乌鸦传媒

SAN FRANCISCO -- Early response to preoperative targeted therapy for metastatic renal cell carcinoma may indicate efficacy, while treatment-induced hypertension may be another marker after surgery, researchers reported here in separate studies.

Just 5.6% of patients had a downstaging of at least 30% in tumor size on neoadjuvant vascular endothelial growth factor (VEGF) inhibitors, according to E. Jason Abel, MD, of the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues.

Those who did typically responded rapidly. Those with at least a 10% tumor shrinkage in the first 90 days went on to have a 24.3% reduction on average, while those without at least a 10% response in the early period averaged only a 10.36% shrinkage overall.

"If you don't see an early response, there is no point to continuing therapy for the primary tumor," Abel told attendees here at the Genitourinary Cancers Symposium.

In a second study reported here, new onset hypertension while taking sunitinib (Sutent) for metastatic disease (typically after surgery) was associated with substantially better overall and progression-free survival.

Developing or not developing treatment-induced hypertension wouldn't be a reason to stop the drug at this point, said Brian Rini, MD, of the Cleveland Clinic, who presented these results here and at the International Kidney Cancer Symposium last fall as well.

"I think if we understand the biology of why it happens, then we can maybe select patients," he told 乌鸦传媒.

The search for clinically-useful biomarkers "has been a holy grail for over 50 years" across cancer therapies, but especially now for expensive targeted agents, noted Nicholas J. Vogelzang, MD, medical director of the Developmental Therapeutics Committee of US Oncology, who was not involved in either study.

Hypertension is well known as a side effect of VEGF blockers, among which sunitinib is the most commonly used for metastatic kidney cancer in the U.S.

But whether it will turn out to be a good patient selection biomarker for all the various VEGF blockers remains to be seen, Vogelzang cautioned.

The link makes biological sense, since VEGF inhibition reduces nitric oxide synthase and thus likely causes vasoconstriction, Rini said.

However, while considered an "on-target" effect, the mechanism isn't entirely clear so it remains an association rather than a direct indication of efficacy like rash is for EGFR targeted therapies in other cancers, he noted.

In Rini's analysis of 455 patients from pooled phase II and III studies of sunitinib who had well controlled blood pressure initially, 81% developed a systolic pressure over 140 mm Hg and 67% developed diastolic blood pressure over 90 mm Hg while on treatment.

Treatment-induced hypertension was associated with (all P<0.001):

• Objective response of 54.8% versus 8.7% for no systolic hypertension, and 57.3% versus 24.6% for no diastolic hypertension
• Progression-free survival of 12.5 versus 2.5 months for no systolic hypertension (adjusted hazard ratio 0.241), and 13.4 versus 5.3 months for no diastolic hypertension (adjusted HR 0.553)
• Overall survival of 30.9 versus 7.2 for no systolic hypertension (adjusted HR 0.284), and 32.2 versus 14.9 months for no diastolic hypertension (adjusted HR 0.516)

Antihypertensive therapy did not affect clinical outcome.

The only adverse event associated with hypertension in the trial was kidney toxicity, though survival in this metastatic setting might not be long enough to see any related cardiovascular effects, Rini said.

Following on small case series showing a preoperative tumor downstaging effect with these drugs, Abel's group studied sequential CT scans for metastatic kidney cancer patients followed for an average of 12.6 months after starting neoadjuvant targeted therapy (most commonly sunitinib).

Most patients were treated before surgery as part of a clinical trial (35.0%), whereas the rest typically were not candidates for surgery due to other health issues, widespread or brain metastasis, or an unresectable primary tumor.

The maximum tumor response was:

• More than 30% reduction in size among 5.6%
• An 11% to 30% reduction in 35.7%
• No more than a 10% increase or decrease in size for 51.7%
• An 11% to 30% increase in tumor size among 4.2%
• An increase of more than 30% in 2.8%

The average time to maximum response was six months. Responses were similar across the different targeted therapies used in these patients.

These results affirm the clinical assumption regarding early response, Vogelzang said, calling it "useful" information for clinicians.

"Everyone has to get these drugs," he noted in an interview. But if the tumor fails to shrink in the first three months, "it may change the way you treat. You might then switch to a different drug."