NCCN Debuts Three New Sets of Guidelines

Focus on Uveal Melanoma, Cancer and HIV, Immune-Related Toxicities


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THE NATIONAL Comprehensive Cancer Network® (NCCN®) debuted three sets of completely new guidelines for treating patients with uveal melanoma, for treating patients who have cancer and the human immunodeficiency virus (HIV), and for managing immune-related toxicities. 

Cancer in People Living With HIV 

KEY POINTS of the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) on Cancer in People Living With HIV were described at the conference by Gita Suneja, MD, of Duke University School of Medicine in North Carolina. The new guidelines focus on Kaposi sarcoma and cervical cancer (considered part of the spectrum of acquired immunodeficiency syndrome [AIDS], ie, “AIDS-defining” cancers) and three other non–AIDS-defining malignancies, including anal cancer, non–small cell lung cancer, and Hodgkin lymphoma. Other cancers will be added later. 


“HIV status alone should not be used for cancer treatment decision-making.”
— Gita Suneja, MD

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“Cancer is now a leading cause of death in people living with HIV, and HIV status alone should not be used for cancer treatment decision-making,” Dr. Suneja said. 

The new NCCN Guidelines were prompted by recent surveys in which 20% to 25% of practicing oncologists said they would not treat a patient living with HIV for cancer, 70% said that guidelines for this population were insufficient, and 45% said they rarely discussed management of these patients with an HIV specialist.1 

As one of the first cancers shown to be linked to HIV infection, Kaposi sarcoma has its own set of NCCN Guidelines (AIDS-Related Kaposi Sarcoma) separate from the newly developed NCCN Guidelines for Cancer in People Living With HIV. Dr. Suneja highlighted from the latter some of the key points related to its treatment: 

  • When lesions are asymptomatic and cosmetically acceptable: antiretroviral therapy and observation 
  • When lesions become symptomatic or are cosmetically unacceptable to the patient: antiretrovirals and clinical trial participation; other acceptable treatments include topical remedies, systemic therapy, intralesional chemotherapy, radiation therapy, and local excision. 
  • When disease responds or is stable with treatment: continued antiretroviral therapy, with active surveillance, until disease progression. 

For Hodgkin lymphoma as well as cervical, anal, and lung cancers, clinicians are advised to follow algorithms already developed for persons without HIV infection, with some considerations: 

  • The ABVD regimen (doxorubicin/bleomycin/vinblastine/dacarbazine) is recommended for treating Hodgkin lymphoma in people with HIV infection, but dose reductions may be required for prolonged severe neutropenia. 
  • Women with cervical cancer should be evaluated for vulvar or anal cancer as well, both of which are also linked to human papillomavirus (HPV) infection. 
  • Patients with anal cancer should be monitored after treatment every 3 to 6 months for 3 years. 
  • Smoking cessation should be promoted, and screening according to the NCCN Guidelines for Lung Cancer Screening is recommended. 

The new guidelines also offer detailed recommendations for supportive care, including treatment of opportunistic infections and prevention of fungal infections. Multidisciplinary care is important for this population. “All people living with HIV should be co-managed by an oncologist and an HIV specialist,” Dr. Suneja emphasized. 

During cancer treatment, modification of HIV therapy may be required, particularly if it results in better tolerance of cancer treatment, higher response rates, or improved survival. Patients need more frequent monitoring for CD4-positive T-cell counts and viral load (once a month for the first 3 months and every 3 months thereafter) due to potential drug interactions that may make antiretroviral therapy less effective. Clinicians should watch for drug-drug interactions and overlapping toxicities. When cancer treatment is deemed curative, some patients might temporarily discontinue antiretroviral therapy (only if severe drug-drug interactions or overlapping toxicities are expected and no alternative antiretroviral drug is available). 

She referred clinicians to a table in the guidelines that outlines Principles of Systemic Therapy and Drug-Drug Interactions by antiretroviral drug class as well as potential clinically significant pharmacokinetic interactions. Also included are Principles of Radiation Therapy and Surgery and Principles of Supportive Care and Imaging. 

Uveal Melanoma 

UVEAL MELANOMA and cutaneous melanoma share a name, but they are very different cancers. The NCCN Guidelines for Uveal Melanoma were introduced at the conference by Christopher A. Barker, MD, of Memorial Sloan Kettering Cancer Center, New York. “It’s been recognized for some time that uveal melanoma is a distinct entity, and we have needed a set of guidelines pertaining to it,” Dr. Barker said. “These new guidelines in the management of uveal melanoma are the first pathway-based guidelines to be developed.” 


“These new guidelines in the management of uveal melanoma are the first pathway-based guidelines to be developed.”
— Christopher A. Barker, MD

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Uveal melanoma differs from cutaneous melanoma in several major ways. Its primary treatment is based on tumor size and is commonly radiotherapy rather than surgery. Mutations are important, but molecular testing is prognostic rather than predictive. Recurrences are mostly at distant metastatic sites, specifically the liver, rather than the skin or lymph nodes. 

The Collaborative Ocular Melanoma Study (COMS) was a series of landmark trials that helped define the management of primary uveal melanoma. They investigated the different strategies based on tumor size, and the findings are reflected in the new guidelines. 

The COMS small tumor trial found that growth and mortality associated with small tumors is rare.2 Characteristics that predict for tumor growth are programmed into the risk assessment3; tumors that grow are primarily treated with radiation or laser. For medium-sized tumors, the COMS trial found no difference in overall survival (approximately 80% at 5 years) between patients randomized to receive definitive plaque brachytherapy or enucleation.4 The COMS large tumor trial found no difference in survival between neoadjuvant radiotherapy followed by enucleation, or enucleation alone (approximately 60% at 5 years)5; therefore, neoadjuvant therapy is not in the recommendations. 

“In this day and age, enucleation is only being done for some large tumors,” Dr. Barker indicated. The management of primary uveal melanoma is predominantly based on the size of the tumor. Options include radiation therapy, laser therapy, and surgical removal, with some additional adjuvant options in select situations. 

“Specific genomic alterations are not associated with response to treatment, but they are associated with prognosis and the probability of metastasis,” he said. Genetic profiling, therefore, helps with risk assessment, along with clinical (T-stage and T-stage modifiers, ciliary body involvement, extraocular extension) and histopathologic (spindle vs epithelioid cell type) factors. 

The guidelines recommend surveillance according to risk for metastasis. Since recurrences are primarily in the liver, surveillance of patients with high-risk uveal melanoma should include specific imaging of that organ. For distant metastasis, no single systemic therapy has proved to be effective; therefore, clinical trial enrollment is encouraged. Liver-directed therapy may be part of managing advanced disease. 

Immunotoxicity 

IMMUNE CHECKPOINT inhibitors are revolutionizing the treatment of cancer. These agents are now approved by the U.S. Food and Drug Administration for eight different types of cancer, and more approvals are expected, including the use of immune checkpoint inhibitors in combination with other therapies. As experience is gained, a full spectrum of immune-related adverse events has been described. Some of them are rare but can be life-threatening. Many physicians and other health-care providers may be new to using these drugs, and it is important to be informed about how to recognize potential immune-related adverse events and how to manage them. 

In recognition of this need, the NCCN and ASCO collaborated on guidelines for management of immune-related toxicities. ASCO published its guidelines in February 2018.6 At the 2018 NCCN Annual Conference, John A. Thompson, MD, of Fred Hutchinson Cancer Research Center, University of Washington, Seattle, presented the new NCCN Guidelines on the recognition and Management of Immunotherapy-Related Toxicities. 


“These guidelines are based on expert opinion. There are no prospective trials on the management of immunotherapy-related adverse events."
— John A. Thompson, MD

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“Along with the good news, we have seen an emergence of a spectrum of immune-related adverse events. The common mechanism is that when these drugs “release the brakes” on the immune system, the immune system can also attack normal tissue,” he explained. 

The new set of guidelines contains a wealth of information. Immune-related toxicity can attack virtually every organ system, including dermatologic, gastrointestinal, central nervous, pancreatic, ocular, hepatic, endocrine, respiratory, and cardiac. The toxicities range from mild to severe and life-threatening. Management is based on the severity of toxicity. The pattern of onset varies, and toxicities can occur early, during treatment, and even after treatment is ended. For the full details on each toxicity, consult the new NCCN Guidelines at https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 

“These guidelines are based on expert opinion. There are no prospective trials on the management of immunotherapy-related adverse events,” he stated. 

Dr. Thompson noted that grades 3 to 5 immunotherapy-related adverse events occur with much greater frequency with cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors than with programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. Immunotherapy-related toxicity is more severe with combinations of CTLA-4 with PD-1 or PD-L1 checkpoint inhibitors than with either class of agent alone. 

Thus far, it has been difficult to identify a biomarker for response and benefit of immune checkpoint inhibitors. PD-L1 expression has been studied, but both patients who are PD-L1–positive and those who are PD-L1–negative may respond to these agents. More recently, tumor mutational burden plus PD-L1 expression has been proposed as a biomarker. The presence of tumor mutation burden-high and PD-L1–high suggests that durable clinical benefit is more likely.7 

“In certain adjuvant therapy situations, it is important to balance the risk of autoimmune toxicity vs potential anticancer effect. For patients who are on immunotherapy, have a high level of suspicion and tell your patients and caregivers what to look out for. Hold immunotherapy for most grade 2 adverse events. Stop immunotherapy for grade 3 and higher adverse events and start high-dose steroids. When toxicity reverts to grade 1 or less, resumption may be offered, but caution is advised, especially in patients with early-onset adverse events. I would not use immunotherapy in a patient with immunologic disease. Take a thorough family history and check for autoimmune disease,” he stated. ■

DISCLOSURE: Dr. Barker has received research funding paid to Memorial Sloan Kettering Cancer Center from Amgen, Bristol-Myers Squibb, and Merck and honorarium from Pfizer for participating in scientific advisory board meetings. Drs. Suneja and Thompson reported no conflicts of interest. 

REFERENCES 

1. Suneja G, Boyer M, Yehia BR, et al: Cancer treatment in patients with HIV infection and non-AIDS-defining cancers: A survey of US oncologists. J Oncol Pract 11:e380-e387, 2015

2. Collaborative Ocular Melanoma Study Group: Mortality in patients with small choroidal melanoma. COMS report no. 4. Arch Ophthalmol 115:886-893, 1997

3. Collaborative Ocular Melanoma Study Group: Factors predictive of growth and treatment of small choroidal melanoma: COMS report no. 5. Arch Ophthalmol 115:1537-1544, 1997

4. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors. COMS report no. 28. Arch Ophthalmol 124:1684- 1693, 2006

5. Hawkins BS, Collaborative Ocular Melanoma Study Group: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report no. 24. Am J Ophthalmol 138:936-951, 2004

6. Brahmer JR, Lacchetti C, Schneider BJ, et al: Management of immune-related events in patient treated with checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. February 14, 2018 (early release online)

7. Rizvi H, Sanchez-Vega F, La K, et al: Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 36:633-641, 2018.


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