NCCN Guidelines Update: NCCN 18th Annual Conference, Advancing the Standards of Cancer Care

Evidence-Based Oncology, May/June, Volume 19, Issue SP4

At the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN), experts presented the latest updates to the NCCN Clinical Practice Guidelines in Oncology. The conference also featured 2 roundtable discussions that covered topics including cancer treatment costs, disparities in the quality and value of oncology care, the implications of big data in the field of oncology, and personalized cancer care. Here are perspectives from key opinion leaders on the NCCN Guidelines Updates.

Ovarian CancerRobert J. Morgan, MD

City of Hope Comprehensive Cancer Center

"There are no major changes to the ovarian cancer guidelines this year. The biggest management change may occur in the

coming year due to our improved understanding of the role of bevacizumab in treating recurrent epithelial ovarian cancer. The publication of the OCEANS trial resulted in an addition to the guidelines of the regimen of carboplatin/gemcitabine/bevacizumab to the list of acceptable recurrence therapies.We’ll have more clarity next year when the results of the AURELIA trial in platinum-resistant disease are published. In this trial, a progression-free survival benefit in patients with platinum-resistant disease has been reported.”

  • Bevacizumab (Avastin) currently carries a category 2B recommendation in recurrence therapy, but the results of the AURELIA trial may have an impact on clinical guidelines going forward. In frontline treatment, bevacizumab is a category 3 recommendation.
  • The new guidelines refine the guidance for physicians following patients with less-common histopathologies, including sex cord stromal tumors and germ cell tumors. Germ cell tumors, which are often seen in young people, can be exquisitely sensitive to chemotherapy. The 2013 edition of the guidelines adds published surveillance strategies for patients postchemotherapy, including a suggested follow-up regimen after completion of treatment during and after the first 5 years that specifies recommendations for performing radiographic imaging and serum tumor marker tests, for example. The recommendations for follow-up for germ cell tumors include serum tumor markers for the first 2 years after treatment is completed. They can then be omitted because virtually all of these tumors recur within that time frame if they are destined to recur. However, sex cord stromal tumors must be followed more aggressively, even following the first 5 years, due to their tendency to exhibit late recurrences.
  • Surgical treatment recommendations have also been updated.Appendectomy has been added to other reasonable surgical options in staging and debulking for both early- and late-stage disease as a strategy to optimize cytoreduction in aggressive gynecologic cancers. The definition of optimal surgical debulking is evolving.

Colorectal CancerLeonard Saltz, MD

Memorial Sloan-Kettering Cancer Center

“For the treatment of metastatic disease, 2 new drugs [zivaflibercept and regorafenib] not previously available to colorectal cancer patients have been incorporated into the guidelines, and there is 1 change of substance in how we use existing drugs. These 3 therapies all involve to some degree targeting vascularendothelial growth factor, a protein that stimulates production of new blood vessels, and all produced modest benefits. The gains we see are statistically significant, but it’s open to discussion whether they are clinically significant.”

  • Regorafenib (Stivarga) was approved by the US Food and Drug Administration following an expedited review as a single-agent, last-line salvage therapy for patients with good performance status whose cancer has progressed after treatment with all other standard therapies.
  • Bevacizumab (Avastin) is now recommended for use as a secondline therapy in combination with chemotherapy (fluoropyrimidineirinotecan or fluoropyrimidine-oxaliplatin) for the treatment of patients whose disease has progressed after a first-line program with a bevacizumab-containing regimen. Previously, the guidelines supported its use in first- or second-line therapy, but did not support its use in both first- and second-line treatments.
  • Ziv-aflibercept (Zaltrap) was added as a second-line treatment used in combination with FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) for patients whose cancer is resistant to or has progressed following treatment with a first-line oxaliplatin-containing regimen.
  • While the guidelines were changed to allow for either second-line use of bevacizumab or second-line use of ziv-aflibercept, it’s important for clinicians to understand that the data do not support using both—meaning they do not support using second-line bevacizumab and then second-line ziv-aflibercept with the same chemotherapy.Second-line use of ziv-aflibercept is an alternative option to secondline bevacizumab, but not a new treatment paradigm.
  • For earlier-stage patients, there is 1 important change to the guidelines: The guidelines allow for use of oxaliplatin in patients with stage II disease with higher risk, but this is no longer a preferred option. Instead, the guidelines now state that good-risk stage II patients should not receive oxaliplatin.

Breast CancerClifford A. Hudis, MD

Memorial Sloan-Kettering Cancer Center

“A key change in the guidelines in HER2-positive breast cancer is the incorporation of pertuzumab [Perjeta], the second monoclonal antibody targeting this receptor. A related and recent addition is ado-trastuzumab emtansine [Kadcyla, or T-DM1] for patients with tumors refractory to conventional trastuzumab. Outside of HER2-positive disease, the use of the first available agent targeting the PI3 kinase pathway, specifically the mammalian target of rapamycin (mTOR), represents a new approach to the palliative use of aromatase inhibitors. All of these changes are exciting as they suggest that ongoing translational clinical trials may lead to rapid improvements in the management of patients.”

  • Ado-trastuzumab emtansine was added as a preferred therapeutic option for the treatment of HER2-positive metastatic breast cancer, including patients who have been previously treated with trastuzumab.
  • Consider use of everolimus (Afinitor) in addition to exemestane for women with hormone receptor—positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors, based on the results of the BOLERO-2 trial.

Melanoma

Anthony J. Olszanski, MD

Fox Chase Cancer Center

“The NCCN Guidelines for melanoma are relatively mature, reflecting clinically significant updates occurring over the last 2 years, including the addition of 2 new drugs—the first to show a survival benefit in advanced disease. Ipilimumab is an immunomodulator and vemurafenib is available to patients with mutations in the BRAF gene. Data on emerging medicines is even more promising. In disease management and decision making, there is an ongoing evolution toward risk-based management as compared to stage-based management.”

  • Ipilimumab (Yervoy), vemurafenib (Zelboraf), high-dose IL-2, and clinical trials are now listed as preferred regimens in advanced disease. Patients receiving ipilimumab must be monitored for immune-mediated complications, and those taking vemurafenib, for dermatologic complications.
  • Of note, a recent trial combining ipilimumab and vemurafenibshowed signs of excessive toxicity. Combination strategies should only be attempted within a clinical trial setting.
  • Imatinib is now a potential treatment for c-KIT—mutated tumors.
  • Guideline updates clarified that routine imaging is not recommended for patients with stage I and II melanoma. The panel left the extent of imaging in patients with stage III disease to the discretion of the treating physician, given that data on its usefulness remain inconclusive.
  • The panel continues to refine the guidance on sentinel lymph node biopsies. For patients with very thin tumors (<0.76 mm), the likelihood of nodal disease is low and sentinel lymph node biopsy is not routinely recommended.
  • The panel is developing guidelines for ocular melanoma, which may be in place by 2014.

SurvivorshipCrystal S. Denlinger, MD

Fox Chase Cancer Center

“I think the most important aspect of these guidelines is that they are a first attempt to develop a standard of care and guidelines for addressing the issues of cancer survivorship that are prevalent in the cancer survivor population. The committee has developed an assessment tool for clinicians to highlight which issues are important for each patient.”

The first-ever expert and consensus-driven standardized guidelines on survivorship were published this year, defining the major issues that arise among cancer survivors and providing a framework to manage potential long-term and latent side effects of cancer and treatment. The guidelines provide screening, evaluation, and treatment recommendations for the most common issues cancer survivors face, and are to be used in the multidisciplinary care of survivors. The guidelines focus on 8 major issues: anxiety and depression, cognitive function, exercise, fatigue, immunizationand infections, pain, sexual function, and sleep disorders. The multidisciplinary team that developed the guidelines included oncologists, gynecologists, mental health professionals, infectious disease experts, exercise physiologists, and primary care nurses.

  • The NCCN defined cancer survivor as a patient diagnosed with cancer who is balancing his or her life.
  • Different from the standard NCCN Guidelines based on tumor type, these are a library of algorithms that can each be used independently.
  • The guidelines recommend periodic assessment for all survivors at regular intervals to assess disease status, performance status,medications, comorbidities, and evaluation of prior cancer and treatments.

Renal Cell CarcinomaRoberto Pili, MD

Roswell Park Cancer Institute

“The changes to the NCCN Guidelines are minor this year. There have not been any new therapies this year. We are still trying to understand how to best sequence the therapies we have already. Recent combination trials, unfortunately, have shown that these agents together are either not effective or too toxic. But other combinations and sequencing trials are under way…What is anticipated and could have an impact is the anti—PD-1 antibody that is currently in phase III. This immunotherapy appears to have significant activity in renal cell carcinoma, and hopefully we will see an anti–PD-1 approved in the future.”

  • Interferon alpha was removed as a treatment option for patients with clear cell histology who have been previously treated.
  • As a post-first-line therapy option for metastatic clear cell or nonclear cell renal cell cancer with predominantly sarcomatoid features, the chemotherapy combination of gemcitabine plus doxorubicin or gemcitabine plus capecitabine was added as a category 3 option.

Thyroid CancerRobert I. Haddad, MD

Dana-Farber Cancer Institute

“Of the 3 main types of thyroid cancer, the second most common is medullary thyroid carcinoma (MTC). [This] is where we have seen recent important advances for thyroid cancers. Medullary thyroid carcinoma has lacked any therapies, and now with 2 therapies approved, this is a really exciting advance.”

  • Molecular diagnosis of follicular and Hürthle cell neoplasms are now recommended. Particularly, several mutations, including BRAF mutations, are relevant in thyroid cancer, and testing patients for the presence of these mutations is recommended because BRAF-mutated tumors are more likely to be aggressive.Additionally, studies testing the relevancy of BRAF inhibitors for thyroid cancer in the clinic are currently enrolling patients. “Oncology in general is moving toward the genomic characterization of tumors,” said Haddad.
  • Cabozantinib (Cometriq) was added as a category 1 treatment for progressive, metastatic MTC. Vandetanib was also changed from category 2A to category 1 for the same indication.
  • The small-molecule inhibitors sorafenib and sunitinib are recommended for advanced, metastatic MTC if vandetanib,cabozantinib, or clinical trials are not available.
  • The investigative agent selumetinib, though not yet part of the guidelines, may become an important tool in the arsenal against thyroid cancer. In a small proof-of-concept study (N Engl J Med. 2013;368:623-632), selumetinib was able to reverse the resistance of advanced thyroid cancer to radioactive iodine. The role of selumetinib in advanced thyroid cancer will be tested in a large-scale phase III trial slated to start later this year.

Leukemia and LymphomaAndrew D. Zelenetz, MD, PhD

Memorial Sloan-Kettering Cancer Center

“There are exciting, emerging drugs that could well prove to be revolutionary treatments for chronic lymphocytic leukemia [CLL] and mantle cell lymphoma [MCL] in particular. Ibrutinib is an oral agent that inhibits Bruton’s tyrosine kinase…In early studies, this agent has shown a broad range of activity in B-cell lymphoma;however, the responses in CLL, MCL, and Waldenström’s macroglobulinemia have been particularly dramatic. Two other agents demonstrating substantial activity in CLL and MCL are idelalisib, an inhibitor of the delta isoform of PI3K, and ABT 199,a small-molecule inhibitor of the pro-apoptotic Bcl protein. These

small-molecule pathway inhibitors likely represent the future of treatment for these diseases.”

  • For younger patients with MCL, including high-dose cytarabine (as in R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin] or in R-HiDAC [rituximab and high-dose cytarabine]) as part of the cytoreductive therapy prior to autologous stem cell transplantation was found to produce superior overall survival (OS) benefits as compared with induction with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) alone. The finding was incorporated into the NCCN Guidelines as a recommendation for the frontline management of younger patients with MCL.
  • For older patients with MCL, treatment with R-CHOP followed by maintenance therapy with rituximab was determined to improve OS.
  • In managing CLL, there is a heightened focus on determining ageappropriate treatment by using a comorbidity score to better identify patients who are fit, and therefore eligible for chemotherapy. Patients have been broken down into the “young fit” group able to undergo treatment with the standard FCR (fludarabine, cyclophosphamide, rituximab); the “older with comorbidities” group for whom FCR is too toxic and gentler therapy such as rituximab and chlorambucil is preferred; and the “very frail patients” group of older patients whose lives are not limited by the disease.
  • In patients with previously untreated follicular lymphoma, bendamustine plus rituximab is an acceptable alternative to R-CHOP. However, the previously reported improvement in progression-free survival (PFS) and in reducing toxic effects has been called into question by a more recent study presented at the American Society of Hematology in December 2012.
  • Post-remission therapy with either radioactive antibodies or maintenance rituximab improved PFS in patients with follicular lymphoma; however, to date, there has been no impact on OS. Thus, these are listed in the NCCN Guidelines as potentially appropriate options after first-line therapy, but not required as part of standard of care.

Prostate CancerJames Mohler, MD

Roswell Park Cancer Institute

“There is still a lot of uncertainty in the development of the treatment paradigm for advanced prostate cancer. We are interested in understanding how to sequence abiraterone acetate and enzalutamide relative to older treatments—whether these should be used upfront and which one should be used first. There are also novel CYP17A1 enzyme inhibitors and antiandrogen therapies in development, and we look forward to better information on these, and how to apply these new agents in the clinic to improve survival for patients.”

  • For patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with docetaxel, both enzalutamide (Xtandi) and abiraterone acetate (Zytiga) in combination with prednisone are now category 1 treatment options.
  • For patients with asymptomatic mCRPC who have not yet been treated with chemotherapy, abiraterone is now a category 1 therapy and enzalutamide is a category 2A therapy. “In this setting, enzalutamide will most likely become category 1 as soon as the survival data from the [phase III PREVAIL trial] are published,” said Mohler.
  • In the next year, the NCCN is focusing on distinguishing adjuvant and salvage radiation, creating more precise definitions and continuing to recommend a comprehensive risk-benefit discussion with patients centered around salvage and adjuvant therapy not solely focused on PSA levels.
  • PSA monitoring is now recommended every 3 months for high-risk patients. This note is added due to the increased risk of progression for high-risk men during the first 12 months of active surveillance. The guideline also emphasizes that for men who are not high risk, frequent PSA monitoring is not necessary, as it only captures the natural variability in PSA levels.

Multiple MyelomaKenneth C. Anderson, MD

Dana-Farber Cancer Institute

“There are only a few changes in the treatment of multiple myeloma, but they’re very important ones. Within the last 7 months, 2 novel agents to treat relapsed and refractory disease have received accelerated approvals from the FDA, based on the results of phase II clinical trials. These additions represent major new treatment options and improved outlook for patients; they promise to extend the progression-free survival and overall survival of patients who previously had no other therapies.”

  • Carfilzomib (Kyprolis), a second-generation epoxyketone proteasome inhibitor that irreversibly blocks chymotryptic proteasome activity, was incorporated into the guidelines as salvage therapy. Carfilzomib was approved in July 2012 for the treatment of patients who have received at least 2 prior therapies, including treatment with bortezomib (Velcade) and an immunomodulatory therapy, and whose disease progressed on or within 60 days of the completion of the last therapy. Patient response to carfilzomib in clinical trials was durable and prolonged.
  • Pomalidomide (Pomalyst), a second-generation immunomodulatory drug that augments host antitumor immunity, was added to the guidelines as salvage therapy. Pomalidomide was approved in February 2013 for treatment of patients who have received at least 2 prior therapies, including lenalidomide (Revlimid) and bortezomib (Velcade), and whose disease progressed within 60 days of the last treatment.
  • In terms of treatment options for newly diagnosed myeloma, the combination of bortezomib with lenalidomide and dexamethasone is already included in the NCCN Guidelines. A new treatment regimen of carfilzomib in combination with lenalidomide and dexamethasone has now been added to the guidelines as a primary therapy for newly diagnosed patients. Due to the high frequency and extent of response demonstrated in newly diagnosed myeloma, this new regimen provides further evidence of the efficacy of combining a proteasome inhibitor with an immunomodulatory drug and dexamethasone as initial therapy.

Penile CancerPhilippe E. Spiess, MD

Moffitt Cancer Institute

“The penile guidelines came out because there was no consensus for treatment of penile cancer. We had experts around the world contribute to these standardized guidelines consistent with US and international practices...This year is the first time these penile cancer guidelines are published in the Journal of the National Comprehensive Cancer Network.”

  • Patients who do not have aggressive local tumors can potentially be candidates for nondebilitating surgical management of their disease, while patients with more aggressive local tumors require more aggressive resections.
  • Patients who do not have suspicious lymph nodes that are palpable are candidates for surgery.
  • “The guidelines emphasize that penile cancer patients with advanced disease greatly benefit from a multidisciplinary approach to treatment and follow-up, including the involvement of urologists and oncologists,” said Spiess.
  • The 2013 guidelines provide a more stringent consensus on the role of surveillance, including how often patients should be followed up after surgery and use of combination chemotherapy and radiotherapy.
  • While evidence for the role of PET-CT scans still requires larger prospective studies, smaller studies show that PET-CT scans may have a role in penile cancer. The guidelines cautiously state that the role of PET-CT imaging for penile cancer diagnosis and management is still evolving.
  • Many new clinical trials for penile cancer are in progress, testing therapies such as EGFR inhibitors. Enrollment in these clinicaltrials is encouraged. “I think these are ways to offer patients who have failed chemotherapy [more] treatment options. Because nonchemotherapy treatment for penile cancer is still lacking, clinical trial considerations are important for these patients,” said Spiess.

Bone CancerKenneth Hande, MD

Vanderbilt-Ingram Cancer Center

“Primary bone cancers are relatively uncommon. Recommended treatments vary depending on the type and location of the bone cancer. The most important take-home message from the recent NCCN Guidelines updates is that patients need to be treated in a center where orthopedic surgeons, radiation therapists, and medical oncologists, experienced in treatment of bone cancer, are available and working together in planning treatment. Additionally, the guidelines have been expanded to include recommendations for management of some less-common bone cancers, such as giant cell tumors of bone and chordomas.”

  • Chordoma management recommendations include extensive initial imaging of the primary site, spinal axis, chest, abdomen, and pelvis; wide excision with adequate margins; radiation therapy for lesions that are not resectable or present positive margins after surgery; and surveillance every 6 months for 5 years, and then annually, including annual cross-section abdominal imaging.
  • In treating giant cell tumors of the bone, intralesional excision with or without an effective adjuvant is considered an adequate primary treatment for resectable tumors.
  • A more detailed section on principles of radiation therapy has been added, including the recommendation that the procedure take place at the same center providing surgery and other systemic treatment, and that specialized techniques such as particle-beam radiation therapy with protons and stereotactic radiosurgery, among others, be considered in order to allow high-dose therapy while sparing normal tissue.
  • Denosumab (Xgeva) has been found to be effective in the management of giant cell tumors of bone, a disease for which there have been few treatments in patients who could not undergo surgical resection.
  • Because primary bone cancers are uncommon, these updates will not have a major impact on clinical practice. However, they should be a major aid to oncologists who do not see primary bone cancers frequently. By reading the guidelines, these oncologists should have an idea of an overall treatment strategy, but realize that input from other cancer specialists is needed to provide optimal patient care.