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Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/−), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR

Early switching to de-intensified maintenance regimen is still a matter of debate in metastatic colorectal cancer (mCRC). The MARTHA trial, a S.I.C.O.G. phase III randomized trial, compared FOLOFIRI+bevacizumab (B) for 12 cycles (6 months) followed by B for up to 12 months (FOLFIRI +B*12 arm) vs FOLFIRI+B for 6 cycles (3 months) followed by capecitabine+B for 4 cycles followed by B for up to 12 months (FOLFIRI+B*6 arm). Chemotherapy-naive mCRC patients were randomized, primary endpoint was progression free survival (PFS), with overall survival (OS) as a secondary endpoint. A novel analysis, the Death Pace Analysis (DPA), was performed to identify patients who benefited from a specific treatment. No PFS difference was seen in 198 enrolled patients (101 in FOLFIRI+B*12, 97 in FOLFIRI+B*6). A non-significant superior OS was observed for FOLFIRI+B*6 (HR 0.74, p 0.098). The DPA demonstrated that 14% of patients were identifiable as FOLFIRI+B*6-benefiting patients. According to a logistic regression analysis including 23 clinicopathological variables, baseline Hb was the only independent predictor of DPA-defined FOLFIRI+B*6-benefit status. Among patients with Hb ≤ 11.1 gr/dL a statistically significant prolonged OS was observed for FOLFIRI+B*6 over FOLFIRI+B*12 (median OS: 20.7 vs 12.6 months, respectively, HR 0.54, p 0.048). No survival difference was observed between arms in patients with Hb > 11.1. mCRC patients with low baseline Hb levels are better treated with FOLFIRI+B*6 first-line strategy. Possible biological explanations for this finding are being investigated.

Early switching to de-intensified maintenance regimen is still a matter of debate in metastatic colorectal cancer (mCRC). The MARTHA trial, a S.I.C.O.G. phase III randomized trial, compared FOLOFIRI+bevacizumab (B) for 12 cycles (6 months) followed by B for up to 12 months (FOLFIRI +B*12 arm) vs FOLFIRI+B for 6 cycles (3 months) followed by capecitabine+B for 4 cycles followed by B for up to 12 months (FOLFIRI+B*6 arm). Chemotherapy-naïve mCRC patients were randomized, primary endpoint was progression free survival (PFS), with overall survival (OS) as a secondary endpoint. A novel analysis, the Death Pace Analysis (DPA), was performed to identify patients who benefited from a specific treatment. No PFS difference was seen in 198 enrolled patients (101 in FOLFIRI+B*12, 97 in FOLFIRI+B*6). A non-significant superior OS was observed for FOLFIRI+B*6 (HR 0.74, p 0.098). The DPA demonstrated that 14% of patients were identifiable as FOLFIRI+B*6-benefiting patients. According to a logistic regression analysis including 23 clinicopathological variables, baseline Hb was the only independent predictor of DPA-defined FOLFIRI+B*6-benefit status. Among patients with Hb ≤ 11.1 gr/dL a statistically significant prolonged OS was observed for FOLFIRI+B*6 over FOLFIRI+B*12 (median OS: 20.7 vs 12.6 months, respectively, HR 0.54, p 0.048). No survival difference was observed between arms in patients with Hb > 11.1. mCRC patients with low baseline Hb levels are better treated with FOLFIRI+B*6 first-line strategy. Possible biological explanations for this finding are being investigated.

Background: The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer. Patients and methods: Patients were randomly assigned to EC (E 120 mg/m 2 , C 600 mg/m 2 , arm A) for four cycles or four cycles of D (100 mg/m 2 ) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety. Results: There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75–1.31; P = 0.95)], respectively. Grade 3–4 toxicity was more common in arm B. Conclusions: This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.

Background It is widely assumed that patients (pts) who achieve a pCR have a good prognosis and better outcomes compared with pts with Aim of our study was to evaluate the relative risk of recurrence (RR) over time in ER-positive (ER+) and ER-negative (ER-) Material and Methods: We analyzed 139 consecutive Results: For all 139 pts, the total number of pts with recurrence was 95 (68%), 54 (63%) in ER+ and 41 (76%) in ER-.tumors. For the entire group and both in ER+ and in ER-, the RR of recurrence was greatest for the interval between 0–24 months, then decreased rapidly in ER- and slowly in ER+ through the 25–120 m interval. For the 0–24 m and 25–60 m intervals the RR of recurrence was higher for ER-pts and after 60 m it crossed and beyond 60 m the RR of recurrence was higher in ER+ than in ER- pts. Notably, beyond 120 months we observed a little second peak of recurrence, higher in ER+ (7) than in ER- (3) pts. Nine of these 10 relapses occurred between 120 to 180 m interval, 7 in ER+ (13%) and 2 in ER- (5%) subgroup. In the first 24 m ER- pts were 86% more likely to relapse compared with ER+, vice versa between 61–120 and beyond 120 m intervals, ER- pts were 19% and 18% less likely to relapse, respectively, compared with ER+ pts. Conclusions: The present study confirmed the previous reports which showed unfavorable prognosis of the Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-07.

Background We have extensively assessed a biweekly regimen of irinotecan plus folinic acid and fluorouracil bolus (IRIFAFU) in metastatic colorectal cancer (MCRC). Here, we report on the safety and activity of BIFF (bevacizumab plus IRIFAFU) regimen in 94 mCRC patients. Patients and Methods Bevacizumab 5 mg/kg (1 hour), and irinotecan 180 mg/m 2 (1hour) were given intravenously on day 1, 6S-folinic acid 250 mg/m 2 (2 hours), and fluorouracil 850 mg/m 2 (bolus) were given intravenously on day 2 every 2 weeks for a median of 9 cycles per patient (range, 1-12), and maintenance bevacizumab alone was delivered in 16 cases. Results Grade ≥ 3 hematologic toxicities were neutropenia (50%) and febrile neutropenia (5%). Most common grade 3 nonhematologic side effects were diarrhea (20%), vomiting (7%), nausea (4%), and stomatitis (4%). Severe hypertension (1%) and epistaxis (1%) rarely occurred. Six complete responses and 44 partial responses were registered, giving a response rate of 53% (95% CI, 43%-64%). Median progression-free survival was 11.5 months (95% CI, 9.0-14.0 months). Forty-three (46%) patients eventually died, and the median overall survival was 24.0 months (95% CI, 20.2-27.8 months). Conclusion Bevacizumab appeared to increase the activity of the IRIFAFU regimen without worsening its tolerability. Efficacy of BIFF was comparable with that reported with other bevacizumab plus irinotecan-based combinations.

Breast cancer represents the most common cancer among women in Italy. In the last decade, an increase in incidence and a decrease in mortality from breast cancer have been observed in Italy. These findings may be explained at least in part by the implementation of organized screening programs (SMPs). The screening programs are not diffused homogeneously throughout Italy, where approximately 60% of the population in covered, which explains in part the different outcomes observed across Italy. On the basis of the available data, the authors of this report performed a retrospective analysis on the incidence of 2 different groups of breast cancer patients: those covered or and those not covered by SMPs in Italy. The rates of incidence of T4a, T4b, and T4c breast cancer and of T4 inflammatory breast cancer (IBC) overtime appeared to be lower for the population that was covered by SMPs. On the basis of the estimated 40,000 new cases of breast cancer in Italy per year, the authors attempted to extrapolate the approximate incidence of new cases of T4 breast cancer and calculated that there were between 2800 and 3600 new cases per year taking into account the differences in incidence observed in areas covered or not covered by SMPs. Following the same extrapolations, the estimated incidence of IBC was approximately 200 to 800 new cases per year, representing from 0.6% to 2% of all breast cancers diagnosed every year in Italy.

A large proportion of human tumors show deregulated expression of a variety of proteins that play a crucial role in the execution of the apoptotic program. Survivin belongs to the family of inhibitor of apoptosis proteins which were originally identified in baculoviruses. Ectopic expression of survivin conveys resistance to apoptosis to a variety of stimuli, and survivin is one of the most abundantly overexpressed genes in human tumors such as breast cancer. In this study we examined the expression of survivin protein in a series of T4 breast cancers to identify any correlation with long-term patient outcomes. Moreover, we investigated the hypothesis of a possible association between p53 and survivin as a factor further complicating the outcome. Archival specimens from 53 T4 breast cancer patients were included in the study and treated for the immunohistochemical localization of survivin and p53 using the streptavidin-biotin alkaline phosphatase method. The immunoreactivity was evaluated semiquantitatively according to the percentage of cells stained. Forty percent of tumors were positive for survivin. Statistical analysis revealed that survivin expression negatively influenced the 5- and 10-year disease-free and overall patient survival. In multivariate analysis, survivin expression was a significant independent prognostic indicator of worse outcome in overall survival [hazard ratio (HR)=2.61]. Our results showed that survivin is associated with a worse prognosis in patients with T4 breast cancer, and remarkably its prognostic relevance is maintained even long-term. Notably, p53 (HR=3.2) seems to negatively enhance the effect of survivin on survival.

It is believed that the insulin-like growth factor receptor type 1 (IGF-1R) signaling pathway plays a pivotal role in cancer growth, progression, and resistance to anticancer therapies. Strategies are being developed to block IGF-1R as an anticancer treatment. We reviewed several potential strategies for disrupting the IGF axis. We also reviewed the effects of two drugs that target the IGF-1R: monoclonal antibodies and tyrosine kinase inhibitors. Preliminary results of studies involving these agents provided a foundation for ongoing clinical trials, whose results in the near future will help us understand how to incorporate anti IGF-1R strategies into the current anticancer armamentarium.

Summary Purpose This study was undertaken to select the best schedule of administration for the paclitaxel plus gemcitabine combination in fit elderly patients affected by locally advanced or metastatic non-small cell lung cancer (NSCLC). Patients and methods Ninety-eight patients in stage III or IV NSCLC, aged 70 years or more and in ECOG performance status (PS) ≤ 1, were randomly allocated to receive: paclitaxel 80 mg/m 2 plus gemcitabine 1000 mg/m 2 i.v. on days 1 and 8, with an intra-patient alternated dose escalation up to 100 and 1200 mg/m 2 , respectively, over three cycles (arm A); or paclitaxel 80 mg/m 2 followed by gemcitabine 1000 mg/m 2 i.v. (100 min) on days 1 and 8 (arm B). Treatment was repeated in both arms every 3 weeks for a maximum of six cycles. Results With a median of 3 (range, 1–6) delivered cycles, the two schedules yielded a similar response rate (25% versus 26%), failure-free survival (median, 3.3 months versus 3.2 months), progression-free survival (median, 5.1 months versus 5.2 months), and overall survival (median, 9.7 months versus 9.6 months). Survival was independently affected by the PS of patients and by the metastatic spread. Severe side effects were comparable and negligible in both arms. Conclusion A substantial difference between these two schedules in terms of efficacy and safety can be ruled-out. Paclitaxel plus gemcitabine is an advisable combination for treating fit elderly patients with advanced NSCLC.

Objective: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. Methods: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1–2), FU (400–600 mg/m2 days 1–2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1–2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

This study was performed to determine the activity of adding continuous infusion (CI) of 5-fluorouracil (5-FU) to gemcitabine (GEM) vs GEM alone in advanced pancreatic cancer (APC). In all, 94 chemo-naïve patients with APC were randomised to receive GEM alone (arm A: 1000 mg m(-2) per week for 7 weeks followed by a 2 week rest period, then weekly for 3 consecutive weeks out of every 4 weeks) or in combination with CI 5-FU (arm B: CI 5-FU 200 mg m(-2) day(-1) for 6 weeks followed by a 2 week rest period, then for 3 weeks every 4 weeks). Overall response rate (RR) was the primary end point and criteria for decision were planned according to the Simon's optimal two-stage design. The overall RR was 8% (arm A) and 11% (arm B) (95% confidence interval: 0.5-16% and 2-22%), respectively, and stable disease was 29 and 28%. The median duration of RR was 34 weeks (range 25-101 weeks) for GEM and 26 weeks (range 16-46 weeks) for the combination. The median progression-free survival (PFS) was 14 weeks (range 2-65 weeks) and 18 weeks (range 4-51 weeks), respectively. The median overall survival (OS) was 31 weeks (range 1-101 weeks) and 30 weeks (1-101 weeks). Toxicity was mild in both arms. This study does not show promising activity in terms of RR, PFS and OS for the double combination arm in APC.

Oxaliplatin 100 mg/m(2) iv on day 1, and capecitabine 1,000 mg/m(2) orally bid from day 1 (evening) to day 11 (morning) were administered every 2 weeks (OXXEL regimen) to 38 patients as first-line treatment for metastatic colorectal carcinoma. A total of 318 cycles were administered, with a median of 8 (range, 4-12) cycles per patient. Response rate (RR) was 45% (95% confidence interval (CI), 29%-62%), with 7 complete responses and 10 partial responses; furthermore, 12 patients showed a stable disease, so that a disease control was achieved in 29 (76%) patients. RR was greater among patients with performance status 0 (52%), without weight loss (52%), younger than 65 years (50%), and previously unexposed to adjuvant chemotherapy (48%), while no correlation was found with the actually delivered oxaliplatin dose intensity. Overall, haematological side effects were negligible, with no case of grade 4 toxicity, and only one patient suffering from an episode of grade 3 neutropenic fever. Severe anaemia occurred in 4 (11%) patients, and grade 3 neuropathy affected 9 (24%) patients. Median progression-free survival was 7.9 (95% CI, 6.2-9.6) months, and median overall survival has not been reached yet. In conclusion, the OXXEL regimen resulted safe and active, and it deserves further evaluation in metastatic colorectal cancer patients.

From September 2001 to November 2002, 35 patients aged 70–81 (median, 75) years, with measurable metastatic lesions from colorectal carcinoma, were treated with a combination of oxaliplatin (OXA) infused i.v. over 2 h on day 1, and capecitabine, assumed orally twice a day (12-h apart) from day 2 to day 15. An alternated dose escalation for both drugs was planned over the first three cycles for each patient, in the absence of WHO grade ≥2 toxicity on previous cycle: starting doses were 85 mg/m2 for OXA, and 2000 mg/m2 (day) for capecitabine on first cycle; on second cycle, OXA was planned at 100 mg/m2, while capecitabine was planned at 2500 mg/(m2 day) on third cycle. Treatment was repeated every 3 weeks until progression, or for a maximum of 12 cycles. A total of 212 cycles were administered, with a median of 6 (range, 1–12) cycles/patient. Dose escalation was performed in 18 (51%) patients for OXA, and in 4 (11%) patients for capecitabine. No grade 4, and 10 (29%) cases of grade 3 toxicity of any type were reported. Abdominal symptoms (pain, nausea, or vomiting) affected 66% of patients, but they were of grade 3 in only 2 (6%) patients. Grade 3 diarrhoea occurred in 3 (9%) patients. Two complete and 12 partial responses (PR) were reported, for an overall response rate of 40% (95% CI, 24–58%). Progression of disease occurred in 23 (66%) patients, and 18 (51%) died. The actuarial median progression-free and survival time were 6.9 and 14.1 months, respectively.

The aim of this study was to assess whether a combination of gemcitabine (GEM) with either paclitaxel (PTX) or vinorelbine (VNR) could be more effective than GEM or PTX alone in elderly or unfit advanced non-small-cell lung cancer (NSCLC) patients. A total of 264 NSCLC patients aged70 years with ECOG performance status (PS)or =2, or younger with PS=2, were randomly treated with: GEM 1200 mg m(-2) on days 1, 8 and 15 every 28 days; PTX 100 mg m(-2) on days 1, 8 and 15 every 28 days; GEM 1000 mg m(-2) plus PTX 80 mg m(-2) (GT) on days 1 and 8 every 21 days; GEM 1000 mg m(-2) plus VNR 25 mg m(-2) (GV) on days 1 and 8 every 21 days. In all arms, an intra-patients dose escalation was applied over the first three courses, provided that no toxicity of WHO gradeor =2 had previously occurred. At present time, 217 (82%) patients had died. The median (months) and 1-year survival probability were 5.1 and 29% for GEM, 6.4 and 25% for PTX, 9.2 and 44% for GT, and 9.7 and 32% for GV. Multivariate analysis showed that PSor =1 (hazard ratio (HR)=0.67; 95% CI 0.51-0.90), and doublet treatments (HR=0.76; 95% CI 0.59-0.99) were significantly associated with longer survival. Doublets produced no more toxicity than single agents. GT should be considered a reference regimen for elderly NSCLC patients with PSor =1.

Background: Over the last decade several papers have dealt with the possible interference of allergies in both the infectious disease incidence and tumour development. In the light of all these observations we analysed several tumour patients for a possible interaction between a state of allergy and tumour development and progression after primary cancer therapy. Methods: This study included 1,055 patients with different types of solid tumours admitted consecutively between 1994 and 2002 to the Cagliari University Polyclinic. After primary surgery or medical therapy (or both), 92 allergic subjects and 182 non-allergic patients were studied over a follow-up period of 6–96 months (median 23). Results: Among 1,055 tumour-bearing patients, the prevalence of allergy was found to be about 8% versus 16–37% in a population of non-tumour-bearing subjects. After primary cancer therapy, allergic patients turned out to have a 20% higher probability of being cured and about a 50% lower risk of tumour progression as compared to non-allergic ones. The observed differences were statistically significant (p = 0.013). Conclusions: On the basis of our findings, we suggest that allergic subjects seem to have a better prognosis than non-allergic ones for disease outcome after cancer therapy.

A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis.A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy.Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P0.24). Adverse events incidence was not significantly different between the two treatments.In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity.NCT00869310.

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II–III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3–4 CTCAE toxicity events (grade 2–4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.

Background: Polymorphisms in the excision repair cross-complimentary group 1 (ERCC1) gene have been involved in the prognosis of various cancers. In the present study, we evaluated the prognostic role of the two most common ERCC1 polymorphisms in patients with T4 breast cancer receiving platinum-based chemotherapy. Methods: A total of 47 patients with T4 breast cancer undergoing treatment with a platinum-based regimen were collected and followed up (median 159 months; range, 42–239 months). ERCC1 C8092A (rs3212986) and T19007C (rs11615) polymorphisms were genotyped, using an automated sequencing approach. The same series was screened for BRCA1/2 mutations by DHPLC analysis and DNA sequencing. Results: Among the tested patients, 16 (34%) and 25 (53%) presented the 8092A (homo-zygosity A/A or heterozygosity A/C) and the 19007C (homozygosity C/C or heterozygosity C/T) genotypes, respectively. The 8092A and 19007C genotypes in ERCC1 were significantly associated with overall survival in T4 breast cancer patients treated with chemotherapy containing platinum (p-values = 0.036 and 0.004, respectively). Univariate and multivariate Cox regression analyses showed that combination of 8092A and 19007C genotypes acts as a significant prognostic factor in women with T4 breast cancer receiving platinum-based chemotherapy (p-values = 0.022 and 0.049, respectively). Two (4.3%) out of 47 cases were found to carry BRCA1/2 mutations; they presented the highest overall survival rates into the series. Conclusions: The ERCC1 8092A and 19007C genotypes or their combination may predict a favorable prognosis in T4 breast cancer patients undergoing a platinum-based treatment. Further large-scale, prospective studies are needed to validate our findings.

Although the subjective nature of quality of life is generally accepted, less attention has been paid to the procedure of selecting domains to be explored with questionnaires. To explore what contributes to cancer patients' quality of life, a survey was conducted with the aim of identifying contents of quality of life using cancer patients as 'experts'. A questionnaire with open-ended items aimed at exploring the meaning of quality of life and at determining the contents of health and not health related quality of life, was submitted to a sample of cancer patients stratified by residence, cancer site and stage of disease. The 248 questionnaires received were transcribed and broken down into phrases to allow coding. A content analysis was performed, using as a conceptual framework, the domains identified by the Italian Society of Psycho-Oncology. Overall, 43 domains and a list of symptoms were identified. The two most frequently reported symptoms were pain (21.4% patients) and fatigue (14.1% patients). Social relationships and psychological domains were heavily represented. Twenty sub-domains related to the domain 'psychological well-being'. This study suggests that information on the content of quality of life questionnaires to be submitted to people affected by a specific disease, should be derived by studying people suffering the specific disease. These results reinforce the criticism that available quality of life instruments are more likely to reflect the perspective of health professionals than patients.

BACKGROUND: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations. PATIENTS AND METHODS: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m(2) and VNR 25 mg/m(2) on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m(2) and PTX 125 mg/m(2) on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m(2) on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m(2) on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles. RESULTS: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens. CONCLUSIONS: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.

Background Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer. Methods 120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria. Results 55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy. Conclusion A significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.

The peculiar characteristics of the italian neoplastic patients, as far as their knowledge concerning the disease (information, prognosis, therapeutic options, etc) and the different cultural, environmental and health realities, place different problems on the routine application of the quality of life questionnaires wich were constructed and edited in North European or North American Countries, even if correctly translated and validated in Italy. The QVonc (Quality of Life in Oncology) Project started five years ago from the common interest of medical oncologists who felt the need to make a careful study on some aspects regarding the evaluation of italian patient's quality of life. A multidisciplinary working group, comprehensive of statisticians, epidemiologists, psychologists, nurses and methodologists, was then put together. During the last three years the Group produced a deep analysis of the different aspects and determinants of the italian patient's quality of life, mainly about their disease and medical environment perception. A prospective research was started in 1995 with the aims of identifying the contents of quality of life, using a sample of cancer patients as “experts” and of measuring the relevance of selected contents in different subgroups of patients. In the first study the quality of life dimensions were analysed as perceived from 248 neoplastic patients, uniformely and randomly distributed for pathology and place of residence in Italy, through an open questionnaire and interviews conducted by our psychologists. Some peculiar aspects of the quality of life perception in italian patients were evidenced: relationship with the family, with the medical team and health facilities, economic problems and occupational difficulties. The study confirmed that the information on the contents of quality of life can be derived only studying people suffering the specific disease and cast a doubt on the available QL instruments currently used. The second study evaluated the quality of life perception in 6939 consecutive cancer patients referred in the second week of July 1996 to 79 Italian medical oncology/radiotherapy Institutions. Patients were asked to fill out a questionnaire concerning the importance of 46 domains of QL, each one scored on 4 levels (not at all, a little, much and very much). Domains were derived from a previous content analysis of 268 pts answers to 4 questions related to their own QL: “in your experience, what is QL?”, “what is a bad QL?”, “what is a good QL?”, “Did the diagnosis and treatment received modify your QL?”. 6939 patients entered the study; of these, 820 (11.8%) did not fill out the questionnaire due to various reasons. Among the 6,119 evaluable pts, the most frequent cancers were: breast (2,328), colo-rectal (968), lung (517), lymphoma (351), gastric (225). The most frequently chosen domains (much or very much) were related to health facilities or communication between patient-physician/nurse. Family relationship and general well being were also found important, while from the negative perspective the presence of the disease and the related anxiety were the most relevant problems. In conclusion, when choosing or constructing QL instruments, at least for Italian cancer pts, factors such as health facilities and pt ‘- physician/nurse relationship should be more adequately considered. Most currently used QL questionnaires are probably lacking in this regard.

Background The effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial. Methods A total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D). Results Addition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events. Conclusions No significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine. Trial registration ClinicalTrials.gov: NCT01359956

The aim of this survey was to describe the attitude of Italian oncologists towards palliative care.A survey on palliative care was carried out among 400 Italian oncologists.Seventy-two percent indicated that the management of patients with advanced stage cancer represents the majority of their practice. They are often involved in the management of pain (78%) and complications of chemotherapy (61%), and frequently, in the treatment of terminal patients (60%). Only 8.5% reported having frequent collaboration with psychiatrists in support of emotional and psychological patients' disturbances. About 40% are often directly involved in the management of existential or spiritual distress. Discussions on euthanasia and assisted suicide, which are illegal in Italy, took place never (68%) or occasionally (27%).Respondents agreed that all oncology centres should have access to palliative care service. These results are in line with those of the European Society of Medical Oncology survey and may be usefully employed to improve the organisation of palliative care.

Background Prognostic factors in patients who are diagnosed with T4 breast carcinomas are widely awaited. We here evaluated the clinical role of some molecular alterations involved in tumorigenesis in a well-characterized cohort of T4 breast cancer patients with a long follow-up period. Methods A consecutive series of 53 patients with T4 breast carcinoma was enrolled between 1992 and 2001 in Sardinia, and observed up for a median of 125 months. Archival paraffin-embedded tissue sections were used for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses, in order to assess alterations in expression levels of survivin, p53, and pERK1-2 proteins as well as in amplification of CyclinD1 and h-prune genes. The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis. Results Overall, patients carrying increased expression of pERK1-2 (p = 0.027) and survivin (p = 0.008) proteins as well as amplification of h-prune gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as independent prognostic factors in our series. Conclusions Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients.

Learning Objectives After completing this course, the reader will be able to: Summarize the main risk factors for relapse in patients with T4 breast cancer after neoadjuvant chemotherapy.Evaluate the role of hormone receptors and HER-2 as determinants of risk of relapse after neoadjuvant treatment.Compare the difference in outcomes between patients who achieve less than pCR in relation to receptor status. This article is available for continuing medical education credit at CME.TheOncologist.com. Purpose. Pathological complete response (pCR) to primary chemotherapy is the main determinant for improved disease-free survival (DFS) and overall survival (OS). The primary endpoints of our study were the long-term DFS and OS rates in homogeneously treated stage IIIB breast cancer patients who failed to achieve a pCR ( Methods. We analyzed 58 of 74 consecutive stage IIIB patients treated between 1996 and 2001 who achieved Results. Fifty-eight (78%) of 74 patients achieved Conclusions. Our data suggest that, in stage IIIB patients who achieve

Purpose: This phase II trial assessed the tolerability and efficacy of a triplet of oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer. Methods: Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m 2 iv and irinotecan 150 mg/m2 iv on day 1, 6S-folinic acid 250 mg/m2 iv and fluorouracil 750 mg/m2 iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. Results: Sixty-three patients were treated, with a median of eight (range 1-12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22-46%]). Median progression-free survival was 7.5 (95% CI, 5.6-9.4) months, and median overall survival was 12.1 (95% CI, 10.8-13.4) months. Most common grade ≥3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity affected 33% of patients. Conclusions: Oxaliplatin, irinotecan, and fluorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer.

Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting.169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

Background: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations. Patients and methods: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m2 and VNR 25 mg/m2 on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m2 and PTX 125 mg/m2 on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m2 on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m2 on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles. Results: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens. Conclusions: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.

Background: Primary chemotherapy as part of multidisciplinary approach is the established treatment for inoperable stage III B breast cancer. The primary endpoints were conversion to operable disease and feasibility of conservative surgery (breast-conserving therapy: BCT); secondary were clinical and pathological complete response rate, local and distant control and safety of the primary regimen. Methods: Between 1998 and 2001, 40 inoperable breast cancer patients ≤60 years, 72% T4abc and 28% T4d, received 6 cycles of primary PEV dose-dense regimen: cisplatin 50 mg/m2, epirubicin 100 mg/m2 and vinorelbine 25 mg/m2, i.v. (q 14). Modified radical mastectomy (MRM) or BCT was performed, followed by adjuvant chemotherapy, radiotherapy and hormone therapy. Results: All patients were converted to operable disease, and BCT was feasible in 24% of T4abc patients. After a median follow-up of 84 months (range 58–96), local and distant relapses were 7.5% (0% in BCT ) and 25% (25% in BCT), respectively. Clinical response was 80% (clinical complete response [cCR]: 20%); pathological complete response (pCR) was 40% in breast, 50% in axilla (pLN0); 32% both in breast and axilla. Neutropenia (G4, 30%), leukopenia (G4, 25%), alopecia (G2, 100%), nausea and vomiting (G4, 20%) were the most common toxicities. Conclusions: The PEV dose-dense regimen seems to be highly effective in terms of resectability and pCR. Toxicity, mainly hematological, was acceptable. Successful BCT is feasible, in selected patients, without compromising local and distant control.

BACKGROUND. To date, the standard treatment for patients who have carcinoma of unknown primary site has not been established. METHODS. In this randomized Phase II study, 66 previously untreated patients (33 patients per arm) with carcinomas of unknown primary site received cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) with either paclitaxel (70 mg/m2) or vinorelbine (25 mg/m2), and all drugs were administered intravenously on Days 1 and 8 of a 21-day cycle. Twenty-nine patients (44%) presented with ≥2 involved sites. The pathologic diagnosis was mainly adenocarcinoma (48 patients; 72.7%) and squamous carcinoma (7 patients; 10.6%). RESULTS. In the first arm, 16 patients (48.5%) experienced an objective response, and 9 patients (27.2%) had disease stabilization. In the vinorelbine-containing arm, 14 patients (42.3%) experienced an objective response, and 8 patients (24.2%) had disease stabilization. The median response duration and the median time to progression were similar in both treatment arms; the median overall survival was 9.6 months (95% confidence interval, 7.11–12.09 months) for patients who received the cisplatin/gemcitabine/paclitaxel regimen and 13.6 months (95% confidence interval, 6.61–20.59 months) for patients who received the vinorelbine combination. Grade 3 and 4 toxicities were more frequent in the paclitaxel-containing arm. CONCLUSIONS. Both combinations satisfied the 2-step design, demonstrating antitumor activity without relevant differences in response rates or response duration; however, the vinorelbine-containing regimen yielded superior results both in terms of overall survival (13.6 months vs 9.6 months) and in terms of treatment tolerability. Therefore, according to a pick the winner attitude, the combination of cisplatin/gemcitabine/vinorelbine may be considered in the design of future randomized, Phase III trials for patients with carcinomas of unknown primary site. Cancer 2006. © 2006 American Cancer Society.

This study was undertaken to select the best schedule of administration for the paclitaxel plus gemcitabine combination in fit elderly patients affected by locally advanced or metastatic non-small cell lung cancer (NSCLC).Ninety-eight patients in stage III or IV NSCLC, aged 70 years or more and in ECOG performance status (PS)or=1, were randomly allocated to receive: paclitaxel 80 mg/m(2) plus gemcitabine 1000 mg/m(2) i.v. on days 1 and 8, with an intra-patient alternated dose escalation up to 100 and 1200 mg/m(2), respectively, over three cycles (arm A); or paclitaxel 80 mg/m(2) followed by gemcitabine 1000 mg/m(2) i.v. (100 min) on days 1 and 8 (arm B). Treatment was repeated in both arms every 3 weeks for a maximum of six cycles.With a median of 3 (range, 1-6) delivered cycles, the two schedules yielded a similar response rate (25% versus 26%), failure-free survival (median, 3.3 months versus 3.2 months), progression-free survival (median, 5.1 months versus 5.2 months), and overall survival (median, 9.7 months versus 9.6 months). Survival was independently affected by the PS of patients and by the metastatic spread. Severe side effects were comparable and negligible in both arms.A substantial difference between these two schedules in terms of efficacy and safety can be ruled-out. Paclitaxel plus gemcitabine is an advisable combination for treating fit elderly patients with advanced NSCLC.

Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. On the basis of sensitivity to previous treatment, 19 patients were considered as chemo-resistant and 14 patients as chemo-refractory. OXA 110 mg/m (over 2 h) and IRI 175 mg/m (over 1 h) were delivered on day 1, followed by LFA 250 mg/m (2-h infusion) plus 5FU 800 mg/m as intravenous bolus on day 2. Cycles were repeated every 2 weeks. A total of 348 cycles were delivered, with a median of nine cycles per patient (range, 1-12 cycles per patient). Five complete and 13 partial responses were reported on 40 assessable patients, giving a response rate of 45% [95% confidence interval (CI), 29-62%]; eight of 19 (42%) resistant patients and five of 14 (36%) refractory patients achieved a major response, which was also obtained in four of eight (50%) patients pretreated with IRI and in three of eight (38%) patients pretreated with OXA. Grade 3 or higher neutropenia occurred in 68% of patients, but febrile neutropenia or infections affected only seven (17%) patients. No episodes of grade 3 or higher thrombocytopenia or anemia were recorded. Occurrence of severe non-hematologic toxicities by patients were: diarrhea, 34%; vomiting, 17%; peripheral cumulative neuropathy, 15%; stomatitis, 10%; acute cholinergic syndrome, 7%. Actually delivered dose intensities of all three drugs resulted in about two-thirds of the planned ones. After a follow-up of 39 months, median progression-free survival was 7.5 months. Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.

Background A biweekly regimen of irinotecan 200 mg/m2 on day 1 and levo-leucovorin (LV) 250 mg/m2 plus 5-fluorouracil (5-FU) 850 mg/m2 via intravenous bolus on day 2 was assessed in 2 consecutive randomized trials in metastatic colorectal cancer (CRC). Patients and Methods Individual data of 254 patients were merged, and baseline features potentially affecting overall response rate (ORR), progression-free survival (PFS),overall survival (OS), and occurrence of severe toxicity were analyzed by univariate and multivariate analyses. Results In the pooled series, ORR was 33% (95% confidence interval [CI], 27%-39%). Liver-only disease (47% vs. 25%; P = 0.0012) and absence of previous weight loss (38% vs. 20%; P = 0.0189) were significantly associated with a higher ORR on the multivariate analysis. Absence of weight loss (hazard ratio, 1.40; 95% CI, 1.02–1.93; P = 0.0377) was significantly associated with a longer PFS (7.5 months vs. 6 months). Median OS was 15.1 months (95% CI, 13.5–16.6 months). Primary surgery, good performance status (PS), only one metastatic site, and oxaliplatin-based second-line treatment independently predicted a longer OS. Grade 4 neutropenia was significantly associated with a PS ≥ 1, whereas risk of grade ≥ 3 diarrhea was directly related to age and previous weight loss. Conclusion Patients with no weight loss and/or preserved PS and with a limited disease extent appeared to obtain the greatest benefit from our irinotecan/5-FU/LV regimen, with acceptable toxicity. Notably, the regimen was effective and well tolerated by elderly patients. This regimen may represent the rationale for assessing the addition of novel antiangiogenic drugs to the treatment of metastatic CRC.

Purpose: The primary end point of this phase III trial was to compare the response rate (RR) of oxaliplatin (OXA) plus levo-folinic acid (l-FA) and 5-fluorouracil (5-FU) bolus with that of irinotecan (IRI) plus l-FA and 5-FU bolus in advanced colorectal carcinoma. Patients and methods: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200 mg/m 2 on day 1, l-FA 250 mg/m 2 intravenously plus 5-FU 850 mg/m 2 on day 2 (IRIFAFU); or OXA 100 mg/m 2 on day 1, l-FA 250 mg/m 2 plus 5-FU 1050 mg/m 2 on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85 mg/m 2 and 5-FU to 850 mg/m 2 [OXAFAFU low dose (ld)]. Results: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P = 0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade > 3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P = 0.046) and overall survival of patients (18.9 versus 15.6 months; P = 0.032) were significantly prolonged with OXAFAFU. Conclusions: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred

BACKGROUND In patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression-free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5-fluorouracil/leucovorin (5-FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5-FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5-FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5-FU/LV in combination with oxaliplatin, especially in older patients. METHODS Elderly (≥ 70 years) patients with MCC were treated with a 3-weekly regimen of oxaliplatin at an initial dose of 85 mg/m2 intravenously on Day 1 plus capecitabine 1000 mg/m2 orally twice daily from Days 2 to 15 (XELOX regimen). In the absence of Grade ≥ 2 hematologic toxicity, oxaliplatin was increased to 100 mg/m2 in the second cycle, and in the absence of Grade ≥ 2 nonhematologic adverse events during Cycle 2, capecitabine was increased to 1250 mg/m2 twice daily in the third and subsequent cycles. After the first 35 patients (first series), the treatment protocol was amended so that only an oxaliplatin increase to 110 mg/m2 and 130 mg/m2 during Cycles 2 and 3, respectively, was planned in the remaining 41 patients (second series). RESULTS Seventy-six patients with a median age of 75 years (range, 70–82 years) entered the current study. In the first series, the oxaliplatin dose was increased in 18 (51%) patients, and the capecitabine dose was increased in 4 (11%) patients. In the second series, the oxaliplatin dose was increased to 110 mg/m2 in 26 (63%) patients, and to 130 mg/m2 in 19 (46%) patients. In all, 2 complete and 29 partial responses were observed, for an overall RR of 41% (95% confidence interval [CI], 30–53%). The median PFS was 8.5 months (95% CI, 6.7–10.3 months), and the median OS was 14.4 months (95% CI, 11.9–16.9 months). In a multivariate analysis, the presence of disease symptoms affected both PFS and OS, whereas OS also was independently affected by male gender and disease spread. Age had no independent effect on PFS or OS. Five percent of patients developed Grade ≥ 3 hematologic toxicity during treatment, Grade 3 peripheral neuropathy occurred in 8% of patients, and severe hand-foot syndrome in 13% of patients. CONCLUSIONS Fit elderly patients with MCC showed a good RR to XELOX with only mild toxicity observed in most patients. XELOX, should, therefore be considered as an important therapeutic option for elderly patients with MCC. Cancer 2005. © 2005 American Cancer Society.

Objectives: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. Methods: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m2 and gemcitabine 800 mg/m2 i.v. on days 1, 8, 15 every 28 days. Results: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53–28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71–16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3–4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. Conclusion: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study.

From September 2001 to November 2002, 35 patients aged 70-81 (median, 75) years, with measurable metastatic lesions from colorectal carcinoma, were treated with a combination of oxaliplatin (OXA) infused i.v. over 2 h on day 1, and capecitabine, assumed orally twice a day (12-h apart) from day 2 to day 15. An alternated dose escalation for both drugs was planned over the first three cycles for each patient, in the absence of WHO gradeor =2 toxicity on previous cycle: starting doses were 85 mg/m2 for OXA, and 2000 mg/m2 (day) for capecitabine on first cycle; on second cycle, OXA was planned at 100mg/m2, while capecitabine was planned at 2500 mg/(m2 day) on third cycle. Treatment was repeated every 3 weeks until progression, or for a maximum of 12 cycles. A total of 212 cycles were administered, with a median of 6 (range, 1-12) cycles/patient. Dose escalation was performed in 18 (51%) patients for OXA, and in 4 (11%) patients for capecitabine. No grade 4, and 10 (29%) cases of grade 3 toxicity of any type were reported. Abdominal symptoms (pain, nausea, or vomiting) affected 66% of patients, but they were of grade 3 in only 2 (6%) patients. Grade 3 diarrhoea occurred in 3 (9%) patients. Two complete and 12 partial responses (PR) were reported, for an overall response rate of 40% (95% CI, 24-58%). Progression of disease occurred in 23 (66%) patients, and 18 (51%) died. The actuarial median progression-free and survival time were 6.9 and 14.1 months, respectively.

605 Background: Primary chemotherapy, as part of multimodality treatment, has become the standard of care for locally advanced breast cancer (LABC) to increase DFS, OS and conservative surgery. Stage III B is renowned as the worst of LABC, and despite appropriate therapy the majority of patients (pts) will experience distant metastases and death within 2–3 years. The optimal regimen and schedule of primary chemotherapy is uncertain. Aim of our study was to verify the efficacy of an original cisplatin-based regimen (PEV) in terms of response and survival. Methods: Between 1996 and 2001 72 consecutive III B pts were treated with primary chemotherapy: Cisplatin 50 mg/m2, Epirubicin 100 mg/m2, Vinorelbine 25 mg/m2 every 14 (44%) or 21 (66%) days for 4 (33%) or 6 (67%) cycles, followed by surgery, radiation, adjuvant CMF 1, 8 q28 x 6 cycles + - TAM. Median age was 50 y (29–70); 47% premenopausal; 75% T4 abc, 25% T4 d; 45% ER-; 69% PgR-; 46% Ki 67+; 40% G3; 87,5% clinical axillary nodes positive. Results: All p...

Objective: We conducted a multi-institutional phase II study to evaluate the tolerability and activity of a sequential schedule of treatment with doxorubicin and docetaxel in chemotherapy-naive women with advanced breast cancer. Methods: A total of 73 patients with PS (ECOG) 0–2, aged 2 by intravenous (i.v.) 30 min injection on day 1 followed the day after by docetaxel 75 mg/m2, by i.v. 60 min infusion. Cycles were repeated every 28 days. Results: Overall, the median number of administered cycles was 6 (range 1–14). The most common toxicity was hematological, with 56.2% of the patients who experienced grade 3–4 neutropenia. However, febrile neutropenia occurred only in 2.8% of the cases. The median cumulative dose of doxorubicin was 350 mg/m2 (range 50–700 mg/m2). Eleven patients (15.4%) were documented to have >10% but Conclusion: This sequential treatment with doxorubicin and docetaxel is an effective, feasible and a well-tolerated regimen. The main toxicity was neutropenia. The lack of cardiotoxicity is an important advantage of such a doxorubicin-docetaxel combination and it justifies phase III comparative studies with other anthracyclines/taxanes containing schedules in both advanced and early-stage breast cancer.

Aim: Six months FOLFOX4 or XELOX is the standard adjuvant chemotherapy in radically resected stage III colon cancer, however a shorter duration of therapy could be equally efficacious. Methods: This is an Italian, multicenter, non-inferiority phase III trial randomizing patients (pts) with stage III and high risk stage II colon cancer to receive 3 (arm 3) vs 6 (arm 6) months of FOLFOX4 or XELOX. Primary end-point is relapse free survival (RFS), and the arm 3 will be considered non-inferior if the superior margin of the 95% CI of the HR is Results: From June 2007 to March 2013, 3,759 patients were accrued and 3,738 (1860 in arm 3 and 1878 in arm 6) included in the intent-to-treat (ITT) population, since 21 pts were excluded due to major violations. The proportion of FOLFOX4 vs XELOX was 64% vs 36% in both arms. Among the ITT population, demographic factors (including gender and age) were balanced in the two arms. As expected, compliance was higher in arm 3 than in arm 6: treatment completion rate without any modification of planned dose and timing was 35% in arm 3 and 12% in arm 6, while approximately 55% pts in both arms completed treatment with modifications of dose and/or timing, resulting in 90% vs 67% pts receiving all the planned cycles. Therapy was permanently interrupted due to toxicity in 5% of pts in arm 3 and 17% in arm 6. The overall incidence of grade 3-4 toxicity (including grade 2 oxaliplatin neurotoxicity) events was 37% in arm 3 and 60% in arm 6. Grade 2+ neuropathy was more frequent in arm 6 than in arm 3: 32 % vs 9%, respectively. With a median follow-up of 30 months, 476 pts relapsed, 195 died and 520 relapsed and/or died. Conclusions: TOSCA is the first trial completing the accrual among the international initiative of comparing 3 vs 6 months of adjuvant treatment in colon cancer (IDEA). In general, reported toxicity was low, but, as expected, significantly higher in the 6-month arm compared to that of the 3-month arm; accordingly, compliance was lower in the standard 6-month arm. Data for efficacy analysis are premature. Disclosure: All authors have declared no conflicts of interest.

OBJECTIVE: This phase III study was aimed at evaluating whether the addition of gemcitabine (G) to vinorelbine (V) could improve the survival and quality of life (QoL) of elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, aged >or=70 years, were randomly allocated to receive V 30 mg/m(2) on days 1 and 8 every 3 weeks or G 1200 mg/m(2) plus V 30 mg/m(2) on days 1 and 8 every 3 weeks. Survival was the main end point of the study. The estimated sample size was 120 patients per arm, but an interim analysis of survival was planned on the first 60 patients per arm. RESULTS: In May 1999, an interim analysis was performed with the survival data of the first 120 eligible patients (V(arm)=60, G+V(arm)=60). Forty-nine patients had stage IIIB disease and 71 patients stage IV disease, median potential follow-up of 14 months (range; 3-22), 93 patients had died (G+V(arm)=41, V(arm)=52). Median survival time (MST) was 29 weeks and projected 1-year survival was 30% in the G+V(arm); these values were 18 weeks and 13% in the V(arm). At multivariate Cox analysis, the risk of death in the G+V(arm) compared with V(arm) was 0.48 (95% C1=0.29-0.79; P

Aim This phase II trial evaluated the biomodulation of 5-fluorouracil (5-FU) plus folinic acid (FA) with or without ifosfamide (IFO) in chemotherapy-naive patients with colorectal cancer. Patients and methods Forty-eight patients were randomized to receive: FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3), arm A; or FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3) plus IFO (2,000 mg/m2 in 1000 mL 5% dextrose in a 2-hr infusion, days 1 to 3), arm B. Mesna was added during and after IFO to prevent hemorrhagic cystitis. Treatment was repeated every 21 days in both arms. Results Forty-five patients were assessable for response: in arm A, 5 patients achieved a partial response (overall response, 25%), and in arm B, 2 patients achieved a complete and 1 a partial response (overall response, 12%). Time to failure was 3.5 months (range, 1–38) in patients treated with 5-FU plus FA, and 3 months (range, 1–21) in patients treated with the IFO combination. The median survival time was 13.5 months (range, 1–49 months) in arm A and 16 months (range, 1–43 months) in arm B. Diarrhea, stomatitis and vomiting were the most common nonhematologic toxicities in both arms. The most notable hematologic toxicity was leukopenia; 15% and 20% of patients experienced grade 4 in arm A and arm B, respectively. Conclusions IFO does not increase the activity of the 5-FU plus FA combination in advanced colorectal cancer.