NCCN Guidelines Updates: Solid Tumors

Ovarian Cancer

Robert J. Morgan, MD

“There are no major changes to the ovarian cancer guidelines this year,” said Robert J. Morgan, MD. “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 ofoptimal surgical debulkingis evolving.

Colorectal Cancer

Leonard Saltz, MD

“For the treatment of metastatic disease, two new drugs [ziv-aflibercept and regorafenib] not previously available to colorectal cancer patients have been incorporated into the guidelines, and there is one change of substance in how we use existing drugs,” said Leonard Saltz, MD. “These three therapies all involve to some degree targeting vascular endothelial 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 second-line therapy in combination with chemotherapy (fluoropyrimidine-irinotecan 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 second- line bevacizumab, but not a new treatment paradigm.
• For earlier-stage patients, there is one 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 Cancer

Clifford A. Hudis, MD

“A key change in the guidelines in HER2-positive breast cancer is the incorporation of pertuzumab [Perjeta], the second monoclonal antibody targeting this receptor,” said Clifford A. Hudis, MD. “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.

Renal Cell Carcinoma

Roberto Pili, MD

“The changes to the NCCN Guidelines are minor this year. There have not been any new therapies this year,” said Robert Pili, MD. “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 alfa 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 non-clear 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.

Prostate Cancer

James Mohler, MD

“There is still a lot of uncertainty in the development of the treatment paradigm for advanced prostate cancer,” said James Mohler, MD. “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 CYP-17A1 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.

Melanoma

Anthony J. Olszanski, MD

“The NCCN Guidelines for melanoma are relatively mature, reflecting clinically significant updates occurring over the last two years, including the addition of two new drugs—the first to show a survival benefit in advanced disease,” said Anthony J. Olszanski, MD. “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 vemurafenib showed 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.

Thyroid Cancer

Robert I. Haddad, MD

&ldquo;Of the three main types of thyroid cancer, the second most common is medullary thyroid carcinoma (MTC),&rdquo; said Robert I. Haddad, MD. &ldquo;[This] is where we have seen recent important advances for thyroid cancers. Medullary thyroid carcinoma has lacked any therapies, and now with two therapies approved, this is a really exciting advance.&rdquo;

• Molecular diagnosis of follicular and H&uuml;rthle 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. &ldquo;Oncology in general is moving toward the genomic characterization of tumors,&rdquo; 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 proofof- 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.

Bone Cancer

Kenneth Hande, MD

&ldquo;Primary bone cancers are relatively uncommon,&rdquo; said Kenneth Hande, MD. &ldquo;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.&rdquo;

• 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.