ΕΜΠΑΣΕ Η ΒΑΡΚΑ ΡΩΜΙΕ

Avastin fails to prevent colon cancer recurrence, clinical trial indicates.
The New York Times (4/22, Pollack) reports, "The drug Avastin [bevacizumab] failed to prevent colon cancer from recurring by a significant amount in a clinical trial," Roche's Genentech Inc. unit "said early Wednesday." The results of the trial "had been closely watched because a success would have paved the way to a new use of the drug." Data from the trial is expected to "be presented at the American Society of Clinical Oncology meeting" late May. The trial included "2,700 patients who received six months of the standard chemotherapy or six months of that chemotherapy plus a year of Avastin." But, because "the existing chemotherapy already keeps about 70 percent of colon cancer patients free of the disease three years after their surgery," the company "had rated the chance of success in the trial at 61 percent." 
  Bloomberg News (4/22, Doherty) reports that the drug is "already approved for patients with cancers that have spread beyond the breast, colon, and lung." Roche said that it "plans further tests for early stage use" of the drug, and, according to Bill Burns, head of Roche's pharmaceutical division, the company "doesn't view the results as a setback." In fact, "the study only ever had a 50:50 chance of success," he stated. Dow Jones Newswires (4/22, Schoemaker) also covers the story. 

KOS AND NAFPLIO ARE HERE

Am J Ther. 2009 Apr 4. [Epub ahead of print]

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Efficacy and Safety of Capecitabine and Oxaliplatin Combination as Second-Line Treatment in Advanced Colorectal Cancer.

Heras P, Kritikos K, Hatzopoulos A, Xourafas V, Kritikos N, Karagiannis S, Mitsibounas D.

1Department of Internal Medicine, General Hospital of Cos, Cos, Greece; 2Department of Internal Medicine, General Hospital of Nafplio, Nafplio, Greece; and 3Hellenic Medical Society for the Study of Psychosomatic Problems, Athens, Greece.

INTRODUCTION: The aim of this study was to determine the efficacy and safety of administering a combination of capecitabine and oxaliplatin in patients with advanced colorectal cancer, resistant to leucovorin/5-fluorouracil and irinotecan. PATIENTS AND METHODS: Fifty-four patients with advanced colorectal cancer were prospectively evaluated (mean age 63 years, male/female 2:1) who had been previously treated with schemes containing fluoropyrimidines and irinotecan. All patients received oxaliplatin (130 mg/m as 2-hour intravenous infusion) the first day of the cycle and capecitabine (1000 mg/m) twice daily, days 1-14. Cycles were repeated every 21 days until either disease progression or unacceptable toxicity. Patients were evaluated regarding their response to treatment every 9 weeks (toxicity was evaluated every 3 weeks). RESULTS: Total response rate was 28.3%. Median total survival was 13.5 months, and median time to progression was 5.3 months in a follow up of 24 months. Major adverse events were neutropenia, nausea, diarrhea, hand/foot syndrome, and neurotoxicity. No treatment-related or grade 4 toxicity-related deaths were observed. Additionally, no dosage decrease was required, and only 4 cycles were withheld for 1 week because of neutropenia. CONCLUSIONS: The combination of oxaliplatin and capecitabine is efficient and safe for patients with advanced colorectal cancer who have been previously treated with other therapeutic schemes. Furthermore, this is a convenient and well-tolerated scheme.

PIK3CA MUTATION AND CETUXIMAB

Clin Cancer Res. 2009 Apr 14. [Epub ahead of print]

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PIK3CA Mutations Are Not a Major Determinant of Resistance to the Epidermal Growth Factor Receptor Inhibitor Cetuximab in Metastatic Colorectal Cancer.

Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S.

Authors' Affiliations: Department of Digestive Oncology, University Hospital Gasthuisberg, Center for Human Genetics K.U.Leuven, and The Vesalius Research Center, K.U. Leuven and VIB, Leuven, Belgium.

PURPOSE: It has been reported that activating KRAS mutations negatively affect response to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. The mutation status of signaling molecules downstream of the EGFR target is thus crucial to predict clinical benefit to EGFR-targeted therapies. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the PI3K/PTEN/AKT pathway.EXPERIMENTAL DESIGN: We analyzed the PIK3CA and KRAS mutation status in a large group (n = 200) of chemorefractory metastatic colorectal cancers treated with cetuximab (Erbitux) in monotherapy or in combination with irinotecan, and correlated the mutation status with outcome.RESULTS: Twenty-three (12%) of the 200 samples carried 1 of the PIK3CA mutations included in our assay. We found no correlation between the presence of a PIK3CA mutation and impaired response to cetuximab.CONCLUSIONS: Our findings do not provide any evidence for a strong role of PIK3CA mutations as a single marker in determining response to cetuximab in chemorefractory metastatic colorectal cancer.

P53 MUTATIONS AND CETUXIMAB

Br J Cancer. 2009 Apr 21;100(8):1330-5.

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TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy.

Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, Bougeard G, Charbonnier F, Blanchard F, Tougeron D, Ychou M, Boissière F, Le Pessot F, Sabourin JC, Tuech JJ, Michel P, Frebourg T.

Inserm U614, Faculty of Medicine, Institute for Biomedical Research, University of Rouen, Rouen, France.

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.

SURGERY FOR STAGE IV BREAST CANCER PATIENTS

Breast Surgery for Stage IV Breast Cancer

Lisa A. Newman, MD, MPH

Published: 04/06/2009

Question
A 42-year-old premenopausal woman presented with locally advanced right breast infiltrating ductal carcinoma, estrogen/progesterone receptor (ER/PR) negative, HER2 3+, with an osteolytic lesion measured at L3. No response was noted after 3 cycles of doxorubicin plus cyclophosphamide (AC), but there is good partial response after 6 cycles of docetaxel, carboplatin, and trastuzumab (TCH). Primary tumor size has decreased from 9x9 cm to 5x5 cm. Is surgery or radiotherapy to the primary tumor advised at this stage?

Response from Lisa A. Newman, MD, MPH Professor of Surgery, University of Michigan, Ann Arbor, Michigan; Director, Breast Care Center, University of Michigan, Ann Arbor, Michigan

If this patient's primary breast tumor and metastatic disease are both responding to systemic therapy, then it indeed seems appropriate to proceed with definitive breast management. Depending on the patient's breast size and personal wishes, potential management options include either lumpectomy and breast radiation or mastectomy. Optimal management of the axilla has not been addressed in published studies of surgery for Stage IV breast cancer, but it seems reasonable to perform axillary dissection very selectively (ie, in cases of overt, clinically evident nodal metastases.

Most patients with invasive breast cancer require primary breast and axillary surgery for definitive locoregional control of disease, as well as for staging information. Systemic therapies (delivered pre- and/or postoperatively) provide substantial survival advantages by eradicating occult, micrometastatic disease in distant organs. Application of multimodality therapy to patients with Stage I-III disease results in long-term control of disease for most patients. In contrast, survival of patients with established Stage IV disease (defined by documented, clinically evident metastatic disease in distant organs) is less favorable, and these patients are generally referred for primary palliative management. Breast surgery for Stage IV breast cancer is therefore usually limited to resections that aim to control ulcerated or fungating tumors that are resistant to nonoperative measures.

This conventional approach to metastatic disease has been challenged recently, largely due to 2 arguments. First, systemic therapies for breast cancer have advanced, and survival with metastatic breast cancer has indeed improved over the past few decades.^[1,2] This improved outcome has led to renewed interest in durable locoregional disease control. A second argument in favor of breast surgery for metastatic disease is related to its potential therapeutic value: resection of the primary breast lesion may improve outcome by minimizing the total body tumor burden and also by removing a source of ongoing tumor seeding. Conversely, however, others have speculated that resection of the primary breast tumor could disrupt the immunologic balance achieved by the small fraction of patients with metastatic disease that remains indolent for a prolonged interval. From the perspective of cancer research, aggressive attention to the primary tumors of patients with Stage IV disease could expand tissue bank resources.

As illustrated in the Table , several investigators, using very different datasets, have shown that primary breast surgery for Stage IV breast cancer is associated with a survival advantage. The outstanding question in all these studies, however, is whether significant selection bias may be contributing to these outcome patterns. Factors associated with improved outcome after breast surgery include age, limited site metastases (especially if osseous-only), and evidence of response to preoperative systemic therapy.

Table.

Author	Year	Dataset	Findings
Khan and colleagues[3]	2002	National Cancer Data Base, 1990-1993N = 16,023	Mortality HR = 0.61 for resection (95% CI = 0.58-0.65)
Rapiti and colleagues[4]	2006	Geneva Cancer Registry, 1977-1996N = 300	Mortality HR = 0.6 for resection (95% CI = 0.4-1.0)
Babiera and colleagues[5]	2006	University of Texas M.D. Anderson Cancer Center,1997-2002N = 224	Overall survival RR = 0.5 (95% CI = 0.21-1.19)
Cady and colleagues[6]	2008	Massachusetts General Hospital and Brigham and Women's Hospital,1970-2002N = 622	Survival advantage for patients undergoing surgery, but most of survival advantage explained by selection bias in matched-pair analyses

CI = confidence interval; HR = hazard ratio; RR = relative risk

Outcome for Patients Undergoing Primary Breast Surgery for Stage IV Breast Cancer

Definitive answers regarding this controversial issue will likely require a large, multicenter phase 3 clinical trial. In the absence of such high-level data, an aggressive approach to primary breast surgery with curative intent in selected, physically fit patients whose metastatic disease appears to be well-controlled with systemic therapy is at least a reasonable option for consideration. The pros and cons of surgery and the limited data supporting an outcome benefit should be presented in detail to the patients under consideration; the discussion should include perspectives offered by the multidisciplinary treatment team.

PET/CT AFTER 1 CYCLE OF CHEMOTHERAPY PREDICTS RESPONSE FOR SARCOMA PATIENTS

April 17, 2009 — The effectiveness of chemotherapy can be accurately determined in sarcoma patients — after only 1 treatment cycle, according to investigators at the University of California at Los Angeles (UCLA).

In a single-center study, imaging of tumor metabolic activity with a combination positron emission tomography/computed tomography (PET/CT) scanner predicted histopathologic response to neoadjuvant chemotherapy in high-grade sarcoma patients — about a week after the first treatment cycle.

"I was surprised that we could tell that early," study senior author Frtiz C. Eilber, MD, told Medscape Oncology. Dr. Eilber is director of the Sarcoma Program at UCLA's Jonsson Cancer Center.

Being able to identify responders and nonresponders to a chemotherapy regimen early on is of great importance, he said. "Neoadjuvant therapy is highly toxic and frequently ineffective. This approach accelerates the identification of the correct therapy for patients and reduces morbidity from chemotherapy," he said.

Patients who are not responders to therapy could also potentially undergo surgery earlier, he added.

The new study was published April 7 in Clinical Cancer Research.

Dr. Eilber is part of a group of UCLA researchers who at the forefront of using PET/CT imaging and biological probes to more quickly and accurately assess the effectiveness of chemotherapy.

"Noninvasive molecular evaluations of treatment effectiveness are part of the future of oncology," he said.

In the current study, the PET portion of the PET/CT scanner is used in conjunction with a glucose-uptake probe called fluorodeoxyglucose (FDG), which allows the investigators to see how much sugar is being consumed by the cancer cells. This metabolic activity makes cancer cells light up under PET scanning.

All 8 of the 50 patients in the study who had eventual histopathologic evidence of a response to therapy had a 35% or greater reduction in their glucose metabolism after their first cycle of chemotherapy.

The histopathologic response to chemotherapy was defined as 95% or greater necrosis in tumor tissue when the tumor was surgically removed at the end of the regimen.

"If you did not get an initial 35% or greater reduction in activity of the tumor, then the chemotherapy was not working," Dr. Eilber said, explaining that 28 patients in the study did not reach this level of tumor-activity reduction.

The remaining 14 patients in the study had a 35% or greater reduction in tumor activity but the necrosis in their tumor tissue was less than 95%; thus, they were not considered responders to chemotherapy.

"Using a 35% or greater reduction in FDG uptake as an early metabolic response threshold resulted in a sensitivity and specificity of FDG-PET for histopathologic response of 100% and 67%, respectively," conclude the study authors.

The investigators are now following the patients to see how those with tumor-activity reduction fare in terms of survival, compared with the patients who did not meet the cut-off level of activity reduction.

The study and its methods are not novel. Glucose metabolic imaging has been used successfully in patients with esophageal cancer to determine whether neoadjuvant treatment should be continued or discontinued, noted Dr. Eilber.

Standard for Evaluation is Tumor Size

Currently, sarcoma patients are typically evaluated after 2 or 3 cycles of chemotherapy by PET, said Dr. Eilber. However, metabolic activity of tumor cells is not measured — the size of the tumor is. The guidelines for this evaluation are known as RECIST (Response Evaluation Criteria in Solid Tumors). In brief, if the tumor shrinks, compared with the baseline PET, the therapy is deemed to be working in this standard of care.

In a previous study (Clin Cancer Res. 2008;14:715-720), Dr. Eilber and colleagues showed that changes in glucose metabolic activity were more accurate than tumor size in predicting the histopathologic response of tumors to chemotherapy.

"We've known for a long time that change in tumor size does not correlate well with outcomes," he said.

The insufficiency of the standard approach and the results of the new research have led to a change in practice for Dr. Eilber, who now employs FDG-PET in his clinic.

"We are already using this in the clinic. For example, we had a woman with a breast sarcoma who did not have a change in tumor activity after the first cycle of a taxane regimen. So we switched the regimen and saw a metabolic activity decrease well over the 35% cut-point. We subsequently excised the tumor and she was a pathologic responder," he said.

Dr. Eilber believes that moving up the assessment of chemotherapy in a wide variety of oncology patients is key to improving treatment. For example, the early metabolic activity assessment of tumors could be used in metastatic colon cancer and gastric cancer, he said.

He also pointed out that many community hospitals have PET/CT technology and could be trained to use FDG, the glucose-uptake probe.

According to Dr. Eilber, there are also other noninvasive methods for assessing tumor response to therapy in development, including the thymidine analog 18F-3'-deoxy-3'-fluorothymidine, which is being used clinically for PET imaging of tumor proliferation.

MULTIFOCAL LUNG CANCERS ORIGINATE FROM THE SAME CLONE

Multifocal lung cancers appear to originate from single cancer clone

09.04.09

Category: Scientific News

Findings support the current classification of multifocal lung cancers as advanced-stage cancers rather than separate primary cancers

Multiple, anatomically distinct lung cancer tumors may frequently arise from a single cancer cell, according to a retrospective analysis of patient tumor samples published in the April 7 online issue of the Journal of the National Cancer Institute.

Some lung cancer patients have multiple anatomically distinct tumors at the time of diagnosis. Although such multiple tumors usually share a common appearance, it has been unclear whether they arise from a single tumor or are independent primary cancers.

In the current study, Dr Liang Cheng from the Indiana University School of Medicine in Indianapolis, USA and colleagues examined 70 lung cancer tumors from 23 female and seven male patients to determine whether multiple tumors from an individual patient shared a common genetic pattern. The investigators analyzed the tumors for chromosome loss at six loci previously associated with lung cancer and for mutations in the TP53 gene. They also analyzed the X-chromosome inactivation pattern in tumors from female patients.

Based on these three analyses, the investigators concluded that the multiple tumors in 23 of the 30 patients (77 percent) arose from a single cancer clone.

These findings support the current classification of multifocal lung cancers as advanced-stage cancers rather than separate primary cancers and the use of therapeutic strategies tailored for patients with advanced-staged cancers, the authors write.

The results of these studies pose both important biological and clinical management questions, according to Adi F Gazdar, MBBS, and Dr John D Minna, from the University of Texas Southwestern Medical Center in Dallas, who wrote an accompanying editorial. The editorialists review what is known about the biology of multifocal cancers and note that as many as 8 percent of lung cancer patients have multiple anatomically distinct tumors at the time of diagnosis.

An updated lung cancer classification system is expected sometime in 2009 and will distinguish between patients with regional metastatic disease, including those with multiple tumors at diagnosis, and patients with distant metastases. Clearly, multifocal lung cancers (without distant metastases) constitute a unique set of tumors having heterogeneous origins and better than

PARP INHIBITORS AND TOPOTECAN

A phase I combination study of ABT-888 and topotecan hydrochloride in adults with refractory solid tumors and lymphomas

08.04.09

Category: Scientific News

Coadministration of the PARP inhibitor potentiated the toxic effects of topotecan

Poly (ADP-ribose) polymerase (PARP) is an essential nuclear enzyme important for recognizing DNA damage and facilitating DNA repair. PARP inhibitors may prevent efficient repair of DNA damage induced by topoisomerase 1 inhibitors such as topotecan.

Dr S Kummar from the National Cancer institute, Bethesda, USA presented the study at the 7th International Symposium on Targeted Anticancer Therapies in Amsterdam, the Netherlands, on 23–25 March 2009. The objectives of the trial were to establish the safety, tolerability, and maximum tolerated dose of the combination of the oral PARP inhibitor ABT-888 with topotecan, to evaluate the pharmacokinetics of each agent alone and in combination, and to determine drug effects on the level of PARP inhibition in peripheral blood mononuclear cells (PBMCs) and tumor samples.

Patients with histologically documented solid tumors and lymphoid malignancies whose disease had progressed following standard therapy were eligible. Treatment consisted of 21-day cycles of ABT-888 po and topotecan iv. PBMCs and optional biopsies were collected, and PARP activity was determined using a validated ELISA assay comparing pre- and post-treatment PAR levels.

Two of 6 patients developed dose-limiting toxicities (DLTs; grade 4 thrombocytopenia and grade 4 neutropenia) at the starting dose; myelosuppression was also observed at level 1. ABT-888 dosing was reduced to 5 days and the dose of topotecan lowered. However, significant myelosuppression was still seen at level 2. Six patients on study had stable disease for ≥ 2 cycles but 5 were removed due to toxicities. One patient with thyroid cancer on level 3 continued on study for > 6 months. PARP activity was inhibited in PBMCs in 14 of 18 patients. In 2 patients for whom paired tumor and PBMC data are available, there was a > 75% decrease in PAR levels 3-7 hours after treatment.

PARP inhibitors are being developed as chemopotentiating agents. However, coadministration of the PARP inhibitor ABT-888 potentiated the toxic effects of topotecan in this trial.

SHARED MEDICAL EQUIPMENT AND HEPATITIS B

Shared Medical Equipment Results in Hepatitis B Outbreaks in Healthcare Settings

April 8, 2008 — The routine clinical use of shared medical equipment, such as multivial drugs and multipatient devices for capillary blood sampling in glucose monitoring, can be responsible for patient-to-patient transmission of hepatitis B virus in healthcare settings, according to a review study published online April 8 in BMC Medicine.

In the study, researchers analyzed 30 papers that reported on 33 outbreaks of hepatitis B virus infection among 471 patients, including 16 fatal cases, in the United States and European Union. The highest number of outbreaks occurred in dialysis units (30.3%), followed by medical wards and nursing homes (21.2%), surgery wards (15.2%), and outpatient clinics (15.2%). The reasons for the hepatitis B virus outbreaks included routine clinical practices such as the use of multivial drugs (30.3%) and nondisposable devices for performing capillary blood sampling in diabetic patients (27.2%), the spread of blood droplets during transvenous endomyocardial biopsy procedures (9.1%), and multiple errors in applying standard infection control measures (9.1%).

"We have found that several breaches in infection control measures, related to some routine clinical practices thought to be risk-free (e.g. point of care blood glucose monitoring or preparation and administration of common parenteral drugs with multi-vial compounds) could result in patient-to-patient transmission of the hepatitis B virus within healthcare settings," write Simone Lanini, MD, and colleagues from the Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani in Rome.

"Moreover some outbreak reports underlined that heart-transplant recipients are at risk of contracting hepatitis B virus infection during the transvenous endomyocardial biopsy (TEB) procedure through indirect contact with infected blood as a result of environmental contamination," the authors note.

The authors analyzed studies published between January 1992 and December 2007 and considered only outbreaks in the United States and the European Union because they both have high health standards and comparable sociodemographic indicators. The researchers excluded cases of healthcare worker-to-patient transmission of the hepatitis B virus. A PubMed search resulted in 93 papers, 23 of which met the researchers' inclusion criteria; 7 additional papers came from references and the Outbreak Database, the worldwide database for nosocomial outbreaks.

The researchers found that dialysis units had the highest number of hepatitis B virus outbreaks but that these outbreaks had the shortest duration and the fewest cases. The authors note that dialysis units have improved mandatory protocols for surveillance of blood-borne infections, which might explain the higher frequency of hepatitis B virus outbreak reports in these settings.

"Consistent with the Centers for Disease Control and Prevention (CDC) data, the results of this review strengthen the idea that dialysis itself is nowadays a rather safe procedure and that outbreaks are largely due to 'substantial deficiencies in recommended infection control practice, such as the use of multi-vial drugs, as well as failure to vaccinate hemodialysis patients against hepatitis B,' " according to the authors. In June 2007, the CDC recommended against the use of multivial compounds in its guidelines on preventing infection in healthcare settings.

The authors also note that multipatient capillary blood sampling devices for glucose monitoring in diabetic patients are presumed to be safe because of their disposable lancets. However, the transmission of the hepatitis B virus through the nondisposable components of these multipatient devices is possible, and they should be reserved for personal home use, according to the authors.

Heart transplant recipients are also at increased risk for infection with hepatitis B virus, largely through the TEB procedure, a method used to evaluate the status of cardiac transplant rejection. In the reports analyzed by the authors, however, infection occurred through the spread of blood droplets during purging of syringes and catheter withdrawal in TEB. These blood droplets can contaminate unwrapped TEB biopsy material and could then contaminate the next patient to undergo the procedure, the authors write.

The authors found no outbreaks related to endoscopic procedures and little difference in the pattern of outbreaks observed in the United States and European Union. Most of the outbreaks originated among patients already suffering some degree of immunosuppression, such as those with end-stage renal disease, diabetes, or neoplasms or those undergoing heart transplantation.

To prevent the transmission of blood-borne pathogens such as hepatitis B virus, healthcare workers should strictly adhere to standard safety procedures as well as infection control principles, the authors caution. They conclude that using sterile single-use disposable needles and avoiding multivial compounds is crucial. "These principles and practices need to be made explicit in institutional policies and reinforced through in-service education for all personnel involved in direct patient care," the researchers write.

RADIOTHERAPY FOR STAGE I SEMINOMA AND CRYPTORCHISM

Int J Radiat Oncol Biol Phys. 2009 Apr 11. [Epub ahead of print]

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Is Radiotherapy A Good Adjuvant Strategy for Men with A History of Cryptorchism and Stage I Seminoma?

Martin JM, Gorayski P, Zwahlen D, Fay M, Keller J, Millar J.

Department of Radiation Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Radiation Oncology Queensland, Toowoomba, Queensland, Australia.

PURPOSE: Men with cryptorchism can have aberrant abdominopelvic lymph node (LN) drainage or a different natural history if they develop Stage I seminoma. If so, the nodal echelons for metastases will not be reliable, and adjuvant radiotherapy (RT) would not be an ideal strategy. METHODSAND MATERIALS: Two prospectively maintained oncology databases were reviewed for men with a history of testicular seminoma and cryptorchidism. The primary endpoint was the 5-year relapse-free rate. RESULTS: A total of 23 men were identified, most (n = 13) had had a tumor in a scrotal location after orchiopexy. After orchiectomy, 5 men were managed with surveillance, and 18 underwent RT to a median dose of 25 Gy (range, 20-30 Gy). All the radiation fields included the para-aortic LNs, and 13 included the ipsilateral pelvic LNs. After a median follow-up of 64 months (range, 2-148), 2 patients developed a relapse. One did so 4 months into a surveillance program in the para-aortic and ipsilateral pelvic LNs, sites that would have been treated had he undergone RT. The other patient developed a relapse in the contralateral testis 46 months after having undergone RT. It is likely that the latter patient had a metachronous primary rather than a relapse; hence, the 5-year relapse-free rate was 80% for surveillance and 100% for RT. Both patients underwent successful salvage treatment, and all patients were disease free and alive at the last follow-up visit. CONCLUSION: A history of cryptorchism does not appear to confer a greater risk of relapse for men with Stage I seminoma managed with radiotherapy. RT, surveillance, and adjuvant carboplatin chemotherapy are treatment options for these patients.

REDUCING LDL REDUCES STROKE RISK

Reducing LDL Cholesterol With Statins Reduces Stroke Risk: Meta-Analysis

April 16, 2009 (Paris, France) — Reducing LDL-cholesterol levels with statins is effective in reducing initial and recurrent stroke, according to an updated meta-analysis [1]. Data from 24 randomized clinical trials showed that lipid lowering with statins cut the risk of stroke by one-fifth compared with controls, report investigators.

The meta-analysis, published in the May 2009 issue of Lancet Neurology, includes more than 165 000 patients and shows that for every 39-mg/dL decrease in LDL-cholesterol levels, there was a 21% reduction in the relative risk of stroke.

The researchers, Drs Pierre Amarenco and Julien Labreuche (Paris-Diderot University, France), who also include a review of the field in their paper, point out that the relationship between total and LDL cholesterol and stroke risk is inconsistent or weak. Despite this, statin therapy is an important treatment in stroke prevention, with studies showing that lowering cholesterol levels with statins reduces the risk of stroke in high-risk populations and patients with noncardioembolic stroke or transient ischemic attack (TIA).

"The most important challenges for clinicians will be to implement evidence-based therapy and expert opinion recommendations in clinical practice," write Amarenco and Labreuche. They note that just 35% of patients in one recent European survey were treated to target after a vascular event.

Other Meta-Analyses Found No Benefit With Statins

In their review, the authors point to some of the inconsistencies in the literature regarding cholesterol and stroke risk. One recent meta-analysis of 61 prospective observational studies, reported by heartwire , failed to find any association of total cholesterol (TC) with stroke mortality. Other studies have suggested it is important to account for stroke types, however, with previous trials showing reductions in ischemic stroke with lower serum cholesterol concentrations.

In this most recent meta-analysis, the authors included 24 studies, among them the recent SEARCH and JUPITER trials, as well as SPARCL, TNT, IDEAL, PROVE-IT, and the Heart Protection Study (HPS). The majority of studies included were for the primary prevention of stroke, while SPARCL was a secondary-prevention trial, and HPS, LIPID, and CARE included patients with prior cardiovascular disease.

Overall, the incidence of all strokes was reduced 18%, and there was also a statistically nonsignificant 13% reduction in the risk of fatal stroke. In secondary prevention, reducing LDL-cholesterol levels with statins significantly reduced the risk of recurrent stroke and major cardiovascular events. Overall, the incidence of hemorrhagic stroke did not increase, which is in contrast to SPARCL and HPS, two studies that suggested an increased risk of hemorrhagic stroke in secondary prevention.

Effect of Statins on All Strokes, Fatal Stroke, and Hemorrhagic Stroke

Studies	Relative risk reduction
All stroke (total)	0.82 (0.77–0.87)
All stroke (primary-prevention studies)	0.81 (0.75–0.87)
All stroke (secondary prevention: SPARCL, HPS, LIPID, and CARE)	0.88 (0.78-0.99)
Fatal stroke (total)	0.87 (0.73–1.03)
Fatal stroke (primary-prevention studies)	0.90 (0.76–1.05)
Fatal stroke (secondary prevention: SPARCL)	0.59 (0.36–0.97)
Hemorrhagic stroke (total)	1.03 (0.75–1.41)
Hemorrhagic stroke (primary-prevention studies)	0.81 (0.60–1.08)
Hemorrhagic stroke (secondary prevention: SPARCL and HPS)	1.73 (1.19–2.50)

"Because of increased risk incidence of hemorrhagic stroke seen in HPS and SPARCL, we recommend caution when considering statin therapy in patients with prior cerebral hemorrhage," write Amarenco and Labreuche. "Pending further data from other secondary-prevention trials in patients with stroke, we would only prescribe statins to patients who are at high risk of major coronary or other atherothrombotic events and would not aim to aggressively reduce cholesterol concentrations."

They suggest future areas of study involve testing intensive lipid-lowering strategies for stroke prevention, similar to the host of lower-is-better cholesterol trials in the past few years. Other drugs that raise HDL-cholesterol levels should also be tested, as epidemiological evidence suggests raising HDL cholesterol reduces the risk of stroke, while other studies have shown the LDL:HDL cholesterol ratio to be the best predictor of stroke and MI. Triglyceride-lowering therapies also need to be tested in randomized, controlled trials, they add.

MARIJUANA USE AND NON SEMINOMA TESTICULAR CANCER

Marijuana Use Linked to Nonseminoma Testicular Tumors

[EPID] - Marijuana use linked to nonseminoma testicular tumors
Last Updated: 2009-04-14 8:00:44 -0400 (Reuters Health)
NEW YORK (Reuters Health) - New research suggests that marijuana use may increase the risk of testicular germ cell tumors (TGCTs), primarily nonseminoma types.
According to the report in the March 15th issue of Cancer, current marijuana use increased the odds of TGCTs by 70%.
A rise in TGCT rates has been seen in the last 4 to 6 decades, but the cause of the increase has been unclear, Dr. Janet R. Daling, from Fred Hutchinson Cancer Research Center, Seattle, and colleagues write. Since marijuana use increased during the same period and chronic use has been shown to harm the reproductive system, there may be an etiologic link.
To investigate, the researchers assessed marijuana use in 369 men who were diagnosed with TGCT from January 1999 to January 2006 in three counties in Washington State and compared it with that of 979 age-matched controls.
Overall, current marijuana users, compared with those who never used marijuana, had a 70% increased risk of TGCT. For nonseminoma tumors, however, current use increased the risk by 130%.
Among current marijuana users, the risks of TGCT were highest in those subjects who began use before 18 years of age and who used marijuana on at least a weekly basis.
Further studies, the authors note, are needed to verify these findings. Molecular analyses of cannabinoid receptors and related signaling may help to clarify the underlying mechanisms of TGCT development, they add.

METRONOMIC CYCLOPHOSPHAMIDE FOR PROSTATE CANCER

: Med Oncol. 2009 Apr 14. [Epub ahead of print]

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Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy.

Nelius T, Klatte T, de Riese W, Haynes A, Filleur S.

Department of Urology, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 7260, Lubbock, TX, 79430-7260, USA, thomas.nelius@ttuhsc.edu.

For patients with docetaxel-resistant hormone-refractory prostate cancer (HRPC) no standard chemotherapeutic treatment exists. In this study, we evaluate the efficacy of cyclophosphamide (CP)-based metronomic chemotherapy in this patient population. Patients with metastatic HRPC with disease progression under docetaxel-based chemotherapy were eligible. The primary endpoint was prostate-specific antigen (PSA) response. Secondary endpoints were survival and toxicity. Low-dose CP (50 mg/d) and dexamethasone (1 mg/d) were administered orally in a metronomic manner. Treatment was continued until disease progression or intolerable side effects occurred. Seventeen patients were enrolled in this study. The median follow-up was 12 weeks (range: 4-60). Median age was 68 years (range: 42-85). Median PSA at study entry was 134 ng/ml (range: 46.0-6554). Nine patients had a PSA response (median 44.4%), four patients >/=50% and five patients <50%. Eight patients had a PSA progression. Overall survival was 24 months. Five patients reported a decrease in bone pain after 4 weeks' treatment. No grade 3 and 4 toxicities were noted. In this study, low-dose metronomically administered CP demonstrated efficacy as a second-line treatment in patients with docetaxel-resistant HRPC. The treatment was well tolerated and almost without toxicity. Further advantages of low-dose CP were its convenient oral administration, dosing schedule, low cost, and low-toxicity profile. These attributes in combination with immunoregulatory and antiangiogenic potentials make CP also a prime candidate for combination with other treatment regimens.

RETINOBLASTOMA AND OTHER MALIGNANCIES

Retinoblastoma Survivors Often Die From Other Malignancies

NEW YORK (Reuters Health) Apr 15 - Survivors of hereditary retinoblastoma are 35 times more likely to die from cancer than are people in the general population, according to a report in the Journal of the National Cancer Institute for April 15. For survivors of non-hereditary retinoblastoma, the risk is increased 2.5-fold.

Prior research has shown that subsequent cancers are common among survivors of hereditary retinoblastoma, but data from long-term survivors who were treated with radiotherapy is limited, lead author Dr. Chu-Ling Yu, from the National Cancer Institute, Rockville, Maryland, and colleagues explain.

In the current analysis, the researchers examined cause-specific mortality among 1854 patients who were survivors of retinoblastoma diagnosed between 1914 and 1996 at two centers.

A total of 151 cancer-related deaths were recorded among the 1092 survivors of hereditary retinoblastoma. Twelve such deaths were noted among the remaining 762 patients who survived non-hereditary retinoblastoma.

Malignancies often seen in survivors included sarcomas, melanomas, and cancers of the central nervous system. The elevated risk of a cancer-related death extended for more than 40 years after the retinoblastoma diagnosis.

Commenting on an earlier analysis they conducted, the authors note that the 13 additional years of follow-up in the present analysis uncovered a link between retinoblastoma survival and mortality from cancers of the corpus uteri, mostly sarcomas.

Consistent with previous reports, subjects treated with radiotherapy were at greater risk for developing cancer than those who did not receive radiation.

At 50 years after diagnosis of retinoblastoma, the cumulative mortality from subsequent cancers was 25.5% for hereditary retinoblastoma and 1.0% for nonhereditary retinoblastoma.

By contrast, survivors of both types of retinoblastoma were not at increased risk for non-neoplastic causes of death.

"The temporal patterns of site-specific excess risks of subsequent neoplasms in retinoblastoma survivors should inform screening programs designed for the early detection and treatment of subsequent malignant neoplasms," the authors conclude.

DEGREE OF HER2 AMPLIFICATION AND ADJUVANT HERCEPTIN

J Clin Oncol. 2009 Apr 13. [Epub ahead of print]

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Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial.

Dowsett M, Procter M, McCaskill-Stevens W, de Azambuja E, Dafni U, Rueschoff J, Jordan B, Dolci S, Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart M, Leyland-Jones B.

Department of Academic Biochemistry, Royal Marsden Hospital, London, United Kingdom; Frontier Science (Scotland) Ltd, Kincraig, Kingussie, Scotland; National Cancer Institute, National Institutes of Health, Bethesda, MD; Departments of Medical Oncology and Medicine, Institut Jules Bordet, Université Libre de Bruxelles; Breast European Adjuvant Studies Team, Brussels, Belgium; Department of Public Health, School of Nursing, University of Athens, Athens, Greece; TARGOS Molecular Pathology GmbH, Kassel, Germany; Roche Professional Diagnostics, F. Hoffmann-La Roche Ltd, Basel, Switzerland; VM Institute of Research, Montreal, Quebec, Canada; Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan, Milan, Italy; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and Emory Winship Cancer Institute, Atlanta, GA.

PURPOSE: To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. PATIENTS AND METHODS: IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. RESULTS: Central FISH results were available for 2071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. CONCLUSION: There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.

FOLIC ACID AND COLORECTAL CANCER

Folic-Acid Fortification of Flour and Increased Rates of Colon Cancer

April 15, 2009 — Data from Chile show that there has been an increase in the rate of colorectal cancer since 2000, when the government introduced a mandatory program of fortification of wheat flour. A similar increase was reported in the United States and Canada in the late 1990s, after the introduction of folic-acid fortification there.

The aim of folic-acid fortification is to reduce neural tube defects, a result of folate deficiency during pregnancy and, in this, the programs have been successful. In Chile, these complications were reduced by 40% in 1 year.

But could the downside be an increase in the risk for colorectal cancer?

The latest data, published online February 2 in the European Journal of Gastroenterology & Hepatology, suggest that it might be. Sandra Hirsch, MD, MSc, and colleagues from the University of Chile, in Santiago, analyzed hospital-discharge data for two 4-year periods — before folic-acid fortification (1992–1996) and after (2001–2004) — and found a significant increase in reported cases of colon cancer. The increase was 162% in people 45 to 64 years and 190% in people 65 to 79 years.

Most other diseases showed no consistent patterns of change, they note. There was a small increase in breast cancer, smaller than that seen for colon cancer, but the authors note that this could probably be attributed to 2 programs for breast cancer introduced in 2000, one for early detection and the other guaranteeing universal access to treatment.

The researchers acknowledge that there could be other explanations for the finding, such as the rise in obesity (which increased from 19.7% in 1997 to 22% in 2003). However, Dr. Hirsch pointed out to Medscape Oncology that there were no changes in the hospital-discharge data for cardiovascular disease during that time.

"Our data provide new evidence that a folate-fortification program could be associated with an additional risk of colon cancer," Dr. Hirsch and colleagues conclude.

One problem with this study is that it uses indirect data for the incidence of colon cancer, say critics. There are no cancer registries in Chile, so the researchers used the diagnosis indicated on hospital-discharge forms as a proxy for disease incidence.

This is an important limitation of the study, said Reinhold Stockbrugger, MD, one of the editors of the European Journal of Gastroenterology & Hepatology. "Discharge rates are influenced by healthcare politics, increasing access to healthcare for new strata of the population with increased cancer risk, and so forth," he comments in a press release issued by the Journal.

"This study provides only a weak indirect indication of a causal relationship between folate enrichment and colorectal cancer," Dr. Reinhold said. However, he added that the finding is "similar to that reported in the United States and Canada."

Those data appeared nearly 2 years ago (Cancer Epidemiol Biomarkers Prev. 2007; 16:1325-1329), in a study by Joel Mason, MD, and colleagues from the Jean Mayor US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, in Boston, Massachusetts. That study used incidence data from nationwide cancer registries and showed significant increases in colorectal cancer rates in both the United States and Canada.

Folic-acid fortification began in the United States in 1996 and in Canada in 1997, and became mandatory in both countries in 1998, Dr. Mason and colleagues note. Concurrently, both countries experienced "abrupt reversals" of the downward trend in colorectal cancer incidence that they had enjoyed. In the United States, rates started to increase in 1996 and peaked in 1998; in Canada, rates began to rise in 1998 and peaked in 2000. Both rates have continued to exceed pre-1996/97 levels.

At the time, Dr. Mason and colleagues stressed that the observations did not prove a causal link, and they emphasized the "very compelling body of scientific evidence that has accrued over the past 15 years that indicates that supplemental folic acid protects against neural tube defects."

Total Amount of Folic Acid Important?

Dr. Mason and colleagues also note that there is evidence that "habitually high intakes of dietary folate are protective against colorectal cancer." They suggest, however, that the pharmaceutical form of folate (i.e., folic acid, which is used in fortification of foods and in vitamin tablets) might act differently than dietary folate, and they note that there is literature to suggest that a high intake of folic acid can accelerate the growth of established neoplasma. Adding substantial quantities of folic acid to the food supply in the mid-1990s might have facilitated the transformation of colorectal adenomas (which are found in 35% to 50% of Americans) into larger cancers, they suggest.

In the United States, folic acid was added to flour at a concentration of 140 μg/100 g (compared with 150 μg/100 g in Canada and 220 μg/100 g in Chile). But Dr. Mason and colleagues note that many breakfast cereals are fortified and that many Americans take vitamin supplements that include folic acid at a dose of 400 μg per pill.

In an interview with Medscape Oncology, Dr. Mason said that the new data from Chile "contribute to this concern that the total amount of folic acid present in the food stream can potentially contribute to an increase in certain types of cancer." However, he also said that the Chilean data are "weak in some regard," in that they rely on a surrogate end point of hospital-discharge data rather than cancer-incidence data.

Another recent publication has added to the concern about folic acid and cancer, he noted. New data from the Aspirin/Folate Polyp Prevention Study, published last month (J Natl Cancer Inst. 2009;101:432-435), show a 3-fold increase in prostate cancer among men who took the folate supplement, compared with men who took placebo.

This is cancer in a different organ, and the folic acid was in a supplement rather than in fortified foodstuff, but this observation "contributes to the concern," Dr. Mason commented. "There is a real concern that there are certain types of cancers common in the older population that are in an indolent phase of slow development, but their development may be accelerated by too much folic acid," Dr. Mason said. One example is the colorectal adenoma, "which sits in the colon for a decade before it evolves into a cancer, as far as anyone can tell." A second example is dysplastic prostatic nodules, which are seen in most men when they reach 70 to 90 years of age; the majority of these do not become clinically significant, and these men die of other causes, he added.

"In both situations, these are indolent precancerous lesions, which, with a bit of tweaking, might be pushed over the edge to evolve into clinically significant cancer," Dr. Mason said.

Is folic acid one of the factors that could push an indolent lesion into cancer?

"We cannot prove causality," Dr. Mason said, "but this is highly biologically plausible." This is a "smoldering concern," but at the moment there are not enough data to lead to any changes in the current policy of folic-acid fortification in those countries that have already implemented it, Dr. Mason said. But the matter is being debated, particularly by countries around the world (and the European Union) that are considering whether or not to implement such a policy. Dr. Mason recently took part in a meeting of experts in Sweden to discuss these matters, and has written a comprehensive review of the issue (Nutr Rev. 2009,67;206-212).

It is not just a question of folic-acid fortification of food, however; there is also the issue of folic-acid supplementation, such as in multivitamin pills. Dr. Mason noted that recent data from the US Centers for Disease Control suggest that 70% to 80% of the general adult population has detectable levels of folic acid in the blood, but "under more natural conditions, folic acid would not even be present in the blood."

Dr. Mason said he is attracted to the proposal that has been suggested in the United Kingdom, namely that, if folic-acid fortification goes ahead, there should be a reduction in the folic-acid component of vitamin and other supplement products. The dose of folic acid would need to be cut quite dramatically, he suggested, from the current 400 μg in a daily tablet to around 50 to 100 μg.

DOSE AND SCHEDUALE OF PREOPERATIVE CHEMOTHERAPY FOR BREAST CANCER PATIENTS

J Clin Oncol. 2009 Apr 13. [Epub ahead of print]

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Intensive Dose-Dense Compared With Conventionally Scheduled Preoperative Chemotherapy for High-Risk Primary Breast Cancer.

Untch M, Möbus V, Kuhn W, Muck BR, Thomssen C, Bauerfeind I, Harbeck N, Werner C, Lebeau A, Schneeweiss A, Kahlert S, von Koch F, Petry KU, Wallwiener D, Kreienberg R, Albert US, Lück HJ, Hinke A, Jänicke F, Konecny GE.

Helios Klinikum, Campus Berlin Buch, Berlin; Klinikum Frankfurt Höchst, Frankfurt; Bethesda Krankenhaus, Mönchengladbach; University of Halle (Saale), Halle (Saale); Klinikum Landshut, Landshut; Technical University of Munich; Klinikum Grosshadern, University of Munich, Munich; University of Cologne, Cologne; Frauenklinik, Evangelisches Bethesda Krankenhaus, Duisburg; University of Hamburg-Eppendorf, Hamburg; University of Heidelberg, Heidelberg; Städtisches Klinikum, Wolfsburg; University of Tübingen, Tübingen; University of Ulm, Ulm; University of Marburg, Marburg; Gynäkologisch-Onkologische Praxis, Hannover; Wissenschaftlicher Service Pharma, Langenfeld, Germany; and David Geffen School of Medicine, University of California, Los Angeles, CA.

PURPOSE: To compare preoperative intense dose-dense (IDD) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer (BC). PATIENTS AND METHODS: In this randomized phase III trial a total of 668 eligible primary BC patients stratified for tumors >/= 3 cm (n = 567) or inflammatory BC (n = 101) were randomly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks. All patients received three cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy after surgery. RESULTS: IDD treatment significantly improved pathologic complete response rate (18% v 10%; odds ratio [OR] 1.89; P = .008), disease-free survival (DFS; hazard ratio [HR], 0.71; P = .011), and overall survival (OS; HR, 0.83; P = .041) compared to epirubicin/paclitaxel. Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial (DFS HR, 1.10; P = .739; OS HR, 1.25; P = .544). In contrast, patients with noninflammatory BC significantly benefited from IDD treatment (DFS HR, 0.65, P = .005; OS HR, 0.77, P = .013). Treatment effects in multivariate analysis were significant for noninflammatory BC (DFS HR, 0.65, P = .015; OS HR, 0.79, P = .034), but not for all patients (DFS HR, 0.76; P = .088; OS HR, 0.82; P = .059). IDD therapy was associated with significantly more nonhematologic toxicities, anemia, and thrombocytopenia, but with similar neutropenia and infection rates. CONCLUSION: Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy. IDD was less well tolerated compared to standard treatment, but improved clinical outcomes in patients with noninflammatory high-risk primary BC.

ΒΑΨΤΕ ΑΧΕΠΑ ΚΑΙ ΕΥΑΓΓΕΛΙΣΜΟ ΜΠΑΣ ΚΑΙ ΓΛΥΤΩΣΕΙ ΚΑΝΕΝΑΣ ΦΟΥΚΑΡΑΣ

New paint may kill antibiotic-resistant microbes on hospital surfaces, research suggests.

WebMD (4/17, Hendrick) reports that a group of scientists "has invented a new super-paint strong enough to kill superbugs that infect hospital patients and kill thousands of people annually," according to research published in the American Chemical Society's journal, Applied Materials & Interfaces. The paint, "which is designed to decorate and disinfect homes, businesses, and healthcare settings, kills disease-causing bacteria, mold, fungi, and viruses"; and shows promise as "a killer of antibiotic-resistant microbes that infect hospital surfaces and cause about 88,000 deaths in the US every year." The researchers say the paint "provides 'potent antimicrobial activities' against dangerous bugs, including methicillin-resistant Staphylococcus aureus. The new paint "won't completely eliminate transmission of such infections, they say, but has the potential to significantly reduce it." 

ALIMTA-CARBO in NSCLC 2nd LINE

Originally published as JCO Early Release 10.1200/JCO.2008.19.1650 on March 23 2009


Journal of Clinical Oncology, Vol 27, No 12 (April 20), 2009: pp. 2038-2045
© 2009 American Society of Clinical Oncology.
Randomized Phase II and Pharmacogenetic Study of Pemetrexed Compared With Pemetrexed Plus Carboplatin in Pretreated Patients With Advanced Non–Small-Cell Lung Cancer
Egbert F. Smit, Sjaak A. Burgers, Bonne Biesma, Hans J.M. Smit, Pier Eppinga, Anne-Marie C. Dingemans, Markus Joerger, Jan H. Schellens, Andrew Vincent, Nico van Zandwijk, Harry J.M. Groen 

From the Department of Pulmonary Diseases Vrije Universiteit Medical Centre; Department of Medical Oncology, Netherlands Cancer Institute; Nederlandse Vereniging Artsen voor Longziekten en Tuberculose Data Centre, Amsterdam; Jeroen Bosch Hospital, 's-Hertogenbosch; Rijnstate Hospital, Arnhem; Nij Smellinghe, Drachten; Academisch Ziekenhuis Maastricht, Maastricht; University Medical Centre Groningen, Groningen, the Netherlands; Department of Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland; and Bernie Banton Centre, University of Sydney, Sydney, Australia. 

Corresponding author: Egbert F. Smit, MD, PhD, Department of Pulmonary Diseases, Vrije Universiteit Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: ef.smit@vumc.nl.

Purpose We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy. 

Patients and Methods Main eligibility criteria were histologic or cytologic proof of advanced non–small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m2 (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m2 (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm ( = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, -glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients. 

Results Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03). 

Conclusion PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone. 

Written on behalf of the Nederlandse Vereniging Artsen voor Longziekten en Tuberculose Lung Cancer Group. 

Supported by an unrestricted educational grant from Eli Lilly Co. The translational part of this study was supported by a gift from the legacy of Liesbeth van Vuuren-Martens. 

Presented as a poster at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL. 

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. 

Clinical Trials repository link available on JCO.org.