NCCN Clinical Practice Guidelines in Oncology: 2013 Updates
At the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN), representatives of NCCN Guidelines panels presented two new sets of guidelines along with updates for several tumor types, summarized in this issue of The ASCO Post.
New NCCN Guidelines for Survivorship
“The survivorship guidelines are intended as a library of tools for a provider to use when assessing a cancer survivor.”
—Crystal S. Denlinger, MD
To better address the issues faced by cancer survivors and their families and to offer practical recommendations for clinical use, the NCCN Guidelines Panel for Survivorship Care created its inaugural practice guidelines, said Crystal S. Denlinger, MD, of Fox Chase Cancer Center, Philadelphia. Subtopics covered in the initial version of the guidelines are anxiety and depression, cognitive function, exercise, immunizations/infections, fatigue, pain, sexual function, and sleep disorders.
“These survivorship guidelines are meant to be a companion to the disease guidelines,” said Jennifer Ligibel, MD, of Dana-Farber Cancer Institute, Boston, who with Dr. Denlinger reviewed several of the topics.
The guidelines recommend physical activity and return to daily activities as soon as possible after cancer treatment, tailored to the individual’s abilities and preferences. The general recommendation is at least 150 minutes of moderate-intensity activity a week, coupled with strength training and stretching.
NCCN also includes an assessment pathway. Clinicians are advised to evaluate the patient’s risk for exercise-induced adverse events, as high-risk patients should avoid physical activity. Practical advice for specific populations (such as those with lymphedema, transplant, ostomy, peripheral neuropathy, and bone loss/metastases) is provided. The guidelines give examples of light, moderate, and vigorous exercise, and strategies to increase physical activity.
General principles about cognitive dysfunction as a complication of cancer treatment are presented, with the acknowledgement that evidence-based guidance is lacking. The guidelines include an evaluation pathway that indicates the need to screen for reversible contributing factors, specific assessments, and practical interventional strategies that center on patient/family education and counseling.
Vaccinations are encouraged based on age and medical condition as part of standard practice. Vaccines considered safe for cancer and transplant survivors include influenza, pneumonia, meningitis, and hepatitis; live attenuated vaccines such as for measles, mumps, and rubella are contraindicated or advised with caution. Patients should be vaccinated at least 3 weeks prior to initiating cancer treatment, in order to receive the full benefit of immunity. Patients should be assessed for disease status, prior and current treatments, time from treatment completion, exposure to endemic infections or epidemics, and overall immune system viability. Principles for herpes zoster (shingles) vaccination in cancer or transplant survivors are provided.
General assessments for sexual dysfunction should focus on the level of sexual activity (past and present), the impact of cancer therapy, sexual concerns or symptoms, comorbidities, risk factors, and psychosocial factors. The guidelines include validated tools for assessment: a brief sexual symptom checklist for women and a sexual health inventory for men. “We tried hard to minimize the interventions to things an oncology provider could do vs things that need to be referred,” Dr. Denlinger noted.
New NCCN Guidelines for Penile Cancer
“With 5-FU or imiquimod, you can get excellent outcomes.”
—Philippe E. Spiess, MD
New NCCN Guidelines were issued for penile cancer, which is diagnosed in about 1,250 men each year and constitutes 0.4% to 0.6% of all malignancies. Management of penile cancer has been very heterogeneous; therefore, these guidelines were clearly needed, said Philippe E. Spiess, MD, of the H. Lee Moffitt Cancer Center, Tampa, Florida.
“The standard of care in the management of primary penile tumors remains complete tumor excision and eradication with negative margins,” he said, but less invasive or even noninvasive management is sometimes appropriate.
Radical surgery (partial or total penectomy with a negative surgical margin) is the primary recommendation for invasive disease, but less invasive options can being considered based on the stage and grade of the primary penile tumor. In the new guidelines, the algorithm for primary treatment of superficial lesions (Tis or Ta) includes topical treatment with either imiquimod 5% or fluorouracil (5-FU) cream (category 2A, ie, based on lower-level evidence, with uniform NCCN consensus that the intervention is appropriate) or wide local excision with circumcision; laser therapy and complete glansectomy are less evidence-based options.
For more extensive tumors (T1), grade dictates treatment, the spectrum of which includes wide local excision, laser, radiation therapy, glansectomy, and partial/total penectomy. Penile-preserving surgery maintains function and quality of life in a select cohort of patients, but “clinical stage consideration is critical,” Dr. Spiess said. This approach is indicated only for patients with small lesions, where negative margins can be obtained.
“The treatment paradigm for bulky nodal disease is clearly evolving to a multimodal approach,” he noted. Good outcomes with neoadjuvant chemotherapy followed by surgical resection led to its recommendation as a preferred approach for palpable inguinal lymph nodes > 4 cm.
For diagnostic workup, the guidelines support the use of a nomogram to predict metastatic lymph node involvement, which outperforms the conventional clinical risk categories. Dynamic sentinel node biopsy has low sensitivity and remains an insufficient way to detect occult inguinal disease at most centers with limited experience with this technique. For patients with nonpalpable inguinal nodes considered at low risk, surveillance is indicated; inguinal lymph node dissection is recommended for those at high risk and is the gold standard for aggressive primary tumors. For palpable nodes (nonbulky disease), the size of the unilateral lymph node dictates the subsequent workup.
Nonchemotherapy Option for Acute Promyelocytic Leukemia
“For the first time, the NCCN Guidelines have taken chemotherapy out of the upfront treatment for APL.”
—Margaret R. O’Donnell, MD
The NCCN Guidelines for acute promyelocytic leukemia (APL) were changed as a result of a study presented at the 2012 Annual Meeting of the American Society of Hematology,1 which compared the gold standard for newly diagnosed non‒high-risk APL—simultaneous all-trans retinoic acid (ATRA) and chemotherapy (idarubicin)—with the chemotherapy-free combination of ATRA and arsenic trioxide (Trisenox). Complete responses were observed in 97% of each arm, but 2-year event-free survival was higher in the nonchemotherapy arm (97%) vs controls (87%).
For treatment induction of patients with low- or intermediate-risk APL, ATRA in two divided doses plus arsenic trioxide is recommended until bone marrow remission, according to Margaret R. O’Donnell, MD, of City of Hope Comprehensive Cancer Center, Duarte, California.
New Agents in Multiple Myeloma
“We have wonderful new agents, at least a log more potent than prior-generation drugs.”
—Kenneth C. Anderson, MD
Upon the approval of the second-generation proteasome inhibitor carfilzomib (Kyprolis), the guidelines for transplant candidates were updated to include the triplet of carfilzomib/lenalidomide (Revlimid)/dexamethasone as an initial treatment option under “other regimens.” This joins a growing list of triplets that greatly increase response rates, according to Kenneth C. Anderson, MD, of Dana-Farber Cancer Institute, Boston.
The 2013 update also includes carfilzomib as a preferred salvage therapy option for relapsed/refractory disease, as well as the new immunomodulatory drug pomalidomide (Pomalyst) plus low-dose dexamethasone. The improved activity and safety profiles of carfilzomib and pomalidomide over older agents in their respective classes has elicited enthusiasm about using them together, he added.
Updates in Bone Cancer
“Giant cell tumor of bone has a 2% incidence of metastasis, and that together with the significant local morbidity is why it deserves special treatment.”
—J. Sybil Biermann, MD
New treatment pathways for giant cell tumor of bone and chordoma debuted in the updated version of the guidelines for bone cancer, joining those for osteosarcoma, nonmetastatic Ewing’s sarcoma, and chondrosarcoma. These are especially important, given the rarity of these neoplasms and most clinicians’ lack of familiarity with them, said J. Sybil Biermann, MD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Although considered a benign disease, “Giant cell tumor of bone has a 2% incidence of metastasis, and that together with the significant local morbidity is why it deserves special treatment,” Dr. Biermann suggested.
Intralesional excision with the use of a high-speed burr is preferred over more extensive surgery requiring skeletal reconstruction. The typically high recurrence rate after surgery has been greatly reduced with the use of adjuvant therapy, either thermal or chemical. In patients with unresectable or recurrent tumor, denosumab (Xgeva) is active and has become an emerging component of treatment. Denosumab can help restore the skeletal architecture to allow a joint-conserving procedure, or avoidance of surgery altogether, Dr. Biermann noted.
The recommended workup includes history, physical examination, cross-sectional imaging of the primary site, chest imaging, and biopsy, with optional bone scan. For localized disease, excision is recommended; if resection carries unacceptable morbidity or the tumor is unresectable, options include serial embolization, denosumab, interferon, pegylated interferon, and/or radiotherapy (as a last resort).
Updates in Thyroid Cancer
“Two new drugs have become available for metastatic disease. These are exciting times in thyroid cancer.”
—Robert I. Haddad, MD
When thyroid cancer patients become refractory to radioactive iodine, there have been few effective treatment options, but the availability of multitargeted tyrosine kinase inhibitors is changing this. In medullary thyroid cancer, cabozantanib (Cometriq) and vandetanib (Caprelsa), both recently FDA-approved for advanced or metastatic disease, have more than doubled progression-free survival. The guidelines now list both drugs as category 1 treatments for unresectable disease that is symptomatic or asymptomatic and structurally progressive.
While not FDA-approved for thyroid cancer, other small-molecule tyrosine kinase inhibitors (sorafenib [Nexavar], sunitinib [Sutent], and pazopanib [Votrient]) can be considered, said Robert I. Haddad, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, Boston.
New Agents in Colorectal Cancer
“We had hoped ziv-aflibercept would be the next step forward, but in the registration study it provided only a 1.4-month overall survival benefit.”
—Leonard Saltz, MD
Two new agents recently approved for metastatic colorectal cancer are now included in the NCCN Guidelines: ziv-aflibercept (Zaltrap, a fusion protein that blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor) and regorafenib (Stivarga), a multikinase inhibitor. Unfortunately, while they were shown to improve overall survival, the benefit is small, according to Leonard Saltz, MD, of Memorial Sloan-Kettering Cancer Center, New York.
In the VELOUR trial, ziv-aflibercept plus FOLFIRI (leucovorin, 5-FU, irinotecan) as second-line treatment improved overall survival from 12.06 to 13.50 months (P = .0032), and progression-free survival from 4.7 to 6.9 months (P = .0007).2 This benefit is similar to what is seen when bevacizumab (Avastin) is added to chemotherapy, but the newer drug is more expensive and potentially more toxic, Dr. Saltz noted.
In the updated guidelines, ziv-aflibercept is acceptable when added to FOLFIRI or irinotecan, but should not be used as a single agent, in combination with FOLFIRI after failure of FOLFIRI-bevacizumab (or vice versa), or added to a failed regimen. Bevacizumab was also added as an option after first progression, in combination with FOLFIRI, irinotecan, FOLFOX (leucovorin, 5-FU, oxaliplatin) or CapeOx (capecitabine [Xeloda], oxaliplatin).
Regorafenib was added to the guidelines as a treatment option after first, second, or third progression, depending on previous lines of therapy, based on the 1.4-month survival advantage seen in the CORRECT trial.3
Melanoma: No Sentinel Lymph Node Biopsy for Thin Lesions
“The Panel tried to set a threshold for the practitioner, and we have said that thin melanomas do not warrant sentinel lymph node biopsy.”
—Daniel G. Coit, MD
The most recent updates in melanoma pertain not to treatment but to the diagnosis and workup of new patients, especially the indication for sentinel lymph node biopsy. According to the updated guidelines, sentinel lymph node biopsy is not warranted for thin lesions, ie, those ≤ 0 .75 mm.
“That is a big change in the guidelines,” said Daniel G. Coit, MD, of Memorial Sloan-Kettering Cancer Center, New York. Since nearly three-quarters of primary melanomas are < 1 mm, “this change in the guidelines has the potential to affect many patients,” he said.
Conventional risk factors such as ulceration, high mitotic rate, and lymphovascular invasion are quite uncommon in these very thin melanomas, but, when present, sentinel lymph node biopsy may be considered. Patients with lesions ≤ 0 .75 mm without these features can proceed to wide excision. For lesions 0.76 to 1.0 mm, a sentinel lymph node biopsy can be considered. For lesions > 1 mm, sentinel lymph node biopsy is recommended.
New Drugs in Prostate Cancer
“We have learned a lot in the past 10 years about the importance of androgen signaling, even in castration-resistant prostate cancer.”
—Philip W. Kantoff, MD
New drugs in prostate cancer take advantage of the persistence of androgen receptor expression, even in castration-resistant disease. Two drugs targeting this pathway were recently approved—abiraterone acetate (Zytiga), an androgen synthesis inhibitor, and enzalutamide (Xtandi), an antiandrogen—and these have changed the treatment landscape, said Philip W. Kantoff, MD, of the Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston.
The NCCN Guidelines include abiraterone/prednisone as a category 1 recommendation in both the pre- and postchemotherapy settings, and enzalutamide as a category 2A recommendation for docetaxel-naive men and a category 1 recommendation postchemotherapy. “These drugs have a clinically meaningful impact on survival,” Dr. Kantoff said.
Updates in Non-Hodgkin Lymphoma
“The combination of lenalidomide plus rituximab is very encouraging in relapsed/refractory follicular lymphoma.”
—Jeremy S. Abramson, MD
For follicular lymphoma that is low-grade but has a high tumor burden, the combination of bendamustine plus rituximab (Rituxan) now carries a category 2A recommendation and is expected to become a category 1 ranking (ie, based on high-level evidence) in future updates. New to the guidelines for the second-line treatment of stage I/II disease is lenalidomide with or without rituximab, which has a category 2A ranking, said Jeremy S. Abramson, MD, Massachusetts General Hospital Cancer Center, Boston.
In mantle cell lymphoma, rituximab maintenance received a category 1 recommendation following R-CHOP therapy in older adults not considered candidates for intensive therapy. For young, fit patients, the role of induction therapy with a cytarabine-containing treatment program followed by high-dose chemotherapy with autologous stem cell transplant was reviewed based on phase II and recent phase III data.
For chronic lymphocytic leukemia, first-line therapy now includes lenalidomide (continuous or intermittent dosing) as a treatment option, and bendamustine with or without rituximab. For relapsed/refractory disease, lenalidomide with or without rituximab is a treatment option. ■
Note: For a more complete listing of these and other updates, visit www.nccn.org.
Disclosure: Drs. Spiess, Denlinger, Ligiel, Saltz, Abramson, Kantoff, and Coit reported no potential conflicts of interest. Dr. Anderson is an advisor for Celgene, Onyx, Sanofi-Aventis, and Gilead; and is a scientific founder of Acetylon and OncoPep.
1. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide versus ATRA and idarubicin for newly diagnosed, non-high-risk acute promyelocytic leukemia: Results of the phase III, prospective, randomized, intergroup APL0406 study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG. Blood 120:Abstract 6, 2012.
2. Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer. J Clin Oncol 30:3499-3506, 2012.
3. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicenter, randomized, placebo-controlled, phase 3 trial. Lancet 381:303-312, 2013.