Cisplatin: process and future.

One of the most important anticancer agents is cisplatin (CDDP). Numerous studies with a CDDP-based combination have been reported over the last 30 years. The use of CDDP in the 1980s and 1990s showed responses in advanced stage non-small-cell lung cancer (NSCLC). Over the years it was found that the side effects of this agent (particularly nephrotoxicity) were a common problem. Agents such as carboplatin, taxanes, gemcitabine, irinotecan and pemetrexed proved to be effective in NSCLC with reduced or no nephrotoxicity. The administration of these newer agents improved several side effects, but without improving efficacy. When prophylactic (adjuvant) treatment for NSCLC was introduced, CDDP was the agent selected, which indicated the value of the drug. Recently, a novel formulation of CDDP, liposomal cisplatin, which has shown very low toxicity, no nephrotoxicity and equal effectiveness was produced; its importance is its higher effectiveness than standard CDDP in lung adenocarcinoma.

High-dose tamoxifen in breast cancer bone metastasis.

High-dose tamoxifen was used as a treatment for bone metastasis in 16 patients with breast cancer. All of them had been pretreated with hormonal therapy, including lowdose tamoxifen. The results were extremely positive with clinical amelioration and also disappearance of osteolysis in 5 patients.

Combination of three cytotoxic agents in small-cell lung cancer.

PURPOSE: The established treatment for small-cell lung cancer has been a cisplatin-etoposide combination, as the most effective chemotherapy regimen. Paclitaxel has also been used in combination with cisplatin and etoposide but this has been unacceptable due to the toxicity. This toxicity could be attributed to the three consequent days of treatment with etoposide plus the doses of each of the three drugs. Our objectives were to determine an equal or longer survival and lower toxicity by administering all 3 drugs with low dosage on day one, compared to the established guideline of 3-day administration. METHODS: We tested the aforementioned three-drug combination and avoided the toxicity in the majority of patients by administering all 3 drugs on day one. Fifty-one patients (50 evaluable) were recruited from 4 oncology clinics. All patients had histologically or cytologically confirmed small-cell lung cancer with limited and extensive disease in 40 and 60 % of the patients, respectively. The treatment was: cisplatin 75 mg/m(2), etoposide 120 mg/m(2) (maximum 200 mg), and paclitaxel 135 mg/m(2). The agents were administered on day one and repeated every 3 weeks for 6 cycles. RESULTS: The median survival was 15 months (95 % CI 13.6-16.4) (mean 16 months). Forty-five (90 %) patients achieved a response: 20 (40 %) patients, a complete response and 25 (50 %), a partial response. Adverse reactions included grade 3 and 4 neutropenia in 12 and 2 % of the patients, respectively. Other side effects were of very low toxicity. CONCLUSION: The 1-day, three-agent (cisplatin-etoposide-paclitaxel) treatment of small-cell lung cancer is beneficial with respect to response rate and survival, and the toxicity is low and well-tolerated.

Two consecutive days of treatment with liposomal cisplatin in non-small cell lung cancer.

Liposomal cisplatin (Lipoplatin) is a new agent, a cisplatin formulation that has been investigated in a number of studies and compared with cisplatin with respect to toxicity and effectiveness. It has been administered once weekly and in combination with a second agent, once every two weeks. The main outcome of the studies was that lipoplatin has no renal toxicity and is as equally effective as cisplatin. The present study investigated toxicity and effectiveness when lipoplatin is administered on two consecutive days, repeated every two weeks. Between January 2011 and November 2011, a total of 21 patients with histologically- or cytologically-confirmed non-small cell lung cancer (NSCLC) were enrolled in the study. All but two patients, who had not been pretreated, had received one or two series of chemotherapy and some had undergone radiotherapy. Lipoplatin monotherapy was infused for 8 h the first and second days and repeated every 2 weeks with the aim of administering 6 cycles. The dose per day was 200 mg/m(2). Eight out of 21 (38.10%) patients had a partial response, 9 (42.86%) had stable disease and 4 (19.05%) had progressive disease. Results showed that there was no renal failure toxicity and no other adverse reactions apart from grade 1 myelotoxicity in only 2 patients who had been heavily pretreated, and grade 1 nausea/vomiting in 4 patients. Liposomal cisplatin is an agent with negligible toxicity and reasonably high effectiveness even when administered to pretreated patients with NSCLC.

Lipoplatin formulation review article.

Patented platform technologies have been used for the liposomal encapsulation of cisplatin (Lipoplatin) into tumor-targeted 110 nm (in diameter) nanoparticles. The molecular mechanisms, preclinical and clinical data concerning lipoplatin, are reviewed here. Lipoplatin has been successfully administered in three randomized Phase II and III clinical trials. The clinical data mainly include non-small-cell lung cancer but also pancreatic, breast, and head and neck cancers. It is anticipated that lipoplatin will replace cisplatin as well as increase its potential applications. For the first time, a platinum drug has shown superiority to cisplatin, at least in non-squamous non-small-cell lung cancer as reported in a Phase III study which documented a simultaneous lowering of all of the side effects of cisplatin.

Maintenance chemotherapy or not in ovarian cancer stages IIIA, B, C, and IV after disease recurrence.

PURPOSE: Ovarian cancer may have a high percentage of residual disease after chemotherapy. It is questionable whether second or more lines of chemotherapy are needed in patients with slow-growing residual disease. In the present trial we compared the median survival of patients with residual or recurrent disease who received 1-2 lines of chemotherapy with those who received 3-9 lines. METHODS: Two hundred and five patients with advanced stage IIIA, B, C and IV ovarian cancer were divided into two groups based on the number of chemotherapy lines they received. All patients had prior first-line chemotherapy; the criteria for recruitment in the study were: a) residual or recurrent disease and b) failure to respond to first-line therapy. Group A included patients who received 1 or 2 lines of chemotherapy and group B, 3-9 lines. RESULTS: The median survival of group A was 76 months and of group B 53 months (p<0.001). Complete response (CR) was observed in 80 out of the 193 7lpar;41.45%) evaluable patients, partial response (PR) in 37 (19.17%), stable disease (SD) in 54 (27.987percnt;) and progressive disease (PD) in 22 (11.40%) patients. CONCLUSION: In ovarian cancer patients with advanced disease, multiple chemotherapy lines (3=9) offer no advantage over 1 or 2 lines, with respect to overall survival.

Metastatic lung disease treated with pemetrexed-docetaxel combination chemotherapy.

PURPOSE: According to the ASCO guidelines 4 cytotoxic agents are used in colorectal cancer. Numerous agents have not been used or tested and thus their effectiveness is not known. Herein we present the preliminary data of a trial whose objective was to investigate the effectiveness to 2 combined agents in patients with heavily pretreated adenocarcinomas. METHODS: Ten patients have been recruited up until now. Colorectal adenocarcinoma was the primary disease in 7 patients, gastric cancer in 2, and endometrial adenocarcinoma in one. All patients had undergone at least 2 lines of previous chemotherapy during 2-3 years before the trial. The lungs were the only or main site of metastases in all patients. Chemotherapy agents used were pemetrexed 500 mg/m(2) and docetaxel 75 mg/m(2), repeated every 3 weeks, with a plan to administer 6 cycles. RESULTS: The mean number of cycles were 3 (range 1-6). Total number of cycles 33. No serious toxicity was detected. One patient had complete response, 3 partial response, 5 stable disease, 1 disease progression. Median survival was 6 months (range 2-12+ months). CONCLUSION: The effectiveness of the pemetrexed-docetaxel combination in heavily pretreated adenocarcinoma patients justifies their use when no other alternative exists.

Granulocyte colony-stimulating factor expression as a prognostic biomarker in non-small cell lung cancer.

Hematologic paraneoplastic alternations may not be very common, but they have been observed in a small number of patients. Granulocytosis has been described in several malignancies and its common mechanism may be associated with granulocyte colony-stimulating factor (G-CSF) production by the tumor. High neutrophilia (150,000-240,000 white blood cell count) observed in two patients with non-small cell lung cancer led us to run the present trial. The purpose of this study was to compare the white blood cell counts and the G-CSF plasma levels of the patients and classify the results into groups, as well as to determine the survival rates of the patients in each of the groups. The histological specimens and plasma of two patients as well as the plasma of another 87 patients with several malignancies, were examined. The plasma G-CSF levels were determined using a quantitative sandwich immunoassay technique (Quantikine; RySD systems) according to the manufacturer's instructions and all samples were tested in triplicate. It was found that 12 patients had a white blood cell count increased beyond normal as well as a high G-CSF plasma level and the survival of these patients was shorter as compared to the rest of the patients. We assume that these findings may indicate that increased G-CSF levels may function as a biomarker of survival.

Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer.

PURPOSE: Liposomal cisplatin was developed to reduce the systemic toxicity of cisplatin, particularly the nephrotoxicity, and it has been used in combination with other agents in pancreatic and head and neck cancers and non-small-cell lung cancer (NSCLC). Our objective was to compare the effectiveness of lipoplatin combined with paclitaxel versus cisplatin with paclitaxel in advanced non-squamous NSCLC. METHODS: During 2007-2010, 202 patients with non-squamous NSCLC (stage IIIB and IV) were recruited from the two participating institutions and divided into two arms: Arm A was treated with liposomal cisplatin 200 mg/m(2) combined with paclitaxel 135 mg/m(2) and Arm B with cisplatin 75 mg/m(2) in combination with paclitaxel 135 mg/m(2), repeated every 2 weeks. The number of cycles administered was 632 (Arm A) and 640 (Arm B), totaling 1,272. RESULTS: A partial response was achieved by 59.22% of Arm A patients versus 42.42% of Arm B, and the difference was statistically significant (P 0.036). The median survival time in months was 10 for Arm A and 8 for Arm B (P 0.1551). After 18 months, the number of surviving patients was double for Arm A versus Arm B. CONCLUSION: Liposomal cisplatin in combination with paclitaxel produces a statistically significantly higher response rate than cisplatin combined with paclitaxel in non-squamous NSCLC.

Survival of untreated advanced colorectal cancer patients.

Colorectal cancer has specific biological characteristics that distinguish it from other malignancies. One such characteristic is its slow growth in patients in advanced stages. For the past 15 years, no effective systemic treatment has been available in clinical practice. The present study involved a retrospective evaluation of patients with advanced colorectal cancer in order to assess the median and overall survival of patients. Concurrently, the study aimed to describe the biological characteristics of this slow-growing disease and the quality of life of the patients. The key characteristic of this patient group was the lack of any systemic treatment. The study included 40 patients (25 male and 15 female, median age 67 years) who were evaluated between 1993 and 1996. Only supportive treatment was provided. One patient underwent 2 cycles of chemotherapy. Liver surgery was unsuccessfully performed on 3 patients. Two patients underwent radiofrequency once and 2 had intra-arterial treatment, also once. The results showed the median survival of patients to be 24 months (range 16-42). One-year survival was found to be 65% while the 2-year survival was found to be 25%. A satisfactory quality of life was also observed. In conclusion, colorectal cancer is a slow-going malignancy, as indicated by the long-term survival of patients and the biological characteristics of the tumor.

Treatment of colorectal cancer with and without bevacizumab: a phase III study.

OBJECTIVE: The objective of this phase III trial was to compare chemotherapy combined with bevacizumab versus chemotherapy alone in the treatment of patients with advanced colorectal cancer. METHODS: From September 2004 till September 2008, 222 treatment-naive patients were enrolled and divided into 2 arms: 114 arm A patients were treated with leucovorin, 5-fluorouracil plus irinotecan in combination with bevacizumab, and 108 arm B patients were treated as above without bevacizumab. All patients were stage IV with histologically confirmed adenocarcinoma. RESULTS: The median overall survival of arm A patients was 22.0 months (95% CI: 18.1-25.9) and 25.0 months (CI: 18.1-31.9) for arm B patients. There was no statistically significant difference between the 2 arms (p = 0.1391). No statistically significant difference between the 2 arms regarding the response rate was observed: partial response, 42 patients (36.8%) and 38 patients (35.2%) for arms A and B, respectively. Hematologic toxicity did not differ in the comparison of the 2 arms. Nonhematologic toxicity in arm A involved hypertension in 23 (20.2%) of the patients and proteinuria in 7 (6.1%); 3 patients experienced hemorrhage and 1 patient intestinal perforation. None of these side effects was observed in arm B patients. CONCLUSION: No statistically significant difference in median overall survival in patients with advanced colorectal cancer treated with bevacizumab plus a combination therapy (arm A) and those treated with the combination only, without bevacizumab (arm B), was observed.

Liposomal cisplatin dose escalation for determining the maximum tolerated dose and dose-limiting toxicity: a phase I study.

BACKGROUND: The aim of the present trial was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of liposomal cisplatin (lipoplatin) using nephrotoxicity, gastrointestinal toxicity and myelotoxicity as the main adverse reactions. PATIENTS AND METHODS: Lipoplatin, a liposomal formulation of cisplatin was first tested as monotherapy starting at a dose of 125 mg/m(2) and escalating up to 350 mg/m(2). Lipoplatin was then escalated in combination with paclitacel starting at a dose of 100 mg/m(2) escalating up to 250 mg/m(2) for the former and 100 mg/m(2) escalating up to 175 mg/m(2) for the latter. RESULTS AND CONCLUSION: The present trial determined the DLT for lipoplatin monotherapy at 350 mg/m(2) and the MTD at 300 mg/m(2); for lipoplatin-paclitaxel combination therapy, the DLT was 250 mg/m(2) for lipoplatin and 175 mg/m(2) for paclitaxel whereas the MTD was 200 mg/m(2) for lipoplatin and 175 mg/m(2) for paclitaxel.

Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial.

BACKGROUND: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival. PATIENTS AND METHODS: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m² of liposomal cisplatin and 135 mg/m² paclitaxel (arm A) or 75 mg/m² cisplatin and 135 mg/m² paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned. RESULTS: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively. CONCLUSIONS: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms.

Serious hematologic complications following erlotinib treatment.

BACKGROUND: Erlotinib is an oral, small-molecule targeting therapy which inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. PATIENTS AND METHODS: In the present report, unusual hematologic complications were detected after erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Four patients pre-treated with cisplatin or its analog-based combinations, were evaluated. Erlotinib was given at a dose of 150 mg daily. In cases of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a maximum of two weeks. RESULTS: Serious hematologic toxicity (or complications) developed in these 4 patients after 4-8.5 months of treatment. Two patients developed leukemias (AML, CML) and two, myelodysplastic syndrome. CONCLUSION: Whether or not these hematologic complications were related to erlotinib treatment is comprehensively discussed.

Erlotinib treatment in pretreated patients with non-small cell lung cancer: A Phase II study.

Erlotinib is an oral, small-molecule targeting therapy that inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. In the present trial, erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Our objectives were to determine response, survival and toxicity. Fifty-four patients pretreated with cisplatin or its analogue-based combinations were evaluated. The disease stage of the patients was IIIB and IV. Thirty-eight patients were male, 16 were female, the median age was 65 years, and the WHO performance status was 0-2. Twenty-five cases were adenocarcinomas, 19 squamous cell carcinomas and 10 were undifferentiated. Erlotinib was administered at a dose of 150 mg daily. In case of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a maximum of two weeks. A partial response was observed in 10 (18.52%) and stable disease in 40 (74.07%) patients. The median time to disease progression was 3 months (95% CI 1.7-10.3), and the median survival was 6 months. Concerning toxicity, 53 patients (98.15%) developed a grade 1-2 skin rash, and 1 (1.85%) grade 3. Diarrhea occurred in 9 (16.67%) patients, nausea and vomiting in 4 (7.41%) and gastritis in 2 (3.70%). The majority of patients tolerated the erlotinib treatment. Of note were the 18.52% response rate and 74.07% stable disease.

Plasma VEGF levels in breast cancer patients with and without metastases.

Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis since it stimulates the formation of new blood vessels. Basic fibroblast growth factor (bFGF) is related to the promotion of endothelial cells into tube-like structures, and it is therefore expected to promote angiogenesis with a greater potency than VEGF. VEGF and bFGF are considered to be biomarkers that predict treatment effectiveness. Elevated plasma VEGF and bFGF levels have been reported in a variety of different malignant tumors, and patients with metastatic disease have also been reported to present with higher serum VEGF and bFGF levels. Other studies have documented controversial results with respect to the prognostic and predictive value of the aforementioned biomarkers. This study aimed to determine the plasma VEGF and bFGF levels in breast cancer patients without metastatic disease compared with breast cancer patients with advanced metastatic disease. The study included 93 patients with breast cancer, 46 without recurrent disease (group A) and 47 with metastatic disease (group B), as well as 21 healthy individuals. The median age was 58 years (range 34-78) for group A and 59 years (range 37-75) for group B. All 93 patients underwent chemotherapy, adjuvant for group A, and adjuvant plus chemotherapy for group B patients with advanced disease. Plasma VEGF and bFGF levels were determined using a quantitative sandwich immunoassay, and samples were tested in triplicate (ELISA). The plasma levels of VEGF and bFGF varied greatly, i.e., from extremely low to extremely high in the two groups, as well as in the healthy individuals. No statistically significant difference was found between the two groups or between the patients and healthy individuals. Data of the present study therefore showed that VEGF and bFGF levels are not valuable biomarkers for predicting treatment outcome.

Governmental strategies for cancer control, prevention, care and management in Greece.

The Greek government through the Ministry of Health and the World Health Organisation (WHO) are concerned about the increase in cancer cases and are implementing actions related to its control. The WHO produced a guide which is a response to the World Health Assembly Resolution on Cancer Prevention and Control, adopted in May 2005. This WHO guide calls on member states to intensify action against cancer by developing and reinforcing cancer control programs. The Greek Ministry of Health has established a strategy unit and relevant health policies. The need to act comes from the fact that 11 million new cancer cases are diagnosed yearly, worldwide. The most common deaths globally are from lung cancer (1.3 million), from gastric cancer (1 million), liver cancer (662.000), colorectal cancer (665.000) and breast cancer (502.000), yearly. Some cancers in Greece are more common. There are certain risk factors on the basis of which one can take preventative measures related to the numerous chemical, biological and natural factors in the environment. Recently, the Greek Ministry of Health organized a national plan of action against cancer. This starts with monitoring scientific societies and social groups and organizations in order to promote prevention as well as an improvement in the quality of cancer management. The targets are the collection of reliable information, primary and secondary prevention, effective treatment and a better quality of life for the patient.

Differences in gene expression between individuals with multiple primary and single primary malignancies.

Cytogenetic and molecular studies have identified imbalanced chromosomal regions leading to the characterization of several candidate genes. Differences in gene expression were examined in the blood by whole genome microarray analysis among individuals with double or single primary malignancies and healthy individuals. Twenty-four individuals with at least two primary malignancies of the breast and/or colon and/or ovary were compared with 32 individuals with single breast, colon or ovarian cancer. The single malignancy group had a median duration of disease of 9 years (range 5-23 years). Validation was obtained by examining each patient separately with quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis for the determined genes. Overall a large number of genes were determined to be deregulated. From the classifiers built, a 9-probe signature was determined between second primary and single tumor patients. Four other genes were determined to be repressed (p<1x10(-4)) in individuals with two primary malignancies when compared with individuals with a single malignancy and also when comparing single malignancies and healthy subjects. The levels of gene deregulation were confirmed by validation with quantitative RT-PCR analysis. Functional analysis, suggested that these genes are associated with protein biosynthesis and folding, inhibition of apoptosis and intracellular signalling via GTP cascade. The outcome of the present study was 13 genes had a statistically significant difference in expression between individuals with double primary malignancies compared to individuals with single primary malignancies. Nine of those were confirmed by the classifier analysis.

Lung carcinoid tumor biology: treatment and survival.

A carcinoid tumor is a rare malignant disease which can be cured when localized and treated by surgery. Chemotherapy is not effective, and somatostatin is used for palliation. Rarely is the disease aggressive, and thus does not contribute to a shortening of patient survival. The aim of this study was to define the treatment and survival of patients with primary lung carcinoid tumors. Forty-three patients (26 males, 17 females; median age 43 years, range 11-73 years), from 1993 to 2007, were included in this study. All patients had histologically confirmed carcinoid tumors. The site of the disease at diagnosis was the lung in all 43 patients. All patients underwent surgery which involved mainly typical or sleeve lobectomy. Eight patients had a pneumonectomy. One patient had the primary tumor excised for palliation as there were metastases in the liver. Somatostatin palliative treatment was administered to 4 patients; 1 with liver and 3 with lung recurrence. Two of the 43 patients died within 2 years after surgery. The median survival was not reached as all patients, apart from 2, were alive after a median follow-up of 5 years (mean survival 159 months). As a rule, a carcinoid tumor is an extremely slow-growing disease with some rare exceptions. All of our patients had primary lung disease. All, apart from 2, were alive at the end of the study, and 93% were without recurrence for a duration of 6 months to 13 years. The patients with liver metastases who underwent no specific treatment had a median survival as long as 8 years.