Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a randomized trial. This study compared two chemotherapy regimens (FOLFIRI versus XELIRI) combined with bevacizumab, as first-line treatment for metastatic colorectal cancer. DNA was extracted from blood samples of 173 patients participating in the trial. Genotyping was performed for selected SNPs (VEGF-1154, +936, -634, -2578 and -1498). All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate (RR). There were no significant differences with respect to the distribution of genotypes in the treatment groups. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (65.5 versus 39.8%, P = 0.032). Furthermore, the VEGF-1154 GG genotype was associated with inferior median OS compared with GA (hazards ratio = 1.68; 95% confidence interval: 1.10-2.57; P = 0.016) or with the alternative genotypes (GA and AA) combined (hazards ratio = 1.62; 95% confidence interval: 1.09-2.40; P = 0.017). In multivariate analysis, the VEGF-1154 GG genotype remained a significant adverse factor for OS. Our results support the potential predictive ability of VEGF genotypes in patients with metastatic colorectal cancer receiving irinotecan-based chemotherapy plus bevacizumab, in terms of RR and OS. However, current results should be validated prospectively, in larger cohorts.

Human papilloma viruses and cancer in the post-vaccine era.

Human papilloma viruses (HPV) are strong human carcinogens, in fact today they are considered as the second most frequent carcinogen. In the middle of the 1970s the hypothesis that cervical cancer may arise from viruses was established and in the 1990s the relationship between HPV and cervical neoplasia was confirmed. HPV infections are the most common sexually transmitted infections. Specific subtypes of human papilomaviruses are now considered as the etiological agents in nearly all cases of cervical cancer and cervical epithelial neoplasia. Approximately 470,000 new cases and 23,000 deaths of cervical cancer occur each year, with the majority taking place in developing countries. Cervical cancer remains among the three leading causes of cancer deaths among women below the age of 45. Human papilomaviruses are classified into two groups: high-risk (oncogenic) types and low risk types. HPV types 16, 18, 45 and 31 are considered to be the most important oncogenic types. Subtypes 16 and 18 are the causative agents of more than 50% of cervical pre-cancerous lesions, and more than 70% of cervical cancer cases. High risk subtypes are also implicated with anal, perianal and oropharyngeal carcinomas. Recently, the prophylactic bivalent HPV 16/18 and the quadrivalent HPV 6/11/16/18/ vaccines have been approved. The development of prophylactic vaccines against human papilomavirus has been hailed as one of the most significant advances of recent years and it is expected to reduce dramatically the mortality of human papilomavirus associated cancers, but has also given rise to some of the most intense scientific debates.

Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone.

BACKGROUND: The use of bisphosphonates is associated with osteonecrosis of the jaw (ONJ). Antiangiogenic agents are used with increasing frequency and may induce the risk of ONJ, especially when administered concurrently with bisphosphonates. PATIENTS AND METHODS: We retrospectively reviewed data of 116 patients receiving bisphosphonates, 78 zoledronic acid and 38 ibandronic acid, with or without antiangiogenic agents for osseous metastases from various tumors in our department from June 2007 to June 2008. RESULTS: ONJ developed in: 2 patients with breast cancer and 1 with colon cancer receiving concurrently bisphosphonates and bevacizumab, 1 patient with renal cell carcinoma receiving sunitinib and zoledronic acid concurrently, and 1 patient with prostate cancer receiving zoledronic acid without antiangiogenic agents. The incidences of ONJ among patients receiving bisphosphonates with or without antiangiogenic agents were 16 and 1.1%, respectively. The difference was statistically significant (p = 0.008). The treatment duration of bisphosphonates did not differ significantly between the 2 groups. CONCLUSIONS: The combination of bisphosphonates and antiangiogenic factors induces ONJ more frequently than bisphosphonates alone. These preliminary observations should be evaluated in large cohorts of patients and in prospective studies.

Economic evaluation of taxane-based first-line chemotherapy in the treatment of patients with metastatic breast cancer in Greece: an analysis alongside a multicenter, randomized phase III clinical trial.

BACKGROUND: An economic evaluation was undertaken alongside a randomized phase III trial comparing three regimens for metastatic breast cancer (MBC). MATERIALS AND METHODS: Trial resource utilization and unit price data were combined to evaluate the cost of chemotherapy, concomitant medications, hospitalizations, diagnostic and laboratory tests. Treatment cost was combined with survival to estimate the incremental cost per life year saved. Quality-of-life data were used to estimate cost per quality-adjusted life year saved. Sensitivity analysis was used to compute results for various subgroups and for discounting cost and effects. RESULTS: The combination of gemcitabine (Gemzar, Eli Lilly, Indianapolis, USA) with docetaxel (Taxotere, Aventis Pharma, Dagenham, UK) (GDoc) is the least costly but least effective treatment. The combination of paclitaxel (Taxol) with carboplatin (Paraplatin, Bristol-Myers Squibb, Princeton, USA) is associated with higher cost and effectiveness compared with GDoc, while weekly paclitaxel (Pw), associated with the highest cost, is the most effective option. The incremental cost per life year saved of Pw versus GDoc was 3660 Euros (95% uncertainty interval dominance-9261). This result remained fairly constant in sensitivity analysis. CONCLUSIONS: The corresponding economic evaluation indicates that Pw represents an attractive treatment option for patients with MBC from an economic perspective in the context of the Greek National Health Service.

Concurrent M. tuberculosis, Klebsiella pneumoniae, and Candida albicans infection in liver metastasis of bowel carcinoma.

We describe the case of a 62-year-old patient with fever and abdominal pain of the right upper quadrant with a known history of adenocarcinoma of the colon and presence of hepatic metastases. One of the liver lesions underwent aspiration, and pus was sent for microbiological testing. Cultures of the pus were positive for Klebsiella pneumoniae and Candida albicans and polymerase chain reaction for Mycobacterium tuberculosis was concurrently positive; the patient received treatment for all three pathogens and improved clinically. One may consider searching not only for the usual pathogens of liver abscesses (gram-negative bacteria, anaerobic bacteria and gram-positive bacteria), but in special cases might consider pursuing a more detailed search for coexistence of fungi and mycobacteria in patients with cancer.

Performance status (PS): a simple predictor of short-term outcome of cancer patients with solid tumors admitted to the intensive care unit (ICU).

BACKGROUND: Admission of cancer patients with serious medical complications to the Intensive Care Unit (ICU) remains controversial. The aim of this study was to examine the 30-day all-cause mortality in cancer patients with solid tumors admitted to the ICU and to identify factors predicting 30-day mortality. PATIENTS AND METHODS: A retrospective study was conducted in 69 consecutive cancer patients with solid tumors admitted to the ICU of a 400-bed general hospital in Greece, between October 2001 and October 2005. Demographics, ECOG performance status (PS) prior to hospitalization, stage of cancer, metastases, number of metastatic sites, prior chemotherapy, primary site of tumor, APACHE II score on ICU admission, development of ICU acquired infection, sepsis, multiple organ failure (MOF), need for mechanical ventilation (MV), length of ICU stay, hospital stay and 30-day mortality were examined. RESULTS: The observed 30-day hospital mortality rate was 66.6% (n=46) with most deaths (n=32) occurring in the ICU. Univariate negative predictors of 30-day mortality were PS 3-4 (p=0.03), APACHE II score (p=0.001), MOF (p=0.001) and need for MV (p=0.001). Only PS 3-4 was an independent predictor in multivariate analysis (p=0.02). CONCLUSION: ECOG PS 3-4 prior to hospitalization was found to be a simple negative predictor of short-term outcome of cancer patients with solid tumors admitted to the ICU.

Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with suboptimally debulked, advanced epithelial ovarian cancer. A phase II trial of sequential doublets. The GO-First Study.

OBJECTIVES: Gemcitabine and oxaliplatin are active in epithelial ovarian cancer with minimal overlapping toxicity. We studied the efficacy and toxicity of this combination in patients with advanced ovarian cancer when given prior to carboplatin and paclitaxel. METHODS: Chemonaive patients with epithelial ovarian cancer and measurable disease were eligible for the study. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days (GO) for 4 cycles. This was followed by carboplatin AUC = 6 and paclitaxel 175 mg/m2 on day 1 every 21 days (CP) for 4 cycles. RESULTS: Twenty patients, median age 62 years (range 39-78), FIGO stages III (16) and IV (4) received treatment. The response rate (RR) after 4 cycles of GO was 80% (95%CI 61-99%) (4 complete responses (CR), 12 partial responses (PR)). Interval debulking surgery was performed in 7 patients (35%). After CP chemotherapy, RR increased to 85% (95%CI 68-100%) (CR = 13, PR = 4). Median time to progression was 14.5 months. Estimated median overall survival was 31.5 months. Toxicities of GO were mild; grade 3/4 nausea in 3 patients (15%) and vomiting in 2 patients (10%), grade 3/4 neutropenia in 5 patients (25%). Grade 2/3 peripheral neuropathy occurred in 5 patients (25%). After sequential administration of CP, grade 2/3 neuropathy occurred in 13 patients (72%). CONCLUSION: The sequential doublet regimen of GO followed by CP resulted in unacceptable neurotoxicity and is not recommended for further study; however, the doublet gemcitabine and oxaliplatin has significant activity in the first line treatment of patients with ovarian cancer.

Correlation of MDR 1 expression and CA 125 in ovarian cancer.

BACKGROUND: The serum CA 125 marker is elevated in 80% of patients with ovarian adenocarcinoma. MDR 1 gene expression has been identified in a variety of tumor types and its expression has been correlated with multidrug resistance. Whether there is a correlation between CA 125 levels and MDR 1 expression has not been sufficiently investigated. Therefore, the aim of this study was to examine whether an association between serum CA 125 levels and MDR 1 expression exists. PATIENTS AND METHODS: Serum CA 125 levels were measured during the diagnosis of ovarian cancer. Fresh tumor specimens or ascitic fluid samples were studied for MDR 1 expression by the polymerase chain reaction method (PCR). RESULTS: Forty patients with ovarian cancer were studied, 34 (85%) of whom had elevated CA 125. Twenty-eight out of the 40 patients were tested for MDR 1 expression; 20 expressed the gene and 8 did not. The median level of CA 125 in specimens expressing the MDR1 gene was 327, and in specimens that did not it was 376. There was no correlation between the CA 125 levels and MDR 1 expression (p = 0.484). CONCLUSION: There does not seem to be an association between CA 125 levels and expression of the MDR1 gene in patients with ovarian cancer.

Carboplatin hypersensitivity reactions: a single institution experience.

Carboplatin-related hypersensitivity reactions, frequently encountered in the heavily pretreated subpopulation of patients with gynecologic malignancies, can be severe and even potentially lethal-precluding these patients from an effective salvage treatment. We describe our experience in the management of such reactions and the application of a pretreatment protocol with corticosteroids, antihistamines and a slow infusion rate in order to safely re-administer carboplatin to the above patients. From 1998 to 2004, twenty patients developed an allergic reaction to carboplatin. Sixteen of them (80%) suffered from ovarian cancer. Upon resolution of the acute reaction, thirteen patients were pretreated according to our protocol and were re-exposed to carboplatin. Fifteen patients experienced the reaction during second-line carboplatin-based treatment and 5 patients after 3 or more regimens. Fifteen of the reactions (75%) were severe. Thirteen patients were re-treated with carboplatin after the application of our protocol, all of them successfully, even though 10 patients (77%) experienced minor symptoms during subsequent courses. On the contrary, only one of the 6 patients who were re-treated without the application of the protocol was able to receive further platinum-based treatment. In conclusion, pretreatment with corticosteroids, antihistamines and a slower infusion rate may make re-treatment possible in patients having experienced hypersensitivity to carboplatin.

Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients.

BACKGROUND: More elderly patients are being treated with chemotherapy. Reliable and accurate measures of renal function are needed to obtain predictable, safe and effective exposure to renally excreted drugs. The Jelliffe, Cockroft-Gault and Wright formulae have been used to evaluate renal function, although they have not been validated in elderly oncology patients. We performed a retrospective evaluation of these formulae using the [51Cr]-ethylenediamine tetraacetic acid ([51Cr]-EDTA) method of measuring glomerular filtration rate (GFR) as the 'gold standard'. PATIENTS AND METHODS: Inclusion criteria were age > or = 70 years and serum creatinine <250 micromol/l, performed within 4 weeks of glomerular filtration rate (GFR) measurement. Creatinine clearance was calculated using the Cockroft-Gault, Jelliffe and Wright formulae. The precision and accuracy of the three formulae were compared with the gold standard. RESULTS: Two hundred and twenty-five patients were evaluated: median age, 74 years (range 70-89); males, 108; females, 117; median creatinine, 84 micromol/l (range 44-186). Correlation coefficients of the Jelliffe, Cockroft-Gault and Wright formulae were similar. In the specific GFR ranges of 50-70, 70-90 and 90-120 ml/min, the bias [mean percentage error (MPE)] was +8%, -4% and -13%, respectively. The degree of bias was greater with the Cockroft-Gault and Jelliffe formulae across the same range of GFR with the MPE being -15%, -25%, -32% and -12%, -19% and -23%, respectively. All three formulae have reduced precision and greater bias at the extremes of GFR. CONCLUSIONS: The Wright formula is the most accurate, precise and least biased formula for the calculation of GFR in elderly patients with a GFR >50 ml/min. These results allow the physician to make a decision regarding the use of the formula based on an expected degree of bias.

Pseudomyxoma peritonei: the 'controversial' disease.

Pseudomyxoma peritonei (PMP) is a rare disease that is characterized by a large amount of mucinous ascites with peritoneal and omental implants. The etiology of the disease remains unclear. Histologically, two main categories have been described: disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). It is commonly diagnosed incidentally at laparotomy. Most investigators agree that radical surgical debulking and appendectomy are the cornerstone of treatment, but the optimal management of the disease remains controversial. The role of intraoperative and intraperitoneal chemotherapy has been evaluated by a number of authors. The clinical outcomes vary widely between the benign and the malignant forms and between the different treatment modalities. We discuss the pathology, origin, clinical presentation, diagnosis, treatment, and prognosis of PMP.

Thalidomide and dexamethasone combination for refractory multiple myeloma.

BACKGROUND: Thalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. We investigated the combination of thalidomide with dexamethasone as salvage treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. PATIENTS AND METHODS: Forty-four patients with refractory myeloma were treated with thalidomide, 200 mg p.o. daily at bedtime, with dose escalation to 400 mg after 14 days, and dexamethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12, 17-20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone-based regimens and 32% had previously received high-dose therapy. RESULTS: On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuropathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. CONCLUSION: The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active myeloma, should be considered.

Treatment of Waldenstrom's macroglobulinemia with thalidomide.

PURPOSE: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom's macroglobulinemia (WM). PATIENTS AND METHODS: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. RESULTS: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. CONCLUSION: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.

Correlation of in vitro cytotoxicity and clinical response to chemotherapy in ovarian and breast cancer patients.

During the last years, a number of assays have been developed aiming at predicting the most effective chemotherapy regimen for each individual, avoiding possible toxicity of ineffective drugs. In the present study we have used an in vitro chemosensitivity/chemoresistance assay in order to evaluate cytotoxic treatment in ovarian and breast cancer patients. The assay was applied in 77 ovarian and breast cancer samples and the observed in vitro responses to various chemotherapeutic drugs or combinations of drugs were then correlated to the in vivo responses and the overall clinical data of the examined patients. Direct comparison was possible for 25 cases. The overall positive predictive value of the assay was 50% and the negative predictive value was 57%. However, it was observed that the positive predictive value for ovarian patients was 69% and that the negative predictive value for breast patients was 100%. Therefore this study indicates that although in vitro chemosensitivity/chemoresistance is a valuable assay, further analysis and implications of other factors are required for a general evaluation of cytotoxic treatment for patients with ovarian and breast cancer.

Randomized trials of adjuvant and neoadjuvant chemotherapy in bladder cancer.

Data of randomized studies of adjuvant and neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer were reviewed. Four adjuvant studies have been published. The interpretation of their data is compromised primarily because of small patient numbers. Thus, a possible survival advantage cannot be documented, and significantly larger, prospective studies are needed. However, there is some evidence of improved disease-free survival for patients with non-organ-confined tumors treated with cisplatin-based combination chemotherapy. More data are available for neoadjuvant chemotherapy. The already published randomized studies, including a large trial of who was designed to detect a 10% survival benefit, do not indicate a significant advantage for neoadjuvant chemotherapy. Radical cystectomy remains the standard treatment to which other therapeutic modalities must be compared.

Waldenström's macroglobulinemia.

Waldenström's macroglobulinemia is an unusual low-grade lymphoplasmacytic lymphoma characterized by the production of monoclonal IgM. The clinical manifestations associated with WM can be classified as those related to direct tumor infiltration, by the amount and specific properties of circulating IgM, and by the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. The management of the disease relies on the administration of systemic chemotherapy to reduce tumor load and on the application of plasmapheresis to remove circulating IgM. Standard treatment consists of oral chlorambucil, which induces response in at least 50% of patients, resulting in a median survival of approximately 5 years. Nucleoside analogues (cladribine, fludarabine) are effective in most previously untreated patients. These agents are the treatment of choice for patients with disease resistant to alkylating agents. New treatment approaches include high-dose therapy with stem-cell support and administration of monoclonal anti-CD20 antibodies.