Conference Coverage: NCCN

Helping Cancer Patients Quit Smoking Through Counseling and Pharmacotherapy

Christina Mattina

At the 22nd Annual Conference of the National Comprehensive Cancer Network (NCCN), in Orlando, Florida, Paul M. Cinciripini, PhD, of The University of Texas MD Anderson Cancer Center, delivered a presentation on a mission he said he has spent the better part of his life working on: getting patients with cancer to quit smoking cigarettes.

Cinciripini, who serves as professor and chair for the Department of Behavioral Science as well as director of the Tobacco Treatment Program at MD Anderson, acknowledged that the audience of mainly oncologists did not need to be convinced that smoking is harmful. He discussed data which indicate over 480,000 deaths per year in the United States are attributable to cigarette smoking, and summarized the beneficial effects of cessation, including reduced depression, anxiety, and stress, along with improved positive mood and quality of life (QOL).

These outcomes, both the dangers of smoking and the benefits of cessation, are magnified in cancer patients, Cinciripini explained. Smoking during cancer treatment is associated with an increased risk of recurrence, greater symptom burden, and reduced survival. Response to radiotherapy is diminished in smokers, and they have an increased risk of pulmonary embolism, infection, and poor wound healing. Smokers also experience worsened toxicities and immune impairment while undergoing chemotherapy, and the efficacy of the treatment is diminished.

In one study, patients who quit smoking had a 78% overall survival rate 2 years after radiotherapy compared with 69% among those who continued to smoke. From a QOL perspective, cancer patients who quit smoking report easier breathing and a boost in energy. Clearly, Cinciripini said, there is a need for intervention among this population.

The most effective interventions, he explained, involve a combination of counseling and medications. Recommended first-line medications include varenicline, bupropion, and nicotine-replacement therapies like patches or gum. Cinciripini cited the EAGLES trial that found varenicline to be more effective than bupropion, nicotine patch, or placebo in patients with and without psychiatric disorders. The occurrence of severe neuropsychiatric events during treatment, including suicide, was similar across all tested therapies. Cinciripini nonetheless advised clinicians to think about the patient’s psychiatric background and history when prescribing these treatments, and to “be on the lookout for any untoward changes in their psychiatric profile.”

He then highlighted several studies demonstrating better cessation rates associated with higher intensity counseling, defined as more than 4 sessions lasting 30 to 300 minutes, compared with minimal intensity counseling. Although this more intense treatment costs more, Cinciripini explained that its increased effectiveness makes it more cost-effective. He also cited research that found a combination of intense counseling plus the introduction of nicotine replacement therapy before quitting was more effective at 16 and 26 weeks than either intervention alone.

After presenting this literature, Cinciripini discussed the NCCN clinical guidelines for smoking cessation in oncology. First, clinicians must assess patients’ nicotine dependency, history of quit attempts, and readiness to quit. If a patient is ready to quit, the clinician should involve him or her in establishing a plan and setting a quit date. If he or she is not ready, the clinician can help address concerns and suggest pharmacotherapy to reduce the number of cigarettes smoked per day. The goal of this reduction is eventually quitting, Cinciripini emphasized, not just harm reduction.

The primary recommended therapies are a combination of behavioral therapy and either nicotine replacement therapies or varenicline. If a patient succeeds in quitting, the guidelines recommend “motivational strategies for continued abstinence.” If a patient relapses, clinicians can switch the type of therapy, but must be sure to maintain consistent engagement with the patient.

Smoking cessation is “not a one and done” event, Cinciripini emphasized, and requires consistent contact and follow-up by the clinician. “If they quit, great, stay engaged. If they don’t, great, stay engaged,” he summarized. When the audience was invited to ask questions, an attendee asked Cinciripini his opinion on e-cigarettes as a form of risk mitigation, although he’d previously said he was focusing on complete cessation, not harm reduction.

“I knew I was going to get that question,” Cinciripini sighed jokingly. “The answer is, it depends.”

While there isn’t enough data to establish effectiveness and long-term safety for the devices, he said, the reduction in carcinogens makes it preferable to cigarettes and can provide an opening for patients to transition toward eliminating nicotine. Cinciripini said he would not rule out e-cigarettes as a potential tool if researchers had more data, but reiterated he was “most comfortable talking about valid nicotine therapies” as a means for cessation.

Radiation Therapy Updates for Breast Cancer in the NCCN Guidelines

Surabhi Dangi-Garimella, PhD

On the second day of the 22nd Annual Conference of the National Comprehensive Cancer Network (NCCN), in Orlando, Florida, Kilian E. Salerno, MD, of the Roswell Park Cancer Institute, walked the audience through updates to the NCCN Guidelines, explaining clinical situations in which radiation is indicated, appropriate targets of radiation treatment, and optimal approaches for minimizing toxicity.

Understanding the target area is important, Salerno said, because the treatment options and the treatment plan and delivery need to be optimized per the patient’s needs. “The target region to receive the radiation dose can vary. It might be the whole breast; partial breast, where we may target the lumpectomy cavity; the chest wall; or just regional nodes.”

The dose varies according to the target region:

1. Conventional fractionation is a dose of 1.8 to 2 Gy per fraction, for a total dose of 45 to 50.4 Gy.

2. Hypofractionation is typically a shorter course that uses larger doses per fraction. More than 2 Gy may be used per fraction to lower the total dose, which can be:

• 40.05 to 42.56 Gy given in daily fractions for whole breast radiation
• 34-38.5 Gy administered as twice daily fractions for partial breast radiation

3. The accelerated course is usually treatment over a shorter time course. Clinics have several options for the source of radiation to choose from, Salerno said. The sources of radiation include:

• External beam (photons, electrons, proton beam)
• Brachytherapy (radioactive source or catheters)
• Intraoperative devices

The NCCN Guidelines for breast cancer, updated in March 2017,¹ provide guidance on target definition and optimizing therapy for an individual patient as needed. “Greater target dose homogeneity and sparing of normal tissues can be accomplished using compensators such as wedges, forward planning using segments, and intensity-modulated radiation therapy,” the guidelines stated.

The most commonly used techniques include:

• Positioning: supine versus prone. Salerno said that the prone position is used to identify hot spots and minimize damage to normal tissue. It is most typically used for early-stage disease when the whole breast is the target, and it ensures the normal tissue is not affected.
• Computed tomography for based planning
• Three dimensionally planned conformal radiotherapy versus immune-modulated radiation therapy
• Respiratory gating, where the patient controls respiration. This technique requires extra time, personnel, planning, and time for treatment, Salerno said.

The updated guidelines also provide information on patients who have undergone breast conservation but in whom radiation therapy is contraindicated.

An absolute “No” includes:

• Pregnancy
• Diffuse suspicious or malignant-appearing microcalcifications
• Diffusely positive pathologic margins
• Homozygous for ATM mutations

Relative contraindication in case of:

• Prior radiation therapy to the chest wall or breast
• Active connective tissue disease that involves the skin
• Tumors larger than 5 cm
• Positive pathologic margins
• Women with a suspected predisposition to breast cancer

“Identifying an appropriate margin has been a topic of debate, and the new Guideline provides direction,” said Salerno. “We must remember, though, that context matters.” The following 2 recommendations have been added to the Guideline:

• 2 mm is considered an adequate margin² in ductal carcinoma in situ treated with whole-breast irradiation.
• For stage I-II invasive disease treated with whole-breast irradiation, no tumor on ink is considered an adequate margin.

Salerno then spoke about locoregional treatment of clinical stage I, IIA, or IIIB disease or node-positive disease. For negative axillary nodes, the following treatment options have been recommended:

• Radiation therapy to the whole breast, with or without boost to the tumor bed; preferably hypofractionation
• Accelerated partial breast irradiation in some low-risk patients, following guidelines defined by the American Society of Radiation Oncology, which, Salerno said, will be updated in the coming year.

She then provided insight on post-mastectomy radiation (PMRT), classic indications for which include 4 or more positive axillary lymph nodes, positive margins, and tumor size over 5 cm. However, patients with 1 to 3 lymph nodes, close margins and some high-risk features, such as age, extracapsular extension, and certain intrinsic subtypes, could also be considered for PMRT.

Regional node irradiation or RNI is recommended for those with 4 or more positive nodes, strongly considered for 1 to 3 positive nodes, and may be considered for some high-risk node negative patients.

REFERENCES

1. NCCN Guidelines for treatment of cancer by site. National Comprehensive Cancer Network website. https://www. nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed March 24, 2017.

2. Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology—American Society for Radiation Oncology–American Society of Clinical Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. J Clin Oncol. 2016;34(33):4040-4046. doi: 10.1200/JCO.2016.68.3573.

Personalized Care in Lung Cancer Is All About the Molecular Subtype

Surabhi Dangi-Garimella, PhD

At the 22nd Annual Conference of the National Comprehensive Cancer Network (NCCN), held in Orlando, Florida, Gregory J. Riely, MD, PhD, Memorial Sloan Kettering Cancer Center, spoke about the what, when, and how of biomarker testing in non—small cell lung cancer.

Biomarker testing is essential in lung cancer, Riely said, and should be done at diagnosis. “Even if it is not done at diagnosis, testing before the choice of second-line therapy is valuable as well.”

Riley showed the scanned image of the lungs of a woman who presented with an adenocarcinoma. Diagnosis of an adenocarcinoma may not be as bad as it was a decade ago, he said, adding, “We need to identify biomarkers for this, which, today, can start with molecular analysis and PD-L1 testing.”

Based on the results of the molecular analysis, the patient may receive:

• Targeted therapy if positive for EGFR, ALK, or ROS1 mutations
• Platinum-based chemotherapy if PD-L1 expression is <50%
• Pembrolizumab if PD-L1 expression is >50%

“Current NCCN Guidelines for a patient who presents with metastatic disease recommend molecular testing to establish histologic subtype, smoking cessation counseling, and palliative care. For all the various histological subtypes, molecular testing is central,” Riley said. The key thing is to conduct these tests as part of a broad molecular testing profile. An important consideration is multiplexing to be able to maximize on the small biopsy sample.

Molecular testing for lung cancer has focused on DNA-based tests like sequencing and fluorescence in situ hybridization, known as FISH. But over the past few years, protein tests have grown in usage, primarily immunohistochemistry.

Riley then shared phase 3 results from the KEYNOTE-024 trial that were presented at the annual meeting of the European Society for Medical Oncology last year and published in the New England Journal of Medicine, which showed that pembrolizumab was effective in advanced lung cancer, compared with platinum-based chemotherapy, when PD-L1 was expressed in at least 50% of tumor cells.¹

“However, PD-L1 tests are all over the map, so how do you choose?” asked Riley. The fact that each PD-1 inhibitor introduced and approved has developed a complementary assay to test PD-L1 expression in the tumor samples makes it challenging to figure out how all these tests compare.

A recently published study in JAMA Oncology compared 4 such PD-L1 assays, and found that while the tests were analytically interchangeable, they had not been cross-validated. Further, only 3 of the 4 assays were concordant and reproducible.²

An important point that Riley noted during his presentation was that PD-L1 expression is probably stable and there is no clear benefit to repeat a biopsy unless the prior sample is exhausted.

It’s also important, to customize biomarker testing needs based on the institution.

“Often, institutions use a combination of tactics to achieve comprehensive evaluation in a timely manner,” Riley said.

REFERENCES

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.

2. Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non—small cell lung cancer [published online March 9, 2017]. JAMA Oncol. 2017. doi: 10.1001/jamaoncol.2017.0013.

Multigene Panels Important for Precision Cancer Care; Variance and Coverage Barriers Remain

Surabhi Dangi-Garimella, PhD

While we have long forgotten the Mendelian models and single-gene testing panels in the field of oncology, we have not yet reached agnostic testing or population screening for cancer—although we are headed in that direction, according to Kenneth Offit, MD, MPH, from Memorial Sloan Kettering Cancer Center (MSKCC).

Speaking at the 22nd Annual Conference of the National Comprehensive Cancer Network held in Orlando, Florida, Offit explained that hereditary factors are responsible for 16% of cancers, behind smoking (33%) and obesity (20%). Paying attention to these known risk factors of cancer can reduce the possibility of cancer-related deaths by 60%.

The Utah genealogical experiment led to the discovery of the BRCA gene and its importance in familial cancers, Offit explained, and paved the way for the role of BRCA in cancer development among Ashkenazi Jewish women.¹ While a single BRCA1 mutation has been noted in 20% of Ashkenazi Jewish women with early onset breast cancer; add to that a frameshift mutation in BRCA2 could lead to 25% of all early-onset breast cancer cases in Ashkenazi Jewish women who have a personal or family history of ovarian cancer.

Knowledge of personal and inherited predisposition to mutations can help oncologists device a more informed approach to treatment decisions.

A more recent study, published in JAMA Oncology, followed BRCA1-positive women and found they have an increased risk of serous or serous-like endometrial cancer.² These findings bring into perspective the need to discuss the advantages of preventive hysterectomy in these women, Offit explained. In the case of familial adenomatous polyposis, where a 100% penetrance of adenomas is seen, and there is a high risk of extracolonic tumors.

“If left untreated, these polyps can lead to cancer,” said Offit. “Testing for a mutation in APC becomes important, and a prophylactic colectomy may be needed in teen years.” He then provided a list of the various tumor sites and the known mutations associated with that form of cancer:

• Gastrointestinal stromal tumor (KIT)
• Thyroid (RET)
• Stomach (CDH1)
• Kidney (STK11, VHL, BHD, TS)
• Basal cell (PTCH)
• Colon (MLH1, MSH2)
• Colon (APC)
• Breast/ovary (BRCA1/2, PALB2, CHEK2)

He explained that while multiple genes may be mutated with a specific cancer type, the risks vary.

“For example, in breast cancer, mutations in BRCA1/2 have a significant bearing on the risk on developing the cancer, while mutation in ATM have a lower risk.” Despite this knowledge, the “forces of change have led to commercialization of multigene testing,” he said.

Offit explained that scientists like himself were concerned with the rate at which these tests were being developed and introduced in the market. They raised their voices through editorials and at meetings, warning against inadequate knowledge to use these panels in decision making.

About 20% to 30% of multigene panels yield variants of uncertain significance, which may not necessarily affect protein function or be clinically relevant, Offit said. This might be because not many sequencing studies have been conducted, he added.

The Prospective Registry of MultiPlex Testing or PROMPT registry,³ developed by MSKCC in collaboration with other academic research institutions and laboratories, allows patients to input information from their multiplex genetic testing and have a mutation in any gene other than BRCA1/2.

“This will provide healthcare providers and researchers better access to uncommon or rare gene variants,” Offit said.

But will payers provide coverage for these tests?

A study recently published in the Journal of the National Comprehensive Cancer Network, which conducted semi-structured interviews with 11 major US payers, found that main barriers to coverage for hereditary cancer panels included poor fit with coverage frameworks, insufficient evidence, departure from pedigree-based testing for genetic screening, and lack of clinical testing rigor.⁴

Offit concluded his talk by stating that next generation sequencing has made multigene panel testing possible. “While the time for agnostic testing may be approaching, it’s not here yet, mainly because of variance and lack of payer coverage.”

REFERENCES

1. Neuhausen S, Gilewski T, Norton L, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet. 1996;13(1):126-128.

2. Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol. 2016;2(11):1434-1440. doi: 10.1001/jamaoncol.2016.1820.

3. Prospective Registry of Multiplex Testing. PROMPT website. https://connect.patientcrossroads.org/?org=prompt. Accessed March 23, 2017.

4. Trosman JR, Weldon CB, Douglas MP, Kurian AW, Kelley RK, Deverka PA, et al. Payer coverage for hereditary cancer panels: barriers, opportunities, and implications for the precision medicine initiative. J Natl Compr Canc Netw. 2017;15(2):219-228.

Addressing the Roots of Disparities in Cancer Care: Inherent Bias, Resources, and InsuranceSurabhi Dangi-Garimella, PhD

At the 22nd Annual Conference of the National Comprehensive Cancer Network: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, held March 23-25, 2017, in Orlando, Florida, policy researchers with interest in cancer care disparities discussed the source of existing disparities and how they can be successfully addressed.

Cliff Goodman, PhD, senior vice president, The Lewin Group, led the panelists—Shauntice Allen, PhD, University of Alabama at Birmingham Comprehensive Cancer Center; Moon S. Chen, Jr, PhD, MPH, associate director for cancer control, University of California Davis Comprehensive Cancer Center; Anne Filipic, Enroll America; Edith Mitchell, MD, Sidney Kimmel Cancer Center at Jefferson; and Phyllis Pettit Nassi, MSW, Huntsman Cancer Institute at the University of Utah&mdash;through a very interesting discussion that touched on racial, gender, genomic, perspective, economic, and geographic bias.

“Disparities, even if they are not made worse by the replacement healthcare law, are at risk of getting worse,” Goodman said, addressing the panel. “What do these disparities look like? Has [the Affordable Care Act] done anything to reduce them? Financial toxicity: is it harder for certain populations? Can providers introduce bias?”

Allen, who has been diagnosed with cancer herself, said that her motivation to work in the field of cancer disparities is to show that cancer is not a death sentence. “We need to be open to having the conversation and till we are open to doing that, disparities will continue. I think there are differences in how individuals are treated and how the discussions are introduced to people,” she said.

Filipic believes that developing outreach strategies for Americans and figuring out ways to talk about the advantages of enrolling on a healthcare plan to the common man is a viable strategy.

“It is important to ensure that physicians and researchers understand how difficult it is to make it right and how bad it would be if they get it wrong,” Nassi said. “American Indians are dealing with a different health system: the Indian Health Service. This brings geography into play. We have to consider here the fact that this is a medical service that is underfunded—for every dollar they request, they get 13 cents to 24 cents.”

Mitchell explained that African American women have triple the levels of triple-negative breast cancer, so although the incidence is not high, death rate due to the genomic nature of their disease augments the death rate. “Understanding disparities in America, working with the population and understanding the genomics that defines the population, is what I do,” she explained.

Another example that Mitchell provided was of colon cancer, which has a 20% higher incidence in African Americans and a 40% higher death rate. Further, incidence is much earlier in this population. “So understanding these individuals, understanding their disease profile and treating them accordingly is important,” she added.

Mitchell emphasized the importance of having an open conversation with patients on clinical trial participation. “Don’t assume, because that can introduce bias. Open a conversation and understand what the individuals want,” she said.

Filipic said that the Affordable Care Act (ACA) tried to address these disparities. “Since the ACA was passed in 2010, over 22 million gained health coverage with the available provisions. The uninsured rate nearly halved from 2014 (about 16%) to 2016 (under 9%). Across all demographic groups, a reduction in the uninsured rate has been seen.”

“Congress will be voting on the AHCA [American Health Care Act] later today,” Filipic said. [Ed note: The new version of the AHCA passed the House and is now waiting for a vote in the Senate¹]. When questioned about her own leaning for the ACA, she said, “While I have bias, many cancer societies have expressed concerns about the AHCA. The Congressional Budget Office, which is a nonpartisan institution, has projected that 14 million would lose coverage by 2018.² Cost is king…whether it is Medicaid expansion or the tax credits that bring affordable coverage within reach. So ultimately, we are seeing that lower income and sicker individuals stand to lose in this proposal.”

“Disparities are already hard to manage, and with 14 million losing coverage will have an interesting effect on the population,” said Allen.

Nassi emphasized the importance of reaching out to community clinics that often work under constrained resources. “Those of us working within cancer systems, we forget that providers in clinics or in the community do not have the same resources. Doctors tell us ‘If we don’t treat it, we don’t look for it.’ So sometimes the bias is inherent because of financial situations.”

“One potential area of bias is who gets recruited in clinical trials. So, if a provider cannot speak the patient’s language, he may not spend the time to explain the advantages of participating in a trial or the assumption that the patient may not want to participate,” Chen said.

Tapping into her years of experience as an oncologist, Mitchell said the zip code is a good identifier of disparities. “So one of the things we need to do is give individualized medicine that is not based on where they live but what their medical status is,” she said.

Nassi explained that at Hunstman, “We are doing outreach, pushing screening, trying to educate. But the resources do not exist in the communities. Cancer centers, on the other hand, do have the resources…so we need to go to them with the resources.” She explained, however, that there need to be a plan in place after a person is diagnosed, because treating 1 individual with cancer in the American Indian community can wipe out the budget for the community.

Filipic explained that the perception of affordability is also a bias. She shared an example of a woman from a focus group conducted by Enroll America, who did not have any knowledge on the healthcare coverage options she had available on the ACA because she assumed she would not be able to afford the premium. “Many do not understand that there is affordable insurance and there are tax credits available,” she said.

“I have been a big proponent of the healthcare institution understanding the patient population—who they are and getting their community involved,” Mitchell explained. “For example, mammograms may not be covered by an individual’s insurance plan, but there may be community programs that provide free mammograms.” She added that her institution has made it more convenient for patients receiving cancer treatment to receive their care without having to forego their work hours or income, with extended chemotherapy care on weekends and walk-in clinics with more flexible hours.

“Cancer centers need to accept this challenge of addressing disparities. Once you make the commitment, and look beyond collecting data and getting the grant, we must go to the community and see what can be done there,” said Nassi.

REFERENCES

1. Caffrey M. House Republicans pass replacement for Obamacare. The American Journal of Managed Care^® website. http://www.ajmc.com/newsroom/house-republicans-pass-replacement-for-affordable-care-act. Published April 7, 2017. Accessed April 24, 2017.

2. Caffrey M. CBO projects 24 million would lose coverage by 2026 under Republican health plan. The American Journal of Managed Care^® website. http://www.ajmc.com/newsroom/cbo-projects-24-million-would-lose-coverage-by-2026-under-republican-health-plan. Published March 13, 2017. Accessed March 23, 2017.

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