Making Decisions About New Cancer Treatments With Limited Evidence

11/15/16

An interview with Jim C Hu, MD, MPH, urologic oncologist and director of the LeFrak Center for Robotic Surgery at NewYork-Presbyterian and Weill Cornell Medicine, New York, NY. 

Jim C Hu, MD, MPH

Prostate cancer is one of the most common forms of cancer in men around the world. In the United States, it is estimated that there will be ~180,000 new cases diagnosed in 2016 and that approximately 26,000 men will die from the disease, making it the second leading cause of cancer-related death in American men, behind only lung cancer.1 However, most men diagnosed with prostate cancer do not die from it. The American Cancer Society reports that almost 100% of men with all stages of prostate cancer survive at least 5 years, and 95% will survive 15 years.2

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While treatment options for prostate cancer, including radiation therapy, surgery, hormone therapy, and chemotherapy, are very effective, the side effects from these treatments can have a significant impact on patients’ overall quality of life. Adverse events resulting from androgen deprivation therapy may include gynecomastia, weight gain, depression, and declines in cognitive function.3 Patients who undergo prostatectomy and radiation may experience erectile dysfunction4 and incontinence,5 and these symptoms can persist in the long term.6

To avoid subjecting patients to the toxic side effects of treatment, many clinicians have begun recommending active surveillance for low-risk patients with prostate cancer.7,8 Studies have demonstrated that active surveillance can be an effective way of managing patients with prostate cancer. Though the practice has been endorsed by organizations such as the American Society of Clinical Oncology,9 some patients feel uncomfortable leaving their disease untreated,

High-intensity focused ultrasound (HIFU) has recently emerged as a treatment method for prostate cancer that can destroy cancerous tumors while also preserving quality of life. HIFU was the first ultrasound system to be approved by the US Food and Drug Administration (FDA) for the ablation of prostate tissue; however, the FDA has not explicitly approved HIFU for the treatment of prostate cancer due to insufficient data demonstrating efficacy. One recent study published in European Urology reported that HIFU effectively treated patients with prostate cancer while also preserving continence and erectile function, though the study population was small (111 patients).10

FDA spokesperson and urologist Charles Viviano, MD, PhD, said at the American Urological Association 2016 Annual Meeting (May 6-10, 2016; San Diego, CA) that “clinicians, in consultation with their patients, should decide how best to use this tool.”11 However, because many payers refuse to cover the treatment without FDA approval for prostate cancer specifically, the decision regarding whether to use this treatment is often made for them. At the same time, the lack of sufficient evidence has made many health care providers concerned about the sudden push for HIFU. 

To gain a better understanding of the data regarding HIFU and the appropriateness of its use in practice, the Journal of Clinical Pathways spoke with Jim C Hu, MD, MPH, urologic oncologist and Director of the LeFrak Center for Robotic Surgery at NewYork-Presbyterian and Weill Cornell Medicine (New York, NY). Dr Hu has extensive experience treating patients with all forms of prostate cancer and, in a Viewpoint article in Journal of the American Medical Assocation (JAMA),12 recently cautioned against using HIFU in certain patients due to the lack of supporting evidence.

HIFU has emerged as a popular new treatment approach for patients with prostate cancer. Can you explain how this technique works and summarize the data supporting this approach?

The curiosity about HIFU is due to the fact that, in contrast to traditional therapies such as radiation or surgery that treat the whole gland, it has the potential to treat only part of the gland, or partial gland ablation. In terms of data for partial gland ablation, there are few studies that have accumulated more than 1 year of follow-up. The technique requires general anesthesia, and a transrectal HIFU probe is inserted into the rectum. Ultrasound waves then travel across the rectal wall to destroy parts of the prostate that contain cancer. It may also be used to treat the entire prostate.

How does risk level influence choice of treatment in patients with prostate cancer? Is HIFU more or less appropriate for certain patient populations?

Currently, with limited information from non-industry funded sources, there are little patient selection and long-term outcomes data to guide patients and their doctors in their decision-making. Another attractive feature of HIFU is that if cancer is detected on subsequent biopsy, or a new area is found, HIFU may be repeated. In my personal opinion, HIFU is best reserved for low-volume, intermediate-risk prostate cancer, or for low-risk prostate cancer in men whose anxiety do not allow them to pursue active surveillance. For instance, we know that low-risk prostate cancer uncommonly causes problems within 10 years of diagnosis. However, men may overestimate the malignant potential and be tempted by this novel treatment.

Finally, I think HIFU is also reasonable for men in their 70s who may have ~10-year life expectancy who wish to preserve sexual function and avoid temporary incontinence. HIFU allows them a proactive way to treat the cancer in hopes of cure with the potential to avoid side effects, although data are still needed. 

What men may not realize is that they do need repeat biopsies and imaging to carefully ensure that the treated area is indeed destroyed and to ensure that cancer is eradicated. Biopsies are associated with a 2% to 3% risk of a serious infection that requires hospitalization. 

You recently co-wrote a Viewpoint in JAMA detailing some concerns you and your colleagues have about HIFU. What are some of your chief concerns? What kinds of data would you need in order to feel comfortable supporting, or advising against, the use of HIFU in patients you treat?

Chief concerns are that the FDA approved HIFU for prostate tissue ablation, but, in the real world, it is used to treat prostate cancer. Technically, without the FDA approval for prostate cancer, providers are not supposed to market its use for prostate cancer. However, I suspect that websites and marketing for this purpose is occurring. As we demonstrate in the JAMA paper12 using time-driven activity-based costing, the actual cost of HIFU is $10,685, but patients pay $25,000 out-of-pocket and few insurance companies supplement this cost. Thus, there may be conflict of interest in terms of providers who offer this treatment. While I believe that most physicians are well intentioned, it may be easier to offer a treatment with limited data for partial gland ablation and rationalize that there’s a second at-bat with repeat HIFU or falling back to whole gland treatment with radiation or surgery. However, the main limitation of HIFU is in prostate cancer imaging. Although tremendous improvements have been made in magnetic resonance imaging of the prostate, it still misses cancers, as do prostate needle biopsies. Therefore, while HIFU may be used to treat areas of known cancer within the prostate, there is definitely sampling error with current imaging and biopsy techniques. It is thus critical to study the appropriate patient and disease characteristics for HIFU and to follow these men rigorously to collect meaningful data to educate patients, providers, industry, and the FDA.

In terms of data, we need unbiased (free from industry control and support) 5-year data for preservation of urinary and sexual function, freedom from detectable cancer, and the frequency of cross-over to definitive therapy. If there is a high failure rate, then men have paid $25,000 out-of-pocket only to have more health care dollars spent to try to obtain a cure when the window of curability may have been missed. 

In that article, you also propose implementing a registry of patients who receive HIFU. How would that help to resolve some of your concerns about the limited data we have supporting HIFU? What are the challenges and limitations associated with setting up such a registry? 

Almost all studies of HIFU are single-center studies. A registry would be a nationally representative sample of observational data to study the patient and tumor characteristics that are being treated for HIFU and correlate with long-term outcomes. The challenges of setting up such a registry is the costs associated with data collection and long-term follow-up. Conscientious physicians want this data to ensure that HIFU is effective, as do men with prostate cancer and their loved ones. Although a randomized trial is the highest level of evidence in medicine, such a study is unlikely to be performed in the United States.

Additionally, many insurers currently do not cover HIFU, leading some to pursue treatment in other countries or pay for it out-of-pocket. How do you think issues of limited evidence to support a given treatment approach should be weighed against patients’ rights to have access to FDA-approved treatments? 

At present, this is definitely a patient-driven treatment, and, in the United States, we have always advocated for individual choice. However, patients may also be vulnerable to believing and choosing something that may be too good to be true. If patients cannot pay $25,000 out-of-pocket, there are certainly finance options that are being offered. Therefore, this is a true free-market approach. I am not a regulator nor am I advocating for the restriction of choice; however, I do believe that a registry, which does not interfere with patient choice or medical therapy, makes natural sense to fully detail the risks and benefits of a novel treatment that may be very appropriate to some but not to others. 

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References

1.    Key statistics for prostate cancer. American Cancer Society website. http://bit.ly/2dXF2zX. Updated March 11, 2016. Accessed October 26, 2016.

2.    Survival rates for prostate cancer. American Cancer Society website. http://bit.ly/2ebRc66. Updated March 11, 2016. Accessed October 26, 2016.

3.    Gonzalez BD, Jim HSL, Booth-Jones M, et al. Course and predictors of cognitive function in patients with prostate cancer receiving androgen-deprivation therapy: a controlled comparison. J Clin Oncol. 2015;33(18):2021-2027.

4.    Kumar RJ, Barqawi A, Crawford ED. Adverse events associated with hormonal therapy for prostate cancer. Rev Urol. 2005;(suppl 5):S37-S43.

5.    Chughtai B, Lee R, Sandhu J, Te A, Kaplan S. Conservative treatment for postprostatectomy incontinence. Rev Urol. 2013;15(2):61-66.

6.    Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med. 2013;368(5):436-445.

7.    Ercole B, Marietti SR, Fine J, Albertsen PC. Outcomes following active surveillance of men with localized prostate cancer diagnosed in the prostate specific antigen era [published online August 15, 2008]. J Urol. doi: 10.106/j.juro.2008.06.027.

8.    Roemeling S, Roobol MJ, Postma R, et al. Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance. Eur Urol. 2006;50(3):475-482.

9.    Chen RC, Rumble RB, Loblaw DA, et al. Active surveillance for the management of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol. 2016;34(18):2182-2190.

10.    Rischmann P, Gelet A, Riche B, et al. Focal high intensity focused ultrasound of unilateral localized prostate cancer: A prospective multicentric hemiablation study of 111 patients [published online October 6, 2016]. Eur Urol. doi: 10.1016/j.eururo.2016.09.039.

11.    Johnson K. New FDA-approved prostate ‘tool’: will you HIFU? Medscape website. http://www.medscape.com. Published May 8, 2016. Accessed October 30, 2016.

12.    Hu JC, Laviana A, Sedrakyan. High-intensity focused ultrasound for prostate cancer: novelty or innovation? JAMA. 2016;315(24):2659-2660.