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F Perri,1 G Della Vittoria Scarpati,2 F Caponigro,1 F Ionna,3 F Longo,3 S Buonopane,4 P Muto,4 M Di Marzo,5 S Pisconti,6 R Solla7 1Head and Neck/Sarcoma Medical Oncology Unit, INT IRCCS G Pascale, Naples, Italy; 2Medical Oncology Unit, ASL NA3, Hospital of Pollena Trocchia, Naples, Italy; 3Department of Otolaryngology and Head and Neck Surgery, INT IRCCS G Pascale, Naples, Italy; 4Department of Radiation Therapy, INT IRCCS G Pascale, Naples, Italy; 5Department of Abdominal Surgery, INT IRCCS G Pascale, Naples, Italy; 6Medical Oncology Unit, POC SS Annunziata, Taranto, Italy; 7Italian National Research Council, Institute of Biostructure and Bioimaging, Naples, Italy Abstract: Nasopharyngeal carcinoma is a rare disease in Western countries. Nevertheless, its incidence in China, Singapore, and other Eastern countries reaches 20 cases per 100,000 people. Being an extremely chemo- and radiosensitive disease, upfront treatment often consists in the association of intensity-modulated radiation therapy and concurrent cisplatin. Unfortunately, about 20% of the patients suffer from a radioresistant disease which recurs after upfront therapy. For these patients, mainly available therapeutic options consist in systemic therapy, in particular poly-chemotherapy. In those showing a single locoregional recurrence, chemotherapy is not considered to be the preferred approach and other different strategies may be employed. Re-irradiation and surgery are strategies that are always used more often, albeit related to high risk of morbidity. Immunotherapy and targeted therapy, such as heavy ions-based re-irradiations, are experimental but very intriguing options. Keywords: nasopharyngeal carcinoma, re-irradiation, poly-chemotherapy, radioresistant, immunotherapy &nbsp

Baseline clinical prognostic factors for recurrent and/or metastatic (RM) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy are lacking. CT-based radiomics may provide additional prognostic information. A total of 85 patients with RM-HNSCC were enrolled for this study. For each tumor, radiomic features were extracted from the segmentation of the largest tumor mass. A pipeline including different feature selection steps was used to train a radiomic signature prognostic for 10-month overall survival (OS). Features were selected based on their stability to geometrical transformation of the segmentation (intraclass correlation coefficient, ICC > 0.75) and their predictive power (area under the curve, AUC > 0.7). The predictive model was developed using the least absolute shrinkage and selection operator (LASSO) in combination with the support vector machine. The model was developed based on the first 68 enrolled patients and tested on the last 17 patients. Classification performance of the radiomic risk was evaluated accuracy and the AUC. The same metrics were computed for some baseline predictors used in clinical practice (volume of largest lesion, total tumor volume, number of tumor lesions, number of affected organs, performance status). The AUC in the test set was 0.67, while accuracy was 0.82. The performance of the radiomic score was higher than the one obtainable with the clinical variables (largest lesion volume: accuracy 0.59, AUC = 0.55; number of tumoral lesions: accuracy 0.71, AUC 0.36; number of affected organs: accuracy 0.47; AUC 0.42; total tumor volume: accuracy 0.59, AUC 0.53; performance status: accuracy 0.41, AUC = 0.47). Radiomics may provide additional baseline prognostic value compared to the variables used in clinical practice.

Background B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Patients and methods Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. Results A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72–1.36,P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53–1.11,P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38–1.20,P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%,P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). Conclusion The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. Clinical trial number EudraCT# 2011-002564-24.

Background Nivolumab is an established treatment for recurrent/metastatic (RM) head and neck squamous cell carcinoma (HNSCC) patients (pts) failing platinum-based treatment. However, knowledge about safety and activity data are limited to pts enrolled into clinical trial leading to drug approval. Methods We conducted a single-arm, open-label, multicentre prospective phase IIIb clinical trial with nivolumab 240 mg in subjects with RM HNSCC. Primary objective was to assess the incidence of high-grade (CTCAE v 4.03 grade 3 or higher), treatment-related (TR), selected adverse events (AE); secondary objectives were to characterize the outcome of all AE in terms of duration, time to event onset, and event resolution. Moreover, we assessed Overall Response Rate (ORR), OS and PFS and we analysed in an exploratory way clinical and biomolecular factors associated with improved outcome. A subgroup analysis was also performed in 20 pts to define baseline immunologic profiles and their changes along the treatment. Results We enrolled 127 pts with the following characteristics: male (82%), age higher than 65 years (43%), with primary cancer in oral cavity (33%), oropharynx (31%), larynx (24%), hypopharynx (8%) or other sites (4%). Performance status was 0 in 34% and 1 in 63% pts; 27% of the pts had received 2 or more systemic lines of therapy before. Grade 3-4 TR AE happened in 11% of the pts (anemia 2%, pneumonitis and encephalitis 1%), while all-grade TR AE were 40% (fatigue 20%, hypothyroidism 8%, anemia and pruritus 6%). Median duration of grade 3-4 TR AE was 10 days (4-22) and of grade 1-2 TR AE 63 days (1-336). Median OS and PFS were 7 months (5-NR) and 2 months (1.5-2.5) and ORR 12%. Pts experiencing any TR AE had an improved OS; HR 0.459 (0.254-0.827, p = 0.0096). Analyses of stromal tumor-infiltrating lymphocytes (TILs) status and PD-L1 status (clone 28-8 Agilent) are ongoing. Conclusions In this phase IIIb trial, nivolumab confirmed the safety and efficacy profile of the registration trial. Experiencing any grade TR AE revealed to be a favorable prognostic factor, as possible expression of effective immune response. Legal entity responsible for the study GONO group. Funding Bristol Myers-Squibb. Disclosure P. Bossi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: Angelini; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Voluntis. M.C. Merlano: Honoraria (self), consultancy or A.B.: Bristol M.S.; Honoraria (self), consultancy or A.B.: Merck S.D.; Honoraria (self), consultancy or A.B.: Merck; Shareholder / Stockholder / Stock options, Stocks: Glaxo SK; Research grant / Funding (institution), Support for clinical trials: Merck. M.G. Ghi: Honoraria (self), Advisory role: BMS; Honoraria (self), Advisory role: MSD; Honoraria (self), Advisory role: Merck Serono. G. Rinaldi: Honoraria (self), Research grant / Funding (self), Speaker and PI in clinical Trial: Novartis; Honoraria (self), Research grant / Funding (institution), Speaker and PI in clinical Trial: BMS; Research grant / Funding (self), PI in clinical Trial: MSD. F. Morelli: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): BMS. A. Farnesi: Honoraria (self), speaker: Bayer; Honoraria (self), speaker: Novartis. D. Galizia: Honoraria (self), public speaker: BMS; Honoraria (self), congress travel costs coverage: Merck; Honoraria (self), congress travel costs coverage: Roche; Honoraria (self), congress travel costs coverage: Angelini. L.F. Licitra: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Speaker: BMS; Honoraria (self), Research grant / Funding (institution), Speaker: Eisai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Speaker: MSD; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, Speaker: Merck-Serono; Honoraria (self), Research grant / Funding (institution), Speaker: Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution), Speaker: Novartis; Honoraria (self), Research grant / Funding (institution), Speaker: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Speaker: Roche; Honoraria (self), Travel / Accommodation / Expenses, Speaker: Bayer; Honoraria (self), Travel / Accommodation / Expenses, Speaker: Debiopharm; Honoraria (self), Travel / Accommodation / Expenses, Speaker: Sobi; Honoraria (self), For teaching in medical meetings: Incyte Biosciences Italy srl; Honoraria (self), Expert opinion in advisory board meetings: Doxa Pharma srl; Honoraria (self), For public speaking in medical meetings: Amgen; Honoraria (self), Expert opinion in advisory board meetings: Nanobiotics Sa; Honoraria (self), For public speaking in medical meetings and/or expert opinion in advisory boards: GSK; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2016-2017): Celgene International; Research grant / Funding (institution), Founds to my Institution for 2 clinical trials (2014-2018): Exelixis Inc.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2014-2015): Hoffmann-La Roche Ltd.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2017): IRX Therapeutics, Inc.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2016): Medpace Inc.; Research grant / Funding (institution), Founds to my Institution for a clinical trial (2014): Pfizer; Travel / Accommodation / Expenses, Travel coverage for medical meetings: Stilema, AccMed, Aiocc, Aiom. All other authors have declared no conflicts of interest.

Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN).Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m(2)) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m(2). The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination.Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m(2)). Dose level 2 (brostallicin 7 mg/m(2) and cisplatin 75 mg/m(2)) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3-4 neutropenia was observed in 90.5% of patients, grade 3-4 thrombocytopenia in 38.1%, grade 3-4 anemia in 23.8%. The cycle 1 nadir (ANC500 x 10(9)/L) for neutrophils was Day 14 (median; range 11-17) with recovery to an ANC of1,500 3.5 days after nadir (median; range 2-4) at dose level 3. The cycle 1 nadir (median of 51,000 x 10(9)/L) for platelets occurred on Day 13 (median; range 10-15) with recovery to a platelet count of100,000 4 days after nadir (median; range 2-8). No objective responses were observed, but seven patients had a long lasting (18 weeks) stable disease.Further studies of the combination of brostallicin and cisplatin are warranted.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.

Contains fulltext : 49133ravic.pdf (Publisher’s version ) (Closed access) E7070 is a synthetic chloro-indolyl sulphonamide that is being developed as an anti cancer agent. In this phase II study, 28 patients with metastatic melanoma received 700 mg/m(2) of E7070 as a 60-min infusion repeated every 3 weeks. Although therapy was well tolerated, with one patient receiving 14 courses of treatment, there were only minor responses on independent radiological review. E7070 does not warrant further development as a single agent for the treatment of metastatic melanoma.

Background: Sabarubicin (MEN-10755) is a third generation anthracycline, with a remarkable antitumor activity in human tumor xenografts, including doxorubicin-resistant tumors. Phase I studies have shown that myelosuppression is the main toxicity of sabarubicin, while its cumulative cardiotoxicity is mild. Methods: The aim of the study was to evaluate the activity and safety profile of sabarubicin in patients with locally advanced or metastatic ovarian cancer failing 1st line platinum and/or taxane based chemotherapy, and relapsing earlier than 6 months after the last chemotherapy. Eligible patients received sabarubicin at the dose of 80 mg/m2 (dose level 0) every 3 weeks over 30 minutes. Dose was to be escalated to 90 mg/m2 (dose level +1) after the 1st cycle in case of grade 0-1 toxicity, while it was to be reduced to 60 mg/m2 (dose level −1) in case of toxicity. Response was assessed every 2 courses according to WHO criteria. Toxicity was graded according to Common Toxicity Criteria version 2.0. Gehan's design was used for sample size determination. Results: Nineteen patients were enrolled and received 65 courses. One patient had a confirmed partial response, 9 patients had stable disease, 5 patients had disease progression, 3 patients were not evaluable for response, while one patient had an early progressive disease. The duration of response was 88 days. Mean time to disease progression was 125 days (range 56–188). Median survival was 62 days (range 36–202). Hematologic toxicity was moderate, since grade 3–4 neutropenia was observed in 25 out of 52 courses at 80 mg/m2, and grade 4 neutropenia occurred in one out of 12 courses at 90 mg/m2. Other grade 3–4 toxicities were: fatigue (five cases), nausea (two cases), stomatitis, general health deterioration, anorexia, vomiting, abdominal pain, hyponatremia (one case each). Cardiac toxicity was observed in the study; in fact, left ventricular ejection fraction (LVEF) fell below 50% in 2 patients, and 3 patients had a >15% decrease of LVEF from baseline, but there were no signs/symptoms of congestive heart failure. Conclusions: Sabarubicin showed limited activity in patients with resistant ovarian cancer. However, the observed data on disease stabilization, together with the drug's overall manageable toxicity profile, may prompt to its further investigation in advanced ovarian cancer.

The aim of this study was to determine the patient's preference for oral UFT/leucovorin (LV) or intravenous (i.v.) 5-fluorouracil (5-FU)/LV chemotherapy in metastatic colorectal cancer and to compare 5-FU exposure with these two treatment options. A total of 37 previously untreated patients with advanced colorectal cancer were randomised to start treatment with either oral UFT 300 mg/m2/day plus oral LV 90 mg/day for 28 days every 5 weeks or i.v. 5-FU 425 mg/m2/day plus LV 20 mg/m2/day for 5 days every 4 weeks. For the second treatment cycle, patients were crossed-over to the alternative treatment regimen. Prior to the first and after the second therapy cycle, patients were required to complete a therapy preference questionnaire (TPQ). The pharmacokinetics of 5-FU were determined by taking blood samples on days 8, 15 or 22 and 28 for UFT and on days 1 and 5 for i.v. 5-FU. 36 patients were eligible. 84% of the patients preferred oral UFT over i.v. 5-FU. After having experienced both treatment modalities, patients indicated taking the medication at home, less stomatitis and diarrhoea, and pill over injection as the most important reasons for their preference. The area under the plasma concentration curve (AUC) for 5-FU after UFT administration was 113 microM x min on day 8, 114 on day 15 and 98 on day 28; the peak levels (Cmax) were 1.2, 1.3 and 1.0 microM, respectively. The AUC for the 5-FU/LV courses was 3083 microM x min for day 1 and 3809 for day 5 (P=0.002). The Cmax was 170.1 and 196.2 microM (P=0.06) and the clearance 2.6 and 1.9 l/min, respectively (P=0.002). Patients with metastatic colorectal cancer clearly preferred oral over i.v. chemotherapy treatment. This choice was most importantly influenced by convenience and toxicity considerations. Although i.v. bolus 5-FU leads to higher peak 5-FU concentrations and AUC values compared with oral UFT, this pharmacokinetic advantage of i.v. 5-FU seems to translate mainly into higher toxicity as seen in large randomised studies comparing oral UFT/LV with i.v. 5-FU/LV. Oral UFT/LV compares favourably with i.v. 5-FU/LV in terms of toxicity and patient's preference and leads to prolonged 5-FU exposure, which is comparable to continuous i.v. 5-FU treatment.

Twenty-five patients with pretreated advanced colorectal carcinoma were subjected to second-line chemotherapy with sequential high-dose methotrexate and 5-fluorouracil. In 20 evaluable patients 2 (10%) partial responses, 12 (60%) stable disease and 6 (30%) progressions were observed. Partial responses were maintained for 3 and 4 months respectively; stable disease had a median duration of 4 months. The overall median survival after progression was 7 months. From our results sequential high-dose methotrexate and 5-fluorouracil cannot be recommended as second-line chemotherapy in advanced colorectal cancer.

43 patients with metastatic colorectal Cancer pretreated with 5-fluorouracil-based chemotherapy received vinorelbine plus 5-fluorouracil plus folinic acid with the aim of evaluating vinorelbine activity in advanced colorectal cancer and its potential synergism with commonly used drugs. 9 partial responses were observed, for an;overall objective response rate of 20.9%. 20 additional patients had stable disease (46.5%). Median duration of response was 7 months. Median survival from the start of treatment was 6 months. The main toxic effect was myelosuppression. We conclude that our regimen is active enough to warrant further evaluation in advanced colorectal cancer.

In this study, the feasibility and activity of combined chemotherapy of the farnesyl transferase inhibitor SCH66336 and gemcitabine was evaluated. This therapy was used as second-line treatment in patients with advanced urothelial tract cancer and the influence of SCH66336 exposure on the pharmacokinetics of gemcitabine was also determined. Patients who had received one previous chemotherapy regime for advanced urothelial cancer were treated with a combination of SCH66336 (150 mg in the morning and 100 mg in the evening) and Gemcitabine (1000 mg/m2 on day 1, 8 and 15 per 28-day cycle). Dosages of gemcitabine and its metabolite dFdU were performed on day one of cycle 1 before exposure to SCH66336 and day one of cycle 2. A total of 152 cycles were administered in 33 patients (median 3, range: 1-15). No patients had severe hematological toxicity, defined as Grade 4 thrombocytopenia or febrile neutropenia. Nine partial responses and one complete response were achieved in 31 assessable patients and corresponded to an overall response rate of 32.3% [95% CI:17%-51%]. There was no influence of exposure to SCH66336 on the level of gemcitabine or dFdU in 11 assessable patients. In conclusion, a combination of SCH66336 and gemcitabine is feasible in terms of toxicity and active as second-line treatment in patients with advanced urothelial tract cancer. SCH66336 had no effect on the pharmacokinetics of gemcitabine. Randomised trials should be undertaken to clarify the role of SCH66336 in combination with gemcitabine in cancer treatment.

Background: The purpose of this study was to carry out two randomised phase II trials of S 16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. Patients and methods: S 16020 at either 80 or 100 mg/m(2) was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m(2), was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S 16020 and 12 received methotrexate. Results: A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the turnout sites and erythematous rash; consequently, both studies were stopped. Conclusions: Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of this study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients received XR5000 at the dose of 3010 mg/m(2) as a 120-h central venous infusion every 3 weeks. The 15 patients (median age 56 years, range 48-71 years) enrolled had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (3 patients), 1 (11 patients) or 2 (1 patient). A total of 32 cycles of XR5000 (median 2, range 1-6) were given to 14 patients. No objective response (assessed according to World Health Organization (WHO) criteria) was documented in the 12 evaluable patients by an external review panel; in 4 out of the 12 patients disease stabilisation was recorded. The following toxicities graded according to the Common Toxicity Criteria (CTC) version 2.0. were observed: one grade 3 and two grade 4 granulocytopenia, one grade 3 and one grade 4 thrombocytopenia, one grade 3 deep venous thrombosis, one grade 3 fatigue, and grade 3 undocumented epileptic seizures which led to death in 2 patients. With only 4 out of 12 patients reaching stable disease when using this dose and regimen, further evaluation of XR5000 in advanced NSCLC is not justified.

Item does not contain fulltext BACKGROUND: XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of the present study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with ovarian cancer who had relapsed within 1 year after first-line chemotherapy with taxanes and platinum for advanced disease. PATIENTS AND METHODS: Patients received XR5000 at the dose of 3010 mg/m(2) through a 120-h central venous infusion every 3 weeks. Toxicity was graded according to the Common Toxicity Criteria (CTC), version 2.0. An independent panel assessed response every two cycles according to the World Health Organization (WHO) criteria. Gehan's rule was used for sample size determination. RESULTS: Sixteen patients were enrolled; one patient was ineligible because of prior melphalan single agent treatment. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (eight patients), 1 (five patients), or 2 (two patients). The 15 eligible patients received 43 cycles of XR5000 (median 2, range 1-8). Hematological toxicity was mild with only one grade 3 anemia in one patient. Other drug-related toxicities never exceeded grade 3 and included fatigue (four patients), thrombosis (one patient), nausea (one patient), stomatitis (one patient) as well as dyspnea/cough (one patient). One patient who had refused further therapy and controls after the first cycle was not assessable for response evaluation. No objective responses were observed. Four patients experienced stable disease and 10 patients progressive disease. The median time to progression was 42 days (CI 95% 40; 54). CONCLUSIONS: The complete lack of any objective response does not justify further evaluation of XR5000 in patients with advanced ovarian cancer using this dose and schedule, although the therapy was generally well tolerated.

The aim of this study was to determine the patient's preference for oral UFT/leucovorin (LV) or intravenous (i.v.) 5-fluorouracil (5-FU)/LV chemotherapy in metastatic colorectal cancer and to compare 5-FU exposure with these two treatment options. A total of 37 previously untreated patients with advanced colorectal cancer were randomised to start treatment with either oral UFT 300 mg/m2/day plus oral LV 90 mg/day for 28 days every 5 weeks or i.v. 5-FU 425 mg/m2/day plus LV 20 mg/m2/day for 5 days every 4 weeks. For the second treatment cycle, patients were crossed-over to the alternative treatment regimen. Prior to the first and after the second therapy cycle, patients were required to complete a therapy preference questionnaire (TPQ). The pharmacokinetics of 5-FU were determined by taking blood samples on days 8, 15 or 22 and 28 for UFT and on days 1 and 5 for i.v. 5-FU. 36 patients were eligible. 84% of the patients preferred oral UFT over i.v. 5-FU. After having experienced both treatment modalities, patients indicated taking the medication at home, less stomatitis and diarrhoea, and pill over injection as the most important reasons for their preference. The area under the plasma concentration curve (AUC) for 5-FU after UFT administration was 113 microM x min on day 8, 114 on day 15 and 98 on day 28; the peak levels (Cmax) were 1.2, 1.3 and 1.0 microM, respectively. The AUC for the 5-FU/LV courses was 3083 microM x min for day 1 and 3809 for day 5 (P=0.002). The Cmax was 170.1 and 196.2 microM (P=0.06) and the clearance 2.6 and 1.9 l/min, respectively (P=0.002). Patients with metastatic colorectal cancer clearly preferred oral over i.v. chemotherapy treatment. This choice was most importantly influenced by convenience and toxicity considerations. Although i.v. bolus 5-FU leads to higher peak 5-FU concentrations and AUC values compared with oral UFT, this pharmacokinetic advantage of i.v. 5-FU seems to translate mainly into higher toxicity as seen in large randomised studies comparing oral UFT/LV with i.v. 5-FU/LV. Oral UFT/LV compares favourably with i.v. 5-FU/LV in terms of toxicity and patient's preference and leads to prolonged 5-FU exposure, which is comparable to continuous i.v. 5-FU treatment.

Aim: Patients with R/M HNSCC who progress after first-line platinum-based therapy have a dismal prognosis and no well-defined treatment. Afatinib, an irreversible ErbB family blocker, showed anti-tumor activity in a phase II trial in this setting. Methods: In this phase III trial, patients with R/M HNSCC after progression on/after platinum-based therapy were randomised 2:1 to 40 mg/day oral afatinib (n = 322) or 40 mg/m2/week intravenous MTX (n = 161), stratified by ECOG performance status (0/1) and prior use of anti-EGFR antibody therapy (Yes/No) in the R/M setting. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), patient-reported outcomes (PROs) and safety. Results: Afatinib significantly improved the primary endpoint of PFS vs MTX (median 2.6 vs 1.7 months; HR = 0.80 [95% CI 0.65–0.98; p = 0.03]), but did not significantly improve OS vs MTX (median 6.8 vs 6.2 months; HR = 0.94 [0.75–1.18]). Disease control rate was higher with afatinib vs MTX (49.1% vs 38.5%; p = 0.04); ORR was 10.2% vs 5.6% (p = 0.10). Tumour shrinkage from baseline was observed in 34.8% of afatinib-treated patients compared to 22.4% of MTX-treated patients. Afatinib delayed deterioration of global health status, pain and swallowing vs MTX (all p ≤ 0.03) and provided improvement in pain (p = 0.03). The most frequent grade 3/4 drug-related adverse events were rash/acne (9.7%) and diarrhoea (9.4%) with afatinib, and leukopenia (15.6%) and stomatitis (8.1%) with MTX. Fewer treatment-related dose reductions, discontinuations and fatal events were seen with afatinib. Additional optional biomarker analyses, including p16 status, will be presented. Conclusions: In this phase III trial, second-line afatinib significantly improved the primary endpoint of PFS and delayed deterioration of PROs vs MTX, with a manageable safety profile, in patients with R/M HNSCC after failure of platinum-based therapy. Machiels JPH, Haddad RI and Fayette J contributed equally to this work. Disclosure: J-P. Machiels: Advisory boards for Boehringer Ingelheim, Novartis; R.I. Haddad: Advisory boards for Celgene, Bayer Corporate sponsored research for Boehringer Ingelheim; L.F. Licitra: Advisory boards for Eisai, Bristol-Myers Squibb, GlaxoSmithKline, Merk-Serono, Amgen, Boehringer Ingelheim, Debiopharm, VentiRX, Sobi, F. Hoffmann-La Roche, Celgene; M. Tahara: Advisory boards for Eisai, Boehringer Ingelheim, Otsuka Pharmaceutical Corporate sponsored research for Eisai, Boehringer Ingelheim Other substantive relationships with Merck Serono, Bristol-Myers Squibb; J.B. Vermorken: Advisory boards for Merck Serono, Genentech Other substantive relationships with Steering CIE LUX-HN P.M. Clement: Advisory boards for Merck Serono, Leo Pharma, Grunenthal Corporate sponsored research for Merck Sharp & Dohme, Grunenthal; T. Gauler: Stock ownership with Bayer AG Advisory boards for Boehringer Ingelheim (BI), Merck Serono, Novartis Corporate sponsored research for BI (ITS), Merck Serono (ITS) Other substantive relationships with BI, Merck Serono; G. De Castro Jr: Advisory boards for Boehringer Ingelheim, Bayer, F. Hoffmann-La Roche, Novartis; X.J. Cong, L. Svensson and E. Ehrnrooth: Other substantive relationships with Employee, Boehringer Ingelheim. All other authors have declared no conflicts of interest.

XR 5000 is one of a series of tricyclic carboxamide-based cytotoxic agents. It binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II, thus possibly overcoming the resistance resulting from downregulation of either enzyme. Twenty patients with advanced or metastatic colorectal cancer, unpretreated for metastatic disease, received XR 5000 at the dose of 3010 mg/m(2) in a 120-h central intravenous (i.v.) infusion every 3 weeks. Response was evaluated every two cycles. No complete (CR) or partial responses (PR) were observed in eligible patients (response rate, 0 of 19, 0%; 95% confidence interval (CI): 0-18%). 5 patients had stable disease, which lasted from 79 to 157 days. Haematological toxicity was low, since only one grade 4 neutropenia and two grade 3 anaemia were observed. Other treatment-related grade 3-4 toxicities were: deep venous thrombosis (2 cases), liver toxicity, diarrhoea, anorexia, dyspnoea, chest pain, infection (1 case each). Despite the good toxicity profile, these results do not support further trials with XR 5000 in metastatic colorectal cancer.

Forty-one patients with advanced breast cancer were given carboplatin and vinorelbine as second-line therapy. Overall objective response rate was 46% (95% confidence interval 26-56%). Myelotoxicity was the most frequently observed toxic effect; grade III-IV leucopenia occurred in 46% of the patients. Our regimen is active as second-line chemotherapy for advanced breast cancer and warrants further evaluation.

We describe a case of partial regression of metastatic hepatocellular carcinoma after treatment with thymostimulin. The patient, a 58-year-old man, received no specific therapy for his tumor, but only a thymus extract (« thymostimulin »). At follow-up 6 months later the patient showed clinical improvement, reduction of alpha-fetoprotein level an liver lesions, and a complete regression of lung metastases. The patient died of progression of the disease with 2-year overall survival.

4090 Background: Bortezomib is a potent and reversible inhibitor of the ubiquitin-mediated proteasome pathway, whose inhibition results in the stabilization of p53, p21Cip1, p27Kip1, Bax, in cell-cycle dysregulation and, finally, apoptosis. A phase I study of the combination of 5FU/LV and bortezomib has shown a significant stable disease rate in advanced CRC (Iqbal, ASCO 2004). Methods: In this phase I study bortezomib was given as an IV push over 3 to 5 seconds on days 1, 8 and 15 in combination with standard FOLFOX-4 every 28 days in chemo-naïve pts with advanced CRC. Bortezomib starting dose level was 1.3 mg/m2. A 3+3 study design was utilized at predefined dose levels (DL). Dose-limiting-toxicity (DLT) was assessed during cycle 1. Exploratory pharmacogenetics research was conducted. Results: 15 pts were treated and 46 cycles given. At DL2 (1.6 mg/m2), 2/4 pts experienced a DLT: G3 febrile neutropenia causing treatment delay and bortezomib dose reduction in 1pt and one bortezomib dose skipped due to persistent G2 peripheral neuropathy and myalgia in 1pt. At DL1 (1.3 mg/m2), 2/6 pts had a DLT. Both pts experienced a G3 neutropenia on day 15, which prevented treatment from being given as scheduled. DL-1 (1 mg/m2) was therefore investigated and no DLT was observed among 5 pts. The most frequently reported toxicities in cycle 1 were γGT (64%), nausea, fatigue and sensory neuropathy (53%), pain (33%), diarrhea and fever (27%), vomiting (20%), anorexia, dyspnea and mucositis (13%) and neutropenia 29% (G2,3). 12 pts are currently evaluable for response; 6 had a partial response, 3 stable disease and 3 disease progression. Conclusion: The toxicity profile of this combination is predictable and early evidence of clinical activity has been observed. The recommended bortezomib dose for further investigation within this regimen is 1 mg/m2. No significant financial relationships to disclose.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P < .02) and monocyte (P < .01) counts in patients receiving doses ≥ 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve0-24 hours and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 μmol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. The standard '3 + 3' design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than one-third of patients of a given cohort had dose-limiting toxicity. Dose-limiting toxicity was observed in three of four patients treated at the dose of 500 mg, and included grade 3 stomatitis in three patients and grade 3 liver toxicities in one patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.

CEA, TPA, CA 15-3 were assayed in 238 patients in follow-up for breast cancer after surgery. CA 15-3 showed the best sensitivity and specificity; the predictive value of a positive CA 15-3 test was three times higher than CEA and TPA. No association was found between marker positivity and the number of organs involved by metastases. CA 15-3 positivity was significantly associated with visceral rather than soft tissue recurrences; no significant similar association was observed for CEA and TPA. CA 15-3 serum levels were early predictors of relapse in four out of nine patients within a 6-12 month follow-up period.

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of squamous-cell carcinomas of head and neck (SCCHN). ZD1839 ('Iressa') is an orally active, selective EGFR-TKI (EGFR-tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting EGFR-mediated signaling. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest together with a partial G2/M block; this was associated with increased expression of both p27(KIP1) and p21(CIP1/WAF1) cyclin-dependent kinase (CDK) inhibitors. The activity of CDK2, the main target of CIP/KIP CDK inhibitors, was reduced in a dose-dependent fashion after 24 h of ZD1839 treatment and this effect correlated to the increased amount of p27(KIP1) and p21(CIP1/WAF1) proteins associated with CDK2-cyclin-E and CDK2-cyclin-A complexes. In addition, ZD1839-induced growth inhibition was significantly reduced in cell transfectants expressing p27(KIP1) or p21(CIP1/WAF1) antisense constructs. Overall, these results as well as the timing of the effect of ZD1839 on G1 arrest and p27(KIP1) and p21(CIP1/WAF1) upregulation, suggest a mechanistic connection between these events.

23 citazioni: 22 su Scopus e una citazione presente in GoogleScholar ("Das Taxol-Buch" di Volker Bartsch THIEME Ed. 2004 ISBN 3-13-105462-X) ----- Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer. Both in vitro and in vivo studies have shown that the combined administration of these two microtubule-targeting agents is feasible and worthwhile. Based on the promising preclinical data, patients with metastatic breast cancer no longer amenable to conventional treatment were entered into a phase I/II study in which the vinorelbine dose was fixed at 30 mg/sqm and paclitaxel was started at 90 mg/sqm and then subsequently escalated by 30 mg/sqm per step. Cycles were repeated every 21 days. Hematopoietic growth factor support was provided from the 4th dose level onwards. Grade III neutropenia was observed only in 2 patients treated at the 5th dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occured in all three patients treated at the 6th dose level. Other toxicities were mild. Paclitaxel 210 mg/sqm and vinorelbine 30 mg/sqm was the selected combination for phase II. Overall response rate in 34 evaluable patients was 38% (95% confidence interval (C.I.), 22% to 54%). In particular, 3 complete responses (9%) and 10 partial responses (29%) were observed. The observed level of antitumor activity, with an overall response rate of 38% and a median duration of response of 12 months, is of interest, since the study was targeted only to anthracycline-pretreated patients, most of whom had adverse prognostic features. The evaluation of a combination of vinorelbine and paclitaxel as first-line therapy in metastatic breast cancer seems worthwhile and is currently undergoing.

Twenty-two patients with locally advanced inoperable gastric cancer received neoadjuvant chemotherapy with a modified 5-fluorouracil, doxorubicin, methotrexate (FAMTX) regimen. The patients who achieved at least a stable disease were considered eligible for surgery with curative intent, which was performed in 19 cases. 16 patients (all responsive to neoadjuvant chemotherapy) were rendered disease-free by the combined approach. No treatment-rel ated deaths occurred; grade III leukopenia was observed in only 3 cases. The preliminary results of this study indicate the feasibility of our treatment approach; randomized trials are awaited to properly evaluate the role of neoadjuvant chemotherapy in locally advanced gastric cancer. locally advanced gastric cancer, with the aim of evaluating the ability of such an approach to decrease the tumor mass, to improve the resectability rate and, ultimately, to have a favourable impact on overall survival. The regimen including 5-fluorouracil, doxorubicin, methotrexate (FAMTX) was chosen as neoadjuvant treatment for our study, given its high efficacy in advanced gastric cancer and its lower toxicity when compared with other active regimens (5). We report on the preliminary results of our study, which mainly focus on resectability as therapeutic endpoint. In the future, we plan to report on the definitive results of our study, including the effects of preoperative chemotherapy on survival of patients.