LIPOPLATIN IN NSCLC

Cancer. 2008 Sep 29
Phase 1 trial of lipoplatin and gemcitabine as a second-line chemotherapy in patients with nonsmall cell lung carcinoma.

Froudarakis ME, Pataka A, Pappas P, Anevlavis S, Argiana E, Nikolaidou M, Kouliatis G, Pozova S, Marselos M, Bouros D.

Department of Pneumonology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.

BACKGROUND.: Lipoplatin is a new liposomal cisplatin that already has been tested in solid tumors, with encouraging results. The purpose of the current study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a 21-day regimen of lipoplatin plus a fixed dose of gemcitabine in patients with refractory or resistant nonsmall cell lung carcinoma (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status of growth factors were not allowed. Thirteen patients with advanced stage NSCLC who had been pretreated with platinum combination chemotherapy were enrolled in this phase 1 trial. At least 3 patients were entered at each dose level. RESULTS.: At the fourth dose level, the DLT was reached (grade 3 neutropenia [according to World Health Organization criteria] in 3 of 4 patients 75%]; the fourth patient demonstrated degradation of performance status). Therefore, the third dose level (lipoplatin at a dose of 120 mg/m(2)) was defined as the MTD. At the same dose level, 2 of 4 patients had grade 3 thrombocytopenia. At the fourth dose level, 1 patient achieved a partial response and 1 patient had stable disease. Another patient achieved stable disease at the second dose level. Therefore, the overall disease control rate was 23% (3 of 13 patients). The median overall survival was 29 weeks (range, 4 weeks-59 weeks) and the median time to disease progression was 12 weeks (range, 3 weeks-36 weeks). CONCLUSIONS.: The pharmacokinetic profile of the 2 compounds used in the current study are not modified when they are administered according to the schedule evaluated in this trial. When one considers that the patients in the current study had refractory or resistant NSCLC, the authors concluded that the combination of lipoplatin administered at a dose of 120 mg/m(2) and gemcitabine administered at a dose of 1000 mg/m(2) on Days 1 and 8 every 3 weeks needs to be studied further in phase 2 trials. Cancer 2008. (c) 2008 American Cancer Society.

VITAMIN C AND CHEMOTHERAPY

Vitamin C May Reduce Response to Chemotherapy

October 2, 2008 � Large supplemental doses of vitamin C could interfere with the therapeutic cytotoxic effects of a wide range of chemotherapy agents, suggests a new preclinical study. Although the finding comes from research conducted in cancer cell lines and mice, the authors say the conditions they created are similar to those found in the body, and speculate that the same mechanism might affect patient outcomes.

"It is possible that vitamin C supplementation may alter the effectiveness of commonly used chemotherapeutic agents and adversely influence treatment outcome," the researchers write in the October 1 issue of Cancer Research.

Lead author Mark Heaney, MD, PhD, from Memorial Sloan-Kettering Cancer Center, in New York, New York, told Medscape Oncology that he advises his cancer patients to avoid supplemental vitamin C during chemotherapy. "I recommend that my patients continue to eat a well-balanced diet that includes fruits and vegetables that contain vitamin C."

"Such a diet could be expected to have moderate amounts of vitamin C as well as other important nutrients. There are no data to suggest that vitamin C obtained from fruits and vegetables is intrinsically different from vitamin C supplements. Given that our research was done in experimental model systems and was not a clinical trial, I am reluctant to predict a dose of supplemental vitamin C that could be extrapolated to our work. That said, oral vitamin C supplementation with doses as low as 250 mg over a 1-month period resulted in intracellular vitamin C concentrations in normal white blood cells that were close to those that we studied in white blood cell cancers," Dr. Heaney said.

Reduction in Cytotoxic Effect

Dr. Heaney and colleagues found that pretreatment with dehydroascorbic acid, which is the form that vitamin C takes within the body, produced a dose-dependent attenuation of cytotoxicity for 5 unrelated chemotherapy agents: doxorubicin, cisplatin, vincristine, methotrexate, and imatinib.

The cell culture studies showed that the cytotoxicity was reduced by 30% to 70%, depending on the drug. A similar effect was seen in the animal studies; cancer cells transplanted into mice were held in check by doxorubicin, but grew more rapidly when they had been pretreated with vitamin C.

"It was notable that the concentration of vitamin C measured in the tumors of the mice in this study was similar to what can be achieved in human leucocytes with oral vitamin C supplementation, suggesting that our study conditions were relevant to clinical conditions," the researchers write.

Wide Variety of Chemotherapeutics Affected

"The finding that vitamin C antagonized the cytotoxic effects of such a wide range of antineoplastic agents was unexpected," the researchers comment.

Dr. Heaney and colleagues explain that they had originally hypothesized that vitamin C, being a potent antioxidant, would antagonize the cytotoxic effects of antineoplastic agents that use reactive oxygen species, such as cisplatin and doxorubicin.

However, the finding that the cytotoxicity of other chemotherapeutic agents was also affected suggests that other mechanisms are involved. The researchers speculate that the effects might be mediated by mitochondrial membrane depolarization. All of the chemotherapeutic agents, even the highly targeted product imatinib, appear to act through this pathway. Previous studies, and some of the current results, show that vitamin C stabilizes the mitochondria. In this way, vitamin C antagonizes 1 of the cytotoxic actions of the chemotherapeutic drugs.

Many Cancer Patients Take Vitamin C

"Our study is a preclinical model that addresses only the situation when vitamin C is given in the setting of chemotherapy treatment," Dr. Heaney emphasized. There have been no clinical studies of this topic so far, he said.

However, the finding could be of potential concern because "many people, cancer patients included, take supplemental vitamin C," Dr. Heaney pointed out. Clinical studies of vitamin C supplementation in patients with advanced cancers have had mixed results. There are conflicting hypotheses, he explained. One theory is that vitamin C supplementation protects the cancer and is therefore detrimental to the patient. But there is also the opposite view, that vitamin C supplementation enhances the immune system or prevents indolent cancers from mutating more and becoming aggressive, which would be beneficial for the patient.

Asked to comment on this study, Len Lichtenfeld, MACP, deputy chief medical officer at the American Cancer Society said: "Vitamin C has a long history in cancer prevention and treatment. Although there is no evidence to demonstrate that vitamin C improves the outlook for patients with cancer, there are still reported observations that cancer patients continue to believe in the potential benefits of vitamin C. Although oncologists do not routinely recommend that patients with cancer take excessive doses of vitamin C, there are reports that cancer patients are being treated with vitamin C by alternative practitioners."

"Recently, there have been research papers [indicating] that intravenous vitamin C may be beneficial in reducing the growth rates of cancers in laboratory animals. There are human clinical trials underway to determine whether or not this approach will be helpful in patients being treated for cancer," Dr. Lichtenfeld added.

However, he points out that the current report suggests that in laboratory experiments, adding vitamin C to cancer cells may reduce the effectiveness of cancer chemotherapy drugs.

"Clearly, there remains an open question as to whether or not vitamin C supplementation is helpful or harmful in the treatment of patients with cancer. Until those questions are resolved with further clinical studies, it would be inappropriate to recommend that patients take large quantities of vitamin C if they have cancer," Dr. Lichtenfeld told Medscape Oncology.

The researchers have disclosed no relevant financial relationships.

Cancer Res. 2008;68:8031-8038.

HORMONE THERAPY FOR BREAST CANCER PATIENTS WITH BRCA1 MUTATION

Hormone Therapy Safe and Possibly Protective for BRCA1-Mutation Carriers

September 30, 2008 — Hormone therapy (HT) does not appear to elevate the risk for breast cancer in postmenopausal women with a BRCA1 mutation, researchers report. In fact, according to the study published online September 23 in the Journal of the National Cancer Institute, HT was associated with a reduced risk for breast cancer in this population.

"These data are reassuring in suggesting that [HT] is probably not contraindicated in women with a BRCA1 mutation," the researchers write. "Although the data cannot yet be considered definitive, we observed a statistically significant reduction in the risk of breast cancer following [HT] use, in both the unadjusted and adjusted analyses." However, the authors of an accompanying editorial caution that these results come from a single-observation study, and should be interpreted very carefully in view of the history of hormone replacement therapy (HRT) use and breast cancer risk.

Carriers Often Undergo Prophylactic Oophorectomy

HT is commonly used to alleviate symptoms associated with menopause, but concern has been raised that the administration of exogenous hormones might increase the risk for breast cancer. Because women with a BRCA1 mutation carry a high lifetime risk for breast cancer, many enter menopause prematurely because of prophylactic surgical oophorectomy at a young age. It is estimated that 68% of women in the United States and 54% of women in Canada who have a positive genetic test result for a BRCA1 or BRCA2 mutation undergo oophorectomy, so the potential association between HT and breast cancer is of particular interest to them.

The current case-control study, conducted by Steven Narod, MD, a professor in the department of public health at the University of Toronto, Ontario, Canada, and colleagues, found that the use of HT was associated with a 42% relative reduction in the risk for developing breast cancer among women with a BRCA1 mutation. The estimates were similar in the subgroups of BRCA1-mutation carriers who had undergone surgical and natural menopause. When analyzed by type of HT, an inverse association with breast cancer risk was observed with use of estrogen-only treatment, whereas the association with estrogen plus progesterone was not statistically significant.

The results presented in this study regarding HT use in postmenopausal BRCA1-mutation carriers provide some evidence for safety, but they remain insufficient to reliably inform routine clinical practice, caution Rowan Chlebowski, MD, PhD, of the Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, and Ross Prentice, PhD, of the Fred Hutchinson Cancer Research Center, in Seattle, Washington, in an accompanying editorial.

They point out that although a meta-analysis of observational studies suggested that HT could be administered safely and would not increase the risk for breast cancer recurrence, 2 of 3 randomized trials demonstrated a substantial and statistically significant increase in breast cancer recurrence with HT. "Given this history, the suggestion of safety of [HT], especially of combined estrogen plus progestin, in women with BRCA1 mutations that is based on a single-observational study requires extremely cautious interpretation," they write.

Lower Risk in Women Who Had Used HRT

The current study involved 472 postmenopausal women with a BRCA1 mutation. Patients with a BRCA1 mutation and control patients were matched for chronological age, smoking, age at menopause, oral contraceptive use, and parity.

Compared with patients with a BRCA1 mutation, a higher proportion of control patients had used HT (29% vs 20%), and the difference was statistically significant. The average duration of HT use was similar for patients with a BRCA1 mutation and control patients (4 years vs 3.7 years).

After adjustment for confounders, including parity, oral contraceptive use, and country of origin, the researchers found that BRCA1-mutation carriers who had used HT had a lower risk for breast cancer (odds ratio [OR], 0.58%; P = .03) than those who had never used HT.

The authors acknowledge that the study has limitations, including its relatively small sample size and the exclusion of women who had undergone preventive mastectomy or used tamoxifen. However, they do write that even though the data cannot be considered definitive, "these data are reassuring in suggesting that HT is probably not contraindicated in women with a BRCA1 mutation."

However, the editorialists conclude by emphasizing that "continued caution in prescribing [HT] to women with BRCA1 mutations who are at high risk for breast cancers remains prudent."

The study was funded by the Canadian Breast Cancer Research Alliance and the National Institutes of Health. Dr. Chlebowski has been a consultant for AstraZeneca, Novartis Pharmaceuticals Corp, Eli Lilly & Co, Pfizer Inc, and Wyeth, and is on the speaker's bureau for AstraZeneca and Novartis.

J Natl Cancer Inst. Published online September 29, 2008.

IB NSCLC NO BENEFIT FROM ADJUVANT CHEMOTHERAPY

J Clin Oncol. 2008 Sep 22. [Epub ahead of print]

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Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non-Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.

Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR.

Tufts Medical Center; Brigham and Women's Hospital, Boston, MA; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; Southeast Cancer Control Consortium Inc, Community Clinical Oncology Program, Goldsboro, NC; University of Minnesota, Minneapolis, MN; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Mayo Clinic Jacksonville, Jacksonville, FL; University of Virginia, Charlottesville, VA; and University of Chicago, Chicago, IL.

PURPOSE: Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC. PATIENTS AND METHODS: Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival. RESULTS: Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors >/= 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043). CONCLUSION: Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors >/= 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.

A GREEK STUDY FOR SMALL CELL LUNG CANCER

Oncol Rep. 2008 Oct;20(4):879-84.

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Comparison of cisplatin-paclitaxel combination versus cisplatin-etoposide in patients with small-cell lung cancer: A Phase III study.

Dimitroulis J, Rapti A, Stathopoulos GP, Rigatos S, Stathopoulos J, Koutantos J, Athanasiadis A, Tsikritsaki K, Karaindros D, Katis K, Antoniou D, Toumbis M, Giamboudakis P.

Hospital of Thoracic Diseases, Athens, Greece.

Cisplatin-paclitaxel and cisplatin-etoposide combination therapies were compared in limited and extensive disease in patients with small-cell lung cancer. The primary objectives were to determine median and overall survival, time to tumor progression and tolerance and the secondary objective, the response rate. From January 2003 till July 2007, 108 patients were enrolled in the study. All patients had histologically- or cytologically-confirmed small-cell lung cancer. All patients were chemotherapy and radiotherapy naive. The patients were designated to receive six cycles: in the investigational Arm A, cisplatin, 80 mg/m(2) and paclitaxel 175 mg/m(2) were infused on day 1 (1 cycle) and repeated every 3 weeks. In the control Arm B, cisplatin, 80 mg/m(2) was administered on day 1 and etoposide, 120 mg/m(2) per day was given on days 1-3 (1 cycle), every 3 weeks. In Arm A, 6 (11.3%) patients achieved a complete response and 32 (58.1%), a partial response; in Arm B, 7 (12.7%) patients achieved a complete response and 32 (58.2%) a partial response. The median survival time in Arm A patients was 12 months and in Arm B, 13 months, p=0.354. The time to tumor progression (TTP) was 8 and 6 months for Arms A and B, respectively (p=0.060). Toxicity, although common in both Arms, was acceptable. Neutropenia, anemia and diarrhea were higher in the control Arm. The cisplatin-paclitaxel combination is not superior to cisplatin-etoposide with respect to survival, TTP, toxicity and response rate. The former combination could be applied as an alternative chemotherapy regimen for patients with limited or advanced small-cell lung cancer.

RE-TREATMENT WITH DOCETAXEL

Oncol Rep. 2008 Oct;20(4):891-6.

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Docetaxel chemotherapy for metastatic hormone refractory prostate cancer as first-line palliative chemotherapy and subsequent re-treatment: Birmingham experience.

Ansari J, Hussain SA, Zarkar A, Tanguay JS, Bliss J, Glaholm J.

University Hospital Birmingham NHS Trust, Metchley Drive, Birmingham B15 2TH, UK. drjawaher@yahoo.com.

Three-weekly docetaxel chemotherapy with prednisolone is now considered standard of care for patients with metastatic hormone refractory prostate cancer (MHRPC). This study reports the efficacy and toxicity of first-line docetaxel chemotherapy followed subsequently by re-treatment on biochemical disease progression (BDP). Forty-two patients with MHRPC were treated with three-weekly docetaxel chemotherapy 75 mg/m(2) and 10 mg of prednisolone daily. Median age 73 years (range 58-87) and median initial PSA 182 ng/ml (range 19.9-1500). Of these patients, 10 were re-treated with the same regimen (second-line chemotherapy) on BDP. A further 3 out of these 10 patients received 2nd re-treatment (third-line chemotherapy) with docetaxel chemotherapy on BDP. Fifty-four percent of patients responded to first-line docetaxel chemotherapy and all re-treated patients responded again with a PSA reduction >50%. Median treatment-free interval prior to second and third-line chemotherapy was 24 and 26 weeks, respectively. Grade 3 or 4 neutropenia occurred in 2.5, 7 and 12% of the total number of cycles in patients receiving first-, second- and third-line docetaxel chemotherapy, respectively. Median survival was 13 months (range 3-35) and one-year overall survival 52%. This is the first report of three-weekly docetaxel chemotherapy re-treatment in patients with MHRPC and demonstrates that patients who initially respond to docetaxel chemotherapy maintain their sensitivity to subsequent re-treatment without a significant rise in haematological toxicity.

ERYTHROPOIETIN AGAIN

High-Dose Epogen/Procrit in Ischemic Stroke Patients Linked to Higher Death Rate

September 26, 2008 &8212; Use of high-dose epoetin alfa (Epogen, Amgen, Inc; Procrit, Ortho Biotech) in acute ischemic stroke patients has been linked to an increased risk for death, the US Food and Drug Administration (FDA) warned healthcare professionals today.

The warning was based on preliminary data from a German functional-ability study that employed doses of epoetin alfa (marketed as Eprex) that were considerably higher than those recommended by the FDA for the treatment of anemia, according to an alert issued by MedWatch, the FDA's safety information and adverse-event reporting program.

For the study, 522 adult patients with MRI-confirmed ischemic stroke were randomized to receive either placebo or 40,000 units of epoetin alfa administered intravenously for 3 days. Recombinant tissue-type plasminogen activator (r-TPA) was also used when clinically indicated.

Although investigators sought to demonstrate therapeutic improvements in functional ability, results over the first 90 days showed higher mortality in patients taking epoetin alfa than in those taking placebo (16% vs 9%), with roughly 50% of deaths occurring during the first week of treatment. Approximately 4% of epoetin-treated patients died from intracranial hemorrhage, compared with 1% of those receiving placebo.

According to an early communication, further information concerning this matter should be available from the FDA within the next several weeks. In the interim, close monitoring of adverse events in other clinical trials is advised to ensure that the potential benefits of therapy outweigh the risks to enrollees.

Epoetin alfa is an erythropoiesis-stimulating agent (ESA) approved by the FDA for the treatment of anemia in chronic renal failure patients, zidovudine-treated HIV-infected patients, cancer patients on chemotherapy; and to reduce the need for allogenic blood transfusions in surgical patients.

BE CAREFUL WITH ENERGY DRINKS

Experts Call for Health Warning Labels on Caffeinated Energy Drinks

September 26, 2008 — Experts are calling for health warning labels on so-called "energy drinks" that, due to their high caffeine content, may pose a significant consumer health risk, particularly in adolescents and young adults.

In a review paper published online September 20 in Drug and Alcohol Dependence, investigators at Johns Hopkins University School of Medicine, in Baltimore, point out that a single serving of some of these drinks can contain more than 500 mg of caffeine, an amount equivalent to 14 cans of Coca-Cola.

Despite this, the caffeine content of these products is frequently not indicated, and few brands include warnings about potential health risks, including caffeine intoxication.

"Many products don't label the amount of caffeine they contain, and the amount of caffeine across different brands is quite variable, so you can pick up something called a can of energy drink and it may contain as little as 50 mg of caffeine or it can contain 505 mg of caffeine," lead author Roland Griffiths, PhD, told Medscape Psychiatry.

Vulnerable Population

Furthermore, and even more disturbing, said Dr. Griffiths, is the aggressive marketing of these drinks to young people, who are frequently caffeine naive and therefore more susceptible to the negative physical effects of caffeine.

"A caffeine-naive population is going to be much more sensitive to caffeine, and we really run the risk of caffeine overdose. We don't really know what the prevalence of this is, but we know it occurs and this shouldn't surprise us.

"Caffeine intoxication is a well-recognized psychiatric diagnosis with well-described symptoms, and if you give high doses of caffeine to caffeine-naive people, some of them are going to get into trouble," said Dr. Griffiths.

He added that reports of caffeine abuse to US poison control centers showed negative reaction to energy drinks.

In a 2007 survey of 496 college students, 51% reported consuming at least 1 energy drink during the past month. Of these energy-drink users, 29% reported "weekly jolt-and-crash" episodes and 19% reported heart palpitations from consuming these beverages.

Gateway to Drug Abuse?

The same survey revealed that 27% of the survey respondents reported mixing energy drinks and alcohol at least once in the past month. "When you combine caffeine and alcohol, people are less likely to perceive the extent to which they are intoxicated and are at greater risk of alcohol-related injury," said Dr. Griffiths.

Further, there is a concern that the strong stimulant effect of energy drinks may increase the risk of nonmedical use of prescription stimulants such as amphetamines and methylphenidate. A 2008 study of 1253 college students showed energy-drink consumption significantly predicted subsequent nonmedical prescription stimulant use.

Potentially fueling this "transition" market, there are other energy drinks, such as the powdered energy drink Blow, which is sold in vials, and the energy drink Cocaine, that use language on their products suggesting illicit drugs.

Energy drinks first came on the market in 1987 with the launching of Red Bull in Australia. Since then, the industry has grown exponentially worldwide and stands at an estimated $5.4 billion in the United States and is expanding at a rate of 55% annually.

Given all these factors, Dr. Griffiths believes the US Food and Drug Administration (FDA) should move to require warning labels on these drinks. However, it does not appear likely this will occur in the foreseeable future.