Weighing the Pros and Cons of Extended Therapy

Weighing the Pros and Cons of Extended Therapy

Dr. Mariana Chavez MacGregor
Dr. William J. Gradishar
Dr. Michael J. Hassett
Can some patients with cancer benefit from more aggressive treatment than standard regimens? Can some patients be treated less aggressively while retaining safety and efficacy? Can the financial toxicity of some recently introduced agents be blunted or minimized? These questions and others were addressed during the Education Session on June 1, “Progress With a Price? The Pros and Cons of Extended Therapy.”

Session Chair William J. Gradishar, MD, FASCO, of Northwestern University, noted in his introduction that “the subtext of that title is that we will be looking at both the clinical aspects of the question as well as the financial aspects.”

Mariana Chavez MacGregor, MD, of The University of Texas MD Anderson Cancer Center, spoke about the clinical implications of escalating or de-escalating adjuvant therapy in HER2-positive breast cancer (BC). Anti-HER2 therapies have changed the natural history of HER2-positive BC, she said, and new agents have become a part of standard practice, leading to unprecedented improvements in outcomes, but it is still of foremost importance to optimize therapy regimens.

Trials have explored the value of escalating therapy, either with longer duration of trastuzumab therapy or the use of new agents or combinations. With 12 months of trastuzumab therapy, most patients with HER2-positive BC achieve good outcomes, but almost one-third of patients still relapse after treatment. This has prompted researchers to seek better regimens. The HERA trial compared 12 and 24 months of trastuzumab in a large group of HER2-positive patients and found no significant difference in disease-free survival (DFS) between the two regimens, with follow-up as long as 9 years after randomization.

Other HER2-targeted therapies have also been investigated in HER2-positive BC, including neratinib and pertuzumab. The U.S. Food and Drug Administration (FDA) has approved pertuzumab for use in combination with trastuzumab and chemotherapy as adjuvant treatment in patients with HER2-positive breast cancer at high risk of recurrence. The FDA also approved neratinib for extended adjuvant treatment of patients with HER2-positive breast cancer following adjuvant trastuzumab-based therapy.

A recently published ASCO Clinical Practice Guideline Focused Update addressed the selection of optimal adjuvant chemotherapy and targeted therapy for early BC.1 Dr. Chavez MacGregor was a coauthor of the update, published online last month in the Journal of Clinical Oncology. The Expert Panel preferentially supported use of pertuzumab in the node-positive, HER2-positive population, noting that a clinically insignificant absolute benefit has been observed in node-negative patients. The Panel also preferentially favored use of neratinib in patients with hormone receptor (HR)–positive and node-positive disease. Because neratinib causes substantial diarrhea, diarrhea prophylaxis must be used with this therapy.

When clinicians consider escalating treatment, Dr. Chavez MacGregor said, they should keep in mind that neratinib and pertuzumab provide modest benefits in invasive DFS, and no data on overall survival (OS) are available. These agents should be considered for use in high-risk patients, she said.

On the other side of the coin, trials have investigated de-escalating therapy in HER2-positive BC with shorter duration of trastuzumab or with less toxic regimens, especially in patients at lower levels of risk. Dr. Chavez MacGregor called attention to the PERSEPHONE trial, with results to be presented on June 4 (Abstract 506). In this randomized, phase III noninferiority trial comparing 6 versus 12 months of adjuvant trastuzumab in more than 4,000 patients, 4-year DFS was 89% in both arms (HR 1.05, 95% CI [0.88, 1.25]). The results demonstrated the noninferiority of the 6-month regimen.

Trials have also investigated less toxic regimens, including chemotherapy-free regimens. Dr. Chavez MacGregor noted the RESPECT trial, presented June 1 (Abstract 510), which assessed trastuzumab as a single agent compared with trastuzumab plus chemotherapy in elderly patients with HER2-positive invasive BC. In that trial, 3-year DFS was 89.2% with trastuzumab alone versus 94.8% with the drug-chemotherapy combination. In light of less toxicity and a better quality-of-life profile, trastuzumab monotherapy can be an option as adjuvant therapy for elderly patients with HER2-positive BC.

Dr. Chavez MacGregor said treatment algorithms will continue to change, and clinicians must learn how to optimize anti-HER2 therapy at all stages. The goals of adjuvant therapy should be to minimize recurrence risk (primarily distant recurrence), improve survival, and minimize short- and long-term toxicities.

“Identification of predictive biomarkers will help us identify which patients will receive greater benefit from our therapies, thus giving us tools to better determine if we should escalate or de-escalate anti-HER2–targeted therapies and chemotherapy,” she said. “In the absence of these biomarkers, as our treatment landscape becomes more complex, decisions regarding escalation and de-escalation of treatment will be influenced by clinical risk factors. We will use available data and make recommendations incorporating age, comorbidities, HR status, and lymph node involvement into our decision-making process.”

Dr. Gradishar spoke next, addressing similar issues with regard to extended adjuvant endocrine therapy. He noted that adjuvant endocrine therapy is the mainstay of treatment for estrogen receptor–positive, early-stage BC, and tamoxifen and aromatase inhibitors (AIs) are established standards of care. However, optimal duration of adjuvant therapy remains an important question.

Regarding the use of tamoxifen, he asked the question, “Why did we stop at 5 years?” He said early trials did not show the benefit of extending tamoxifen therapy beyond 5 years, but later trials such as ATLAS and ATTom, with longer follow-up and larger numbers of patients, began to show benefit, with improvements in survival.

By contrast, longer duration of AI therapy has not demonstrated a benefit in DFS, he said.

From the patient perspective, side effects and toxicities—including hot flashes, blood clots, and depression with tamoxifen, and joint pain, stiffness, and elevated risk of fractures with AI inhibitors—may prevent patients from starting or completing courses of therapy.

All things considered, Dr. Gradishar said, extended therapy with tamoxifen or AIs beyond 5 years can be considered. In the absence of a survival advantage, as with AIs, the decision should be selective rather than universal. Consideration should be given to how well patients tolerated the first 5 years of therapy. Other factors to be considered include the patient’s comorbidities and risk of late recurrence. Molecular assays may aid in identifying appropriate candidates, he said, and patient education to ensure compliance and ongoing assessment of adverse events is essential.

Finally, Michael J. Hassett, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, addressed concerns regarding the financial toxicity of therapies for BC and patients’ ability to afford recommended care, including adjuvant therapy for HER2-positive BC and adjuvant endocrine therapy for HR-positive BC.

Dr. Hassett noted that financial toxicity from cancer treatment includes both costs to society and costs to the patient. Societal concerns include how much is spent on BC treatments and how to determine the value of those treatments. In the United States in 2010, total expenditures for BC treatment were $16.5 billion, or 13% of all cancer spending—more than for any other cancer. That expenditure is expected to rise to more than $20 billion by 2020.

Hospitalizations and chemotherapy make up much of that cost, he said. During the first 6 months after an advanced-stage cancer diagnosis, acute hospital care accounts for 48% of total medical costs, and chemotherapy another 16%.

From the patient’s perspective, questions include how much must be paid out of pocket and how this spending affects other factors in their lives.

Health care costs are increasing for patients. Treatments themselves are getting more expensive, and cost-sharing by insurers is increasing, with higher deductibles and copays. In addition, patients are living longer and therefore incurring more health care expenses.

Costs for new cancer drugs are high and still increasing, Dr. Hassett noted. In the United States, the median monthly price for a new drug is approximately $10,000, which is more than twice what it was 20 years ago. Growth in U.S. spending on cancer drugs has increased at a compound annual growth rate of 5.3% during the past 5 years. The United States accounts for 42% of total global spend in the oncology market, which reached $100 billion in 2014.

The costs for patients lead to other problems in their lives. People with cancer are 2.65 times more likely to go bankrupt than people without cancer. High deductibles lead to delays in seeking care. Material financial hardships associated with cancer include borrowing money or going into debt, being unable to cover the costs of medical care, and making other financial sacrifices. In addition, there are psychological costs from worrying about paying medical bills.

Clinicians should bear these factors in mind when they consider escalating therapies. Extending tamoxifen therapy is relatively inexpensive, but escalating or adding a second HER2-targeted drug involves considerable additional costs.

Dr. Hassett encouraged clinicians to be alert for patients who could be at risk for financial toxicity. Relevant factors might include employment status, young age, underinsurance, and low income.

Potential resources for patients with economic distress include some pharmaceutical manufacturers’ medication assistance programs, national service organizations, local service organizations, and charities.  

–Tim Donald, ELS