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Oncology Times:
doi: 10.1097/01.COT.0000383061.74286.fc
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Point-Counterpoint: Have Targeted Agents Significantly Altered the Long-Term Outcome for Patients with Advanced Hepatocellular Carcinoma?

Victorian, Brande

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NEW YORK CITY—While the incidence of hepatocellular carcinoma (HCC) in the United States and Europe is fairly low, the prevalence of the disease, which is one of the most common cancers worldwide, is steadily on the rise in this population. In response to increased incidence rates, the targeted agent sorafenib has been introduced as a promising new treatment modality, and although progress has been seen with use of the drug, the significance of its impact remains in question.

GI Malignancies Conf...
GI Malignancies Conf...
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At the Great Debates and Updates in GI Malignancies conference here, two experts in the development of novel therapies for the treatment of gastrointestinal malignancies weighed the evidence in the field and addressed that very question: Have targeted agents significantly altered long-term outcomes for patients with advanced hepatomas?

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YES

Ghassan Abou-Alfa, MD, began with a Phase II study he led at Memorial Sloan-Kettering Cancer Center (MSKCC) in which 137 patients with HCC received sorafenib at 400 mg twice per day. Although the study didn't achieve its primary endpoint, with a partial response rate of only 2.2%, the observation got the ball rolling in terms of sorafenib's effect on progression-free survival, he said.

“Despite the trials's being negative and not meeting the primary endpoint 33% of the patients had stable disease for four months. That translated into an improvement in time to progression of 4.2 months, which compares very favorably with the historical control of doxorubicin or nothing, which is 2.5 months.” Additionally, this improvement increased median survival to 9.2 months, compared with 6.5 to 7 months for doxorubicin or placebo.

The study also provided insight into sorafenib's effect on tumors, Dr. Abou-Alfa said. Looking at one patient with a peritoneal deposit from a previously resected liver hepatoma, the researchers measured the tumor's volume and found that it had necrosed. At baseline, tumor necrosis was 2%, while four months after follow-up, the tumor necrosed nearly 52%.

“With a peritoneal deposit like this, the patient is going to feel abdominal pain, but all of this patient's abdominal pain is gone, and alphafetoprotein—not necessarily endorsing it as being a true prognostic marker—dropped five-fold as well.”

When the researchers looked at the rest of the patients in the study, they saw the same effect: “We found that tumor necrosis over volume ratio, allowing for the effect that you might see, does correlate with response, and this is what we are currently trying to validate prospectively.”

GHASSAN ABOU-ALFA, M...
GHASSAN ABOU-ALFA, M...
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Same Patients Seen in the Clinic

The Phase II SHARP (Sorafenib HCC Assessment Randomized Protocol) trial by Josep M. Llovet, MD, is the most significant study looking at the targeted agent in this disease, Dr. Abou-Alfa said. The 602 patients included in the study were randomized to 400 mg of sorafenib twice daily or placebo.

The primary endpoints were overall survival and time to symptomatic progression. Median survival was 10.7 months with sorafenib vs 7.9 months for placebo.

“Clinically, this was significant enough to have the FDA approve the drug as a standard of care for unresected HCC, so we have a standard of care and this should be used as such,” he said.

The best thing about the SHARP study is that the patients included in the trial—about 33% of whom had hepatitis C; 20%, hepatitis B; and 25%, alcohol-related problems—are the patients oncologists actually see in the clinic, he said.

In a retrospective analysis of 500 patients at MSKCC, one-third had hepatitis C, and another third alcohol abuse. There were slightly more cases of hepatitis B, although that is likely a result of the large number of immigrants in the metropolitan area, Dr. Abou-Alfa noted. Moreover, about 80% of the patients saw a medical oncologist, which is similar to what was seen in SHARP.

“For the counterargument that the patients that we see in the studies don't present to us, look carefully. We are definitely seeing these patients.”

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Asia-Pacific Study

A similar trial by Cheng et al looking at the safety and efficacy of sorafenib was conducted in patients in the Asia-Pacific region. The study, published in Lancet Oncology last year (2009;10:25-34) found a survival benefit for patients treated with sorafenib—6.5 vs 4.2 months—but overall, the survival was not as long as what was seen in the SHARP study.

Citing a presentation by Dr. Llovet at last year's ASCO Annual Meeting that compared the two studies, Dr. Abou-Alfa noted that patients in the Asia-Pacific study were more ill, presenting with more ethanol abuse, more hepatic spread, and more lung metastasis. The difference is cultural, he said.

“Patients in the Asian Pacific countries stay with their hepatologists for a longer period of time and as such don't come to the medical oncologist until later in the game. They probably were able to get some improvement in outcome, but not to the same extent.”

While there are still a number of variables to assess regarding treatment with this antiangiogenic therapy, particularly how the benefits for patients with hepatitis B versus hepatitis C differ, the development of sorafenib is good news for patients, Dr. Abou-Alfa concluded.

“Sorafenib just started in 2002, and now we have a lot of drugs being tested. We're moving forward, and we're not stopping at the 10.7 months survival seen with sorafenib.”

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No

Even though there has been success with sorafenib, the benefit remains modest, Andrew X. Zhu, MD, PhD, said, beginning his argument.

“We take a lot of pride in the success of a very few examples. Everybody will probably agree that targeting the oncogene addiction has been the most successful story in oncology. If we know the specific target, we know the tumor cell is dependent on this particular target, and we can make the right drug to target this tumor.

“Unfortunately for hepatocellular carcinoma, we are just at the beginning. We don't have this kind of success yet.”

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Highly Selected Patients

It's undeniable that sorafenib works, Dr. Zhu said, also citing the SHARP study. However, the benefit is seemingly applicable only to those with a better biology and prognosis.

“The SHARP study shows that when you treat selected patients with sorafenib, the drug does improve the overall survival from 7.9 to 10.2 months, but there will be patients regardless of whether you give them the drug or not who will have a poor prognosis, and they will progress. Likewise, if you give them the drug, they will still have a long way to go. The benefit is very moderate.”

Furthermore, the patient population included in SHARP was highly selective, Dr. Zhu added. “In my clinic, this population accounts for only one-third of the patients I see.”

Rapid response to treatment was also very low, at 2% and although tumor necrosis was observed, “we don't know how to quantify tumor necrosis, and more importantly whether tumor necrosis is a valid surrogate endpoint of the overall outcome,” he said. Symptomatic improvement remains unclear as well, although patients in the study did not feel worse after treatment with sorafenib.

ANDREW X. ZHU, MD, P...
ANDREW X. ZHU, MD, P...
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Toxicities, Cost

The safety and efficacy profile of patients with underlying Child B cirrhosis remains to be assessed as well, Dr. Zhu noted. “Even though the safety profile is comparable to that of patients with underlying Child A disease, for those with underlying Child B, the length of therapy was only 50 percent of that of patients with underlying Child cirrhosis.”

Overall, the toxicities for these patients are manageable, but oncologists still need to do a better job of managing them for patients treated with this agent, he said. The hand and foot skin reaction, fatigue, and diarrhea seen in the SHARP trial can be very debilitating and even require reductions in treatment doses.

Moreover, treatment with sorafenib is costly, and if the patients being treated are not seeing a tremendous improvement in outcome, oncologists might want to think twice before subjecting patients to this treatment modality, Dr. Zhu said.

“We're not seeing the blockbuster drug that you want to see for this disease. We should make the effort in the field to really identify the predictive markers while we're assessing these agents so that we can get a better sense of who are the patients that are most likely to benefit from these drugs while being spared the toxicity and the cost.”

© 2010 Lippincott Williams & Wilkins, Inc.

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