Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO.

Background: Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status. Patients and methods: Patients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status. Results: Information about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N = 173) presented shorter OS [23.7 versus 31.0 months, HR = 1.42 (95% CI 1.09-1.84), P = 0.010] and a trend toward shorter PFS [10.2 versus 11.5 months, HR = 1.24 (95% CI: 0.98-1.56), P = 0.083] than those with left-sided tumors (N = 185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR = 0.59 versus 0.89, P for interaction = 0.099) and OS (HR = 0.56 versus 0.99, P for interaction = 0.030) and this advantage was independent of their RAS and BRAF status. Conclusions: FOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.

FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials.

BACKGROUND: FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available. PATIENTS AND METHODS: A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters. RESULTS: Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59-0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56-0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81-2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68-1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported. CONCLUSIONS: Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients. TRIALS' NUMBERS: NCT01219920 and NCT00719797.

Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest.

BACKGROUND: Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy ± anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev. PATIENTS AND METHODS: A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index. RESULTS: A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS ≥20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response. CONCLUSION: FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation.

Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial.

BACKGROUND: The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy. PATIENTS AND METHODS: In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and ß error of 0.05 and 0.20, respectively, 262 patients were required. RESULTS: In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52-0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56-1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data. CONCLUSIONS: This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC. ClinicalTrials.gov number: NCT00720512.

The process of truth disclosure: an assessment of the results of information during the diagnostic phase in patients with cancer.

BACKGROUND: Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients' awareness conducted after the first training period. PATIENTS AND METHODS: In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase. RESULTS: Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%. CONCLUSIONS: Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment.

Formestane is feasible and effective in elderly breast cancer patients with comorbidity and disability.

Age is a major risk factor for solid tumors, including breast cancer. The majority of elderly breast cancer patients have oestrogen-dependent tumors, thus, tamoxifen is widely administered. However, it has been noted that tamoxifen-related thrombotic events are not exceptional. Due to the increasing prevalence of comorbidity, including vascular diseases, with age, such events are more frequently observed in the aged patients. Formestane, a selective steroidal aromatase inhibitor, may represent a therapeutic option after failure with tamoxifen, or in the presence of vascular diseases contraindicating its administration. The present report provides a new clinical experience on a consecutive series of 45 elderly breast cancer women affected by moderate to severe degree of comorbidity and disability measured by a Comprehensive Geriatric Assessment (CGA) scale validated on oncological patients. Formestane was given intramuscularly at the dose of 250 mg every 2 weeks. The study included 31 patients who had metastatic disease, and 14 who received formestane as an adjuvant treatment. Median age was 74 years (range 65-93), with nine patients > 80 years. Median ECOG Performance Status (PS) was one. The more frequent comorbidities observed in our series were arthrosis-arthritis (64.4% of patients), hypertension (44.4%), vascular diseases (35.5%), CNS diseases (28.8%). Twenty percent of patients presented at least one dependency in Activities of Daily Living (ADL) and 51.2% in Instrumental Activities of Daily Living (IADL). The treatment was well tolerated - only two patients interrupted formestane because of minor adverse reaction at the injection site and generalised itching. In particular Formestane was not responsible for any worsening of pre-treatment comorbidities, especially hypertension and vascular diseases. Objective responses (OR) were observed in 11.1% of advanced patients, while the disease was stabilised in 51.8% subjects. Median duration of OR was 12 months; median overall survival was 11 months. Among patients receiving formestane as adjuvant treatment, three relapsed, with a time to failure (TTF) of 12 months. Formestane is effective and minimally toxic in an elderly breast cancer population with comorbidities and disabilities measured by CGA.

Sentinel node mapping for malignant melanoma.

Sixty-seven patients with malignant melanomas were seen in our institute since 1998. We looked for a sentinel node in 26 (38%) patients with lesions thicker than 1 mm, employing a double technique: staining with methylene blue and gamma probe mapping after injection of 99mTc. Forty-six nodes were retrieved, 25% of them containing tumor cells. This approach enabled us to choose between a wait-and-see policy and radical surgery.

Mitoxantrone in elderly patients with advanced breast cancer: pharmacokinetics, marrow and peripheral hematopoietic progenitor cells.

The aims of this study were to evaluate the pharmacokinetics, tolerability and hematopoietic toxicity of mitoxantrone in elderly women. Thirteen patients with advanced breast cancer, median age of 73 years, received escalating doses of mitoxantrone 8, 10, 12 and 14 mg/m2 on day 1, q 21. There was a linear relationship between the mitoxantrone dose administered and the mitoxantrone exposure (AUC) in plasma (r = 0.856, pc0.001). After 4 courses of treatment, a significant decrease in bone marrow cellularity (p = 0.0067), and HPC content (BFU-E p = 0.0077) was observed. A remarkable, though not statistically significant decrease in circulating HPCs was observed after 4 courses and was still present 8-12 months after the termination of treatment. Therapy with mitoxantrone in elderly women was well tolerated at the dose of 12 mg/m2 for four courses. The significant hematological toxicity observed in marrow cellularity and HPC content warrant further studies.

Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasia and elderly patients without neoplastic conditions.

BACKGROUND: Elderly people constitute a heterogeneous group and are at an increased risk for the development of cancer. It is not clear whether comorbid conditions and functional status influence clinical decisions and the pattern of referral in elderly cancer patients. The current study investigated functional status measured by Eastern Cooperative Oncology Group performance status, comorbid conditions, and medication taken as well as social environment in three series of patients grouped according to age and diagnosis. METHODS: A total of 593 patients were involved: 138 neoplastic patients age > 70 years with breast, colon, or prostate carcinoma, 177 neoplastic patients age < 70 years with the same types of pathology, and 278 elderly patients with nonneoplastic conditions. Patients with neoplastic disease were recruited from cancer centers; patients with nonneoplastic disease were recruited from either geriatric or general medicine departments. Differences in the distribution of variables were analyzed by univariate and bivariate analyses. RESULTS: No significant differences in social environment, marital status, or education were observed. Statistical differences were noted when comparing the distribution of comorbidities, performance status, and medication taken, elderly neoplastic patients presented in poorer condition compared with younger patients but in better condition compared with elderly patients with nonneoplastic disease. CONCLUSIONS: The overall better health of older cancer patients compared with those without cancer needs to be assessed further. It is possible that cancer is more likely to be diagnosed in healthier elderly, or that primary care providers are reluctant to refer for cancer care patients in poor general health. Studies of comorbidity, function, and social resources are necessary to establish the impact of cancer on survival and quality of life of older patients and to determine the social resources necessary for adequate care.

Home care in the older person.

Life expectancy has progressively increased in Western countries over the last few decades. The number of individuals over age 65 also has increased. Home health care, as an alternative to hospital and ambulatory care, is currently one of the fastest growing sectors of the health care market and has met the favor of most patients and families.

Paclitaxel plus ifosfamide in advanced ovarian cancer: a multicenter phase II study.

BACKGROUND: While ovarian cancer is one of the most sensitive cancers to cytotoxic drugs, with objective response rates of 60-80% routinely being reported in previously untreated patients, the majority of individuals with advanced disease ultimately relapse. Paclitaxel, a new and novel antimicrotubule agent, has shown activity as a salvage therapy in epithelial ovarian cancer. More importantly, in a prior study, it has been shown to be active in tumors that have displayed resistance to platinum compounds, with a reported response rate of 20%. Ifosfamide has shown activity in the treatment of patients who previously demonstrated clinical resistance to a platinum-cyclophosphamide combination. Recently, a synergistic activity of Taxol combined with ifosfamide has been reported in ovarian cell lines. Based on these data, a phase I/II study of a combination treatment with paclitaxel and ifosfamide was performed. PATIENTS AND METHODS: Thirty-one patients with recurrent ovarian cancer or ovarian cancer refractory to cisplatin (CDDP)-containing regimens were treated with paclitaxel at a dose of 135 mg/m2 on day 1; ifosfamide was administered at 1 g/m2 on days 2 and 3 for the first cycle and 1.5 and 2 g/m2 with the same schedule in cycles 2 and 3, respectively. In the absence of toxicity, the dose of ifosfamide was maintained at 2 g/m2 for the last three cycles. Cytotoxic therapy was repeated every 3 weeks. RESULTS: A 30% overall objective response rate was achieved in the 30 patients assessable for response. Among 21 platinum-resistant patients, 4 partial responses (19%) were observed, while in the 9 platinum-sensitive patients 2 complete responses and 3 partial responses (55%) were observed. Myelosuppression was the predominant toxicity. Leukopenia (WHO grade 3-4) occurred in 10% of patients who received ifosfamide at a dose of 1 g/m2 and in 18% of patients treated with ifosfamide at 1.5 g/m2. CONCLUSION: Our results confirmed a low activity of paclitaxel in platinum-resistant patients. The results of this combination treatment with paclitaxel-ifosfamide in our platinum-sensitive patients support further investigations in a randomized study of the combination regimen against paclitaxel alone or retreatment with organoplatinum compounds.

Comorbidity and cancer in the aged: the oncologists point of view.

Cancer in the elderly represents a frequent cause of morbidity and mortality. Moreover, older people frequently present comorbid chronic conditions with functional limitations and it is not known to what extent the coexistence of other disease interferes with referral, diagnosis, therapeutic choice and prognosis of elderly cancer patients. Two cooperative studies were conducted. The first was aimed to investigate comorbid disease burden and functional limitations in older neoplastic and non neoplastic patients and younger neoplastic patients. The second is ongoing and aims to evaluate the role of the Comprehensive Geriatric Evaluation to optimize the management of elderly cancer patients.

Suramin/epidoxorubicin association in hormone-refractory prostate cancer: preliminary results of a pilot phase II study.

PURPOSE: Previous studies indicate that suramin may be an active agent for treating hormone-refractory prostate cancer. However, antitumour responses were observed in initial experiments only when plasma suramin concentrations were maintained in excess of 250 micrograms/ml. Dose-limiting toxicity, especially neurological toxicity, is directly related to the duration of exposure and sustained plasma drug concentrations of 300 micrograms/ml or more. Combination with other agents such as epidoxorubicin, a drug with demonstrable activity in metastatic prostatic carcinoma, could be more effective and allow reduced suramin doses, while maintaining the suramin antitumor effect; this could make suramin therapy more feasible. On the basis of preclinical synergistic activity for combined suramin/doxorubicin in prostate cancer cell lines, a pilot study in patients with metastatic hormone refractory prostate cancer was performed. MATERIALS AND METHODS: Ten patients with hormone-refractory prostate cancer received a fixed dosing scheme of suramin infusion in combination with weekly epidoxorubicin at 25 mg/m2. Therapy was discontinued for dose-limiting toxicity or progressive disease. RESULTS: None of the ten patients achieved a prostate-specific antigen reduction of more than 50% and no objective responses were observed in any patient. Dose-limiting toxicity was observed in four patients: grade 3 neurotoxicity was observed in three patients and grade 3 nephrotoxicity in one patient. CONCLUSIONS: Suramin/epidoxorubicin association, despite the encouraging preclinical results, was not able to improve the antitumour activity of suramin and showed significant toxicity. The results achieved in our study, although in a small number of patients, seem to suggest that this regimen cannot be recommended for use in the treatment of metastatic hormone-refractory prostate cancer.

p53 accumulates in micronuclei after treatment with a DNA breaking chemical, methylnitrosourea, and with the spindle poison, vinblastine.

Micronuclei (MN) induced by N-methyl-N-nitrosourea (MNU) or vinblastine in cultured mammalian cells were analyzed for the accumulation of p53 by immunocytochemical staining with a p53 monoclonal antibody. Our data showed that MN induced by both agents were p53-negative at early post-treatment times, but became positive at late times. Assuming that most MNU-induced micronuclei reflect DNA damage, and most vinblastine-induced micronuclei reflect damage to the mitotic apparatus, we conclude that p53 accumulation in micronuclei is not triggered by DNA damage per se but instead probably stems from DNA degradation occurring during ageing of micronuclei.