2015 NCCN Guideline Updates: New Recommendations for Clinical Practice

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.

Ovarian Cancer

Robert J. Morgan, MD

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.”

Prostate Cancer

James L. Mohler, MD

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.”

Lung Cancer

David Ettinger, MD and Gregory Kalemkerian, MD

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.

Breast Cancer

William J. Gradishar, MD

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.”

• The NCCN now considers a surgical margin to be negative when there is “no ink on the tumor.”
• The NCCN endorses the use of short-course accelerated partial breast irradiation over standard (longer) courses of whole breast radiation.
• Axillary surgery is not recommended for clinically node-negative patients meeting the criteria of ACOSOG Z0011: T1/2 tumors, one or two positive sentinel nodes only, no neoadjuvant therapy, breast-conserving therapy, and whole breast radiation planned.
• For ER-negative, HER2-positive patients with very small (≤0.5 cm) tumors and no positive nodes, adjuvant chemotherapy with trastuzumab can now be considered.
• For postmenopausal patients with metastatic ER-positive disease, the Guidelines list CDK4/6 inhibitor palbociclib plus letrozole as a new therapeutic option.
• The improvement in survival in excess of 1 year, in CLEOPATRA, established trastuzumab/pertuzumab as the legitimate first-line treatment of metastatic HER2-positive breast cancer.
• The achievement of pathologic complete response (pCR) and the meaning of this varies according to tumor type, treatment, tumor genetics, and the microenvironment, eg, tumor infiltrating lymphocytes. The ALTTO trial demonstrated that pCR does not correlate with long-term outcomes.
• For premenopausal ER-negative patients, the Guidelines now recognize that ovarian suppression with GnRH agonists given during adjuvant chemotherapy may preserve ovarian function and diminish the likelihood of amenorrhea.

Metastatic Colorectal Cancer

Axel Grothey, MD

Mayo Clinic

“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.”

• The goal in the palliative setting is to extend duration of life while maintaining quality of life. In this setting, FOLFOX, CapeOX and FOLFIRI are viewed as equivalent.
• The addition of biologics to chemotherapy has improved outcomes, but not as much as anticipated.
• Extended inhibition of the vascular endothelial growth factor (VEGF) enhances disease control. This means employing an anti-VEGF agent (bevacizumab) until progression, as maintenance therapy and beyond progression.
• The two monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are interchangeable.
• The NCCN Guidelines have strengthened the recommendation for testing patients for all RAS mutations to identify those who will benefit from agents targeting EGFR.
• Chemotherapy plus bevacizumab or plus an EGFR antibody are both viable options as first-line therapy in RAS wild-type patients, based on SWOG 80405.
• Other VEGF inhibitors—ramucirumab and ziv-aflibercept—have yielded a modest overall benefit in phase III trials but there are no compelling arguments for using these drugs over bevacizumab.
• Some patients require more active treatment initially (for instance, patients with BRAF-mutated tumors, whose prognosis is poor), and triplets (FOLFOXIRI/bevacizumab) can be useful in these circumstances.
• For refractory patients, multikinase inhibitors (regorafenib) may be a means of challenging the numerous kinases that may play a role in secondary resistance.
• On the horizon for salvage therapy is the novel oral nucleoside agent TAS- 102, which combines trifluorothymidine and tipiracil hydrochloride. In the RECOURSE study last year, a 28% reduction in mortality was observed, versus best supportive care.
• For rectal cancer, the Guidelines recommend FOLFOX and CapeOx as the preferred adjuvant treatment.

Chronic Lymphocytic Leukemia

William G. Wierda, MD, PhD

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.

Bladder Cancer

Peter E. Clark, MD

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.

Multiple Myeloma

Kenneth B. Anderson, MD

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.”

• Panobinostat/bortezomib/dexamethasone is a new Category 1 option for relapsed myeloma in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent (IMID).
• Carfilzomib/lenalidomide/dexamethasone is a new Category 1 option for relapsed myeloma and a Category 2A option as primary therapy for transplant candidates.
• The Guidelines recommend that lenalidomide plus low-dose dexamethasone, as primary therapy for non-transplant patients based on the results of the FIRST trial, should be given continuously until progression.
• The International Myeloma Working Group has listed these requirements for the diagnosis of active disease: bone marrow plasmacytosis ≥60%, abnormal free light chain ratio ≥100 (involved kappa) or <0.01 (involved lambda), focal bone marrow lesions detected by functional imaging, including PET-CT and/or MRI. The new definition will help define the subset of “smoldering myeloma” patients with a 50% change of progression within 18 months.
• Newly diagnosed patients are best served with a triplet combination of an IMID, a proteasome inhibitor and dexamethasone. Lenalidomide/ bortezomib/dexamethasone (RVD) and cyclophosphamide/ bortezomib/dexamethasone (CyBorD) generate responses in more than 90% of patients, including complete responses in more than 60%. The incorporation of a proteasome inhibitor assures that high-risk patients can have equally good outcomes as standard-risk.
• The approval of carfilzomib has enhanced outcomes seen with bortezomib, and the oral proteasome inhibitor ixazomib may be even more beneficial. Ixazomib is now being tested with lenalidomide/dexamethasone in the upfront and relapsed settings, and could be approved in 2015.
• The excellent upfront response to novel therapies has raised the question: is early transplant still warranted? Studies have generated conflicting results, but new strategies can clearly achieve an extent of response that we have not seen before. The value of transplant may be determined by the ongoing IFM/DFCI 1009 study of 1000 newly diagnosed patients.

Melanoma

John A. Thompson, MD

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.”

• The systemic therapy section of the NCCN Guidelines was significantly revised. Rather than list “preferred regimens” and “other active regimens,” the Guidelines now differentiate patients by BRAF status and offer treatment algorithms accordingly.
• The following are the current systemic options for advanced or metastatic melanoma: ipilimumab (category 1), dabrafenib plus trametinib (category 1), nivolumab (category 1), pembrolizumab, high-dose IL-2 (in select patients) and enrollment on a clinical trial. BRAF-mutant patients expected to deteriorate within 12 weeks can also be treated with vemurafenib or dabrafenib as single agents.
• A new “Principles of Immunotherapy and Targeted Therapy” section discusses the effectiveness of these novel treatments, with recommendations for managing their related toxicities.
• The Guidelines continue to emphasize that for lesions <0.75 mm thick, sentinel lymph node biopsy is generally not recommended.

Pancreatic Cancer

Margaret A. Tempero, MD

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.”

• While still yielding outcomes that are less than ideal, adjuvant therapy is clearly superior to observation and should be initiated within 4 to 12 weeks of surgery. Based on their benefit in the metastatic setting, FOLFIRINOX and gemcitabine/nab-paclitaxel are being incorporated into adjuvant trials.
• The benefit of adjuvant chemoradiation, on the other hand, has not been firmly established in clinical trials. The ongoing RTOG 0848 is examining the benefit of adding radiation after gemcitabine monotherapy in 950 patients, and may provide a clearer answer.
• In the neoadjuvant setting, FOLFIRINOX is also increasingly being used, especially to render borderline resectable disease more resectable, but an overall survival benefit has not yet been shown. Results are expected soon from studies evaluating neoadjuvant chemotherapy with and without radiation. These will provide “benchmarking data.”
• In locally advanced, unresectable disease, patients faring well on gemcitabine monotherapy generally should continue on this; radiation is not justified, based on current data. The key question is whether more effective combination chemotherapy plus radiotherapy will change outcomes, and this is under investigation.
• For metastatic disease, FOLFIRINOX has shown a substantial overall survival advantage, thought this regimen can be difficult for patients. An overall survival advantage has also been shown for gemcitabine/nabpaclitaxel. The choice between these approaches often depends on the patient’s acceptance of the different toxicity profiles.
• As alternatives to the preferred regimens of FOLFIRINOX and gemcitabine/ nab-paclitaxel (both category 1 options), the NCCN Guidelines list a number of options as alternatives: gemcitabine/capecitabine for patients not fit enough for the preferred regimens; gemcitabine/cisplatin for patients with mutations in a DNA-damaging pathway (ie, BRCA); fixed-dose gemcitabine/ docetaxel/capecitabine; and gemcitabine/erlotinib.
• Research is now focused on several promising areas: activating or “drugging” RAS (important for tumor escape), targeting the tumor microenvironment, addressing inflammation, and reprogramming the immune system.

Smoking Cessation

Peter G. Shields, MD

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.”

• Even after a cancer diagnosis, for any stage and prognosis, patients with cancer can reap the health benefits of smoking cessation. For example, in 2014, O’Malley et al studied the effects of cigarette smoking on the metabolism and effectiveness of systemic therapies for lung cancer and concluded, based on a narrow therapeutic index, that small changes in plasma concentrations may result in suboptimal therapy and poor outcomes.
• Despite the proven benefits of stopping smoking, only 50% of oncologists advise their patients to quit, and most of them do not provide steps on how to do it. The NCCN Guidelines offer physicians protocols for doing so.
• The NCCN Guidelines center the initial assessment of patient smoking around two questions: Have you ever smoked cigarettes? Do you currently smoke cigarettes or have smoked in the past 30 days? This brief assessment can be accomplished in minutes by any member of the treatment team.
• The management algorithm is specific to current versus former smokers/ recent quitters.
• Current smokers are assessed for their readiness to quit smoking and their level of nicotine dependence; the patient should be asked whether he or she is willing to make a quit attempt in the next 30 days.
• A personalized quit plan should be established, a quit date set, treatment options presented, and risk of relapse discussed. Patients at high risk for relapse may need pharmacotherapy and behavioral therapy.
• The recommended first-line pharmacologic therapy is combination NRT (lozenge, gum, inhaler, nasal spray) or varenicline (Chantix), but both importantly include behavioral therapy (individual and/or group).
• For patients not ready to quit, oncologists should begin motivational talks and review the health risks of smoking and the benefits of quitting. Smoking reduction with a quit goal, for example in 3 months, can be considered. Readiness to quit should be reassessed at each visit.

Chronic Myeloid Leukemia

Jerald P. Radich, MD*

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.}