Marco Tampellini

Phase III Trial Comparing 4-Day Chronomodulated Therapy Versus 2-Day Conventional Delivery of Fluorouracil, Leucovorin, and Oxaliplatin As First-Line Chemotherapy of Metastatic Colorectal Cancer: The European Organisation for Research and Treatment of Cancer Chronotherapy Group

PURPOSE In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. PATIENTS AND METHODS For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. RESULTS Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. CONCLUSION Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patients molecular clock.

Circadian Rhythm in Rest and Activity: A Biological Correlate of Quality of Life and a Predictor of Survival in Patients with Metastatic Colorectal Cancer

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I<O and r24) were used to estimate CircAct. Of 130 patients with baseline CircAct assessments, 96 had baseline HRQoL data. I<O was confirmed to correlate with global quality of life, physical functioning, social functioning, fatigue, and appetite loss (r > |0.25|; P < 0.01). I<O further independently predicted for overall survival with a hazard ratio of 0.94 (P < 0.0001). The associations between CircAct parameters, HRQoL, and survival, which were shown in this international study involving previously untreated metastatic colorectal cancer patients, confirm prior single-institution findings in mostly pretreated metastatic colorectal cancer patients. The circadian timing system constitutes a novel therapeutic target. Interventions that normalize circadian timing system dysfunction may affect quality of life and survival in cancer patients.

Prognostic value in predicting overall survival of two mucinous markers: CA 15-3 and CA 125 in breast cancer patients at first relapse of disease

The role of circulating tumour markers in providing prognostic information has been scarcely studied. We evaluated the prognostic significance of two mucinous markers: CA 15-3 and CA 125 in 115 breast cancer patients at first recurrence of disease. At diagnosis of advanced disease bone involvement was found in 64 patients, lung in 57, skin lymph nodes in 21, liver in 20, and brain in 5. Patients were recruited and treated in the same institution with conventional chemo- or endocrine therapy. The follow-up ranged from 3 to 54+ months (median 35). Serum samples were drawn at first recurrence of disease before the start of any endocrine and/or chemotherapy. Patients with CA 15-3 < 30 U/ml survived significantly longer than those with CA 15-3 > 30 U/ml (median 50+ versus 26 months, P < 0.02). Similarly, overall survival of patients with CA 125 < 35 U/ml was significantly higher in comparison with patients with CA 125 > 35 U/ml (median 34.5 versus 18.5 months, P < 0.001). CA 125, but not CA 15-3, maintained its prognostic value in the subgroup of patients with visceral metastases. Both markers were found to be independent prognostic variables in multivariate analysis according to Coxs model. CA 15-3 and CA 125 appeared to be powerful prognostic indicators, in addition to visceral metastases, in patients with advanced breast cancer.

Relationship between CA 15-3 serum levels and disease extent in predicting overall survival of breast cancer patients with newly diagnosed metastatic disease

In order to study the relationship between circulating levels of CA 15-3 and the disease extent in predicting survival, we prospectively followed 312 breast cancer (BC) patients, from October 1988 to March 1995, from the time of first relapse. CA 15-3 values were assessed before treatment onset. Disease extent was defined as the percentage of liver or lung involvement and the number of bone segments positive at scintigraphy. The covariates were primary tumour characteristics (T, N and hormone receptor status) and patient characteristics at recurrence (menopause, performance status and age). Higher CA 15-3 serum levels were found in patients with visceral metastases or with pleural effusion. A logistic regression model selected disease extent in liver, lung and bone as independent variables for the determination of abnormal CA 15-3 values. Univariate survival analysis confirmed the positive prognostic influence of low CA 15-3 serum levels, absence of visceral metastases and the presence of only one metastatic site. Multivariate Coxs survival analysis selected disease extent in liver, lung, bone and soft tissue but not level of CA 15-3 as prognostic factors. In conclusion, CA 15-3 is not an independent variable in determining survival, its prognostic role being linked to the disease extent. This association suggests that CA 15-3 may be useful in assessing disease extent when this is not easily assessable.

Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience.

From 1990 to 1997, 16 consecutive patients with stage III and IVa invasive thymoma were treated in a single institution with primary chemotherapy consisting in adriamycin (40 mg m–2), cisplatin (50 mg m–2) administered intravenously on day 1, vincristine (0.6 mg m–2) on day 2 and cyclophosphamide (700 mg m–2) on day 4 (ADOC). The courses were repeated every 3 weeks. The aim was to evaluate the impact of this cytotoxic regimen with respect to response rate, per cent of patients radically resected, time to progression and overall survival. Two complete responses (one clinical and one pathological) and 11 partial responses were observed (overall response rate 81.2%); two patients had stable disease and one progressed. Toxicity was mild as only two patients developed grade III/IV neutropenia and one patient grade III nausea/vomiting. Nine patients were radically resected (five out of ten with stage III, and four out of six with stage IVa). Median time to progression and overall survival was 33.2 and 47.5 months respectively. Three patients were alive and disease free after more than 5 years. The ADOC scheme is highly active and manageable in the treatment of locally advanced thymoma. As a preoperative approach it should be offered to patients not amenable to surgery or to those surgically resectable but with a great deal of morbidity.

Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer

The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I

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.

Phase II Study of Vinorelbine With Protracted Fluorouracil Infusion as a Second- or Third-Line Approach for Advanced Breast Cancer Patients Previously Treated With Anthracyclines

PURPOSE To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m(2) administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m(2)/d given continuously over a 24-hour period. RESULTS Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis

BACKGROUND Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07–1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06–1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials.