MMC/UFT/LV in refractory colorectal cancer: phase II study and analysis of predictive variables of progression.

BACKGROUND: The treatment of refractory metastatic colorectal cancer (rmCRC) and the lack of predictive variables are matters of debate. PATIENTS AND METHODS: We conducted a multicentre phase II trial assessing the disease control rate (DCR) of the combination of tegafur/uracil and mitomycin C in rmCRC. The number of previous lines of chemotherapy, carcinoembryonic antigen (CEA) levels, progression-free survival of the last chemotherapy regimen (PPFS), and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio at the time of study entry were evaluated as indicators of early progression. RESULTS: We enrolled 42 patients. The combination was well tolerated with a DCR of 26.2% and median overall survival of 6.9 months. Low CEA levels, PPFS >6 months and low NLR were significantly associated with better prognosis. CONCLUSION: The study failed its primary endpoint. However, some putative indicators of early progressive patients have been described.

Changes in hepatic perfusion assessed by dynamic contrast enhanced MRI, associated with morphologic evaluation, in patients with liver metastases from colorectal cancer treated with first-line chemotherapy.

INTRODUCTION: Blood perfusion of liver metastases can be non-invasively assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The aim of this study was to explore whether the ratio of hepatic arterial to total liver blood flow (Hepatic Perfusion Index-HPI) and the area under the enhancement curve (AUC) of selected liver areas in patients with hepatic metastases from colorectal cancer treated with first-line chemotherapy could predict response and/or be a prognostic variable. PATIENTS AND METHODS: Sequential liver DCE-MRI studies with morphological imaging reconstruction were performed in 43 consecutive patients at baseline and every 3 months during oxaliplatin-based first-line chemotherapy. Data about HPI of the whole liver, and AUC of metastatic and healthy areas were calculated at each time-point and compared both at baseline and sequentially during the treatment. RESULTS: Baseline HPI and AUC values did not discriminate patients responsive to chemotherapy, nor those with better survival outcomes. HPI and AUC values at 3 months decreased significantly more in responders than non-responders. AUCs calculated from areas of the liver with or without neoplastic lesions varied consistently, being increased in progressing patients and decreased in responding patients. DISCUSSION: Our results did not support the hypothesis of a predictive or prognostic role of HPI and AUCs calculated by DCE-MRI in liver metastatic CRC patients, thus the primary endpoint of the study was not reached. However, reduced arterial blood flow in metastatic liver can be obtained by chemotherapy alone, without any anti-angiogenic agent; interestingly, HPI and AUC data suggest a possible relationship between tumor metabolism and entire liver perfusion.

Nivolumab in pretreated pleural mesothelioma: Results from an observational real-world study of patients treated within the AIFA 5% Fund.

BACKGROUND: Pleural mesothelioma is a rare cancer with a dismal prognosis and few therapeutic options, especially in the pretreated setting. Immunotherapy with checkpoint inhibitors as single agents yielded interesting results in refractory pleural mesothelioma, achieving a response rate between 10-20%, median progression-free survival of 2-5 months and median overall survival of 7-13 months. PATIENTS AND METHODS: A retrospective, multi-institutional study of pleural mesothelioma patients treated with nivolumab in second and further line was performed. The endpoints of the study are response rate, disease control rate, progression free survival and overall survival. RESULTS: Sixty-five patients with pleural mesothelioma treated with nivolumab in second and further line were enrolled at seven Italian institutions. The response rate was 8%, disease control rate was 37%, median progression free survival was 5.7 months (95% CI: 2.9-9.0) and median overall survival was 11.1 (95% CI 6.2-19.9) months. A higher neutrophils and neutrophils to lymphocytes ratio at baseline were associated with worse prognosis. CONCLUSION: Nivolumab as a single agent is fairly active in a cohort of unselected pretreated pleural mesothelioma patients. Further investigations on clinical and translational factors are needed to define which patient might benefit most from nivolumab treatment in pleural mesothelioma.

The role of lung metastasis resection in improving outcome of colorectal cancer patients: results from a large retrospective study.

BACKGROUND: The role of surgery for lung metastases (LM) secondary to colorectal cancer (CRC) remains controversial. The bulk of evidence is derived from single surgical series, hampering any definitive conclusions. The aim of this study was to compare the outcomes of CRC patients with LM submitted to surgery with those who were not. PATIENTS AND METHODS: Data from 409 patients with LM as the first evidence of advanced disease were extracted from a database of 1,411 patients. Patients were divided into three groups: G1, comprised of 155 patients with pulmonary and extrapulmonary metastases; G2, comprised of 104 patients with LM only and no surgery; G3, comprised of 50 patients with LM only and submitted to surgery. RESULTS: No difference in response rates emerged between G1 and G2. Median progression-free survival (PFS) times were: 10.3 months, 10.5 months, and 26.2 months for G1, G2, and G3, respectively. No difference in PFS times was observed between G1 and G2, whereas there was a statistically significant difference between G2 and G3. Median overall survival times were 24.2 months, 31.5 months, and 72.4 months, respectively. Survival times were longer in resected patients: 17 survived >5 years and three survived >10 years. In patients with LM only and no surgery, four survived for 5 years and none survived >10 years. CONCLUSIONS: Even though patients with resectable LM are more likely to be those with a better outcome, our study provides evidence suggesting an active role of surgery in improving survival outcomes in this patient subset.

Gemcitabine and protracted 5-fluorouracil infusion as third-line chemotherapy in refractory colorectal cancer patients.

BACKGROUND: There is no standard treatment for patients with advanced colorectal cancer (CRC) progressing after irinotecan and oxaliplatin treatment and having good performance status (PS). PATIENTS AND METHODS: We investigated gemcitabine 1,000 mg/m2 days 1, 8 and 15 q28d combined with protracted 5-fluorouracil continuous infusion at 200 mg/m2/day, in 37 consecutive patients progressing after oxaliplatin-irinotecan-containing chemotherapies. RESULTS: Partial response (PR) was achieved in 4 (10.8%) and disease stabilization (SD) in 19 (51.4%) cases (PR+SD: 62.2%). Median time to progression and survival were 4.2 and 8.9 months, respectively. Grade III toxicities were thrombocytopenia, neutropenia (in 3 patients) and mucositis (in 2 patients). Clinical benefit was observed in 18 patients (48.6% of the entire population; 64.3% of those patients with PS>0 at study entry). CONCLUSION: The combination of gemcitabine and 5-fluorouracil continuous infusion was found to be an active and manageable palliative regimen for heavily pre-treated patients with metastatic CRC.

Six-year stabilisation of a relapsed pelvic mass from rectal cancer after oxaliplatin-containing chemotherapy.

Chemotherapy alone without a multimodality approach has never been demonstrated to cure metastatic colorectal cancer patients. We report the case of a young woman referred in 1999 to our institution for a pelvic relapse of rectal cancer remained stable after oxaliplatin, 5-fluorouracil, and folinic acid therapy and never grown in size up to now, more than 6 years after the last relapse. Death of all the cancer cells, neuroendocrine cells selection, or cell dormancy are some of the discussed explanations to this unique observation. An intriguing question remains open: Should this patient be considered cured?

Co-expression of EGF receptor, TGFalpha and S6 kinase is significantly associated with colorectal carcinomas with distant metastases at diagnosis.

Autocrine tumour growth factor alpha (TGFalpha)/epidermal growth factor receptor (EGFR) stimulation in colorectal carcinoma (CRC) cells regulates cell adhesion and invasiveness via ribosomal protein S6 kinase (S6K) phosphorylation in pre-clinical studies. The aim of this study was to evaluate whether TGFalpha and EGFR expression might be correlated with a higher metastatic behaviour in human tumours. Paraffin-embedded material was retrospectively collected from 101 primitive CRCs including all stage IV patients at diagnosis treated at our Institution from 1999 to 2004 (50 cases, Group B) and 51 stage II-III control cases (Group A). EGFR and TGFalpha expression, together with signalling molecules (including signal transducer and activator of transcription [STAT3], serine-treonine kinase [Akt], mitogen-activated protein kinase [MAPK], mammalian target of rapamycin [mTOR] and S6K) in selected samples, was evaluated by immunohistochemistry using the EGFR Dako antibody. A total of 68/101 (67.3%) cases were EGFR positive and 79/101 (78.2%) cases were TGFalpha positive. EGFR/TGFalpha co-expression differed significantly (p = 0.02) between Group A and Group B tumours (23/51, 45.1% vs 34/50, 68.0%, respectively), whereas no differences in STAT, Akt, mTOR expression was evident between the two groups. Conversely, there was a significantly higher expression of phosphorylated S6K in stage IV cases (Group B) than in the controls (Group A; 70.4% vs 38.7%; p = 0.02). In agreement with in vitro data, EGFR, TGFalpha and S6K co-expression in human CRC was significantly higher in patients with advanced stage at diagnosis.

Pharmacoeconomic comparison between chronochemotherapy and FOLFOX regimen in the treatment of patients with metastatic colorectal cancer: a cost-minimization study.

AIMS AND BACKGROUND: The addition of oxaliplatin to the widely employed De Gramont schedule (FOLFOX regimen) in patients with metastatic colorectal cancer improved their outcome with a moderate toxicity pattern. The adaptation of the delivery rate of 5-fluorouracil, leucovorin and oxaliplatin to circadian rhythms (chronotherapy) resulted in a very high drug tolerability with clinical results at least comparable to those achieved with the FOLFOX regimen. However, chronomodulated infusion seemed to be more expensive, requiring dedicated electronic pumps and several disposable materials. The present study aimed to compare the direct costs of the two regimens and to determine whether chronotherapy was effectively more expensive than the FOLFOX regimen. STUDY DESIGN: The direct costs of drug delivery devices derived from various publicly available sources and of toxicity management as extrapolated from two published studies considering comparable patient subsets were added and compared. RESULTS: Pump, central venous system and disposable materials for a single chronotherapy cycle were Euro 193 or Euro 212 according to whether the pumps were bought or rented, compared to Euro 58 for the FOLFOX regimen. Toxicity management costs were Euro 144 vs Euro 288 for the two schemes, respectively. Globally, a single course of chronotherapy cost Euro 337 or Euro 356, whereas a single FOLFOX cycle cost Euro 346. CONCLUSIONS: Direct costs for a single chronotherapy cycle appeared to be comparable to a single course of the FOLFOX regimen. In fact, the major material cost of chronochemotherapy devices was balanced by a better tolerability profile. The overall improvement in quality of life with chronochemotherapy affecting indirect costs, such as reduction of work, and intangible costs is worthy of further pharmacoeconomic attention.

Acute and fatal thrombocytopenic thrombotic purpura after a single dose of pemetrexed.

CASE: Thrombocytopenic thrombotic purpura (TTP), a life-threatening event consisting of disseminated vascular thrombosis, has never been described before as a possible side effect of the anticancer drug pemetrexed. A 70 years old patient affected by a poorly differentiated non small cell lung cancer, subjected to his first pemetrexed administration, developed an acute thrombocytopenic thrombotic purpura, fatal in a few hours. CONCLUSIONS: Pemetrexed can cause TTP. Clinicians have to be alert for the rapid onset and aggressiveness of this possible side effect. It is difficult to recognise the first signs and symptoms.

Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients.

Tumor response to first-line chemotherapy in advanced breast cancer offers prognostic information and may be used as a surrogate marker for evaluating treatment efficacy. With this study we wanted to determine whether changes in circulating serum CA 15-3 levels during chemotherapy provided additional information for prognostic prediction. Serum CA 15-3 was measured at baseline and after 3 and 6 months during anthracycline-based first-line chemotherapy in 526 patients with advanced breast cancer prospectively enrolled in five phase II-III trials. Changes in marker levels were correlated with disease response, time to progression and overall survival. In all, 336 patients attained a disease response. A significant relationship was found between disease response and CA 15-3 variations, although many individual discrepancies were also observed. At the 6-month time point, the median time to progression was 15.3 months in patients with normal marker levels throughout the study, 11.7 months in those with a CA15-3 reduction >25%, 9.6 months in those with elevated baseline CA 15-3 levels which did not change during therapy and 8.6 months in those with increased marker levels (p < 0.001). The median survival was 42.3, 29.7, 28.5, and 24.8 months, respectively (p < 0.002). The prognostic role of changes in CA 15-3 levels was maintained in the patient subset attaining disease response or stabilization to treatment (p < 0.001) and after adjusting for clinical response and major prognostic parameters in the multivariate analysis (p < 0.001). In conclusion, monitoring serum CA 15-3 levels during first-line chemotherapy in advanced breast cancer patients provides prognostic information independently from tumor response.