Gruppo Oncologico Italia Meridionale Research Articles

Metronomic oral chemotherapy with cyclophosphamide plus capecitabine combined with trastuzumab (HEX) as first line therapy of HER-2 positive advanced breast cancer: A phase II trial of the Gruppo Oncologico Italia Meridionale (GOIM)

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.

The search for a melanoma-tailored chemotherapy in the new era of personalized therapy: a phase II study of chemo-modulating temozolomide followed by fotemustine and a cooperative study of GOIM (Gruppo Oncologico Italia Meridionale)

BackgroundIt is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6–11 months. Therefore, a need for other therapeutic options is still very much apparent.We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients.MethodsA total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21–81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m2 on days 1 and 2 and FM iv 100 mg/m2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients.ResultsWe reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status.ConclusionThis schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed.Trial registrationEUDRACT 2009–016487-36l; date of registration 23 June 2010.

When less is better: Safety and efficacy of combination of trastuzumab and continuous low oral dose chemotherapy (HEX) as first-line therapy for HER2-positive advanced breast cancer (ABC)—First early results from a phase II trial on behalf of Gruppo Oncologico Italia Meridionale (GOIM).

618 Background: Clinical activity of the combination of chemotherapy plus trastuzumab in HER2+ ABC has been well documented. We report the first results in terms of activity and safety of the combination of trastuzumab plus metronomic capecitabine and cyclophosphamide as first line therapy in HER-2 positive ABC. Methods: Patients (pts) at first relapse or with synchronous metastasis, were treated with trastuzumab (4 mg/kg, loading dose 6 mg/kg) plus oral capecitabine (1500mg/daily) and cyclophosphamide (50 mg/daily). Primary end-point was overall response rate (ORR), secondary end-points time to progression (TTP), clinical benefit rate (CBR; PR+ CR + prolonged SD for ≥ 24 weeks) and tolerability. The optimal two-stage design was applied. Results: A total of 31 pts with measurable ABC, tumors scored as +3 positive for HER-2 or FISH +, no pretreated with chemotherapy or trastuzumab for advanced disease have been enrolled, 28 actually valuable for response and toxicity. Median age was 59 years (range 42-87), visceral metastases were present in most patients (61%). Median number of cycles was 12 (range 1-37+). The ORR was 61 % (95% CI, 41-78%), with 1 CR (3.6 %) and 16 PR (57.1%). 9 patients had prolonged SD (32%). The CBR was 82.1% (95% CI , 63%-94%). Five progressions were observed (18%). Median TTP was 7 months (range 2- 19 + months). Ten pts received more than 20 courses. Worst toxicities were grade 2 hand-foot syndrome in 4 pts, grade 2 anemia in 4 pts, grade 2 nausea in 2 pts and diarrhea grade 3 in 1 pt. Cardiac toxicity grade 2 in 1 pts. Alopecia was not reported. Conclusions: Combination of trastuzumab and low dose metronomic oral chemotherapy in HER-2 + breast cancer has shown clinical activity. The tolerability was excellent and allowed the prolonged delivery of the combination. Thus, the patients accrual is ongoing to the pre-set target of 66 patients. Clinical trial information: 2009-017083-16.

A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study

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 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. 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. 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.

First-line cisplatin with docetaxel or vinorelbine in patients with advanced non-small-cell lung cancer: A quality of life directed phase II randomized trial of Gruppo Oncologico Italia Meridionale

Background Quality of life (QoL) has gained greater importance in the management of metastatic non-small-cell lung cancer due to the palliative nature of treatment. Docetaxel (DCT) and cisplatin (CDDP) doublet has been reported to be associated to a better QoL than the weekly vinorelbine (VNR) and CDDP regimen. Recently a newer more tolerated schedule of the VNR/CDDP regimen has been published and is widely employed in medical practice. The impact of these regimens on patients’ QoL as well as symptoms control and type and grading chemo-related side-effects has been compared prospectically. Methods Patients received CDDP 75 mg/m 2 plus DCT 75 mg/m 2 on day 1 every weeks (arm A) or CDDP 80 mg/m 2 on day 1 plus VNR 30 mg/m 2 day 1 and 8 every 3 weeks (arm B). G-CSF and/or EPO were employed as needed. Health-related QoL was assessed at entry and after every cycle by the EORTC-QLQ-C30 and LC13 questionnaires, toxicity by the NCI-NCCN CTC vs 2, and intent-to-treat objective response by the Recist criteria. Results The QoL questionnaires were completed by 37 pts (88%) in the DCT/CDDP arm and 39 pts (87%) in the VNR/CDDP one. Baseline mean scores and rates at which pts failed to complete QoL assessment were similar in the two arms. Global health status of the EORTC QLQ-C30 scale and specific symptoms control (LC13 module) improved during treatment without any statistically significant difference between the two arms. Emotional functioning remained stable in both groups during treatment, whereas physical and role improved slightly. In the DCT/CDDP arm 14 pts (33%; 95%CL 24–40%) had PR, and 10 (24%) SD for a 57% TGCR. In the VNR/CDDP arm 12 pts (27%) achieved PR, 18 (41%) SD a 68% TGCR. Differences were not statistically significant. Median time-to-progression was 4.2 months in the DCT/CDDP arm and 4.5 months in the VNR/CDDP one, and median overall survival was 12.1 (range 1–26+ months) and 12.5 months (range 1–28+ months) for DCT/CDDP and VNR/CDDP arms, respectively. Febrile neutropenia rate was higher in the VNR/CDDP arm ( p = 0.02) as well as G3-4 anemia ( p = 0.005) and G-CSF/EPO use ( p = 0.019). Conclusions Global and specific health-related QoL data similar in both treatment groups with no statistically significant difference. Efficacy measures, overall response rate, time-to-progression and overall survival were equivalent in both arms. However, severe anemia and febrile neutropenia are statistically more frequent in the VNR/CDDP arm than in the DCT/CDDP one. These data should be considered in treatment decision-making for pts with advanced non-small-cell lung cancer and for the design of future trials with chemotherapy plus biologics.

First-line cisplatin (P) with docetaxel (TXT) or vinorelbine (VNR) in patients with advanced non-small cell lung cancer: A randomized phase II trial of the Gruppo Oncologico Italia Meridionale

e19042 Background: P-based doublets are considered standard therapy for advanced NSCLC. The GOIM consider P/VNR as a reference treatment. P/TXT doublet has been reported to be active but it's not well known its real impact on QoL in comparison to P/VNR. Methods: Pts received either 6 courses of P/TXT or P/VNR with QoL and safety being the primary endpoints. Secondary endpoint included response rate, TTP, OS, and tolerability. Patients with stage IV/IIIB, age ≤70, and ECOG PS 0–1, were eligible. Sample size was calculated according to Fleming's single-stage procedure. QoL was analysed using the EORTC questionnaire, responses and toxicity according to the RECIST and NCI-CTC criteria. Pts were randomized to: TXT 75 mg/m2 over 60 min followed by P 75 mg/m2 on d1 every 21 d, or VNR 30 mg/m2 on d 1,8 and P 80 mg/m2 on d1 every 21 d. Results: From 12/06 to 3/08 86 pts were enrolled: P/TXT 42pts, M/F 32/10, IIIB/IV 8/34, squamous/not-squamous:13/29, median age 61 (r 41–70); P/VNR 44 pts, M/F 35/9, IIIB/IV 10/33, squamous/not-squamous 14/30, median age 62 (r 44/70). No statistically significant differences were observed in QoL among the two arms. Detailed analysis of side-effects showed no difference among the two regimens with the exception of G3–4 neutropenia and leukopenia with were slightly higher in the P/VNR arm (p=0.02 and p=0.0005 respectively). The use of G- CSF/darbopoietin was more frequent in pts treated with P/VNR than in the P/TXT arm (p=0019). Conclusions: Final data show an equivalence among the two arms regarding QoL and activity but with a slightly more hematological toxicity in the P/VNR arm. Both regimens are to be considered as standards in the treated of advanced NSCLC. [Table: see text]

First-line cisplatin (P) with docetaxel (TXT) or vinorelbine (VNR) in patients with advanced non-small-cell lung cancer: A phase II randomized trial of Gruppo Oncologico Italia Meridionale

First-line cisplatin (P) with docetaxel (TXT) or vinorelbine (VNR) in patients with advanced non-small-cell lung cancer: A phase II randomized trial of Gruppo Oncologico Italia Meridionale

Correlation between basal bilirubin levels and survival in advanced colorectal carcinoma treated with CPT-11-based chemotherapy: A study of the Gruppo Oncologico Italia Meridionale (G.O.I.M.)

BackgroundThis study was carried out to evaluate total basal bilirubin levels as a predictive factor for survival and toxicity in patients with advanced colorectal carcinoma treated with CTP-11-based regimens. Patients and methodsThe analysis was carried out on a data base including 287 patients affected by advanced colorectal carcinoma all treated with CPT-11 plus bolus and continuous venous infusion intravenous folinic acid and 5-fluorouracil on a biweekly schedule (FOLFIRI regimen). Patients were divided into four groups according to basal bilirubin levels as follows: <0.49mg/dl; >0.50 and <0.99mg/dl; >1.00 and <1.49mg/dl; >1.50mg/dl. Analysis of overall median survival and time-to-progression were correlated to performance status at entry, volume of liver metastases, and carcinoembrionary antigen. ResultsGlobal statistical analysis showed that bilirubin levels were strongly correlated with time-to-progression and overall survival in a statistically significant fashion (p<0.0001). The size of liver metastases represents the only study parameter which is correlated to basal bilirubin levels in a statistically significant fashion. Neutropaenia and diarrhoea were also correlated to baseline bilirubin levels in a statistically significant manner (p=0.001). ConclusionsData reported in this study support the observation that basal bilirubin levels are a biomarker able to predict, at least in part, the clinical efficacy and toxicity of CPT-11-based chemotherapy in patients with advanced colorectal carcinoma.

Second-line chemotherapy in advanced pancreatic carcinoma: a multicenter survey of the Gruppo Oncologico Italia Meridionale on the activity and safety of the FOLFOX4 regimen in clinical practice

BackgroundIn daily clinical practice second-line chemotherapy (SLCT) is frequently given to patients with advanced pancreatic cancer failing gemcitabine-based first-line chemotherapy without solid scientific support. Patients and methodsA retrospective survey was carried out including 42 patients. Patients received standard FOLFOX4 regimen biweekly until progression or unacceptable toxicity. ResultsSix partial responses (14%) and 16 stabilizations (38%) were recorded for a tumor growth control rate of 57%. The median time to progression (TtP) was 4 months (range 1–7 months), and median overall survival (OS) was 6.7 months (range 2–9 months). A stabilization of performance status (PS) and a subjective improvement of cancer-related symptoms were recorded in 27 patients. ConclusionsData presented in this paper support the use of FOLFOX4 regimen in the second-line treatment of adenocarcinoma of the pancreas patients. The use of SLCT, however, should be carefully proposed to patients with good PS or those who had a good response to first-line therapy.