Chemotherapy ± cetuximab modulates peripheral immune responses in metastatic colorectal cancer.

OBJECTIVE: To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5-fluorouracil/leucovorin (IFL) alone or in combination with cetuximab (C-IFL). METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C-IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment. RESULTS: PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-γ, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-γ, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-γ, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency. CONCLUSION: The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome.

Survival in patients with stage IV noncardia gastric cancer - the influence of DNA ploidy and Helicobacter pylori infection.

BACKGROUND: Palliative surgery followed by postoperative chemotherapy is a challenging approach in the treatment of stage IV gastric cancer yet patients must be carefully selected on the basis of likely clinical benefit. METHODS: The records of 218 patients with histological diagnosis of gastric adenocarcinoma who underwent palliative surgery followed by postoperative chemotherapy were retrospectively reviewed. Twelve potential prognostic variables including tumour DNA index and serum IgG anti- Helicobacter pylori (HP) antibodies were evaluated for their influence on overall survival by multivariate analysis. RESULTS: The median survival was 13.25 months [95% Confidence Interval (CI) 12.00, 14.50]. Three factors were found to have an independent effect on survival: performance status (PS) [PS 60-70 vs. 90-100 Hazard Ratio (HR) 1.676; CI 1.171-2.398, p = 0.005], liver metastases (HR 1.745; CI 1.318-2.310, p < 0.001), and DNA Index as assessed by Image cytometry (2.2-3.6 vs. >3.6 HR 3.059; CI 2.185-4.283, p < 0.001 and <2.2 vs. >3.6 HR; 4.207 CI 2.751-6.433 <0.001). HP infection had no statistically significant effect on survival by either univariate or multivariate analysis. CONCLUSION: Poor pre-treatment PS, the presence of liver metastasis and high DNA Index were identified factors associated with adverse survival outcome in patients with Stage IV gastric cancer treated with palliative gastrectomy and postoperative chemotherapy. HP infection had no influence on survival of these patients.

Clinical features of hypersensitivity reactions to oxaliplatin: a 10-year experience.

BACKGROUND: Oxaliplatin has become one of the major cytotoxic agents for the treatment of gastrointestinal tumors. As a result, several cases of the so-called oxaliplatin-associated hypersensitivity reaction have been documented. PATIENTS AND METHODS: We have retrospectively evaluated and characterized these reactions in our patient group by reviewing the files of 1,224 patients exposed to an oxaliplatin-containing regimen in order to provide useful clinical information for diagnosis and management. RESULTS: Three hundred and eight (308) patients who have never been exposed to platinum compounds developed symptoms compatible with a reaction to oxaliplatin that was verified by manifestation of at least similar symptoms on rechallenging. The reactions occurred after the first 5 courses, with a median course number of 9 (range 1-24). These reactions could be distinguished as (1) mild reactions occurring in 195 (63%) patients manifesting with itching and small area erythema either during treatment or within the next hours, and (2) severe reactions occurring in 113 (37%) patients within minutes of drug infusion manifesting with diffuse erythroderma, facial swelling, chest tightness, bronchospasm and changes in blood pressure. Oxaliplatin withdrawal was not required in patients with a mild reaction. Forty-eight (42%) patients having a severe reaction with appropriate premedication and prolongation of the infusion duration could tolerate 2-4 subsequent courses. For the remaining 65 (58%) patients, oxaliplatin withdrawal was inevitable because of the very severe reactions occurring on rechallenging. In addition, 3 patients presented with thrombocytopenia and 3 others with hemolytic anemia, all reversible upon oxaliplatin discontinuation. CONCLUSIONS: Hypersensitivity reactions to oxaliplatin are underestimated. Although the reactions are not frequent during first courses, in extensively pretreated patients, they may become a serious problem. In the majority of patients, drug discontinuation might not be necessary. In patients manifesting a severe reaction, re-exposure to oxaliplatin should be considered only if the patient can tolerate the reaction and there has been clinical benefit from this therapy. Physicians and nursing staff should be aware of the risk and be well prepared.

Evaluation of DNA ploidy in relation with established prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

BACKGROUND: Most patients with ductal pancreatic adenocarcinoma are diagnosed with locally advanced (unresectable) or metastatic disease. The aim of this study was to evaluate the prognostic significance of DNA ploidy in relation with established clinical and laboratory variables in such patients. METHODS: Two hundred and twenty six patients were studied retrospectively. Twenty two potential prognostic variables (demographics, clinical parameters, biochemical markers, treatment modality) were examined. RESULTS: Mean survival time was 38.41 weeks (95% c.i.: 33.17-43.65), median survival 27.00 weeks (95% c.i.: 23.18-30.82). On multivariate analysis, 10 factors had an independent effect on survival: performance status, local extension of tumor, distant metastases, ploidy score, anemia under epoetin therapy, weight loss, pain, steatorrhoea, CEA, and palliative surgery and chemotherapy. Patients managed with palliative surgery and chemotherapy had 6.7 times lower probability of death in comparison with patients without any treatment. Patients with ploidy score > 3.6 had 5.0 times higher probability of death in comparison with patients with ploidy score < 2.2 and these with ploidy score 2.2-3.6 had 6.3 times higher probability of death in comparison with patients with ploidy score < 2.2. CONCLUSION: According to the significance of the examined factor, survival was improved mainly by the combination of surgery and chemotherapy, and the presence of low DNA ploidy score.

Clinical Influence of Ploidy and Cancer Stem Cells and Other Parameters in Stage IV Colorectal Cancer.

BACKGROUND/AIM: The aim of the present study was the evaluation of the influence of cancer stem cells and other parameters in stage IV colorectal cancer patients. MATERIALS AND METHODS: One hundred patients were retrospectively included in the study and 24 variables were examined for their relation with response to treatment and survival. RESULTS: A low ploidy score in the histology of colorectal cancer was associated with improvement of performance status and response to therapy. No significant correlations between the percentage of cancer stem cells from the same tissue and the remaining clinical parameters was revealed. In the multivariate analysis of all the examined parameters in Cox models, independent unfavorable prognostic factors were increased ploidy score, existence of bone metastases, use of epoetin, and existence of side-effects such as anorexia, mucositis, and weight loss. CONCLUSION: Our findings emphasize on the prognostic role of ploidy in advanced colorectal cancer, but further analysis is required to evaluate the role of cancer stem cells.

Prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

BACKGROUND: Most patients with pancreatic adenocarcinoma are diagnosed with locally advanced (unresectable) or metastatic disease. The aim of this study was to investigate possible prognostic factors of survival in such patients. PATIENTS AND METHODS: Two hundred and fifteen patients were studied retrospectively. Twenty-four potential prognostic variables (demographics, clinical parameters, biochemical markers, treatment modality) were examined. RESULTS: Mean survival was 29.0 weeks. 21.9% survived more than 36 weeks. On multivariate analysis, 10 factors had an independent effect on survival: tumour localisation, metastasis, performance status, jaundice, weight loss, C reactive protein, CEA, CA 19-9, palliative surgery and chemotherapy. Patients managed only with palliative care had a hazard ratio of 8.94 versus those offered a combination of palliative surgery and chemotherapy. CONCLUSION: Many factors could be used as predictors of survival in patients with advanced or metastatic pancreatic cancer. Chemotherapy and palliative surgery are associated with increased survival, and should be offered to all eligible patients.

Paclitaxel-ifosfamide-cisplatin as salvage chemotherapy in ovarian cancer patients pretreated with platinum compounds and paclitaxel.

BACKGROUND: The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors previously exposed to platinum compounds and paclitaxel has not yet been defined. The present phase II study evaluated the activity and toxicity of a paclitaxel-ifosfamide-cisplatin combination in the aforementioned group of patients. Given the in vitro and in vivo synergism between these three agents, it was believed that using a three drug combination would overcome tumor resistance to cisplatin. PATIENTS AND METHODS: Thirty-five patients were enrolled in the study. The median age was 55 and the median performance status 1. Thirteen (37%) had potentially platinum sensitive, 12 (35%) had primary platinum-resistant and 10 (28%) patients had secondary platinum-resistant tumors. Treatment consisted of paclitaxel 175 mg/m2 as a 3 h i.v. infusion on day 1, cisplatin 75 mg/m2 i.v. over 2 h fractionated over days 1 and 2, and ifosfamide 5 mg/m2 i.v. over 1 h fractionated on days 1-2 with mesna uroprotection. Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulation factor (G-CSF) was given at a dose of 5 microg/kg/day on days 4-10. A median of 4 cycles were administered with the delivered dose intensity at 85% of the planned dose for the three agents. RESULTS: Among 35 patients evaluable for response and toxicity, there were 10 partial responses with a response rate of 28.6% (95% confidence interval 12%-45%). Stable disease was recorded in 9 (25.7%) and progressive disease in 16 (45.7%) patients. Subgroup analysis revealed a response rate of 38.5% in potentially platinum-sensitive, 16.5% in primary platinum-resistant and 30% in secondary platinum-resistant tumors. The median response duration was 5 months (range 3-14 months), the median time to progression 6 months (range 3-18 months) and the median survival 12 months (range 3-44 months). Myelotoxicity was significant with neutropenia grade 3 and 4 occurring in 35% and 45% of patients, respectively. Eight episodes (5% of all cycles) of febrile neutropenia were documented and well managed with oral or i.v. antibiotics and G-CSF continuation until complete recovery. Grade 1, 2 and 3 peripheral neuropathy developed in 30%, 30% and 10% of patients, respectively. In conclusion, the three drug combination demonstrated a significant effectiveness in potentially platinum-sensitive tumors and a moderate efficacy in platinum-resistant tumors. The regimen, although myelotoxic, is tolerable with G-CSF support. Further investigation via comparative studies is required to define any superiority of the present regimen over doublets of the three agents in this group of patients.

Subsets of patients with advanced gastric cancer responding to second-line chemotherapy with docetaxel-cisplatin.

The role of docetaxel in combination with cisplatin in the management of gastric cancer resistant to first-line chemotherapy has not yet been defined. This multicenter prospective phase II study evaluated the activity and toxicity of the docetaxel-cisplatin combination in gastric cancer patients, whose tumors were primarily resistant to first-line chemotherapy or had tumor recurrence after chemotherapy. Treatment consisted of docetaxel 70 mg/m2 i.v. followed by cisplatin 70 mg/m2 both administered on day one, every three weeks. Thirty-two patients were enrolled in the study. The median age was 60 years and the median performance status (ECOG) was 1. Six (19%) patients had tumor progression during adjuvant chemotherapy, 19 (59%) had tumor recurrence after primary chemotherapy and 7 (22%) had tumor progressing while on first-line chemotherapy. Twenty (62%) patients had received non-platinum agents as first-line chemotherapy, while the rest had received the so-called "new generation" regimen that contained cisplatin. Among 32 patients evaluable for response, there were 5 (16%) (CI 95%-8%-35%) partial responses, all in patients that had received non-platinum agents as first-line chemotherapy. Stable disease was recorded in 8 (25%) and progressive disease in 19 (59%) patients. The median response duration was 4 (range 3-6) months, the median time to progression was 5 (range 3-6) months, the median survival after second-line chemotherapy was 6 (range 2-24) months and the median survival after first-line chemotherapy was 12 (range 4-36) months. Myelotoxicity was the main toxicity with grade 3-4 neutropenia occurring in 19 (59%) of the patients and febrile neutropenia in 4 (12%) patients. G-CSF support was given to 25 (78%) patients. Grade 3-4 thrombocytopenia was recorded in 4 (12%) patients. In conclusion, the combination of docetaxel plus cisplatin appears to be a moderately effective regimen with acceptable toxicity when G-CSF support is provided. According to our results, it seems that patients, whose tumors were not exposed to cisplatin during first-line chemotherapy, were more likely to respond to this regimen.

Distinct patterns of angiogenic factor expression as a predictive factor of response to chemotherapy in stage IIIA non-small-cell lung cancer patients.

The expression of various angiogenic factors was assessed in tumour samples of patients with stage III non-small-cell lung cancer (NSCLC) and further evaluated in terms of response to induction paclitaxel-ifosfamide-cisplatin chemotherapy. Freshly isolated lung tumour specimens obtained by bronchoscopy from 70 stage IIIA NSCLC chemotherapy-naïve patients were sampled and analysed for vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3. Microvessel density was assessed through evaluating the angiogenic markers CD34 and CD105. Immunostaining scores were calculated by multiplying the percentage of labeled cells by the intensity of staining for each examined parameter. The overall mean immunostaining score value from all NSCLC samples was 7.83, 5.56 and 15.86 for VEGFR-1, VEGFR-2 and VEGFR-3, respectively. The overall mean value of the endothelial antigen CD34 was 16.29, whereas the expression of the CD105 antigen in endothelial cells yielded a multivariate distribution. Patients who responded to chemotherapy expressed significantly higher VEGFR-1 and VEGFR-3 mean values compared with non-responders (P<0.001). No significant difference was noted in VEGFR-2 mean values between these two groups (P=0.06). The CD34 mean value was significantly higher in responders (P<0.001), whereas there was no significant difference in CD105 expression between the two groups (P=0.07). Angiogenic marker expression proved to be a potential predictive factor of response to chemotherapy in stage III NSCLC. which merits further investigation.

Pegylated liposomal doxorubicin in the CHOP regimen for older patients with aggressive (stages III/IV) non-Hodgkin's lymphoma.

Pegylated liposomal doxorubicin is associated with a lower risk of cardiotoxocity than conventional formulations of doxorubicin, allowing the use of higher cumulative doses. In this Phase II study, 25 patients aged over 70 years (median 79, range 75-82 years) with aggressive non-Hodgkin's lymphoma (NHL) (International Prognostic Index (IPI) -2, 12 (48%); IPI-3, 10 (40%); IPI-4, 3 (12%)) received CHOP with pegylated liposomal doxorubicin. All completed 6 treatment cycles and were evaluable for efficacy and safety. A complete response was achieved in 13 (52%) patients and a partial response in 12 (48%) patients, which was maintained for at least 12 months. The median time to progression was 26 months (range 14->42) and median overall survival was 32 months (range 26-48). No Grades III/IV toxicity occurred; adverse events included neutropenia, anaemia, nausea and vomiting, diarrhoea and constipation in 16-29% of the cycles. Pegylated liposomal doxorubicin is an effective and well-tolerated component that may be substituted for doxorubicin in the CHOPC (cyclophosphanide, doxorubicin, vincristine, prednizolone) regimen for the treatment of aggressive NHL in elderly people.

DNA ploidy: a prognostic factor of response to chemotherapy and survival in metastatic gastric adenocarcinoma.

BACKGROUND: Metastatic gastric adenocarcinoma confers a dismal prognosis. Several prognostic factors are needed to distinguish patients that will benefit from chemotherapy. In this setting, the prognostic impact of DNA ploidy is still unclear. MATERIALS AND METHODS: The records of 61 patients with metastatic gastric adenocarcinoma were retrospectively reviewed. Response to chemotherapy and overall survival (OS) were assessed and correlated to tumour DNA ploidy index, which was calculated by cytometric image analysis. RESULTS: The median value of DNA ploidy index was 2.3. Patients with a low index responded better to chemotherapy than those with a higher index (p<0.01). Nevertheless, when the median value was used as a cut-off, no significant correlation of DNA ploidy index with response to chemotherapy (p=0.41) or OS (p=0.09) was observed. CONCLUSION: The prognostic role of DNA ploidy in metastatic gastric adenocarcinoma is still debatable. In this study, a low DNA ploidy index was associated with favorable prognosis; however, a suitable cut-off value is not yet available.

Factors Influencing Survival in Stage IV Colorectal Cancer: The Influence of DNA Ploidy.

Objective. To evaluate the prognostic significance of microscopically assessed DNA ploidy and other clinical and laboratory parameters in stage IV colorectal cancer (CRC). Methods. 541 patients with histologically proven stage IV CRC treated with palliative chemotherapy at our institution were included in this retrospective analysis, and 9 variables (gender, age, performance status, carcinoembryonic antigen, cancer antigen 19-9, C-Reactive Protein (CRP), anaemia, hypoalbuminaemia, and ploidy (DNA Index)) were assessed for their potential relationship to survival. Results. Mean survival time was 12.8 months (95% confidence interval (CI) 12.0-13.5). Multivariate analysis revealed that DNA indexes of 2.2-3.6 and >3.6 were associated with 2.94 and 4.98 times higher probability of death, respectively, compared to DNA index <2.2. CRP levels of >15 mg/dL and 5-15 mg/dL were associated with 2.52 and 1.72 times higher risk of death, respectively. Hazard ratios ranged from 1.29 in patients mild anaemia (Hb 12-13.5 g/dL) to 1.88 in patients with severe anaemia (Hb < 8.5 g/dL). Similarly, the presence of hypoalbuminaemia (albumin < 5 g/dL) was found to confer 1.41 times inferior survival capability. Conclusions. Our findings suggest that patients with stage IV CRC with low ploidy score and CRP levels, absent or mild anaemia, and normal albumin levels might derive greatest benefit from palliative chemotherapy.

Modified docetaxel-cisplatin in combination with capecitabine as first-line treatment in metastatic gastric cancer. a phase II study.

The combination of docetaxel, cisplatin and fluorouracil is considered to be one of the reference regimens for advanced gastric cancer, but due to its major myelotoxicity, its use in clinical practice has become limited. This prospective phase II study evaluated the activity and toxicity of a modified regimen with lower doses of docetaxel and cisplatin combined with oral capecitabine instead of fluorouracil for patients with advanced gastric cancer. Treatment consisted of docetaxel at 60 mg/m(2) i.v. followed by cisplatin at 60 mg/m(2), both administered on day one, every three weeks. Capecitabine at 2 g/m(2) per day was administered in two divided doses for 14 days (days 2-15). Thirty six patients were enrolled in the study. The median age was 64 years and performance status (ECOG) was 0-1. All patients had advanced disease, 78% with liver metastases, 100% with intra-abdominal lymph node metastases and 67% with peritoneal implants. Out of the 36 patients, 13 had undergone gastric resection, 13 had received adjuvant chemotherapy with irinotecan-leucovorin-fluorouracil, while seven patients had undergone adjuvant radiotherapy. The remaining 23 patients presented with advanced inoperable disease. Among 36 evaluable for response cases, there were 16 (44.4%) (Confidence Internal (CI) 95%=28-60%), partial responses. Stable disease was recorded in 12 (33.3%), resulting in an overall disease control rate of 78% (CI 95%=69-87%), while 8 (22.3%) patients progressed on chemotherapy. The median response duration was 6 (range=3-8) months. The median time-to-progression was 5 (range=3-6) months and the median survival (after the administration of a second-line chemotherapy in 12 patients), was 12 (range=5-24) months. Myelotoxocity was the main toxicity, with grade 3-4 neutropenia occurring in 18 (50%) and febrile neutropenia in six (16%) patients. Granulocyte-Colony Stimulating Factor (G-CSF) support was given to 16 (44.4%) patients, while grade 3 thrombocytopenia was recorded in two (6%). In conclusion, this modified regimen of docetaxel-cisplatin-capecitabine appears to have comparable efficacy with that reported for the reference regimen, with acceptable toxicity when G-CSF support is provided. However, because due to the small size of the study, further investigation is warranted.

Predictors of survival in stage IV metastatic colorectal cancer.

UNLABELLED: The aim of this study was to evaluate predictors of survival in stage IV metastatic colorectal cancer (CRC). PATIENTS AND METHODS: A total of 541 patients with histologically proven metastatic CRC (UICC stage IV) were retrospectively analysed and 37 variables were tested for their potential relationship to survival. RESULTS: Mean survival time was recorded at 12.8 months [95% confidence interval (CI) 12.0-13.5]. Three factors were independently associated with improved survival: combination chemotherapy, improved performance status and dermatological complications. Eight factors were independently associated with unfavorable survival: worsened performance status, C-reactive protein >5 mg/dl, anemia, anorexia, weight loss > or =10%, fatigue, hypoalbuminemia and blood transfusions. CONCLUSION: A number of factors could be used as predictors of survival in patients with stage IV metastatic CRC. Patients who are relatively fit, have low CRP levels and tolerate combination chemotherapy appear to have a more favorable survival outcome.

Salvage chemotherapy with oxaliplatin and capecitabine for breast cancer patients pretreated with anthracyclines and taxanes.

There is no standard treatment for breast cancer patients whose tumors have been exposed both to anthracyclines and taxanes. Oxaliplatin shows synergism with 5-fluorouracil (5-FU) and capecitabine is an oral prodrug of 5-FU with known efficacy in pretreated patients. This phase II trial studied the efficacy and toxicity of the oxaliplatin-capecitabine combination as salvage treatment in breast cancer patients pretreated with anthracyclines and taxanes. Patients received oxaliplatin 80 mg/m(2) on day 1 followed by oral capecitabine 1800 mg/m(2) divided in two doses for 7 days every two weeks for a maximum of twelve courses or until disease progression. Twenty-eight patients were evaluable for efficacy and toxicity. Objective responses (all partial) were documented in 9 patients [32%; 95% confidence interval (CI): 13-51.2%]. Responses were documented at all metastatic sites. The median response duration was 5 months (range 3-9), median time to progression was 4.5 months (range 2-10) and median overall survival was 10 months (range 2-18). Myelotoxicity was minimal with grade 3 thrombocytopenia as the main toxicity. Hand-foot syndrome was well tolerated. The present regimen was well tolerated with a rather moderate effectiveness but very significant for this group of patients. Further studies where the combination could be compared with single agent capecitabine are warranted.

Cisplatin-Ifosfamide-gemcitabine as salvage chemotherapy in ovarian cancer patients pretreated with platinum compounds and Paclitaxel.

BACKGROUND: The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors previously exposed to platinum compounds and paclitaxel has not yet been defined. The present phase II study evaluated the activity and toxicity of a gemcitabine-ifosfamide-cisplatin combination in the aforementioned group of patients. Given the in vitro and in vivo synergism between the three agents, it was believed that using a three-drug combination would overcome tumor resistance to cisplatin. PATIENTS AND METHODS: Twenty-four patients were enrolled in the study. The median age was 56 years and the median performance status 1. Eight (34%) had potentially platinum-sensitive, 6 (24%) had primary platinum-resistant and 10 (42%) patients had secondary platinum-resistant tumors. Treatment consisted of gemcitabine 1 g/m(2) i.v. on days 1 and 8, cisplatin 75 mg/m(2) i.v. over 2 h fractionated over days 8 and 9, and ifosfamide 5 mg/m(2) i.v. over 1 h fractionated on days 8-9 with mesna uroprotection. Courses were administered every 3 weeks on an outpatient basis. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 microg/kg/day on days 10-14. A median of 4 cycles were administered with the delivered dose intensity at 85% of the planned dose for the three agents. RESULTS: Among 24 patients evaluable for response and toxicity, there were 8 partial responses with a response rate of 33% (95% confidence interval 16.4-55%). Stable disease was recorded in 6 (25.7) and progressive disease in 10 (42%) patients. Subgroup analysis revealed a response rate of 50% in potentially platinum-sensitive, 16.5% in primary platinum-resistant and 30% in secondary platinum-resistant tumors. The median response duration was 5 months (range 3-12 months), the median time to progression 6 months (range 3-16 months) and the median survival 12 months (range 3-24 months). Myelotoxicity was significant, with neutropenia grade 3 and 4 occurring in 35% and 20% of patients, respectively. Four episodes (3.5% of all cycles) of febrile neutropenia were documented and were well managed with oral antibiotics and G-CSF continuation until complete recovery. Grade 1, 2 and 3 peripheral neuropathy developed in 40%, 30%, and 10% of patients, respectively. CONCLUSION: The three-drug combination demonstrated a significant effectiveness in potentially platinum-sensitive tumors and a moderate efficacy in platinum-resistant tumors. The regimen, although myelotoxic, is tolerable with G-CSF support. Further investigation via comparative studies is required to define any superiority of the present regimen over doublets of the three agents in this group of patients.

Isolated leptomeningeal carcinomatosis (carcinomatous meningitis) after taxane-induced major remission in patients with advanced breast cancer.

OBJECTIVES: To identify the incidence of leptomeningeal carcinomatosis (LMC), as the first site of systemic progression, in breast cancer patients after having obtained a major response (CR or near CR) to first-line taxane-based chemotherapy and compare these findings in retrospect with a matched-pair group of historical control patients from our database treated with nontaxane regimens. PATIENTS AND METHODS: Patients with histologically proven breast cancer having either metastatic disease or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155), and compared, as regards the incidence of LMC, to a matched-pair retrospective group of 155 patients treated with nontaxane regimens in our unit. RESULTS: Seven patients with a median age of 54 years (range 40-70) developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range 2-18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while 1 patient received i.t. methotrexate and RT to the lumbar spine. Two patients responded to treatment for LMC, while 2 achieved stable disease and 3 progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range 1-17+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, p = 0.019). Seven out of 86 responders (8.13%) in the taxane group versus 1 out of 72 responders (1.4%) in the non-taxane-treated group developed LMC as the first sign of progression after a major response to first-line chemotherapy (p < 0.1). CONCLUSIONS: LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased, but not significantly so, when compared retrospectively to non-taxane-treated patients. Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multi-institutional trials is warranted and identification of potential prognostic factors might help to identify patients requiring appropriate prophylactic therapy.

Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer.

OBJECTIVES: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naïve patients with advanced biliary tract and gallbladder cancer. PATIENTS AND METHODS: Gemcitabine at a dose of 800 mg/m2 was administered weekly as a 30-min infusion to patients with previously operated, histologically confirmed, metastatic, or unresectable locally advanced cholangiocarcinoma. Treatment was continued until unacceptable toxicity or disease progression. RESULTS: A total of 30 patients (median age 66 years; range 54-72 years) were included in the study. A median of 14 (range, 4-33) weekly doses was administered. Out of 30 patients evaluable for response, nine partial responses were observed (30.0%), while a further 11 patients demonstrated stable disease (36.7%). The median time to disease progression was 7 months (range, 5-34). Overall response rate was superior in patients with cancer of the gallbladder (ORR = 35.7%) compared with those patients with biliary duct cancer (ORR = 27.3%). This correlated to a significantly longer time to progression of 6.4 months (95% confidence interval (CI), 5.6-7.1 months) versus 3.6 months (95% CI, 2.9-4.3 months; p = 0.03) and a significantly better overall survival of 17.1 months (95% CI, 15.8-18.5 months) versus 11.4 months (95% CI, 10.2-12.6 months, p = 0.021). Toxicities were generally mild with only one case of grade 3 neutropenia. There were no cases of febrile neutropenia and no treatment-related deaths. CONCLUSIONS: Weekly administration of gemcitabine provides a safe, well-tolerated, and effective treatment for chemotherapy naïve patients with advanced cholangiocarcinoma, particularly with a gallbladder origin.