TOP CANCER PROFESSOR LEAVES ACADEMIA FOR ROCHE-CAN WE BE SURE THAT HIS RESEARCH WAS NOT BIASED?

Aug 1, 2011 — "An opportunity for one more big challenge in my life," is how Jim Cassidy, MD, PhD, described his move from Scotland to the United States, and out of academia into the pharmaceutical industry.
The move will allow him to be involved in the development of new cancer drugs, "which is what I've done all my life, and what I have enjoyed doing the most," he told Medscape Medical News in an interview.

To join Roche US, Dr. Cassidy leaves his position as professor of medical oncology at Glasgow University, where he was also head of the Department of Cancer Research and head of the division of cancer sciences and molecular pathology.
He is now head of translational medicine in the Oncology Discovery and Translational Area, within Pharma Research and Early Development.
"We are very fortunate to have Jim join," said Mike Burgess, MD, PhD, global head of the Oncology Oncology Discovery and Translational Area and head of large-molecule research in Pharma Research and Early Development at Roche.
"With his rich and deep experience in oncology research, he is the perfect fit," Dr. Burgess said in a statement. "He brings new energy and inspiration to our group, which will allow us to enhance our development of new more effective treatments for cancer."
Moving Across the Pond
Dr. Cassidy spent nearly all of his professional life in Scotland, having studied for both his MD and a doctorate in clinical pharmacology at the University of Glasgow, and having worked there as a senior lecturer in oncology. After stints at the University of Edinburgh and the Western Infirmary in Glasgow, Dr. Cassidy was the first professor of oncology at Aberdeen University, where he developed both an academic unit of clinical oncology and a laboratory-based cancer research group. He then moved back to the University of Glasgow, where he has been professor of oncology for 10 years.
Jeff Evans, MD, professor of translational cancer research and consultant medical oncologist, and former colleague at the University of Glasgow, told Medscape Medical News that "it has been a pleasure to work with Jim Cassidy over the past decade in Glasgow. He has made an enormous impact on cancer medicine and cancer research, both nationally and internationally, and he is a global key opinion leader in his field, especially in developing new treatment strategies for patients with colon cancer."
Dr. Cassidy reported that he is looking forward to living in America, and is moving with his wife and disabled 27-year-old son, who are both "super excited" at the prospect. "We've been over to New Jersey 4 times now, and we've been delighted by what we've seen," he said. "Fabulous houses ... and where we are going to be is fairly rural."
His other 4 children are older and are "doing their own thing," so they won't be coming. The youngest has just completed her first year at Aberdeen University medical school.
Will he miss Scotland? "Of course, and I'll miss the family, but I certainly won't miss the weather," he said.
Mutations Are Key
Dr. Cassidy is enthusiastic about the opportunity that working at Roche has presented him. "I'll be at the top level of drug development, moving products out of the laboratory into early clinical trials, phase 1 and 2 trials," he says. "We'll be deciding which compounds to move into trials, and which trials we might do, and why we design them."
"We'll also be looking at biomarkers to see if we can predict patient responses," he said, noting the big move toward personalized cancer treatment.
Genetic mutations will be absolutely key to how we develop drugs in the future," he emphasized. "This is now not a matter of a wish list, this is now imperative."
The way of the future lies in identifying genetic mutations and then targeting them with specific therapies, he explained. We need to conduct trials of a new drug in the patient population carrying that mutation (or other biomarker), rather than testing [new drugs] in all patients with a particular cancer.
There have been a number of large and expensive phase 3 clinical trials in cancer that have failed recently, and there has been "some anger and anxiety about this," he said. "Pharma is changing very rapidly on account of this," he noted.
"We are learning, and learning very quickly, that the paradigms we have used for developing drugs are faulty," and there is an evolving realization about the need for patient selection. But this is very recent, he emphasized — this has come about only within the last year or 18 months, after some very high-profile failures.
One example of this realization is the story of epidermal growth-factor receptor (EGFR) drugs, which have been shown to be important in both lung cancer and colorectal cancer — but in different ways. In nonsmall-cell lung cancer, patients found to have EGFR mutations are likely to respond to treatment with EGFR tyrosine kinase inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa). However, in colorectal cancer, identifying patients with KRAS mutations, which are on the same pathway, identifies patients who will not respond to treatment with EGFR antibody blockers such as cetuximab (Erbitux) and panitumumab (Vectibix).
The situation is quite different for the 2 cancers, and "we weren't expecting that," Dr. Cassidy said. "We thought that once we had worked it out in one cancer, it would work across the board, but actually it doesn't."
Finding KRAS mutations in colorectal cancer has clinical implications, but they are not the same implications as finding KRAS mutations in lung cancer, he explained. "The significance of the mutation is different between the diseases."
The whole picture is far more complex than anyone could have envisaged, he said. "Our approach so far has been quite naïve and superficial. We need to find out more about the science and apply that science to the drug development process."

SERIOUS CHEMOTHERAPY DRUG SHORTAGES IN U.S.A!!!

(CBS News) 
Fighting cancer is hard enough, even with the best medical care.
Now imagine being a cancer patient and being told that the supply of a chemotherapy drug you need to survive has suddenly run out.
CBS News medical correspondent Dr. Jon LaPook reports that there is one California woman who doesn't have to imagine it. She's living it.
Marcia Goodman, 56, has ovarian cancer. She was supposed to get chemotherapy Wednesday, but her clinic just ran out of her medicine.
"I was just starting to feel hopeful this drug would work. My heart just sank," Goodman says.
Her oncologist had prescribed Doxil, and said the drug had the best chance of controlling the cancer she's battled since 1998.
"You invest all your hope and belief in the drug that your doctor has chosen with you at the moment because clearly that's the one that everybody thinks will help you. And so if that drug is suddenly not available it's like a train that's suddenly left the tracks. You feel like its crashed," Goodman says.
Doxil is just one of nearly 200 chemotherapy drugs in short supply, like Cisplatin, used to treat testicular, ovarian and bladder cancers, and Paclitaxel, commonly used for ovarian & breast cancers. Many new cancer drugs are often made by single manufacturers, so any disruption can result in shortages.
"We're going through an unprecedented period of extreme shortage of many key therapies to treat cancer," says drug supply expert Adan Fein, who blames hoarding for being part of the problem.
"If there's a rumor of a drug shortage, every hospital and every doctor tries to get as much of that drug as they can," Fein says.
The company that makes Doxil recently issued alert of "production delays," and suggested new patients not begin treatment. But Goodman had already started. She cannot believe a drug shortage could now threaten her life.
"Chemotherapy keeps you alive. It's as simple as that," Goodman says.
Janssen, which makes Doxil, told CBS News the company is working closely with the FDA on a plan to get the drug to doctors as soon it becomes available. It expects the supply to improve in late August for the 7,000 people who use it.
Several doctors interviewed by CBS News say they are beside themselves at not having all the tools of their trade.

USE WITH CAUTION PRADAXA IN ELDERLY

August 4, 2011 (Paris, France) — New reports of two elderly women faring badly when taking the novel anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) for stroke prevention in atrial fibrillation (AF) have prompted more discussion about the caution needed with this drug when treating the very old or those with renal impairment [1].
In an accompanying commentary [2], Dr Jeremy M Jacobs (Hadassah Medical Center, Jerusalem, Israel) and Dr Jochanan Stessman (Hebrew University-Hadassah Medical School, Jerusalem, Israel) say: "These cases require careful attention and serve to highlight a unique problem associated with oldest-old patients and novel drug therapy.
"It is of concern that those most likely to need anticoagulation are potentially those most at risk of its adverse effects—ie, frail, oldest-old patients among whom poorly diagnosed renal impairment, sarcopenia, and altered body composition are common. The lack of a specific antidote for dabigatran further renders this vulnerable group at risk," they state.
One of the investigators of the RE-LY study— the pivotal trial on which approval of dabigatran for the prevention of stroke in AF was based—Dr Lars Wallentin (Uppsala Clinical Research Centre, Sweden), told heartwire that while it could not be proven that individuals who have fared badly on dabigatran would not also have done poorly on the alternative, traditional treatment of warfarin, he agrees that caution should be exercised with the new drug in the very elderly and frail. "Both the case reports and the commentary are relevant and appropriate," he observes.
Two Very Elderly, Frail Women Fare Badly on Dabigatran
In most countries in which dabigatran is approved, the choices of dose are 150 mg twice daily, which was shown to be more effective than warfarin in RE-LY but carries a higher risk of bleeding, or 110 mg twice daily, which was shown to be equivalent to warfarin. In Canada, the EU, and other countries, dabigatran was approved for the stroke/AF indication in both the 110-mg and 150-mg doses, but the US made the controversial decision to approve only the 150-mg dose and an untested 75-mg dose for patients with severe renal impairment, stating that the data in favor of a 110-mg dose "were suggestive but not entirely convincing."
Dabigatran is primarily eliminated via the kidneys, so the patient prescribing information advises "dose adjustment" for renal impairment and notes an increased bleeding risk among those older than 75.
In one of the case reports just published, an 84-year-old woman taking 75 mg of dabigatran twice daily for AF, who weighed just 40 kg, developed massive rectal bleeding, had a cardiac arrest, and died, Dr Matthieu Legrand (Lariboisière Hospital, Paris, France) and colleagues report in the July 25, 2011 issue of the Archives of Internal Medicine. In the other case, an 89-year-old woman weighing 45 kg who had been taking 110-mg twice-daily dabigatran for AF for five months was found to have increased bleeding times and an elevated plasma level of dabigatran when tested prior to cochlear implant surgery. She had suffered recurrent nosebleeds for a week prior to this. Treatment with dabigatran was stopped, and the outcome was favorable.
110 Mg Twice Daily a "Good Choice" for the Over-75s
Jacobs and Stessman state in their editorial that they would like to see a subanalysis of the RE-LY data by age group. Another RE-LY investigator, Dr Salim Yusuf (McMaster University, Hamilton, ON), told heartwire that a "detailed analysis of RE-LY by age" is at an advanced stage.
"In the meantime, increased vigilance is warranted for bleeding events among elderly patients, particularly those with renal impairment, as dabigatran enters the market and gains popularity and we accumulate more data via clinical trials, registries, and case reports [such as these]," the editorialists conclude.
Wallentin says: "Based on RE-LY, we have evidence that 110 mg twice daily is as effective as warfarin with a lower risk of bleeding, and some doctors might prefer that dose because usually physicians like to stay on a safety course, especially for elderly patients with many other medications. Many of us in the RE-LY group believe that for those aged >75 years, 110 mg twice daily seems to be a good choice."
He and his coinvestigators believe the decision not to approve the 110-mg twice-daily dose of dabigatran in the US is thus leading to a reluctance to use the drug among doctors there, and they have repeatedly called for the FDA to reconsider its decision.
Monitoring With Dabigatran May Even Be Required in High-Risk Groups
Wallentin also told heartwire that a pharmacokinetic analysis, which is in press, shows that the 75-mg dose "might be recommended for those with a creatinine clearance at or below 30 mL/min," as per the recommendation made by the FDA for those with impaired renal function.
And he says that, in the future, "there might even be a reason to tailor the dabigatran dose based on measurements of dabigatran plasma concentrations or eventually thrombin time in patients at high risk of bleeding or risk of exposure to too-high dabigatran plasma concentrations."
Asked by heartwire whether this would not negate one of the big advantages of dabigatran over warfarin—no monitoring required—he stressed that, if agreed—"and it still needs further discussion"—this would be necessary only in certain select groups, rather than in everyone, as is the case with warfarin.

Case report authors and editorialists report no conflicts of interest. Wallentin and Yusuf are investigators for RE-LY, a collaboration between Boehringer Ingelheim; McMaster University and Hamilton Health Sciences; the Uppsala Clinical Research Centre, Sweden; and Lankenau Institute for Medical Research

CHEMOTHERAPY SENSITIVITY ASSAYS NOT READY FOR CLINIC

August 4, 2011 — Maintaining the stance it took in 2004, the American Society of Clinical Oncology (ASCO) continues to recommend against the use of chemotherapy sensitivity and resistance assays (CSRAs) to select chemotherapeutic agents for individual patients, except in the setting of a clinical trial.
After an extensive review of the data published between December 1, 2003 and May 31, 2010 on MEDLINE and in the Cochrane Library, ASCO's Update Working Group reports that it was unable to identify any CSRAs with enough evidence to support their use in oncology practice; as a result, no changes to the 2004 recommendations are warranted.
"Oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient's health status and treatment preferences," the update committee states.
The updated ASCO technology assessment guidelines on CSRAs were published online July 25 in the Journal of Clinical Oncology.
New Evidence, But No Change
The update reflects new evidence but no change in the recommendations from the original 2004 guideline.
The following assays were included in the review:

• ATP (adenosine triphosphate bioluminescence), which is used in patients with recurrent ovarian cancer and metastatic melanoma
• MTT (methyl-thiazolyl-diphenyltetrazolium bromide), which is used in patients with gastric cancer
• EDRA (extreme drug-resistance assay), which is used in patients with ovarian cancer
• ChemoFX, which is used in patients with ovarian cancer and small breast lesions.

As it did in 2004, the update committee recommends that participation in clinical trials evaluating these technologies remain a priority because of the potential importance of such in vitro analytic strategies.
The members of the Update Working Group have disclosed no relevant financial relationships.
J Clin Oncol. Published online July 25, 2011. Abstract

PROGNOSTIC ROLE OF KRAS MUTATION STATUS IN COLORECTAL CANCER

Anticancer Drugs. 2011 Jul 27. [Epub ahead of print]

Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status.

Modest DP, Stintzing S, Laubender RP, Neumann J, Jung A, Giessen C, Haas M, Aubele P, Schulz C, Boeck S, Stemmler HJ, Kirchner T, Heinemann V.

Source

aMedical Department III, Hospital of the University bInstitute of Medical Informatics, Biometry, and Epidemiology cInstitute of Pathology, University of Munich, Munich, Germany.

Abstract

This retrospective study investigated the clinical characteristics of patients with metastatic colorectal cancer (mCRC) depending on the KRAS status, thereby differentiating KRAS exon 2 mutations in codon 12 versus codon 13. In total, 273 patients with mCRC receiving first-line therapy were analyzed. One hundred patients were treated within the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab), 147 patients within the AIO KRK-0104 trial (cetuximab plus CAPIRI or CAPOX), and further 26 patients received therapy outside the study. Thirty-eight tumors with KRAS mutation in codon 13, 140 tumors with mutation in codon 12, and 95 tumors with KRAS wild type as a comparison were included in this analysis. Bivariate analyses demonstrated significant differences between KRAS wild-type, codon 12-mutated, and codon 13-mutated tumors with regard to synchronous lymph node metastasis (P=0.018), organ metastasis (76.8% vs. 65.9% vs. 89.5%, P=0.009), liver metastasis (89.5% vs. 78.2% vs. 92.1%, P=0.025), lung metastasis (29.5% vs. 42.9% vs. 50%, P=0.041), liver-only metastasis (48.4% vs. 28.8% vs. 28.9%, P=0.006), and metastases in two or more organs (49.5, 61.4, 71.1, P=0.047). Regression models indicated a significant impact of KRAS mutations in codon 12 versus codon 13 for synchronous organ and nodal metastasis (P=0.01, 0.03). This pooled analysis indicates that mCRC is a heterogeneous disease, which seems to be defined by KRAS mutations of the tumor. Compared with KRAS codon 12 mutations, codon 13-mutated mCRC presents as a more aggressive disease frequently associated with local and distant metastases at first diagnosis.

ANOTHER CHEAP COMBINATION REGIMEN

Oncologist. 2011 Jul 27. [Epub ahead of print]

A Phase II Trial of Bevacizumab plus Everolimus for Patients with Refractory Metastatic Colorectal Cancer.

Altomare I, Bendell JC, Bullock KE, Uronis HE, Morse MA, Hsu SD, Zafar SY, Blobe GC, Pang H, Honeycutt W, Sutton L, Hurwitz HI.

Source

Durham, North Carolina, USA.

Abstract

Abstract Purpose. For patients with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Preclinical data demonstrated that combined vascular endothelial growth factor and mammalian target of rapamycin inhibition has greater antiangiogenic and antitumor activity than either monotherapy. A phase I study of bevacizumab plus everolimus demonstrated that the combination is safe; activity was seen in several patients with refractory mCRC. Methods. Fifty patients with refractory mCRC were enrolled and received bevacizumab at 10 mg/kg every 2 weeks and everolimus at 10 mg orally daily. Results. Of the 50 patients enrolled, the median age was 56 years and the median number of prior regimens was four. Forty-seven patients (96%) had prior bevacizumab exposure and 42 patients (84%) had documented progression on prior bevacizumab-based therapy. Forty-nine patients were evaluable for response; eight patients had minor responses (16%) and an additional 15 patients (30%) had stable disease (SD). No complete or partial responses were seen. The median progression-free survival interval was 2.3 months; however, 26% of patients achieved prolonged SD for ≥6 months, and three patients (6%) were on study for >1 year. The median overall survival duration was 8.1 months. The most common grade 1-2 toxicities were mucositis (68%) and hyperlipidemia (64%). Clinically significant grade ≥3 toxicities included hypertension (14%), fistula/abscess/perforation (8%), mucositis (6%), and hemorrhage (2%). Conclusions. Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients.

CONTROVESIAL EFFICACY OF SCREENING MAMMOGRAPHY

August 3, 2011 — Screening has been successful in reducing deaths from cervical cancer and colorectal cancer, but not breast cancer, according to the authors of a new European study published online July 28 in BMJ.
Better treatment and improved healthcare-delivery systems are more likely to have led to reduced deaths from breast cancer than routine screening with mammography, lead author Philippe Autier, MD, from the International Prevention Research Institute, Lyon, France, told Medscape Medical News.
"Deaths from breast cancer are decreasing in North America, Australia, and most Nordic and western European countries, but it is difficult to tell whether this decrease is due to early detection from screening and early treatment, or whether it is due to better healthcare, he said. "We think it's due to better care."
However, his views are hotly contested by mammography experts in the United States.
Trends in Mortality
Dr. Autier and colleagues note that deaths from cervical cancer decreased substantially in Iceland and Finland after nationwide screening programs were initiated in the 1960s. However, in neighboring Norway, where screening programs were delayed, the reduction in mortality did not become apparent until many years later.
The team decided to see if something similar happened with breast cancer. Their hypothesis was that the reduction in mortality in countries that implemented mammography screening early would appear before the reduction in similar countries that started screening later.
To test this hypothesis, Dr. Autier and his team compared trends in breast cancer mortality in 3 pairs of neighboring European countries. In each pair, mammography had been introduced in one of the countries in or around 1990, but was not introduced in the other country until some years later. The pairs examined were Northern Ireland (United Kingdom) vs the Republic of Ireland, the Netherlands vs Belgium and Flanders, and Sweden vs Norway.
The researchers analyzed data from the World Health Organization (WHO) mortality database on cause of death from 1980 to 2006, as well as data sources on risk factors for breast cancer death, mammography screening, and cancer treatment.
They found that although there was a considerable gap between the introduction of mammography screening in the paired countries, breast cancer mortality was fairly similar.
For example, a nationwide mammography program was introduced in Northern Ireland around 1990, but it was not introduced until 2000 in the Republic of Ireland. The WHO data showed that breast cancer mortality was reduced by 29% in Northern Ireland and by 26% in the Republic of Ireland from 1980 to 2006.
In the second group, mammography was introduced in the Netherlands in 1989, in Belgium in 2001, and in Flanders in 2002/03. The WHO data showed that breast cancer mortality decreased by 25% in the Netherlands, by 20% in Belgium, and by 25% in Flanders from 1980 to 2006.
In the third pair of countries, mammography was introduced in Sweden in 1986 and in Norway in 1996. The WHO data show that breast cancer mortality decreased by 16% in Sweden and by 24% in Norway from 1980 to 2006.
Dr. Autier emphasized that "after 1989, the breast cancer mortality in these countries were comparable, despite a 10- to 15-year difference in the implementation of mammography screening."
The decline in mortality started between 1991 and 1996 in Norway, Belgium, the Republic of Ireland, Northern Ireland, and the Netherlands. In Sweden, breast cancer deaths started to decline in 1972, and the mortality from breast cancer has remained stable in that country over time. The reduction after 1989 was modest, compared with other European countries, he noted.
These downward trends in mortality started before or shortly after the implementation of mammography screening. The greatest reductions were in women 40 to 49 years of age, regardless of the availability of screening in this age group.
These pairs of countries are very alike. They have the same access to care, the same demographic structure, and often the same language. The fact that we don't see any difference in mortality over time is a sure sign that mammography did not work very well," Dr. Autier said.
He added that these results were unexpected.
We were surprised. We thought there might not be that strong an effect of mammography, but that we would see something. But we barely saw anything," he said. "The main message is that we really have to work out what is going on with mammography screening in our population. We have plenty of data that screening for colorectal cancer and cervical cancer is worthwhile, but for breast cancer, it looks like mammography really doesn't do the job."
Bemused and Frustrated
These views are hotly contested by the American College of Radiology (ACR), which immediately issued a statement declaring that "the conclusions of the BMJ study authors have little bearing on, or resemblance to, screening in the United States. Improvements in therapy have, likely, played a role in the decrease in breast cancer deaths, but therapy cannot cure advanced cancers. Early detection via mammography is clearly the major reason for the decrease in deaths in the United States."
Carol Lee, MD, a spokesperson for the Breast Commission of the ACR and a radiologist in private practiced in New York City, told Medscape Medical News that she is "frustrated and bemused by continuing attempts to disprove what we've proved over and over again."Dr. Lee said: "We have a number of randomized controlled trials involving a half a million women over the course of many years that showed that screening with mammography results in decreased mortality from breast cancer. We've observed this in this country."
The study had a number of limitations, she added.
"Just because counties are adjacent to each other, it does not necessarily mean that their breast cancer incidence is comparable. They didn't take that into account," Dr. Lee said. "They assumed that screening started all of a sudden in the areas that began a screening program, but this did not happen. In fact, it took a while to implement. They also included breast cancer deaths among cases that were diagnosed before the advent of screening in the screening groups, so there were just a lot of different designs and problems."
Difficult to Compare European and American ScreeningStamatia Destounis, MD, from the University of Rochester Medical Center in New York, noted that it is difficult to compare screening programs in Europe and the United States.
"In our country, in the 1980s, after the initiation of screening mammography, the incidence of breast cancer increased and, within 5 to 7 years, predictably, breast cancer deaths decreased," she told Medscape Medical News.
"Although breast cancer treatment is certainly important, it doesn't cure advanced breast cancer, and the best method of long-term survival after a diagnosis of breast cancer is the early detection of small highly treatable tumors. It is most important to start screening at age 40 to identify tumors early when they are most treatable," Dr. Destounis said.
Dr. Autier countered that the randomized trials that have found a benefit for mammography have been criticized for years because they are flawed.
Our data give some support to the criticisms of these trials.... A Canadian trial did not show any benefit; in contrast, we know that screening for cervical cancer works very well. It is the same for colorectal cancer. But for breast cancer, the benefit is still controversial," he said.
Benefit is Controversial
Weighing in with his opinion, John Keen, MD, attending radiologist at Cook County John H. Stroger Hospital in Chicago, Illinois, supported Dr. Autier's assertion that the benefit of mammography is controversial.
"As usual, Dr. Lee won't accept the evidence and remains the key mammography marketer for the ACR," he told Medscape Medical News.
"I noticed her new line of reasoning — that 'therapy cannot cure advanced cancers.' The problem here is that screening has not decreased the incidence of advanced cancer. Screening inherently misses the fast growing and catches the slow growing; hence, screening causes overdiagnosis with little mortality benefit," he explained.
"Overdiagnosis of small screen-detected tumors that would never become clinically evident results in overtreatment with drugs and needless radiation, which can cause heart disease and increase future deaths," Dr. Keen added.
"The trials have not shown any overall mortality benefit, nor is there any trial evidence to justify aggressive annual screening. Screening also increases overall mastectomies and lumpectomies because of overdiagnosis. The greatest benefit-to-harm ratio occurs for women in their 60s, which is what radiologists should be telling women."
Dr. Autier, Dr. Destounis, and Dr. Keen have disclosed no relevant financial relationships. Dr. Lee is a spokesperson for the American College of Radiology.
BMJ. Published online July 28, 2011. Abstract

REIRRADIATION CAN BE EFFECTIVE IN POST-RADIATION SARCOMAS

NEW YORK (Reuters Health) Jul 28 - Reirradiation plus hyperthermia is an effective treatment for radiation-associated sarcoma (RAS) and could even cure some of these rare tumors, a small new study suggests.
"The reirradiation plus hyperthermia as we used it appears to be quite successful with a very high response rate and reasonable local control rate," Dr. Geertjan van Tienhoven of the Academic Medical Center in Amsterdam, one of the study's authors, told Reuters Health.
RAS develops in areas previously reirradiated with 25 to 80 Gray, usually with a latency period of three years or more, and with a different histology from the original tumor, according to a June 28th online paper in Cancer.
Dr. van Tienhoven predicts that "radiation-associated sarcomas are going to be more frequent in the future, because of an increasing prevalence of breast cancer survivors who are at risk, be it a low risk, for RAS."
These tumors are usually resected with radical surgery and sometimes adjuvant chemotherapy. To date, according the paper, there haven't been any randomized trials or other prospective studies of reirradiation for RAS.
"Many papers and textbooks state that radiation shouldn't be done in these tumors because they are caused by radiation. Indeed it sounds counterintuitive to irradiate again," Dr. van Tienhoven said in an interview.
But using hyperthermia with reirradiation allows for a lower radiation dose, he and his coauthors explain. The Academic Medical Center and the Institute Verbeeten have "extensive experience" with this approach, for example in breast cancer recurrence in previously irradiated areas.
To assess the value of radiation plus hyperthermia (RT-HT) for RAS, the researchers studied 16 patients treated between 1979 and 2009, all of whom had RAS in the thoracic region. The median latency was 86 months, and 11 patients had angiosarcoma. Thirteen patients had unresectable disease, while three of the patients received RT-HT as adjuvant therapy after surgery.
Treated patients survived for up to 204 months, with a median of 15.5 months. Four patients could not be evaluated for response. Of the remaining 12, seven had a complete response, two had a partial response, and three had stable disease.
Six patients remained free of recurrent disease until death (one patient at five months, one at seven months) or last follow-up (eight months, 11 months, 39 months, and 68 months).
"The response and local control rates are promising and appear to contradict the common assumption that reirradiation is not useful in patients with RAS," the authors write.
"I think that treating these radiation-associated sarcomas, particularly the angiosarcomas, with a combination of attempted radical surgery and reirradiation plus hyperthermia has the possibility of a cure," Dr. van Tienhoven told Reuters Health. "I think these tumors are very much more radiosensitive than is often thought."
He added, "We must be very cautious of course because this is a very small series and there are various types of tumors and several aspects of this series are heterogeneous."
Nevertheless, the researcher concluded, "it gives us the suggestion that reirradiation helps."
SOURCE: http://bit.ly/onLfMm

A FIXED LOW DOSE DAILY USE OF CAPECITABINE

Eur J Cancer. 2011 Jul 18. [Epub ahead of print]

Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer.

Fedele P, Marino A, Orlando L, Schiavone P, Nacci A, Sponziello F, Rizzo P, Calvani N, Mazzoni E, Cinefra M, Cinieri S.

Source

Medical Oncology and Breast Unit, "A. Perrino" Hospital, Brindisi, Italy.

Abstract

AIM:

Registered dose capecitabine monotherapy is active against metastatic breast cancer (MBC), but retrospective analyses indicate that lower doses may be as effective and better tolerated. This study was conducted to assess the safety and efficacy of metronomic capecitabine in heavily pretreated patients with MBC.

PATIENTS AND METHODS:

In this phase II study 60 MBC patients received continuous metronomic capecitabine monotherapy (1500mg once a day). Primary endpoint was clinical benefit rate, secondary end points were clinical benefit rates (CBRs), tumour response rates (RRs), overall survival (OS), time to progression (TTP), duration of response (DOR) and toxicity.

RESULTS:

Fifty eight assessable patients received two or more 28-day cycles of metronomic capecitabine. The CBR was 62%. Median DOR was 7months. Median TTP and OS were 7 and 17months, respectively. Two partial responses and 7 cases of stable disease were recorded in 13 patients who had previously received capecitabine intermittently (2000mg/m(2)/day on days 1-14 every 21days) as first- or subsequent-line treatment for MBC. Grade 3-4 adverse events were uncommon; haematologic toxicity was infrequent (5%) and consistently mild.

CONCLUSION:

This regimen of metronomic capecitabine displayed good activity and excellent tolerability in MBC patients, including those who had previously received the drug at standard doses.
Copyright © 2011 Elsevier Ltd. All rights reserved.

AN INTERESTING DRUG COMBINATION

Invest New Drugs. 2011 Aug 2. [Epub ahead of print]

Phase I and pharmacokinetic study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced solid malignancies.

Deenen MJ, Klümpen HJ, Richel DJ, Sparidans RW, Weterman MJ, Beijnen JH, Schellens JH, Wilmink JW.

Source

Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Abstract

Background Everolimus is an oral mTOR-inhibitor. Preclinical data show synergistic effects of mTOR inhibition in combination with 5-fluorouracil-based anticancer therapy. The combination of everolimus with capecitabine seems therefore an attractive new, orally available, treatment regimen. Patients and methods Safety, preliminary efficacy and pharmacokinetics of everolimus in combination with capecitabine were investigated in patients with advanced solid malignancies. Patients were treated with fixed dose everolimus 10 mg/day continuously, plus capecitabine bid for 14 days in three-weekly cycles. Dose escalation of capecitabine proceeded according to the standard 3 × 3 phase I design in four predefined dose levels (500-1,000 mg/m(2) bid). Results In total, 18 patients were enrolled. Median (range) treatment duration with everolimus was 70 days (21-414). Capecitabine 1,000 mg/m(2) bid combined with 10 mg/day everolimus was declared the maximum tolerated dose, at which level one patient developed dose-limiting toxicity (stomatitis grade 3). Drug-related adverse events were mostly grade ≤2 and included mainly fatigue (56%), stomatitis (50%), and hand-foot syndrome (33%). Partial response was documented in three patients, and four had stable disease. There was no pharmacokinetic interaction between everolimus and capecitabine. Conclusion Everolimus 10 mg/day continuously combined with capecitabine 1,000 mg/m(2) bid for 14 days every 3 weeks is a patient-convenient, safe and tolerable oral treatment regimen. This is the first study to demonstrate feasibility of this combination at doses with proven single agent efficacy in a number of tumors. Prolonged clinical benefit was observed in an encouraging 39% of patients with advanced solid malignancies.

NO USE OF ADJUVANT CHEMOTHERAPY IN STAGE II COLORECTAL CANCER IN ADULTS OVER AGE 65

NEW YORK (Reuters Health) Jul 29 - In adults over age 65 with stage II colon cancer and high-risk clinical features, adjuvant chemotherapy likely won't improve survival, a new "real world" study shows.
Survival benefits are generally less than 2% at five years, the study investigators say.
"This lack of benefit must be considered in treatment decisions for similar older adults with colon cancer," said Dr. Erin S. O'Connor and colleagues from the University of Wisconsin in Madison in the Journal of Clinical Oncology.
In their paper, published online July 25th, Dr. O'Connor and colleagues note that adjuvant chemotherapy is typically considered for patients with stage II colon cancer and such poor prognostic features as obstruction, perforation, T4 stage, inadequate nodal resection, peritumoral lymphatic/venous invasion, and poor histology.
Yet there is no evidence that these characteristics, although associated with worse outcomes, predict a good response to adjuvant chemotherapy.
Using the Surveillance, Epidemiology and End Results (SEER) database, Dr. O'Connor's team determined the overall survival benefit of adjuvant chemotherapy in 43,032 Medicare beneficiaries who had colectomy for colon cancer.
The cohort consisted of 6,234 patients with stage II disease but no poor prognostic features, 18,613 with stage II cancer and at least one poor prognostic factor, and 18,185 with stage III disease.
Overall, about 20% of the 24,847 patients with stage II colon cancer received adjuvant chemotherapy, with no difference between risk groups. As expected, survival at five years was significantly lower in stage II patients with poor prognostic features (57%, vs. 69% in those without poor prognostic features).
According to the investigators, adjuvant chemotherapy failed to improve survival in patients with stage II disease, regardless of the presence or absence of poor prognostic features (hazard ratios 1.03 and 1.02, respectively).
A survival benefit from adjuvant chemotherapy was observed only in patients with stage III disease (hazard ratio 0.64), 57% of whom received adjuvant therapy.
In a commentary, Dr. Neal Meropol from University Hospitals Seidman Cancer Center in Cleveland, Ohio said this analysis "should discourage routine use" of adjuvant treatment in older patients with stage II colon cancer.
But, he noted, it does not exclude a potential benefit of adjuvant treatment in patients younger than age 65.
SOURCE: http://bit.ly/njs5mv
J Clin Oncol 2011.

CHEMOTHERAPY BEFORE OR AFTER RADICAL CYSTECTOMY HAS THE SAME EFFICACY

NEW YORK (Reuters Health) Jul 27 - In advanced bladder cancer, the timing of chemotherapy -- before surgery, or after -- doesn't affect survival, as long as it's given perioperatively, according to a new paper from New York City.
Lead author Dr. James M. McKiernan told Reuters Health by email, "There is currently no clear cut randomized data that suggest that chemotherapy is better to be given prior to or after radical cystectomy."
He added," From a patient perspective there are several factors that support each approach." With neoadjuvant chemotherapy, for example, adverse effects are experienced before debilitating surgery. Adjuvant chemotherapy may delay treatment, but it may reduce the incidence of local and metastatic recurrence.
Either way, it's clear chemotherapy is helpful. "We sought to evaluate our own experience with each approach to determine if we could identify any superiority between the two practice patterns," Dr. McKiernan said.
With his colleagues at Columbia University Medical Center, he reviewed data on 146 patients who received multiagent platinum-based systemic chemotherapy for locally advanced bladder cancer between 1988 and 2009. Half of them received neoadjuvant chemotherapy; the other half was treated postoperatively.
As reported online June 29th in Cancer, the researchers found no significant difference in overall or disease-specific survival between groups in the 122 patients treated with cisplatin-based protocols (median survival with neoadjuvant vs. adjuvant therapy, 11 vs. 12.5 months, respectively).
This was also true when patients received methotrexate/vinblastine/adriamycin/cisplatin (median survival, 16 vs. 22.2 months).
In addition, there was no significant difference between neoadjuvant and adjuvant cisplatin- or carboplatin-based chemotherapy.
In the 43 patients who received gemcitabine/cisplatin, however, postoperative treatment was associated with significantly reduced survival. The researchers call for further studies to clarify this finding, but they point out that these patients "likely had worse prechemotherapy characteristics including decreased performance status."
Overall, Dr. McKiernan said, "the study concluded that there were no appreciable differences in survival between patients treated with chemotherapy before or after surgery."
This finding should be "considered when counseling patients regarding the sequence of perioperative chemotherapy and should be validated with a prospective randomized trial," he and his colleagues conclude.
SOURCE: http://bit.ly/pqJxCR
Cancer 2011.

SQUAMOUS SKIN CANCER RESPONDS TO CETUXIMAB

NEW YORK (Reuters Health) Aug 01 - In a phase II trial, cetuximab was a promising first-line therapy for unresectable squamous cell carcinoma of the skin (SCCS), French researchers reported online today in the Journal of Clinical Oncology.
Cetuximab blocks epidermal growth factor receptor (EGFR), which is expressed in SCCS.
Most of the 200,000 to 300,000 new cases in the US each year can be managed with surgical excision or radiotherapy, but some are too advanced.
In the first trial of targeted therapy for unresectable SCC of the skin, the researchers gave weekly cetuximab infusions (median, 15 infusions) to 36 patients with chemotherapy-na�ve unresectable SCCS. The median patient age was 79; 23 were older than 70.
Thirty-one patients were evaluable for tumor response at six weeks, said lead author Dr. Eve Maubec from Hopital Bichat in Paris and colleagues.
The disease control rate at week six was 69% (81% among evaluable patients).
Two patients achieved complete responses that lasted for two and a half years after treatment stopped. The best overall response rate (complete and partial remissions) was 28% (10/36).
Three patients with partial or minor responses to cetuximab underwent complementary surgical excision which resulted in persistent freedom from disease for three years in one patient, and local or regional relapse in two patients at seven months and twenty-four months.
Mean overall survival was 8.1 months and estimated survival at week 48 was 52%. Median progression-free survival was 4.1 months.
The 25 patients with disease control at week six maintained that control for a median of five months.
The median duration of response for the 10 patients who achieved complete or partial remission was 6.8 months.
All 36 patients had side effects consistent with those previously reported for cetuximab. Most frequent was an acne-like rash (grade 1 or 2 in 27/31 patients) that appeared a median 14 days into treatment.
The rash was not significantly associated with disease control at week six. However, patient who developed the rash had a significantly prolonged median progression-free survival (4.5 vs. 1.7 months; p=0.004) and a trend toward longer mean overall survival (8.9 vs. 4 months; p=0.054) compared with patients who did not develop the rash.
Dr. Maubec told Reuters Health in an email that cetuximab might be especially useful in elderly patients for whom chemotherapy is not appropriate.
Along with cetuximab and other EGFR inhibitors, alternatives for unresectable SCCS include cisplatin based chemotherapy and other conventional chemotherapy, retinoids, and interferon alpha, Dr. Maubec said.
These tumors are attractive targets for EGFR inhibition because RAS mutations are infrequent, the authors say in their report. Dr. Maubec added, however, that we still need to find biological factors that will predict response.
"A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option in this setting, particularly for elderly patients in whom chemotherapy is not appropriate," the research team concludes.
SOURCE: http://bit.ly/qulKuC
J Clin Oncol 2011.

ANOTHER FAILURE OF EXAMESTANE

NEW YORK (Reuters Health) Jul 29 - Don't bother with phase III trials of exemestane for hormone-responsive advanced breast cancer in older women, Spanish researchers say.
In a phase II trial, exemestane was no better than anastrozole, they reported online June 29th in Cancer.
Further formal comparisons are not justified, said lead author Dr. Antonio Llombart-Cussac of Arnau de Vilanova University Hospital, Lleida, and his colleagues.
Aromatase inhibitors have varying inhibitory potencies that could lead to differences in clinical outcomes. In particular, the research team notes, exemestane and anastrozole seem to delay recurrence in women with early breast cancer, with steroidal exemestane suppressing estrogen slightly more than nonsteroidal anastrozole.
To explore its possible advantages for advanced postmenopausal breast cancer, the team randomized 103 women, median age 72 years, to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until disease progression.
Both compounds were well tolerated with generally mild adverse events, according to the authors.
But the time to progression was twice as long with the comparator agent: six months with exemestane vs 12 months with anastrozole.
During a median follow-up of nine months, the objective response rates were 36.2% for exemestane and 46% for anastrozole. Clinical benefit rates were 59.6% and 68% for exemestane and anastrozole, respectively.
"The observed results prompted us to discard the planned phase 3 trial," the researchers say.
However, at progression, 28 patients crossed over to the other aromatase inhibitor. Among the 16 patients who switched to exemestane, 7 (43.7%) obtained a clinical benefit as opposed to only 1 of 12 patients who switched to anastrozole after failure on exemestane (8.3%).
This may be worth exploring, the authors observe.
"Although it was not the primary objective of the current study, we observed a dissimilar tumor behavior based in the sequential aromatase inhibitor approach that we used," the research team concluded.
SOURCE: http://bit.ly/pURml2
Cancer 2011.

HIGH PNEUMOTHORAX RISK WITH LUNG BIOPSY

NEW YORK (Reuters Health) Aug 02 - Pneumothorax develops in nearly one in seven patients undergoing transthoracic needle biopsy of a pulmonary nodule, according to a report online August 1 in Annals of Internal Medicine.
"Although our study does not address the long-term risk-benefit trade-off of whether to pursue biopsy, our population-based data on short-term risk for complications of CT-guided biopsy may help both patients with pulmonary nodules and their physicians make more informed decisions," the authors state.
Whether to perform a biopsy is an increasingly common issue, given that up to 25% of chest CT scans show pulmonary nodules, said lead author Dr. Renda Soylemez Wiener, at Boston University School of Medicine in Massachusetts, and colleagues
To determine the risk of complications from transthoracic needle biopsies, the team analyzed 2006 data from California, Florida, Michigan, and New York, from the Healthcare Cost and Utilization Project.
Among 15,865 CT-guided single biopsies of a pulmonary nodule, hemorrhage occurred in just 1% of cases. However, 17.8% of patients required a blood transfusion, the investigators found.
Pneumothorax of any severity occurred in 15% of biopsies, and in 6.6% of cases it required a chest tube.
Respiratory failure occurred more often in patients with hemorrhage (4.3%) or pneumothorax requiring a chest tube (1.4%) than in patients without complications (0.6%), according to the report. The risk of complications was highest in patients between the ages of 60 and 69, in smokers, and in patients with chronic obstructive pulmonary disease.
"Our data suggest that several thousand persons in the United States experience complications of CT-guided biopsy each year," Dr. Wiener and colleagues comment.
"For many patients, including those with a low risk for cancer, those who are too frail to undergo cancer treatment, or those with a high risk for cancer who should proceed directly to surgery, this procedure may be unnecessary" they continue. "Before exposing patients to potential harm from CT-guided biopsy, physicians must ensure that patients understand the risks."
SOURCE: http://bit.ly/o5jtHu
Ann Intern Med 2011;155:137-144.

TWO MUTATIONS FOUND IN OLIGODENDROGLIOMAS

August 5, 2011 — A study that provides a genetic map for oligodendroglioma, the second most common form of brain cancer, has identified 2 recurring genetic mutations that have not been previously associated with these tumors, according to researchers from Johns Hopkins University in Baltimore, Maryland, and Duke University in Durham, North Carolina.
The findings, published online August  4 in Science, might reveal the biologic cause of the tumors, suggest the authors, led by Chetan Bettegowda, MD, PhD, chief resident in the Department of Neurosurgery at Johns Hopkins.
Two thirds of 37 tumor samples had CIC and FUBP1 mutations, report the authors.
"Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor," said coauthor Nickolas Papadopoulos, PhD, in a press statement. He is associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.
"The study illustrates an important pathway that can be further studied for its therapeutic potential," noted coauthor Kenneth Kinzler, PhD, professor and codirector of the Ludwig Center at Johns Hopkins, when speaking with Medscape Medical News.
Another member of the research team explained how a therapy might work with these mutations.
The genes identified are tumor suppressor genes, said coauthor Hai Yan, MD, PhD, associate professor of pathology at Duke. "Tumor suppressor genes like the ones we found, CIC and FUBP1, won't be targeted directly by small molecules, because the mutated gene products result in loss of function, but the pathways that these genes are involved in could be targeted," Dr. Yan explained.
The researchers initially analyzed 7 anaplastic oligodendrogliomas, which are a higher-grade form of the disease. In total, they sequenced the coding exons of 20,687 genes.
They identified 225 nonsynonymous somatic mutations, affecting 200 genes in the 7 tumors. There were an average of 32.1 nonsynonymous somatic mutations per tumor. This is similar to the number found in glioblastomas (35.6), the most common type of adult brain tumor.
There were a number of notable mutations identified, the authors say. On the strength of the findings in the initial 7 tumors, the investigators analyzed 27 more tumors for a select group of mutations, including those of CIC and FUBP1. Overall, 23 mutations of CIC or FUBP1 were identified in the 34 oligodendroglioma samples analyzed.
"Our identification of inactivating mutations of CIC or FUBP1 in a substantial fraction of oligodendrogliomas is likely to provide important insights into the pathogenesis of these tumors, as well as help refine their diagnosis, prognosis, and treatment options," they write.
CIC and FUBP1 genes are known to regulate cell-signaling processes, and CIC mutations have been linked — although rarely — to sarcoma and breast and prostate cancers, note the authors.
Human Genome Help
The CIC and FUBP1 mutations might be the "missing link" in what scientists describe as a "2-hit" theory of cancer development, according to the Johns Hopkins press statement.
In oligodendrogliomas, the first hit occurs in regions of chromosomes 1 and 19, which fuse together, resulting in a loss of genes on both chromosomes. Anywhere from 50% to 70% of oligodendroglioma patients have these DNA fusions, according to authors.
The second hit that allows oligodendrogliomas to develop might be mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19 in these patients.
To date, the best biomarker for oligodendroglioma is the loss of heterozygosity of chromosomes 1p and 19q, note the authors.
In this study, the analysis of the 20,000-plus protein-coding genes in the human genome was greatly enabled by the Human Genome Project, said Dr. Kinzler.
"Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer," he said. "Knowing the genetic roadmap of a cancer is the key to attacking it."
Dr. Kinzler explained that, before the completion of the Human Genome Project, scientists could only look at parts of the genome. He used the metaphor of fingerprinting at a crime scene to compare research before and after the project. In the past, he said, only a few suspects could be finger printed at any one time. With the human genome now detailed, researchers can finger print every possible suspect.
The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, the National Cancer Institute, and the National Institutes of Health. A number of the coauthors are entitled to a share of the royalties received by Johns Hopkins on the sale of products related to genes and technologies described in the study.
Science. Published online August 4, 2011. Abstract

HYPERTENSION AND SUNITINIB EFFICACY

From Journal of the National Cancer Institute

Hypertension as a Biomarker of Efficacy in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib

Brian I. Rini; Darrel P. Cohen; Dongrui R. Lu; Isan Chen; Subramanian Hariharan; Martin E. Gore; Robert A. Figlin; Michael S. Baum; Robert J. Motzer

Abstract

Background Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib. We evaluated the association of sunitinib-induced HTN with antitumor efficacy and HTN-associated adverse events in patients with metastatic renal cell carcinoma.
Methods This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d administered on a 4-week-on 2-week-off schedule (schedule 4/2). Blood pressure (BP) was measured in the clinic on days 1 and 28 of each 6-week cycle. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods; hazard ratios (HRs) for survival were also estimated by a Cox proportional hazards models using HTN as a time-dependent covariate. Efficacy outcomes were compared between patients with and without HTN (maximum systolic BP [SBP] ≥140 mm Hg or diastolic BP [DBP] ≥90 mm Hg). Adverse events were also compared between patients with and without HTN (mean SBP ≥140 mm Hg or mean DBP ≥90 mm Hg). All P values were two-sided.
Results Patients with metastatic renal cell carcinoma and sunitinib-induced HTN defined by maximum SBP had better outcomes than those without treatment-induced HTN (objective response rate: 54.8% vs 8.7%; median PFS: 12.5 months, 95% confidence interval [CI] = 10.9 to 13.7 vs 2.5 months, 95% CI = 2.3 to 3.8 months; and OS: 30.9 months, 95% CI = 27.9 to 33.7 vs 7.2 months, 95% CI = 5.6 to 10.7 months; P < .001 for all). Similar results were obtained when comparing patients with vs without sunitinib-induced HTN defined by maximum DBP. In a Cox proportional hazards model using HTN as a time-dependent covariate, PFS (HR of disease progression or death = .603, 95% CI = .451 to .805; P < .001) and OS (HR of death = .332, 95% CI = .252 to .436; P < .001) were improved in patients with treatment-induced HTN defined by maximum SBP; OS (HR of death = .585, 95% CI = .463 to .740; P < .001) was improved in patients with treatment-induced HTN defined by maximum DBP, but PFS was not. Few any-cause cardiovascular, cerebrovascular, ocular, and renal adverse events were observed. Rates of adverse events were similar between patients with and without HTN defined by mean SBP; however, hypertensive patients had somewhat more renal adverse events (5% vs 3%; P = .013).
Conclusions In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN-associated adverse events, supporting its viability as an efficacy biomarker.