previously treated with 1 line of chemotherapy, and in the latter, patients previously treated with 2, 3 and 4 lines. Seventy-six consecutive patients were enrolled: 45 received L-OHP (85 mg/m2 i.v. 2 h on day 1) + I-FA (100 mg/m2 i.v. 2 h on days 1 and 2) + 5FU i.v. bolus (400 mg/m2 days 1 and 2) + 5FU (600 mg/m2 CI 22 h days 1 and 2 (FOLFOX 4); 31 received L-OHP (100 mg/m2 i.v. 2 h on day 1) + I-FA (250 mg/m2 i.v. 2 h on days 1 and 2), followed by 5FU (1500 mg/m2 Cl 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression and/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disease [SD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. RESULTS: Forty-five patients in 2nd line (22 FOLFOX 4, 23 FOLFOX 2), 23 (17 FOLFOX 4, 6 FOLFOX 2) in 3rd, 4 in 4th and 1 in 5th line were assessable; 3 were lost to follow-up. In 15 patients (11 FOLFOX 4, 4 FOLFOX 2), disease involved the liver only. A total of 533 courses were administered with a range of 1-14 in FOLFOX4 and 1-12 in FOLFOX2; dose intensity was 92.85%, and the total dose of the administered L-OHP was 98.29%. As a 2nd line treatment, FOLFOX 4 achieved TGC in 72.8% of the patients (PR, 18.2%; SD, 54.6%), with a median TTP of 6 months and a median OS of 7 months, whereas in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3rd line treatment, FOLFOX 4 produced TGC in 41.1% of patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median OS of 7+ months, whereas FOLFOX 2 obtained respective values of 50% (PR 16.7%, SD 33.3%), 7 and 9 months. As a 4th line of treatment, TGC was achieved in 2 patients (1 PR, 1 SD); the patient in 5th line therapy obtained a SD. With "de Gramont" as the first-line regimen, patients assessable were 24 in FOLFOX 4 and 18 in FOLFOX 2. In the former population, TGC was 70.8% (PR 37.5%, SD 33.3%), with a TTP of 6 months and OS of 10 months, whereas with FOLFOX2 these values were 61.1% (PR 5.6%, SD 55.5), 5 and 7 months. In patients with liver involvement only, FOLFOX 4 obtained TGC in 63.6% of cases (with a TTP of 7 months and OS of 6+ months), FOLFOX 2 in 100% (with a TTP of 9.5 months and OS of 13.5+ months). Both schedules exhibited an acceptable toxicity: neurologic, hematologic and hepatic grade 3 side effects occurred in a limited number of patients, with a higher frequency in the FOLFOX 2 group. CONCLUSIONS: Treatment with L-OHP, CI +/- bolus 5FU and I-FA was well tolerated. The activity in terms of TGC was interesting and comparable with results reported in the literature for the standard treatment for 2nd line, i.e. irinotecan alone. Treatment was effective in 2nd line and in patients previously treated with more than two chemotherapy lines; in particular, treatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we could not define from the study the better regime.

[Current status of the use of vitamins (A, E, C, D), folates and selenium in the chemoprevention and treatment of malignant tumors]. / Stato attuale dell'impiego di vitamine (A, E, C, D), folati e selenio nella chemioprevenzione e nel trattamento dei tumori maligni.

The role of vitamins A, E, C, D, folates and selenium in the chemical prevention of tumours and/or precancerous conditions is examined in the light of epidemiological studies and experimental observations. Particular mention is made of significant clinical studies that provide valuable indications about the use of vitamin A and its derivates in particular for the treatment of precancerous and cancerous conditions. Vitamin A and its derivates apparently play a fundamental role not only in the treatment of proliferating malignancies of the skin (carcinomas, severe aclinic keratosis) or involving the skin (fungoid mycosis, skin metastases of solid tumours) but also in the prevention of recurring bladder tumours and the treatment of several bronchial dysplasias.

[Locoregional chemotherapy of liver metastasis from colorectal carcinoma]. / Chemioterapia locoregionale delle metastasi epatiche da carcinoma del colon-retto.

Hepatic metastases are a major cause of death in patients with colorectal carcinoma. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients and surgical resection is feasible in approximately 20% of patients. Infusion of cytotoxic agents into the hepatic artery is the most promising form of therapy for unresectable hepatic metastases. The recent development of a totally implantable pump has allowed prolonged infusion of chemotherapeutic agents with a good compliance and quality of life of the patients. The rationale for hepatic arterial infusion (HAI) present an anatomical and pharmacological basis with the use of agents with high hepatic extraction resulting in minimal systemic toxicity. The results of eight randomized trial assessing the value of HAI Floxuridine shows that such regional chemotherapy increases the likelihood of hepatic response compared with systemic treatment (52% vs 15%). Survival information is difficult to evaluate because some of the studies are small, some had a crossover design and some others had bias factors. Extrahepatic disease develops in 40-70% of patients undergoing HAI; the use of systemic therapy plus HAI may produce a decrease in extrahepatic disease. Further studies of combined systemic/arterial regiment are necessary.

Factors influencing response rates for advanced colorectal cancer chemotherapy.

BACKGROUND: The activity of various chemotherapy regimens used in the treatment of advanced colorectal cancer is assessed by different groups of investigators and in various trials by what appear to be common criteria. However, there may be substantial inter-trial variation in the interpretation and application of these criteria which contributes to differences in response rates reported for the same regimen. MATERIALS AND METHODS: This paper reviews the most prominent studies in this field and examines the factors which may influence the assessment of activity in clinical trials such as patient selection, the definition and application of response criteria, the methods of assessment of time to progression and duration of response, factors related to the therapeutic regimen and statistical methods. Each factor is critically discussed. RESULTS: The analysis confirms that there is a large variability among the different studies and that an inter-trial comparison is often impossible, with subsequent difficulties for clinicians in determining the true impact of therapies. DISCUSSION: After briefly commenting on the various issues, this review makes recommendations about how to achieve consistency among trials, for instance by using standard criteria, by extending the use of randomization even in phase II trials and by evaluating high quality, well conducted clinical trials in a meta-analysis, thereby making possible comparison across trials. The conclusions, although specific to colorectal cancer, are also applicable to other advanced malignancies.

[The evolution of the liver metastases from colorectal carcinoma treated with hepatic intra-arterial chemotherapy. The echographic and CT aspects]. / Evoluzione delle metastasi epatiche da carcinoma del colon-retto trattate con chemioterapia intra-arteriosa epatica. Aspetti ecografici e tomodensitometrici.

The response of liver metastases to chemotherapy relies mainly on quantitative US and CT investigations, the two techniques being indifferently used. The morphologic changes of metastatic lesions during treatment have received little attention and their significance is still questionable. Based on the review of 53 US and 41 CT examinations of 15 patients treated with hepatic arterial chemotherapy for colorectal liver metastasis, our study was aimed at assessing: 1) the relationship between US and CT measurements of metastasis response to chemotherapy and 2) changes in the US and CT patterns of liver metastases during treatment and the existence of specific patterns of favorable response to chemotherapy or of disease progression. We concluded that: 1) as to quantitative response to chemotherapy, US and CT, performed on 13 patients within 1 month, were in agreement in all but 1 case, 2) US and CT patterns of treated liver metastases were different in case of favorable response and of disease progression; lesion outline, homogeneity and calcifications are useful diagnostic criteria to this purpose, 3) liver perfusion abnormalities may occur at various times during and after chemotherapy; these ischemic lesions must be differentiated from new metastases.

Cisplatin + 5-fluorouracil versus 5-fluorouracil alone in advanced colorectal cancer: a randomized study.

Sixty patients with advanced colorectal cancer were randomized between cisplatin (60 mg/mq i.v. every 3 weeks) + 5-fluorouracil (600 mg/mq i.v. bolus/weekly) and 5-fluorouracil alone (same schedule). In the 54 evaluable patients, no CR was observed. PR rate was 19.2% for the combination, and 14.5% for the monochemotherapy. Also the overall median survival time was similar for the two arms (10 and 13 months, respectively). Toxicity was acceptable, with more side-effects in the combination arm. Both treatments are of limited activity in advanced colorectal cancer and no advantage comes out from the use of this polychemotherapy.

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Local extension prevents curative resection in more than two-thirds of gastric cancer patients. Unfortunately, resectability is one of the main prognostic factors in these patients, and survival is longer when tumours are completely removed. Preoperative chemotherapy is an attractive concept for obtaining curative resection. Thirty-two locally advanced unresectable gastric cancer patients were enrolled in five Italian Group for the Study of Digestive Tract Cancer (GISCAD) centres. For 16 patients, surgical unresectability was based on computerized tomography scan evaluation of tumour size (four patients) and invasion of adjacent structures (12 patients), whereas in another 16 patients locally advanced disease was confirmed by laparotomy. They received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S-stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 g m(-2). From the day after to the day before each chemotherapy administration, filgrastim was administered by subcutaneous injection at a dose of 5 microg kg(-1). One cycle of therapy consisted of eight weekly treatments. Fifteen of 32 patients (47%) responded to chemotherapy, whereas 13 (41 %) had stable disease and four (12%) progressed on therapy. Of the 15 responding patients, 13 were completely resected after chemotherapy and two of them had a complete pathological response. Two clinically responding patients were found unresectable at operation because of peritoneal seeding. At a median follow-up from the start of treatment of 24 months (range 11-39 months), 10 of 13 resected patients are alive and eight are relapse free. Three patients died after 11, 12, and 14 months respectively. Toxicity was acceptable: side-effects consisted mainly of grade II National Cancer Institute common toxicity criteria (NCICTC) leucopenia and thrombocytopenia in ten patients. Neither treatment-related death nor surgical complications in patients undergoing surgery were observed. This weekly intensive regimen enabled resection in half of previously inoperable tumours with a moderate toxicity. It can be offered to patients with locally advanced unresectable gastric cancer to obtain curative resection.

Folinic acid + 5-fluorouracil (5-FU) versus equidose 5-FU in advanced colorectal cancer. Phase III study of 'GISCAD' (Italian Group for the Study of Digestive Tract Cancer).

In a multicentre Phase III trial, 182 patients were randomized to either folinic acid (FA) (200 mg/sqm i.v. x 5 days) + 5-fluorouracil (5-FU) (400 mg/sqm i.v. in 15' x 5 days) every 4 weeks (Arm A), or to 5-FU alone at the same dosage (Arm B). Response rates were 20.6% (Arm A) and 10% (Arm B) with a significant (p = 0.046) advantage for FA + 5-FU. Median time to progression (6 and 6 months) and overall survival (11.5 and 11 months) were similar in the 2 groups of patients, while neither treatment was effective in reducing pain or improving performance status. Univariate analysis showed that no prognostic factors other than treatment influenced response, although survival was affected by the number and site of metastases, performance status, and the presence and degree of pain. Toxicity was acceptable and lower in comparison with other Phase II-III trials, with no significant difference between the 2 arms. However, in individual patients, grade 3-4 side effects (mainly stomatitis and diarrhoea) were observed, particularly in patients receiving FA: this led to interruption of the treatment in 7 cases. The superiority, in terms of objective response, of FA + 5-FU over 5-FU alone would seem to justify a large-scale evaluation of this combination in the adjuvant setting. Further improvements in relation to advanced disease (i.e., modifications to the schedule and/or introduction of other modulators) are warranted.