STAGE I SEMINOMA

J Clin Oncol. 2011 Mar 10;29(8):957-62. Epub 2011 Jan 31.

Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214).

Oliver RT, Mead GM, Rustin GJ, Joffe JK, Aass N, Coleman R, Gabe R, Pollock P, Stenning SP.

MSc, MRC Clinical Trials Unit, 222 Euston Rd, London, NW1 2DA, United Kingdom; ss@ctu.mrc.ac.uk.

Abstract

PURPOSE Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported. PATIENTS AND METHODS Random assignment was between RT and one infusion of carboplatin dosed at 7 × (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0). Results Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 × AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38). CONCLUSION These updated results confirm the noninferiority of single dose carboplatin (at 7 × AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

STAGE I SEMINOMA

BJU Int. 2011 Apr;107(7):1074-9. doi: 10.1111/j.1464-410X.2010.09658.x. Epub 2010 Sep 21.

Retrospective multicentre study of carboplatin monotherapy for clinical stage I seminoma.

Steiner H, Scheiber K, Berger AP, Rein P, Hobisch A, Aufderklamm J, Pilloni S, Stoehr B, Aigner F, Fritzer A, Zangerl F.

Medical University Innsbruck - Urology, Innsbruck, *Department of Urology, General Hospital Hall in Tirol, Hall, †General Hospital Feldkirch - Urology, Feldkrich, Austria, ‡General Hospital Meran - Urology, Meran, Italy.

Abstract

Study Type - Therapy (prospective cohort) Level of Evidence 2a What's known on the subject? and What does the study add? The debate concerning standard treatment following unilateral inguinal orchiectomy for patients with clinical stage I seminoma is ongoing. The MRC TE19/EORTC 30982 trial has proven the non-inferiority of carboplatin to radiotherapy, representing a strong argument for the potential use of carboplatin especially with respect to a good long-term side-effect profile. More data and a longer follow-up for carboplatin are required. Different guidelines state that 'two courses of adjuvant carboplatin seem to further reduce the relapse rate. . . . but further experience and long-term observations are needed'. The present study retrospectively evaluated the long-term oncological efficacy and morbidity of this approach in a multicentre setting to add further long-term data to this topic.
OBJECTIVE: •  To evaluate, in a retrospective multicentre study, the long-term oncological efficacy and morbidity of using carboplatin as an alternative treatment for patients with clinical stage I seminoma.
PATIENTS AND METHODS: •  Patients with clinical stage I seminoma treated with two cycles of adjuvant single-agent carboplatin (400 mg/m(2) body surface) from February 1990 until September 2008 were retrospectively identified. • A database was created (including information on patient characteristics, initial tumour staging, tumour marker levels, follow-up, oncological outcome, treatment side effects and long-term side effects), descriptive analyses were performed and the data were compared with those available in the literature.
RESULTS: •  Of 282 stage I seminomas identified in 276 patients, risk factors for progression (pT2/3, vessel invasion or tumour diameter ≥4 cm) were detected in 48.2% of tumours. • Chemotherapy was well tolerated, with patients experiencing only mild nausea. Bone marrow suppression was common (leucopaenia in 36.7% and thrombocytopaenia in 50.5% of patients, mainly grade 1/2). Neither neutropenic fever, nor any bleeding complication occurred. • During a mean follow-up of 75 months, three patients (1.06%) developed a retroperitoneal recurrence within the first 2 years after receiving adjuvant treatment and were salvaged by cisplatin-based chemotherapy. A contralateral second testicular germ cell tumour was diagnosed in five patients.
CONCLUSIONS: •  Two cycles of carboplatin monotherapy are highly effective and very well tolerated by all patients. The frequency of contralateral tumours appears to be reduced. • Despite the lack of a randomized trial, the available data in the literature suggest that the administration of two cycles instead of one cycle could lead to a reduction in recurrence rates of ≈50%.

CABAZITAXEL APPROVED IN EU

March 25, 2011 (Vienna, Austria) — Cabazitaxel (Jevtana, Sanofi-Aventis) has been approved by the European Commission for use in combination with prednisone in the treatment of patients with metastatic hormone-refractory prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The approval applies to 27 member states of the European Union, as well as Iceland, Lichtenstein, and Norway.
The news was announced here at the European Association of Urology (EAU) 26th Annual Congress, where a subanalysis of secondary end points from the phase 3 TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a Taxotere-Containing Regimen) trial was also presented, reigniting discussion about the drug. The European Commission approval follows a positive opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency in January, and approval by the US Food and Drug Administration and authorities in Brazil last year.
In the phase 3 TROPIC clinical study, presented at the American Society of Clinical Oncology 2010 annual meeting, as reported by Medscape Medical News, the cabazitaxel–prednisone combination was the first to show a significant survival benefit for patients with mHRPC.
TROPIC's initial findings showed that cabazitaxel, used as second-line therapy in mHRPC, increased survival by 28%, compared with standard-therapy mitoxantrone (Novantrone, OSI Oncology). Patients treated with cabazitaxel had a median survival of 15.1 months, compared with 12.7 months for patients receiving mitoxantrone — a statistically significant difference.
Stephane Oudard, MD, head medical oncologist from the Georges Pompidou European Hospital, Paris, France, and Bertrand Tombal, MD, from Clinique Unversitaire Saint Luc, Brussels, Belgium, said the recent European approval is good news for patients.
Dr. Oudard provided an overview of results to date that have been presented at previous meetings. "We have data that show that cabazitaxel improves overall survival, but now there are additional data on the mean overall survival, compared to the median overall survival. Median is useful for oncologists, but mean is useful for economists to make a complete analysis. These data showed that the mean overall survival is 18 months [with cabazitaxel], compared to 14 months [with mitoxantrone]."
Dr. Oudard also commented on the need to lower the occurrence of febrile neutropenia, which is higher with cabazitaxel. "This is important because if the treatment is working but the patient is suffering from febrile neutropenia, then it's not useful. By lowering neutropenia and febrile neutropenia, we would have a drug that is active and safe."
He added that cabazitaxel is now being tested as first-line therapy in a trial comparing cabazitaxel 25 or 20 mg/m² with docetaxel to determine the incidence of neutropenia with a lower dose. "We might close one dosage arm if we see no difference. The patients in the TROPIC trial were highly treated with docetaxel, and they had a very low bone cell reserve."
During Dr. Tombal's presentation here at the EAU, he reported that "the goal of this poster is to investigate other end points; namely, objective tumor response, defined as disease control, in terms of partial response, complete response, or stable disease, which showed an advantage in favor of cabazitaxel."
In TROPIC, 405 men were evaluated for disease control, which was achieved in 61.7% of patients receiving cabazitaxel and 47.5% of those receiving mitoxantrone (P = .004).
The secondary end point was pain progression assessed by pain score (Eastern Cooperative Oncology Group criteria), decrease in pain intensity, and analgesic use. "There was no difference between men on cabazitaxel and mitoxantrone, and the pain score remained stable during treatment. A similar proportion of men experienced worsening in the 2 groups," Dr. Tombal told Medscape Medical News.
Session moderator N.A. Mottet, MD, a urologist from Clinique Mutualiste, in St. Etienne, France, asked whether cabazitaxel could be considered the standard of care for mHRPC in the light of these results. Dr. Tombal replied that he believes there is no standard of care.
"For me, the only standard of care is sitting with your colleague oncologists and radiation oncologists and using the armamentarium available. We need to take into account patient individuality and tailor treatment — whether abiraterone, or cabazitaxel, or whatever. It's like baseball; it's not until you have a home run that you win the game. It's a nice hit, but we need to keep searching," he replied.
Dr. Tombal added that chemotherapy is about extending survival. "What would be unacceptable is if extending survival comes with a deterioration of quality of life. We have to balance the 2 . . . and of course this is very difficult to measure."
The TROPIC study was supported by Sanofi-Aventis. Dr. Oudard reports associations with Sanofi-Aventis, Roche, and Pfizer. Dr. Tombal is a paid consultant for Sanofi-Aventis and a TROPIC study investigator. Dr. Mottet has disclosed no relevant financial relationships.
European Association of Urology (EAU) 26th Annual Congress; Poster 91. Presented March 21, 2011.

EXCESSIVE PSA SCREENING IN ELDERLY MEN

March 29, 2011 — The "excessive" use of prostate-specific antigen (PSA) screening in elderly men with limited life expectancies is a "significant problem" in the United States, according to a new study of men 40 years and older who participated in the National Health Interview Survey.
About three quarters of a million men are unnecessarily and inappropriately screened each year in the United States, the study authors estimate.
The study, which was published online March 28 in the Journal of Clinical Oncology, also found that men in their 70s were nearly twice as likely as men in their early 50s to have undergone PSA testing in the year before taking the survey (45.5% vs 24.0%).
What this means is that "the men most likely to benefit from PSA screening are paradoxically being screened at markedly lower rates than men highly unlikely to benefit," write the authors, who are led by Michael Drazer, MD, from the University of Chicago Medical Center in Illinois.
The evidence that supports this comment comes from the interim results of the landmark European Randomized Study of Screening for Prostate Cancer (ERSPC), which showed a 20% reduction in cancer-specific mortality for screened men — but only for those 55 to 69 years of age.
The ERSPC is currently the only randomized controlled study to show a disease-specific mortality benefit from screening.
Overall, Dr. Drazer and colleagues report that, in the United States, PSA-based prostate cancer screening patterns are "discordant with recommended guidelines."
The American Urological Association and American Cancer Society recommend, based on expert opinion, screening men with at least 10 years of estimated life expectancy. The US Preventive Services Task Force recently suggested that routine screening be stopped at 75 years of age.
The researchers found that, among men who were 70 years and older with "low" 5-year life expectancies, 30.7% were nonetheless tested for PSA — which is not in keeping with the above guidelines. The authors calculate that about 777,000 men of this age and life expectancy are unnecessarily tested every year in the United States, which then results in a lot of unneeded biopsies and treatment.
They speculate that a possible explanation for this is that physicians are "notoriously poor" at estimating life expectancy and that the screening might represent "defensive medicine."
The problem is not going away, suggested a high-profile oncologist not involved in the study.
"The underuse of PSA testing in younger men and the often unnecessary overtreatment of older men with indolent prostate cancer that will most likely never bother them remain huge concerns for oncologists," said Nicholas Vogelzang, MD, in a press statement. Dr. Vogelzang is from the Nevada Cancer Institute in Las Vegas and is a member of the American Society for Clinical Oncology communications committee.
Study Source and Measures
The goal of the new study was to detail the rates and predictors of PSA screening among older men in the United States. Men were counted as having had a screening if they reported receiving the PSA test as part of a routine physical exam in the year before the survey.
The authors acknowledge that the inability to verify the PSA test was a limitation of the study. However, they also say that the overreporting and underreporting tend to cancel themselves out. "It is likely our data are good estimates," they write.
The data source, the National Health Interview Survey, is a household survey administered through a series of face-to-face interviews conducted by employees of the US Census Bureau. The cancer screening survey is administered every 5 years as a supplement to the standard survey.
Using responses from the 2000 and 2005 surveys, the authors did most of their analyses on 2623 men older than 70 years, representing the 8 million men that age in the United States in 2000 and the 8.1 million in 2005.
Five-year life expectancy was measured with a "validated mortality index," which was based on survey data that included age, sex, smoking status, body mass index, comorbidities, recent hospitalizations, self-perceived health, and functional status measures. The index categorized 5-year mortality risk as high (risk of mortality of 48% or more), intermediate (16% to 47%), or low (15% or less).
The investigators found that the PSA screening rate was lowest among men 40 to 44 years (7.5%), and increased steadily with age until a peak of 45.5% among men 70 to 74 years. Screening rates then gradually declined by age, with 24.6% of men 85 years and older reporting a screening. Notably, this screening rate among 85-year-old men was comparable to that of men 50 to 54 years (24.0%).
Among men 70 years or older, screening rates varied by estimated 5-year life expectancy; they were 47.3% in men with high life expectancies, 39.2% in men with intermediate life expectancies, and 30.7% in men with low life expectancies.
"Our findings show a high rate of elderly and sometimes ill men being inappropriately screened for prostate cancer. We're concerned these screenings may prompt cancer treatment among elderly men who ultimately have a very low likelihood of benefiting the patient and paradoxically can cause more harm than good," said coauthor Scott E. Eggener, MD, from the University of Chicago Medical Center, in a press statement.
In multivariate analysis, the authors also found that estimated life expectancy and age were independently associated with PSA screening (P < .001 for each).
Dr. Eggener reports receiving honoraria and research funding from Centocor Ortho Biotech and AstraZeneca, and research funding from Visualase.
J Clin Oncol. Published online March 28, 2011.

A NEW ERA FOR HCV TREATMENT

March 31, 2011 — Boceprevir is effective in the treatment of previously treated and untreated patients with hepatitis C virus (HCV) infection, according to the results of 2 randomized trials reported in the March 30 issue of the New England Journal of Medicine.
RESPOND-2 Trial
"In patients with chronic infection with [HCV] genotype 1 who do not have a sustained response to therapy with peginterferon–ribavirin, outcomes after retreatment are suboptimal," write Bruce R. Bacon, MD, from Saint Louis University School of Medicine in Missouri, and colleagues from the HCV Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) investigators. "Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3...active site, has been suggested as an additional treatment."
The study goal was to examine the effect of boceprevir added to peginterferon–ribavirin for retreatment of patients with chronic HCV genotype 1 infection. During the lead-in period, the 403 participants all received peginterferon alfa-2b and ribavirin for 4 weeks. Using a 1:2:2 ratio, participants were randomly assigned to group 1 (control group) receiving placebo plus peginterferon–ribavirin for 44 weeks, group 2, or group 3. Participants in group 2 received boceprevir plus peginterferon–ribavirin for 32 weeks, and patients in whom the HCV RNA level was detectable at week 8 received placebo plus peginterferon–ribavirin for 12 more weeks. In group 3, participants received boceprevir plus peginterferon–ribavirin for 44 weeks.
Compared with the control group, the 2 boceprevir groups had a significantly higher rate of sustained virologic response (group 2, 59%; group 3, 66%; control group, 21%; P < .001). Among participants with an undetectable HCV RNA level at week 8, sustained virologic response rate was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients in whom HCV RNA level decreased by less than 1 log₁₀ IU/mL at treatment week 4, rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively.
The boceprevir groups had higher frequencies of anemia than the control group, resulting in administration of erythropoietin in 41% to 46% of boceprevir-treated patients compared with 21% of the control patients.
"The addition of boceprevir to peginterferon–ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon–ribavirin alone," the study authors write.
SPRINT-2 Trial
The second study, a double-blind trial by Fred Poordad, MD, from Cedars-Sinai Medical Center in Los Angeles, California, and colleagues from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) investigators, had a study design similar to that of the RESPOND-2 study except that participants were previously untreated adults with HCV genotype 1 infection. Nonblack patients (n = 938) and black patients (n = 159) were enrolled and analyzed separately.
Sustained virologic response in the nonblack cohort occurred in 40% (125/311) of the patients in group 1, 67% (211/316) of the patients in group 2 (P < .001), and 68% (213/311) of the patients in group 3 (P < .001). For the black cohort, the corresponding rates were 23% (12/52 patients), 42% (22/52 patients; P = .04), and 53% (29/55 patients; P = .004), respectively.
Forty-four percent of patients in group 2 received peginterferon–ribavirin for 28 weeks. Dose reductions caused by anemia occurred in 13% of control patients and 21% of patients receiving boceprevir, and discontinuations caused by anemia in occurred in 1% and 2% of control patients and patients receiving boceprevir, respectively.
"The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection," the study authors write. "The rates were similar with 24 weeks and 44 weeks of boceprevir."
Limitations of this study include relatively small numbers of patients with cirrhosis and relatively small numbers of black patients in whom the HCV RNA level was detectable between weeks 8 and 24, warranting further study to define optimal therapy in these populations.
New Era of HCV Therapy
In an accompanying editorial, Donald M. Jensen, MD, from the Center for Liver Diseases, University of Chicago Medical Center in Illinois, discusses the beginning of a new era of HCV therapy. He noted that adverse effects associated with boceprevir treatment included anemia, rash, dry skin, and dysgeusia. However, only 8% to 12% of patients discontinued boceprevir because of these adverse events.
"HCV protease inhibitors represent a major advance in our ability to treat chronic HCV infection," Dr. Jensen writes. "Future therapy will be more complex, not easier, but the improvement in the rate of sustained virologic response with boceprevir, to nearly 70% in the SPRINT-2 trial and to more than twice the rate in previously treated patients in HCV RESPOND-2, have been eagerly awaited. We will soon embark on a new era of successful HCV therapy."
Schering-Plough (now Merck) supported both studies. Disclosure forms provided by the study authors and editorialists are available with the full text of these articles at NEJM.org.
N Engl J Med. 2011;364:1207-1217, 1195-1206, 1272-1274.

POSTOPERATIVE RADIOTHERAPY FOR HIGH RISK PROSTATE CANCER

March 30, 2011 (Vienna, Austria) — Ten-year follow-up results of the European Organization for Research and Treatment of Cancer (EORTC) trial 22911, which looked at outcomes for men with pathologically high-risk prostate cancer, showed that men who received adjuvant radiotherapy immediately after radical prostatectomy had significantly better survival rates than those assigned to watchful waiting after surgery in terms of biochemical progression.
Hein Van Poppel, MD, urologist from University Hospitals Leuven, Belgium, presented the 10-year follow-up results for the first time here at the European Association of Urology 26th Annual Congress. The data were the results of a longer-term follow-up to the 5-year analysis presented in 2005.
"We've shown that, after 5 years in a former analysis, there was a definite advantage for patients with immediate adjuvant radiotherapy with respect to the biochemical progression-free survival [PFS] and local relapses. We did not show an advantage for metastasis-free survival or overall survival," reported Dr. Van Poppel.
After 2005's 5-year analysis, this year's study presents new, longer-term findings that confirm the 5-year results. "The effects of an older median age in the 2 groups and the impact this has on [PFS] have been thoroughly examined," said Dr. Van Poppel.
"We know that when these patients had immediate postoperative radiotherapy, they do better, and had a longer biochemical [PFS] and clinical [PFS], especially in the case of positive surgical margins and extension of disease to the seminal vesicles. This is a very important message to the urological community," he added.
The EORTC study involved 1005 patients enrolled between 1992 and 2001, and the first 5-year analysis showing a significant difference in clinical and biochemical PFS was published in The Lancet (Bolla et al. 2005). The median follow-up is now 10.6 years. Patients were eligible if they had cT1-3N0M0 tumors treated with radical prostatectomy with adverse postoperative features of extracapsular extension, positive margins, or seminal vesicle invasion.
After surgery, patients either continued under wait-and-see management or received immediate postoperative radiotherapy of 60 Gy delivered over the course of 6 weeks. Groups were well balanced, with an average age of 65 years and median prostate-specific antigen (PSA) levels of 12.4 ng/mL (range, 0.3 - 159.4 mL) presurgery and 0.2 ng/mL (range, 0.0 - 48.7 mL) postsurgery. All patients had performance status 0.
At 10 years, 60.6% of patients who received postoperative radiotherapy showed biochemical PFS compared with 41.1% of the wait-and-see patients; 70.3% of postoperative radiotherapy patients showed clinical PFS compared with 64.8% of the wait-and-see group.
No significant difference was found between the 2 groups in terms of overall survival (80.7% in postoperative radiotherapy patients vs 76.9% in wait-and-see patients). Regarding deaths resulting from prostate cancer, 5.4% of the patients died in the postoperative radiotherapy group, whereas 3.9% died in the wait-and-see group.
"When we look at baseline factors and biochemical PFS, all groups benefited. Patients with positive surgical margins and with seminal vesicle invasion benefit most. Those with negative surgical margins benefit less," Dr. Van Poppel said. "Even patients over 70 still have a clear biochemical PFS advantage. The clinical PFS results are similar, but those with negative surgical margins do not benefit any longer. For patients over 70 there is no benefit at all for having radiotherapy."
Dr. Van Poppel drew a comparison with the US-based Southwest Oncology Group (SWOG) trial, which looked at similar patients and outcomes. "In terms of overall survival in EORTC, there is a trend that patients who did not receive radiotherapy are doing at least as well as the others. Those with negative surgical margins and older [patients] do not benefit from radiotherapy. This is in conflict with the SWOG 8794 trial, which shows, with longer follow-up, that there is an advantage in postoperative radiotherapy patients for metastasis-free survival and overall survival — a difference that we, in this EORTC trial, were unable to confirm," said Dr. Van Poppel.
He provided an overview of patient differences between the 2 trials. In the SWOG trial, not many patients had performance status 0 (19.3%) compared with the EORTC trial (in which 94% of the patients had performance status 0). Twenty-two percent of the patients in the SWOG trial had 3 risk factors vs 12% of patients in the EORTC trial. More radiation was given in the SWOG trial (60 - 64 Gy compared with 60 Gy in the EORTC trial). PSA relapse was evident, with levels higher than 0.4 ng/mL after normalization in the SWOG. Any increase above the nadir was accepted as PSA failure in the EORTC trial.
"Regarding PFS, SWOG found that was 3.1 years in the wait-and-see arm and 6.12 years in the similar arm of the EORTC trial. So this means that in the observation arm, there were major differences, probably due to initial different prognostic factors in the 2 studies," Dr. Van Poppel said. "The same holds for distant metastasis-free survival, with 61% in the wait-and-see SWOG patients and 71.3% in wait-and-see EORTC patients; and also 10-year overall survival [66% in the wait-and-see SWOG patients and 80.7% in the wait-and-see EORTC patients]." Dr. Van Poppel suggested that worse patient prognosis in the SWOG study may account for this finding.
Freddie Hamdy, MD, chairman of the Scientific Congress Office and Nuffield Professor of Surgery at the University of Oxford in the United Kingdom, said, "The European Association of Urology was delighted to offer the opportunity for this important study to be highlighted at our annual congress. It demonstrates the ability of the European urological community to conduct key clinical trials, which are likely to change practice worldwide."
He continued: "In this case, the benefits of immediate postoperative radiotherapy remain uncertain in the absence of overall survival advantages in the EORTC study compared to the SWOG trial, and further research is warranted. The results will guide decision making when offering patients treatment options, and allow men to make informed choices, weighing risks against potential benefits when faced with difficult situations in managing prostate cancer."
Dr. Van Poppel and Dr. Hamdy have disclosed no relevant financial relationships.
European Association of Urology (EAU) 26th Annual Congress. Presented March 22, 2011.

EFFEXOR REDUCES OXALIPLATIN NEUROTOXICITY

March 30, 2011 — The antidepressant venlafaxine (Effexor, Wyeth) has clinical activity against the most severe and dose-limiting cumulative adverse effect of oxaliplatin chemotherapy — neurotoxicity, according to a new study from France.
The phase 3 trial did not reach its targeted accrual of patients, but did reach its primary end point, with a significant reduction of patients experiencing acute neurologic toxicity in the venlafaxine group, report the authors, led by J.P. Durand, MD, from the Université Paris Descartes in France.
Pain scale scores indicated that "full relief" was more frequent in the venlafaxine group (31.3% vs 5.3%; P = .03).
The findings "may have immediate applications in the management of cancer patients under oxaliplatin-based chemotherapy," say the authors, who add that further study is needed.
The paper was published online March 22 in the Annals of Oncology.
"Even though I do not use venlafaxine in this setting, I would certainly use it based on this study," said Matti S. Aapro, MD, from Doyen IMO Clinique de Genolier in Switzerland, and a European Society of Medical Oncology spokesperson who was approached by Medscape Medical News for comment. He added that he might reduce the high loading dose in the protocol, which was associated with vomiting.
Dr. Aapro currently uses glutathione as an alternative method of reducing the chemotherapy-related neurotoxicity, "but this is not available in most countries," he said.
Explanation About Ending the Trial Early
During the trial, "most clinicians were convinced of the effect of venlafaxine and became reluctant to go on" randomizing patients to placebo, according to the authors.
The trial was slow to accrue patients because exclusions such as no concomitant antidepressant treatment barred many potential participants, they report.
The adverse effects associated with venlafaxine include grade 1/2 nausea (43.1%) and asthenia (39.2%), but there were no grade 3/4 events of any kind.
Venlafaxine is a serotonin/norepinephrine reuptake inhibitor that has shown therapeutic effects in the management of chronic and neuropathic pain, particularly in patients with diabetes mellitus, the authors explain.
They previously reported clinical activity of venlafaxine against acute neurotoxicity in a small series of patients receiving oxaliplatin (Anticancer Drugs 2003;146:423-425).
A potential explanation for the efficacy of venlafaxine is its protective effect against oxidative stress. Preclinical models indicate that venlafaxine modulates the oxidative stress in the nervous system, write the authors. At the same time, "there is growing evidence that oxaliplatin induces oxidative stress," they say.
Oxaliplatin is widely used in colorectal cancer and is an alternative option to cisplatin in various cancers, such as ovarian, gastric, and lung. "Because of its lack of nephrotoxicity, oxaliplatin is of particular interest in the growing population of 'unfit' patients," the authors note.
Study Details
The study was conducted in 6 university hospitals in France. Patients reporting acute neurotoxicity after the administration of their oxaliplatin-based chemotherapy were eligible.
Patients were randomized to placebo or to venlafaxine 50 mg 1 hour before oxaliplatin infusion and venlafaxine extended release 37.5 mg twice a day from day 2 to day 11 of chemotherapy. Study treatment was continued as long as oxaliplatin chemotherapy lasted.
The primary end point was the percentage of patients with 100% relief of acute neuropathy.
To determine this outcome, the investigators had patients who presented with oxaliplatin-induced acute neurotoxicity complete a pretreatment evaluation — the Neuropathic Pain Symptom Inventory (NPSI). The NPSI evaluates spontaneous ongoing pain, spontaneous paroxysmal pain, evoked pain, and paresthesia/dysesthesia.
Once therapy with venlafaxine began, patients rated their pain symptoms with the NPSI; each pain category was measured on a 0 to 10 numeric rating scale.
As noted above, about one third of the patients treated with venlafaxine achieved 100% relief of acute neuropathy. Similarly, there were significantly more patients experiencing a relief of 50% or more in the venlafaxine group (68.8% vs 26.3%; P = .02).
A secondary end point was the occurrence of cumulative permanent neurosensory toxicity. At 3 months after the end of treatment, there were more patients in the venlafaxine group than in the placebo group with grade 0 toxicity (38.5% vs 5.6%; P = .06), and significantly fewer patients with grade 3 toxicity (0% vs 33.3%; P = .03)
The toxicity profile of venlafaxine was "acceptable," with no grade 3/4 adverse events, report the authors. Grade 1/2 vomiting was observed more frequently with venlafaxine. Reducing the 50 mg loading dose of venlafaxine might help with vomiting, suggest the authors.
It is not known whether a pharmacokinetic interaction exists between oxaliplatin and venlafaxine, the authors point out. However, oxaliplatin is mainly eliminated by renal clearance and venlafaxine is primarily metabolized by liver CYP2D6. Thus, "the likelihood of a pharmacokinetic interaction is low," write the authors.
The study was promoted by EUREKA, an academic research association that received funds from Sanofi Aventis France for this trial. The researchers have disclosed no relevant financial relationships.
Ann Oncol. Published online March 22, 2011. Abstract

TOMOSYNTHESIS FOR BREAST IMAGING

Tomosynthesis Enters the Breast-Imaging Field

More than a decade has passed since the advent of the first digital mammograms, time enough for more than 70% of US mammographers to adopt this technology. Practitioners maintain that digital imaging makes it easier to see signs of cancer earlier. Even so, approximately 10% of women who are screened with full-field digital mammography are recalled for more tests, according to practitioner reports.
A new device, recently approved by the US Food and Drug Administration (FDA), may improve cancer detection while reducing the number of patient recalls.
Selenia Dimensions® from Hologic® (Bedford, Massachusetts) is like no other breast-imaging platform on the market. It takes 15 successive images, each at a slightly different angle along an arc across the breast. The concept is simple: What is hidden behind fibroglandular tissue in one image might be visible in another if the angle is slightly different (Figure).

Figure. (a) A suspicious lesion seen on standard 2D digital mammography (far left). (b) After examining multiple slices generated using breast tomosynthesis (5 images), the lesion seen on 2D (far left) is determined to be a false positive. (Images courtesy of Hologic. Used with permission.)
"You can see cancer with tomosynthesis that you could not see with routine mammography," said Phil Evans, MD, Director of the University of Texas Southwestern Center for Breast Care in Dallas.
FDA reviewers considered data gathered by Dr. Evans in their early February approval of Hologic's new device. Although the overall value of tomosynthesis has been established, exactly where it fits in the arena of women's health has yet to be determined, Dr. Evans said.
"We know it to be useful for screening, particularly for women with dense breasts, but exactly how it fits into the routine protocols still has to be worked out," he said. Mary Hayes, MD, who is Medical Director of Women's Imaging at Memorial Healthcare in Hollywood, Florida, says the device has proved to be beneficial in evaluating women with dense or fatty breasts.
"When we implement tomosynthesis in our practice, we will implement it across the board for fatty- and dense-breast patients," said Dr. Hayes, who until now has used the system only within a research protocol. "Our goal is to roll it out for routine use initially in the screening population and then in the diagnostic setting on a case-by-case basis."

Will They Buy It?

Currently, Hologic is the only vendor with a breast tomosynthesis device approved by the FDA. However, other vendors, including General Electric and Siemens, already have similar devices in development. At this writing, Hologic has not yet set a price, but the system will almost certainly cost more than the unit configured with only 2D capabilities.
Will price prove a disincentive? Providers will be asked to invest in breast tomosynthesis just a few years after making an investment of $300,000 or more in its 2D counterpart, according to MD Buyline, a Dallas-based business-intelligence firm specializing in medical devices. Still, Rachael Bennett, a clinical analyst at the firm, expects that many will sign on.
"I have been practically bombarded with people wanting this technology," said Bennett, who focuses on mammography and oncology. "They want to know how much it costs and when they can get it."
In addition to the tomosynthesis unit, providers will also need a specially equipped workstation to view the data. Product rollout is scheduled for this spring.

Pros and Cons of Tomosynthesis

Tomosynthesis examinations take a few seconds longer than standard 2D examinations. As with standard mammography, the breast is compressed between a paddle and the detector housing. Instead of 2 views of the breast, 15 are taken across a 15° arc. During this scan, conventional 2D images are also taken.
The volumetric data are reconstructed into slices, similar in appearance to those created using CT. One breast may give rise to 60 or more slices. These slices, along with the 2D images, are transmitted for study to a diagnostic workstation.

More Accuracy, More Data, More Radiation

Although examination time will not be significantly longer, reading time will. Radiologists must, in essence, interpret 2 examinations -- one comprising dozens of image slices and the other comprising standard 2D images. Physicians will not be compensated more for their extra effort because there is no additional reimbursement for breast tomosynthesis, at least not yet. But that does not bother Dr. Evans.
"The main thing we try to do is find cancer and find it early," he said.
Preliminary evidence suggests that tomosynthesis may be able to detect cancer earlier and more accurately than standard mammography. In 2 studies cited by FDA reviewers, the ability of radiologists to distinguish between cancerous and benign lesions improved 5%-12% using a combination of 2D and 3D images as compared with 2D images alone.^[1] In addition, study results presented to the FDA indicate that the combination of 2D and 3D images is associated with a 30% reduction in patient recalls.^[1,2]
To gain the potential advantage offered by tomosynthesis, patients are exposed to about twice the radiation of a typical digital mammogram, according to the FDA. However, the increased risk for cancer as a result of the added radiation is still very small, a little more than 1% compared with the natural cancer incidence, and < 1% more than the risk associated with conventional 2D mammography.^[1]
"The study results suggest that the potential benefit outweighs the risk," said FDA spokesperson Erica Jefferson.
To put the tomo radiation dose in perspective, patients typically absorb about 0.5 mSv during 2D mammography, said Dr. Hayes, citing numbers calculated by Hologic and presented to the FDA. An exam combining 2D and tomosynthesis images exposes patients to about 1 mSv. Americans are annually exposed to about 3.0 mSv from background radiation (or 4 mSv if they live in the mile-high city of Denver).
"I have no reservations about tomosynthesis for myself, for my mother, for my sister, or whomever," Dr. Hayes said.

Interpreting Images Without a Safety Net

To reap the benefits of tomosynthesis, physicians must learn to interpret this new type of breast image. As a condition for approving Selenia Dimensions, the FDA required Hologic to develop an 8-hour training course in the new technique. Mammographers who are already experienced in reading standard 2D digital images should be proficient in this new modality after reading about 100 tomosynthesis cases, according to Dr. Evans.
Proficiency at tomosynthesis is important because mammographers will be reading images without the computer safety net that they have come to depend on when reading 2D images. Today, the vast majority of facilities making digital mammograms use some kind of computer-aided detection (CAD) software to highlight suspicious lesions. These CAD analyses, called "second readings" because they are done after the physician has examined the images, direct the physician back to suspicious lesions that may have initially escaped their detection.
No such back-up systems exist for tomo; the CAD algorithms that work in 2 dimensions do not work in 3 dimensions. Hologic and other developers of tomosynthesis are currently working on new algorithms.
Once algorithms are available, workstations will need the computing horsepower to run them. More than likely, this will not be an issue. Hologic has already equipped its SecurView™ workstation with special software and hardware to run tomosynthesis studies. It is also helping vendors of picture archiving and communication systems (PACS) and workstations to modify their systems to display tomosynthesis images. In addition, the company claims that it is close to having a universal digital imaging and communication in medicine (DICOM) standard for tomosynthesis.

Where Does Tomo Fit in Breast Evaluation?

Hologic's pioneering reach into the third dimension signals an advance for the field of mammography, but how much of an advance is yet to be seen. The need to interpret 3D and 2D images together raises the question of how to best evaluate the breast for disease and what role tomosynthesis should play amid an array of mammography improvements and emerging technologies.

BEVACIZUMAB DOES NOT INCREAE VTE RISK

NEW YORK (Reuters Health) Mar 25 - The largest analysis to date investigating whether bevacizumab increases the risk of venous thromboembolic events (VTEs) in patients on chemotherapy has found no increased risk associated with the anti-vascular endothelial growth factor agent.
The drug increases the risk of arterial thromboembolisms from 1% to 3%, Dr. Herbert I. Hurwitz of Duke University Medical Center in Durham, North Carolina, and his colleagues note in a March 21 online publication by the Journal of Clinical Oncology.
The question of whether bevacizumab increases VTE risk as well is "controversial," they add. One meta-analysis linked the drug to an increased risk of VTEs in cancer patients, but another analysis found no effect.
To further investigate the issue, Dr. Hurwitz and his team looked at patient-specific data from 10 phase III studies comparing bevacizumab plus chemotherapy /immunotherapy to chemotherapy/immunotherapy only. Their analysis included 6,055 patients.
Overall, the researchers found, the unadjusted risk of VTEs was 10.9% for patients given bevacizumab compared to 9.8% of controls; the rate per 100 patient-years was 18.5 and 20.3, respectively. Neither difference reached statistical significance.
This result was consistent for all five tumor types included in the study, and for all chemotherapy regimens. However, tumor type did affect VTE risk, which was highest among pancreatic cancer patients (14.5% of those on bevacizumab, 18.1% of controls) and lowest in patients with renal cell cancer (2.7% for bevacizumab, 1% of controls).
Multivariate analysis identified age over 65, worse performance status, a history of VTE, oral anticoagulant use at the study's outset, and previous surgery as independent risk factors for VTE. All of these risk factors had the same effect in patients on bevacizumab and controls.
"Our data would strongly suggest there is no increased risk related to VTE or VTE management with bevacizumab," Dr. Hurwitz told Reuters Health via email. "While VTE is a real concern for cancer patients, this concern should be considered independent of bevacizumab."
"As known for many years, bevacizumab does confer a small but real increased risk of arterial thrombo-embolic events," he added. "This analysis reminds clinicians that ATE and VTE are not the same."
He concluded: "This controversy emphasizes the importance of having the highest quality safety data and analyses in the public domain -- and for this information to be updated on a regular basis."
Several of the study authors report receiving fees from companies that include Bristol-Myers Squibb, Eli Lilly, Novartis and Merck.

FDA APPROVED IPILIMUMAB FOR METASTATIC MELANOMA

March 25, 2011 — The US Food and Drug Administration (FDA) announced today the approval of ipilimumab (Yervoy, Bristol-Myers Squibb) for the treatment of advanced melanoma as a second-line therapy.
Ipilimumab is the first agent ever proven to improve survival in advanced melanoma. Its Biologics License Application was granted priority review designation in August 2010.
Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010, and about 8700 people died from the disease, according to the National Cancer Institute.
"Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient's life," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. Ipilimumab "is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."
The pivotal study of ipilimumab, known as 020, was conducted in previously treated unresectable stage III or stage IV melanoma patients. Results from this study made headline news when they were presented at last year's meeting of the American Society of Clinical Oncology (ASCO) and then published in full (N Engl J Med. 2010:363;711-723), as previously reported by Medscape Medical News.
In that study, patients receiving ipilimumab plus a peptide vaccine (glycoprotein 100) had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P < .001). Patients receiving ipilimumab alone had a nearly identical median survival — 10.1 months — in the 3-group clinical trial (P < .003).
The response to ipilimumab can be "dramatic," said Patrick Hwu, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, in an editorial that accompanied the study (N Engl J Med. 2010;363:779-781).
Follow-up from the earliest cohort of patients who received ipilimumab "shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years," said Dr. Hwu wrote.
However, on the downside of the data from the 676-patient study, the "best overall response rate" (patients with a complete or partial response) was limited to 10.9% of the ipilimumab recipients. In other words, a minority of patients respond to the new drug.
Nevertheless, experts have predicted great patient demand for the new drug, as reported by Medscape Medical News.
Bristol-Myers Squibb announced on March 21 that ipilimumab is also effective in previously untreated patients with metastatic melanoma.
In the new study, designated 024, ipilimumab met the primary end point of improving overall survival in these patients, according to the company. The study compared ipilimumab in combination with chemotherapy (dacarbazine) and chemotherapy alone.
An abstract of the 024 data will be submitted for potential presentation at the annual ASCO meeting in June, the company reports.
New Class of Drug
Ipilimumab is another targeted therapy for cancer, but represents a new class of drug, known as a targeted T cell antibody, said Steven O'Day, MD, one of the study authors, when the study was first presented last year. Ipilimumab is directed against an antigen on the surface of T cells. The antigen, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), acts as a brake on the T cell, explained Dr. O'Day, who is from the University of Southern California Keck School of Medicine in Los Angeles. By blocking the brake, the T cell goes into attack mode and kills cancer cells.
In the pivotal study, treatment with ipilimumab, which is administered intravenously, included some severe adverse events, including 14 deaths.
"This is a powerful drug," said Dr. O'Day, who noted that 10% to 15% of immune-related adverse effects were grade 3 or 4 and required immunosuppressive therapy with steroids.
"Steroids were quite successful in the vast majority of patients," said Dr. O'Day, "and they did not affect efficacy."
The "serious potentially life-threatening complications" with ipilimumab require a committed multidisciplinary team to manage them, explained Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center in Tampa, Florida, who acted as a discussant of the study at ASCO in 2010.
The FDA noted in its approval announcement that the common adverse effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. When severe adverse effects occurred, the drug was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.
Because of the unusual and severe adverse effects associated with ipilimumab, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential adverse effects.
Dr. O'Day reports serving in a consultant or advisory role for and receiving honoraria and research funding from Bristol-Meyers Squibb, and receiving research funding from Medarex. Dr. Sondak reports being a speakers bureau member and providing consulting and expert testimony for Merck/Schering-Plough; he is also on advisory panels for Bristol-Myers Squibb, Genzyme, GlaxoSmithKline, Pfizer, and Provectus. Dr. Hwu has disclosed no relevant financial relationships.

XELOX IMPROVES PFS IN STAGE III COLON CANCER

NEW YORK (Reuters Health) Mar 23 - Capecitabine plus oxaliplatin should be considered a standard-of-care for adjuvant therapy following stage III colon cancer resection, according to a new study.
The combination, often called XELOX or CAPOX, was previously used for stage IV metastatic disease. However in a head-to-head comparison with a standard bolus fluorouracil (FU) and folinic acid (FA) adjuvant regimen, XELOX improved 3-year disease-free survival for patients with stage III disease.
The study was published online March 7 in the Journal of Clinical Oncology.
"Capecitabine plus oxaliplatin can now be considered a standard of care -- not the standard of care," said Dr. Michael O'Connell, the associate chairman of the National Surgical Adjuvant Breast and Bowel Project, a U.S. colorectal cancer research group.
Dr. James Cassidy, head of Medical Oncology at the University of Glasgow in Scotland, agreed that the study should simply add to oncologists' armamentarium, not completely replace FU/FA regimens, which have been standard since the late 1990s.
"XELOX already is our standard in this situation and I think it should be a standard," Dr. Cassidy told Reuters Health in an email. "I don't really think one has to get down to just one standard. I believe there are good reasons for us to be able to choose between regimens for individual patients."
He added that about 50% of stage III colon cancer patients already receive a XELOX regimen in the United Kingdom, based on enrollment in a current trial that Dr. Cassidy is participating in.
In the U.S. study, patients with locally advanced, node-positive colon cancer were randomized to receive either a standard bolus, FA/FU adjuvant regimen (n=942) or a capecitabine plus oxaliplatin regimen (n=944) within 8 weeks of surgical resection.
The FA/FU treatment regimens were either the Mayo Clinic (n=664; 24 weeks, 6 cycles) or Roswell Park (278; 32 weeks, 4 cycles) standard protocols. Patients in the capecitabine plus oxaliplatin, or XELOX, arm received a 2-hour intravenous infusion of oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1,000 mg/m2 twice daily on days 1 to 14 of a 3-week cycle for eight cycles.
Disease-free survival was the main outcome measure in the study, and patients were followed for a median duration of 55 months.
When enrollment was closed, 31.3% of patients in the XELOX group had relapsed, developed a new colon cancer, or died, compared with 37.5% of the FU/FA group.
In terms of disease-free survival, patients taking XELOX also had a 20% reduction in relative risk (HR 0.80; P=.0045).
Four- and five-year disease-free-survival rates were also better in the XELOX group (68.5% vs. 62.3% and 66.1% vs. 59.8%, respectively), "demonstrating that superior efficacy of XELOX versus FU/FA was maintained over time," the investigators, led by Dr. Daniel Haller at the University of Pennsylvania, write.
Capecitabine, which is given orally, is potentially more convenient to administer than intravenous FU-based regimens. However, the cheaper costs of oral chemotherapy could be outweighed by an increase in adverse events found in the XELOX group.
"A central venous catheter is sometimes required for the administration of oxaliplatin anyway, and management of the increased toxicity with (capecitabine plus oxaliplatin) also costs money," said Dr. O'Connell.
In the study, 55% of patients in the XELOX group suffered a grade 3/4 adverse event, compared with 47% of patients in the FU/FA group (P<.05). Neurosensory toxicity was also far more common in the XELOX group, with 78% of patients reporting some level of neurotoxicity versus 8% in the FU/FA group.
Dr. Cassidy said the adverse events reported with XELOX in the trial were acceptable, but that "some oncologists still feel it's a bit more toxic in everyday usage -- particularly with respect to diarrhea."
Another barrier, he added, is that physicians may be paid less for switching to an oral-based regimen. "In some countries the clinician or institution gets a payment for IV drug administration but gets much less -- sometimes nothing -- for prescription of an oral drug. So there can be perverse incentives for sticking with an all-IV regimen," he said.
The study was supported by F. Hoffman-La Roche, and several of the authors report financial ties with companies that include Merck, Roche, Hoffman-La Roche and AstraZeneca.
SOURCE: http://bit.ly/ec5nwk
J Clin Oncol 2011.