Sunitinib prolongs progression-free and overall survival, and is safe and well tolerated in advanced kidney cancer (metastatic renal cell carcinoma) patients with a poor prognosis such as the elderly and those whose cancer has spread to the brain, finds an Article published Online First (http://www.thelancet.com) and in the August edition of The Lancet Oncology.

Sunitinib is an oral targeted drug that attacks cancer by inhibiting tumour growth and starving the tumour of blood, reducing its ability to divide and grow. In previous trials sunitinib has shown clear benefit in patients with advanced kidney cancer and has been approved worldwide for first and second-line treatment in these patients. However, certain patients with advanced kidney cancer-often those with a poor prognosis such as those whose cancer has spread to the brain, those with a poor performance status (PS), and the elderly-are often excluded or inadequately represented in clinical trials. Thus, little is known about the activity, safety, and tolerability of sunitinib in these patients.

To resolve this uncertainty, Martin Gore and colleagues conducted an international expanded-access trial including subgroups of patients with advanced kidney cancer not usually entered into clinical trials, or those being treated in countries where the drug is not yet approved who would not normally receive the drug.

In total, 4,564 patients from 52 countries were recruited between June 2005 and December 2007. These included four subgroups of patients with brain metastases (321), poor performance status (582), non-clear-cell renal cell carcinoma (588), and patients aged 65 years or older (1,418). Patients received 50mg of sunitinib once daily in repeated 6-week cycles of 4 weeks of treatment followed by 2 weeks off. Tumour response, toxicity, and adverse events were assessed at regular intervals.

Overall, findings showed that sunitinib can be given safely and is well tolerated in all four subgroups of patients that might be expected to have a lower tolerance to therapy than the broader advanced kidney cancer patient population. Indeed, the safety profile was found to be very similar to that reported in previous trials and the overall incidence of adverse events was slightly less.

The most common treatment-related adverse events (AEs) were diarrhoea (44%) and fatigue (37%). Importantly, there were no differences in incidences of grade 3 and 4 AEs between the overall population and patients with brain metastases, poor PS, non-clear RCC, and the elderly-with fatigue (8%) and thrombocytopenia (8%) reported as the most common.

Median progression-free and overall survival were 10.9 and 18.4 months respectively, an improvement on historical data. The overall objective response rate (ORR) was 17%, with all four subgroups showing clear evidence of response-brain metastases (12%), non-clear RCC (11%), poor PS (9%), and the elderly (17%).

The authors say that these results should: “Encourage the study of targeted agents in subgroups of patients otherwise excluded from trials and therefore potentially disadvantaged.”

In an accompanying Reflection and Reaction comment, Dr Joaquim Bellmunt, Hospital del Mar, Barcelona, Spain and and Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA, and Dr Toni K Choueiri, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA, say: “As with sorafenib, the safety and efficacy of sunitinib in an older population are confirmed and evidence shows that age alone should not be a deterrent from attempting therapy. However, patients with brain metastases, non-clear-cell histology, and poor performance status benefit less from sunitinib, despite good drug tolerance, suggesting the need for prospective studies in these subpopulations. Thus, claiming sunitinib as a ’standard’ in these subgroups remains controversial. An oncologist might not have access to such trials in practice, however, and based on available information the use of sunitinib may be justified in these subpopulations.”

Link to article, reflection and reaction

Source
The Lancet Oncology

HOUSTON, July 16 — Patients with poor-prognosis renal cell carcinoma had an encouraging response to sunitinib (Sutent) without undue toxicity, investigators in an international clinical trial reported.

Treatment with the multitargeted receptor tyrosine kinase inhibitor resulted in an overall response rate of 17% and a median progression-free survival that approached one year, Martin E. Gore, MD, of the Royal Marsden Hospital in London, and colleagues reported in the July 16 issue of The Lancet Oncology.

The trial provided evidence that targeted therapies have activity in the types of patients who often have been excluded from clinical trials.

• Explain to patients that a therapy approved for treatment of renal cell carcinoma demonstrated activity even in patients with a poor prognosis.
• Note that patients received open-label therapy as part of an expanded-access program.

“We have shown that sunitinib is safe and toxicity manageable in subgroups of patients that might otherwise have lower tolerance to therapy,” the authors said. “Efficacy appears to be consistent with the benefits shown in prospective renal cell carcinoma studies.

“These results should encourage the study of targeted agents in subgroups of patients otherwise excluded from trials and, therefore, potentially disadvantaged,” they said.

Randomized clinical trials established sunitinib as first-line therapy for metastatic renal cell carcinoma. However, many patients seen in clinical practice often do not meet inclusion criteria for clinical trials, the authors noted.

For example, up to 20% of patients with metastatic renal cell carcinoma have brain metastases, a subgroup that has a short life expectancy and that has been poorly represented in clinical trials. Moreover, clinical trials have tended to focus on patients with clear-cell histologic, the predominant histologic subtype of renal cell carcinoma.

To determine the applicability of clinical trial results to clinical practice, investigators at 246 sites in 56 countries enrolled 4,564 patients ineligible for clinical trials in a compassionate-use program.

Treatment-experienced and treatment-naïve patients received open-label sunitinib 50 mg orally once a day on a schedule of four weeks on treatment and two weeks off.

The patient population included:

• 321 patients (7%) with brain metastases
• 582 (13%) with ECOG performance status ?2
• 588 (13%) with non-clear cell histology
• 1,418 (32%) 65 or older

Patients received a median of five cycles of therapy. About one-fourth of patients discontinued treatment because of lack of efficacy and 8% because of adverse events.

The most common treatment-related adverse events were diarrhea (44%) and fatigue (37%). The most frequent grade 3-4 adverse events were fatigue and thrombocytopenia (8% each).

The 3,464 patients evaluable for response had an overall objective response rate of 17% (603 of 3,464).

Response rates in selected subgroups included:

• 12% in patients with brain metastases
• 9% in patients with ECOG performance status ?2
• 11% in patients with non-clear cell histology
• 17% in patients age 65 or older

Median progression-free survival was 10.9 months, and median overall survival was 18.4 months.

The study confirmed the safety and efficacy of sunitinib in older patients. However, patients with brain metastases, non-clear cell histology, and poor performance status derived less benefit, authors of an accompanying commentary noted.

“Thus, claiming sunitinib as a ’standard’ in these subgroups remains controversial,” said Toni K. Choueiri, MD, of Dana-Farber Cancer Institute in Boston, and Joaquim Bellmunt, MD, of University Hospital del Mar-IMIM, in Barcelona, Spain.

“An oncologist might not have access to such trials in practice, however, and based on available information the use of sunitinib may be justified in these subpopulations.”

Pfizer funded the study. Dr. Gore and coauthors Cezary Szczylik, Georg A. Bjarnason, Se-Hoon Lee, and Patrick Schoffski disclosed relationships with Pfizer, and four other coauthors disclosed that they are Pfizer employees. Coauthor Camillo Porta disclosed relationships with Pfizer, Bayer Schering, Roche, Wyeth, and Novartis. Coauthor Sergio Bracarda disclosed relationships with Bayer, Pfizer, Roche, Wyeth, and Novartis. Stephane Oudard disclosed relationships with Bayer, Pfizer, and Wyeth. Coauthor Ronald Bukowski disclosed relationships with Pfizer, Genentech, Novartis, Wyeth, Bayer, and GlaxoSmithKline . Dr. Choueiri disclosed relationships with Novartis, Pfizer, GlaxoSmithKline , and Bayer-Onyx. Dr. Bellmunt disclosed relationships with Bayer Health Care, Pfizer, Novartis, and Wyeth.

Primary source: The Lancet Oncology

Source reference:

Gore ME et al. “Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial” Lancet Oncol 2009; DOI: 10.1016/S1470-2045(09)70162-7.

A new study by UT Southwestern Medical Center researchers sheds light on the challenges involved in identifying which high-risk population would benefit most from bladder-cancer screening.

Large-scale screening of people at high risk for developing invasive bladder cancer could result in earlier diagnosis and improved survival rates. Bladder cancer is the fourth most common cancer in men and the fifth most common cancer overall. In the early stages of the disease, it’s common to have no signs or symptoms. Smoking has been proven to increase the risk of the disease.

“At this time bladder cancer screening is not the standard of care,” said Dr. Yair Lotan, associate professor of urology and senior author of the study appearing online and in a future edition of The Journal of Urology. “Although progress has been made in diagnosis, those efforts have translated into minimal survival benefit. In order to get the most benefit from the added cost of screening, we need to identify the appropriate population to screen.”

In the study researchers used a point-of-care urine-based test called NMP22 BladderChek to screen 1,502 subjects without symptoms who are at high risk for bladder cancer based on age, smoking history and occupational exposure.

Patients for the study were recruited from well-patient clinics at UT Southwestern and the Dallas Veterans Affairs Health Care System from March 2006 to November 2007. Those selected were over 50 years old, had smoked for 10 years or more, or had worked for 15 years or more in a high-risk occupation, such as in the dye, petroleum or chemical industries. Participants with other conditions that might lead to false-positive tests were excluded from the study.

Of the 1,502 participants, 85 tested positive for proteins that indicate the possible presence of a bladder tumor; 69 of those agreed to undergo cystoscopy. Only two, however, were found to have noninvasive bladder cancer. The majority of these participants had undergone urinalysis within three years of screening. At the one-year follow-up, two more were found to have cancer, and these patients were over 60 and had more than 42 pack-years of smoking.

“We did expect to find more cases,” Dr. Lotan said. “The significance is that even with high-risk patients, only a few had cancer. What that means is we need to find a higher-risk group either by increasing screening to over the age of 60 instead of 50 or looking at individuals with a longer smoking history.”

Dr. Lotan said that abstaining from or quitting smoking is the most effective way to prevent bladder cancer and that people should see a urologist immediately if they see blood in their urine or are found to have microscopic blood in their urine.

Other UT Southwestern researchers involved in the study were Dr. Arthur Sagalowsky, professor of urology; Dr. Brett Moran, associate professor of internal medicine; Dr. Geoffrey Nuss, urology resident; Dr. Aditya Bagrodia, family practice resident; Keren Elias, research study coordinator; and Dr. Robert Svatek, a fellow in urologic oncology at UT M.D. Andersen Cancer Center.

Source:
Erin Prather Stafford

UT Southwestern Medical Center