Mucinous rectal adenocarcinoma can be associated to tumor downstaging after preoperative chemoradiotherapy.

PURPOSE: The aim of this study was to evaluate downstaging as primary end point, and progression-free survival and overall survival as secondary end points, in rectal adenocarcinoma patients treated with preoperative chemoradiation. METHODS: One hundred and thirty-six extraperitoneal adenocarcinoma patients (33 low rectum T2, 74 T3, 29 T4 [without sacral invasion], 25 with mucinous subtype) were treated with posterior pelvis preoperative radiotherapy (5040 cGy total dose, 180 cGy/fr, 5 fr/w, 10-15 MV linac X-rays) and concomitant 5-fluorouracil-based chemotherapy. After 6 to 8 weeks patients underwent surgery and prechemoradiation clinical stage was compared with pathologic stage to evaluate downstaging in each patient. Seventy-four patients received adjuvant chemotherapy. Median follow-up was 39 months (4-84). RESULTS: Forty-four patients had macroscopic complete response, 52 patients had partial response, 37 patients showed no change and 3 patients had progression. At multivariate analysis only histotype showed correlation with downstaging (hazard ratio = 0.350 and 0.138 - 0.885 95 percent confidence interval) because of the evidence for poor downstaging in mucinous subtype. There were no significant differences in overall survival and progression-free survival between adenocarcinoma and mucinous subtype. CONCLUSIONS: The main finding is that mucinous histology is associated with poor downstaging after preoperative chemoradiation but this poor response was not associated with worse outcome in this small study. The good outcome for mucinous histology is at odds with other reports in the literature and requires further study.

Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer.

The aim of this study was to evaluate the safety and efficacy of combined treatment with trastuzumab (T), gemcitabine (gem) and vinorelbine (vin) as second-line therapy for HER-2 overexpressing metastatic breast cancer, pretreated with anthracyclines and/or taxanes and/or trastuzumab. Eligible patients had HER-2/neu-positive disease (IHC 2+ or 3+), performance status (PS) or=2 metastatic sites. Of the patients, 7 (23.3%) had received trastuzumab as first-line therapy. Treatment was well-tolerated with grade 4 neutropenia in 6 patients, grade 3 thrombocytopenia and grade 3 anemia in 1 patient, and grade 3 asthenia in 4 patients. Fifteen patients obtained an objective response (response rate, 50%; C.I. 95%, range, 31.3-68.7%). Among the patients with HER-2/neu 3+, the response rate was 73.3%. Noteworthy were 4 objective responses observed in patients with brain metastasis. Also, 7 patients had stable disease (23.3%). Median progression-free survival was 7 months (range 5-10), and median overall survival was 15 months (range 5-33). T-gem-vin is a safe and active regimen in this subgroup of patients with poor prognosis, and the efficacy of such a schedule was particularly satisfactory in patients with HercepTest 3+.

Short communication: the efficacy of fixed dose rate infusion of gemcitabine combined with IFN-alpha2a in patients with advanced refractory renal cell carcinoma.

The fixed dose rate (FDR) infusion of gemcitabine is based on pharmacokinetic studies demonstrating an increased peak concentration of gemcitabine-active metabolites inside the cell. In this prospective study, for the first time we investigated gemcitabine FDR infusion together with interferon-alpha2a (IFN-alpha) in pretreated patients with advanced renal cell carcinoma (RCC). Twelve patients received 800 mg/m2 gemcitabine (i.v. infusion of 10 mg/m2/min) on days 1 and 8 every 3 weeks, combined with 3.0 x 10(6) U s.c. IFN-alpha on days 1, 3, and 5 of each week. Median age of patients was 64 years, and the Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 in 10 patients. All patients were pretreated, 5 with > or =2 lines of chemoimmunotherapy. A median number of five cycles of gemcitabine per patient were given, with a mean weekly dose intensity of 72% of that planned. Among 11 evaluable patients, 2 (18%) partial responses and 5 (46%) stable diseases (median duration of 9.3 months) were observed. Median time to progression (TTP) and overall survival were 7.1 months and 13.0 months, respectively. The most frequently occurring grade 3 or 4 adverse events were leukoneutropenia (25%), thrombocytopenia (17%), and diffuse edema (25%). One patient developed a cerebrovascular accident potentially related to treatment. These promising results with the combination of gemcitabine infused at FDR and IFN-alpha deserve further investigation.

Raltitrexed plus weekly oxaliplatin as first-line chemotherapy in metastatic colorectal cancer: a multicenter non-randomized phase ii study.

AIM: The primary aims of this study were activity and toxicity evaluation of a new raltitrexed and oxaliplatin-based regimen, as a first-line chemotherapy, in patients with metastatic colorectal cancer (MCC). Survival evaluation was considered a secondary endpoint. PATIENTS AND METHODS: Forty-four patients were enrolled into this phase II trial. Treatment consisted of raltitrexed 3 mg/m2 iv on d 1 and oxaliplatin 70 mg/m2 iv on d 1 and d 8 every 3 wk. RESULTS: Twenty patients (45.5%) achieved a response [95% confidence interval (CI): 30.1% to 54.1%], 18 (40.9%) had stable disease, and only 6 (13.6%) developed progressive disease. After a median follow-up time of 14.7 mo (range 6.3-18.6 mo), the median time to disease progression was 6 mo (range 2.0-16.7) (95% CI: 4.4-7.6) and the overall survival was 14.8 mo (range 3-23) (95% CI: 11.2-18.4). Neutropenia was the most common hematological side effect, while transient AST/ALT increase, neurotoxicity, asthenia, and diarrhea were the most common nonhematological side effects. CONCLUSIONS: Our data confirmed that oxaliplatin administered weekly plus raltitrexed is an active combination in newly diagnosed patients with advanced colorectal carcinoma that merits further investigation versus the classic schedule in a randomized, phase III trial.

Raltitrexed-induced hepatotoxicity: multivariate analysis of predictive factors.

Raltitrexed (Tomudex; TOM) hepatotoxicity is usually characterized by a transient and self-limiting increase in transaminase levels. How this may condition daily clinical practice is still unclear. The aim of this study was to investigate predictive factors of TOM hepatotoxicity. In total, 130 patients were treated at two medical oncology institutions with TOM (3 mg/m2) (52 patients) or TOM plus oxaliplatin (TOMOX) (100 mg/m2 day 1 or 70 mg/m2 day 1, 8) (78 patients). A multinomial logistic regression (adjusted for multilevel data) was performed (on all administered chemotherapy courses) to assess the dependence of hepatic toxicity on a set of clinical factors correlated with patient, disease and treatment characteristics. Creatinine clearance was calculated by the Cockcroft formula before each chemotherapy course. Most of the patients presented colorectal cancer (95%) and metastatic disease (93%). Out of the 130 patients, 41 were aged 70 or more, while 119 (91.5%) had a good performance status (PS) (ECOG 0 or 1). Before chemotherapy, liver metastases were present in 78 (60%) patients and elevated transaminase in 25 (19%). A total of 584 courses were administered (252 TOM and 332 TOMOX). National Cancer Institute Common Toxicity Criteria grade 1/2 and 3/4 transaminase toxicity was observed in 62 and 20% of patients, respectively. To control transaminase increase, glutathione (GSH) or ademethionine (SAMe) was administered in 96 and 129 cycles, respectively. Hepatotoxicity conditioned delays (a week or more) in 60 (10%) chemotherapy cycles and was the reason for the discontinuation of chemotherapy in eight (6%) patients. Among the factors evaluated with multivariate analysis, sex, age, PS, creatinine clearance, previous chemotherapy treatment, presence of liver metastases and oncology centre were not significantly associated with TOM hepatotoxicity. Elevated baseline transaminase levels (p=0.001), number of chemotherapy cycles (p<0.001), TOM cumulative dose (p=0.018), unprolonged intervals between courses (p<0.001) and TOMOX regimen (p<0.001) emerged as factors predictive of hepatotoxicity. In the same analysis, GSH (p<0.001) and SAMe (p<0.001) were hepatoprotective agents. This study confirmed TOM-based hepatotoxicity as a clinical relevant side-effect and a major factor for treatment delays or discontinuation. Predictive and protective factors listed above could assist the management of this toxicity that has probably been underestimated until now.

Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients.

PURPOSE: The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug. EXPERIMENTAL DESIGN: Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. RESULTS: Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050). PDGF levels had returned to values similar to the median basal value at 7 and 21 days. Moreover, a linear regression model with variance analysis showed a significant positive correlation between basal VEGF and PDGF values but not at the following time points. No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after zoledronic acid single infusion. CONCLUSIONS: This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.

Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer.

BACKGROUND: We conducted a phase II randomized study to assess the efficacy, with response as the primary endpoint, and the toxicity of gemcitabine/cisplatin (GP) and gemcitabine/carboplatin (GC) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to GP (gemcitabine 1200 mg/m(2), days 1 and 8 plus cisplatin 80 mg/m(2) day 2) or GC (gemcitabine 1200 mg/m(2), days 1 and 8 plus carboplatin AUC=5 day 2). Cycles were repeated every 3 weeks. RESULTS: Sixty-two patients were randomized to GP and 58 to GC. A total of 533 cycles were delivered (264 GP, 269 GC), with a median of four cycles/patient. The objective response rate was 41.9% (95% C.I., 29.6-54.2%) for GP and 31.0% (95% C.I., 18.2-42.8%) for GC (P=0.29). No significant differences between arms were observed in median survival (10.4 months GP, 10.8 months GC) and median time to progression (5.4 months GP, 5.1 months GC). Both regimens were very well tolerated with no statistical differences between arms in grade 3/4 toxicities. When all toxicity grades were combined, emesis, neuropathy and renal toxicity occurred more frequently on the GP arm (P<0.005). CONCLUSIONS: GC arm did not provide a significant difference in response rate compared with GP arm, with better overall tolerability. Carboplatin could be a valid alternative to cisplatin in the palliative setting.

S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapy-induced liver injury.

BACKGROUND: Liver toxicity can be observed during treatment with most chemotherapic agents, and represents one of the principal causes of dose reduction or chemotherapy delays. S-Adenosylmethionine (AdoMet) plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione (GSH), the major endogenous hepatoprotective agent. Our study was aimed at assessing the protective effect of AdoMet supplementation in cancer chemotherapy-induced liver toxicity. PATIENTS AND METHODS: Fifty cancer patients who developed, for the first time, anticancer chemotherapy-induced liver toxicity were studied. Enrolled patients received oral AdoMet supplementation. RESULTS: AST, ALT and LDH levels recorded at the moment of the recognition of liver toxicity were significantly reduced after one week of AdoMet therapy (respectively p: 0.009, 0.0005 and 0.012). AST, ALT and LDH decrease was confirmed after two weeks of treatment. Furthermore, the effect on these enzyme levels persisted in the following chemotherapy courses, permitting our patients to perform the scheduled chemotherapy courses with a minimal number of dose reductions or administration delays. The efficacy of AdoMet supplementation was not influenced by the presence of liver metastases, and no appreciable side-effects were recognized. CONCLUSION: The results of our study clearly demonstrate a protective effect of AdoMet in cancer chemotherapy-induced liver toxicity. Further large phase III studies are required to assess the real clinical benefit associated with AdoMet supplementation.