Expert panel members highlight the latest NCCN guideline recommendations.
At the recent National Comprehensive Cancer Network (NCCN) 20th Annual Conference, experts discussed this year’s updates to the NCCN Clinical Practice Guidelines in Oncology. We asked NCCN panel members to highlight the latest recommendations for practicing oncologists.
City of Hope
The updated ovarian cancer treatment guidelines recommend the use of two new treatment regimens: a comparatively well-tolerated chemotherapy mixture and a first-in-class targeted therapy.
The first of those—18 weekly doses of paclitaxel at 60 mg/m2 infused over 1 hour followed by carboplatin (AUC = 2) infused over 30 minutes—now receives a category 1 recommendation as a primary chemotherapy regimen or a primary adjuvant therapy regimen for patients diagnosed with stage II to stage IV disease.
It is one of several category-1 options for such patients, but it is a particularly good option for elderly patients.
“Ovarian cancer tends to be a cancer that women develop in their 60s and 70s, and chemotherapy is not as well tolerated by patients in that age bracket as it is by the younger patients with other tumors,” said Robert J. Morgan, MD, co-director of the Gynecological Cancers Program at City of Hope and chairman of the NCCN’s ovarian cancer panel.
“Recent research has shown that this paclitaxel/carboplatin regimen is about as effective as several other alternatives but consistently and significantly less toxic. It should thus make a real difference for older patients or those with poor performance status.”
The other new treatment that appears in the updated guidelines is olaparib (Lynparza), the first poly ADP-ribose polymerase (PARP) inhibitor approved to treat any tumor. The drug is particularly active in tumors with BRCA gene mutations. The new NCCN guidelines list it as a preferred agent in the treatment of platinum-sensitive and platinum-resistant disease when FDA-approved tests show germline BRCA mutations and patients have failed on 3 or more previous regimens.
“There are few targeted therapies that have been shown to be effective in ovarian cancer,” said Morgan. He added that most other changes on this year’s guidelines are semantic improvements designed to clarify older recommendations. “It’s also rare for us to add two new regimens in 1 year, so this really constitutes a pretty exciting update.”
Roswell Park Cancer Institute
The NCCN’s new prostate cancer guidelines feature significant changes to recommendations in two treatment areas and the use of molecular biomarkers.
This year’s document rearranges the section on treating cancer that has recurred after androgen deprivation therapy and a second antiandrogen treatment. The FDA has approved several treatment options for such patients, and the guideline panel decided to bring some order to the chaos by listing treatments in preference order.
“We by no means expect every physician to start at the top of the list with each patient,” said the panel’s chairman, James L. Mohler, MD, who also chairs the Urology Department at Roswell Park Cancer Institute.
“We recognize that every patient is different, that every physician is different and that every insurer is different, but we think it’s helpful to provide one more tool for differentiating among the treatment options.”
The new guidelines are also the first to feature a section on molecular biomarkers that have proven themselves as an early detection tool and are starting to be used, in conjunction with other factors, to decide between treatment and active surveillance. This new section makes few recommendations—the tests are too new and the data too limited to support confident assertions—but it summarizes existing data and highlights concerns such as the relative lack of regulatory oversight for assay makers.
The last addition that Mohler highlighted was a discussion of the use of multiparameter magnetic resonance imaging to help with the staging and characterization of prostate cancer. Imaging can be used to stratify men who are considering active surveillance and to aid in the assessment of extracapsular extension in large or poorly differentiated prostate cancer.
“The discussions of biomarkers and imaging are very preliminary,” Mohler said. “Looking forward, I’d guess that they are the two sections where you’ll find the biggest updates next year, because there are numerous trials right now in both areas.”
Johns Hopkins Medicine and University of Michigan
Of all the updates to the NCCN guidelines, the addition of nivolumab to some non—small cell lung cancer protocols ranks among the most exciting. The new document only recommends the drug as a subsequent therapy for a small subgroup of patients, those whose squamous cell carcinomas have progressed on or after platinum-based chemotherapy and been diagnosed as performance status 0 to 2.
“The trial data we have so far only support its use in this group, but there’s obviously hope that it will prove effective in the very wide range of tumor types that express PD-L1,” said David Ettinger, MD, who is the Alex Grass Professor of Oncology at Johns Hopkins and the chair of the NCCN NSCLC Guidelines Panel.
“The other big hope is for a biomarker test that predicts responders. The current response rate is only about 20%, but it’s still the most exciting thing in years because, for those who do respond, most of those responses last for years, which is utterly unprecedented in stage IV disease.”
Ettinger highlighted one other update among the dozens to arrive over the past year, a strong recommendation that oncologists begin using next generation sequencing tests to identify a wide range of tumor mutations that can affect treatment decisions.
The guidelines for small cell lung cancer saw far fewer updates.
“Targeted therapy has not proven effective against small cell tumors in trials, so our treatment strategies often go years at a time without major changes,” said Gregory Kalemkerian, MD, the chair of the NCCN Small Cell Lung Cancer Guidelines Panel and a professor of medicine at the University of Michigan.
“We did, however, add a recommendation to consider the addition of radiation to the chest, after standard chemotherapy, for patients with extensive-stage small cell. We’re also hopeful that ongoing immunotherapy trials will demonstrate benefit for our patients.”
Kalemkerian noted that the added radiation was not curative, but 1 study had found that it was associated with a significant increase in 2-year survival.
Robert H. Lurie Comprehensive Cancer Center
“We are gaining a true appreciation that breast cancer is a complex disease. Not only are we dealing with a number of intrinsic subtypes, but we are learning that within those subtypes are smaller subsets that may require different therapies. In early-stage breast cancer, the trend is toward less invasive staging and treatment. In HER2-positive disease, duel targeting is impacting outcomes, but we are still facing the challenge of overcoming resistance to anti-HER2 agents. The fact that not all HER2-positive disease is HER2-enriched, and other subtypes can be HER2-positive, also complicates treatment selection. We think broadly about our treatments, but the reality is that intrinsic subtypes may be a little promiscuous. In advanced estrogen receptor (ER)-positive breast cancer, we still rely on multiple lines of endocrine agents alone, but we are developing agents that may combat endocrine resistance. For triple-negative disease, platinumbased therapy has proven active, but its efficacy appears to be influenced by BRCA1/2 mutation status. We are hoping that germline biomarkers will emerge to help guide treatment selection in this challenging patient subset.”
“Long-term survival for patients with metastatic colorectal cancer is not based on choice of first-line therapy, but on the incremental benefits that accrue over time using available agents. With chemotherapy alone, median overall survival never exceeded 2 years. With current strategies, we have improved median overall survival to more than 30 months. It’s not one breakthrough drug but the art of oncology that keeps our patients alive. The emphasis should be on using all the available agents, and it is the clinician’s task to apply them optimally by using ‘tools’ that can help individualize treatment.”
MD Anderson Cancer Center
The updated NCCN guidelines for chronic lymphocytic leukemia (CLL) take the treatment of the disease further into the age of targeted therapies by upgrading recommendations for the use of ibrutinib.
The Bruton’s tyrosine kinase inhibitor, which was first approved for CLL just over a year ago, rose from a “category 2A” treatment to a “category 1” treatment in relapsed or refractory CLL.
It has also become the preferred first line treatment for CLL with deletion 17p.
“Historically, the problem with using targeted treatments on CLL was the lack of good targets. It took a long time to find a vulnerability and develop a medication that could attack it, so we are very glad to finally have ibrutinib and idelalisib, which inhibits PI3-kinase,” said panel chair William G. Wierda, MD, PhD, a professor in the Department of Leukemia at MD Anderson Cancer Center.
Indeed, these drugs were the first to offer any real benefit to patients with deletion 17p. “There is no large study that demonstrates efficacy against 17p yet in the firstline setting. There’s limited first-line trial data for ibrutinib, and the results were encouraging. Also, there is significant data supporting both ibrutinib and idelalisib for relapsed deletion 17p CLL,” Wierda said. “Chemotherapy doesn’t work, so the FDA approved the indication and the panel made the first-line recommendation.”
The new guidelines also add obinutuzumab plus chlorambucil as a first-line therapy for CLL without deletion 11q or 17p in patients 70 and older, in patients with significant comorbidities and in frail patients, with significant comorbidities, who cannot tolerate purine analogs.
Indeed, the treatment now gets first preference for all such patients, though it has been removed entirely from the recommended options for younger, healthier patients. (Chemoimmunotherapy remains the preferred treatment for them, but the panel has used new study results to change preference order for several other first-line treatments in older, frailer patients.)
Looking forward, Wierda says a number of ongoing trials could produce further guideline changes, particularly trials of checkpoint inhibitors.
Vanderbilt University Medical Center
The biggest single change in the bladder cancer guidelines was the decision to upgrade maintenance Bacillus Calmette-Guérin (BCG) therapy from “optional” to “preferred” in patients who received the treatment initially.
“There wasn’t any single study that led to the decision; it was a consensus that grew slowly in response to both published studies and experiences from clinical practitioners,” said panel chairman Peter E. Clark, MD, a professor of urologic surgery at Vanderbilt University Medical Center.
The panel also removed “chemotherapy alone” from the list of recommended primary treatments for patients with extensive comorbid disease or poor performance status. The primary care guidelines for such patients now advise “TURBT alone or RT or concurrent chemoradiation.” The updated guidelines also place a greater emphasis on prescribing neoadjuvant therapy in combination with prostatectomy.
The decision to upgrade the use of BCG may suggest that immunotherapy will eventually prove a very effective weapon against bladder cancer, but trials have yet to prove it.
“A number of trials are accruing rapidly, so we may get some answers relatively soon,” said Clark. “Trial results against other tumor types suggest that immunotherapy has a lot of promise, so everyone is certainly eager to see what those trials produce.”
The most significant change to kidney cancer guidelines was the decision to add axitinib as an option for first-line therapy in patients with predominant clear cell histology.
The panel still prefers other treatments. Indeed, there are five treatments that get category 1 recommendations, while axitinib, a tyrosine kinase inhibitor, receives a category 2A recommendation, but its performance in several phase II clinical trials convinced the panel to add it to the list.
“The progression-free survival figures were very strong in both a randomized trial and a dose escalation study and it has the added benefit of comparatively mild side effects,” said panel chair Eric Jonasch, MD, a professor of genitourinary medical oncology at MD Anderson Cancer Center.
The other significant guideline change gives doctors the discretion to continue scanning high-risk patients for signs of recurrence indefinitely rather than advising them to abandon such efforts after 5 years.
Dana-Farber Cancer Institute
“With the availability of a new proteasome inhibitor, carfilzomib, and a new immunomodulatory drug, pomalidomide, the treatment of multiple myeloma has become more effective. The 2015 NCCN Guidelines provide new recommendations for their use, which, in combination with other agents, can yield response rates of 90% or so. Even more exciting are new classes of drugs on the horizon--monoclonal antibodies, immunotoxins, histone deacetylase inhibitors, and more. By end of 2015, we expect that 14 new strategies will be approved for multiple myeloma. “Myeloma has become a chronic illness in many patients. As we have more classes of novel agents, especially immunotherapies, it will become a chronic illness with curative potential.”
Seattle Cancer Care Alliance
“Immunotherapies, along with the targeted BRAF and MEK inhibitors, have dramatically improved outcomes in advanced and metastatic melanoma. The availability of these novel approaches has necessitated changes to the NCCN Guidelines. Taking into account relevant patient and disease characteristics, we can put the patient with advanced disease on the appropriate pathway for treatment, and we can suggest first- and secondline therapies. In the updated Guidelines, we have elevated the anti—PD-1 agents to the frontline setting as a preferred option because the response rates are higher and toxicity is lower than we see with ipilimumab.”
UCSF Helen Diller Family Comprehensive Cancer Center
“Pancreatic cancer remains a very difficult malignancy to treat, as the “cure rate” has not changed in decades. Even glioblastoma multiforme is a better diagnosis than pancreatic cancer. Two effective regimens—gemcitabine/ nab-paclitaxel and FOLFIRINOX—have substantially improved survival in the metastatic setting, and it is gratifying to have both these approaches to choose from. However, truly meaningful differences in outcomes will only be realized when novel strategies become available in the clinic.”
The Ohio State University Comprehensive Cancer Center
“Treating cancer patients is not simple, and smoking issues easily take second or third or fourth priority, so we wanted to come up with guidelines that would be clear, relevant, and something that could literally be done in the clinic in just a few minutes. The goals of the new NCCN Guidelines for Smoking Cessation are to establish standards of care, facilitate their implementation with clear guidelines, allow for quality-control monitoring, fill a gap among current guidelines, and ultimately improve the health of patients with cancer and their outcomes.”
Seattle Cancer Care Alliance
New guidelines for the treatment of chronic myeloid leukemia (CML) have added ponatinib to the list of recommended treatments for some patients, as well as a new page for managing the drug’s toxicity.
Ponatinib is now recommended as a possible third-line treatment in patients with T315I mutations who fail on two of three other medications: imatinib, dasatinib, and nilotinib. (The other recommended third-line treatment is the last of the three medications. Recommended fourth-line treatments are omacetaxine, hematopoietic stem cell transplantation [HSCT], or clinical trial.) Ponatinib is also recommended, among many other options, as a followup therapy for patients with T315I mutations who respond to HSCT but eventually receive positive results on qPCR tests.
Those recommendations come with a full page of guidelines that explain the risks of ponatinib and suggest strategies for minimizing them.
“Arterial and venous thrombosis and occlusions, including fatal myocardial infarction and stroke, have occurred in patients treated with ponatinib,” state the guidelines, which note that the drug is also associated with heart and liver failure.
“Monitor for evidence of thromboembolism and vascular occlusion. Monitor cardiac function. Monitor hepatic function prior to and during treatment. Interrupt or stop ponatinib immediately for vascular occlusion. Interrupt or stop ponatinib for new or worsening heart failure. Interrupt ponatinib if hepatotoxicity is suspected.”
Ponatinib is a multitargeted tyrosine-kinase inhibitor designed to work against tumors that resisted treatments such as imatinib due to T315I mutations. It was granted an accelerated approval in December 2012 by the FDA based on phase II data. However, in phase III trials, it was associated with serious blood clots and was temporarily withdrawn from the market in October 2013. Two months later, the FDA reauthorized the sale of ponatinib, with a new black box warning and a risk evaluation and mitigation strategy (REMS).
*Dr Radich did not review or contribute to this summary. He spoke on CML in a session at the 2015 NCCN Annual Meeting and is a member of the NCCN CML Guideline Panel and one of the authors of the guidelines.