In 1996, the National Comprehensive Cancer Network® (NCCN®) published its first set of Clinical Practice Guidelines in Oncology® covering eight tumor types. Guidelines are now published for more than 60 tumor types, subtypes, and topics. During the NCCN’s 27th Annual Conference, which was again held virtually, updates to the NCCN Guidelines were presented for several tumor types. We briefly described here the latest key recommendations.
Inaugural Guidelines for Ampullary Adenocarcinoma
“Ampullary adenocarcinoma may have a slightly better prognosis than pancreas cancer, but it remains a highly lethal disease.”
—Stephen W. Behrman, MD
Stephen W. Behrman, MD
Ampullary adenocarcinoma is a rare cancer that accounts for 0.2% of all gastrointestinal malignancies. There are two main histologic subtypes: intestinal, which resembles adenocarcinoma of the colon, and pancreaticobiliary, which resembles pancreatic cancer. Treatment of this cancer is based on the subtype.
The first version of the NCCN Guidelines for Ampullary Adenocarcinoma was released on March 9, 2022. Stephen W. Behrman, MD, Professor of Surgery at the University of Tennessee Health Science Center, Memphis, described ampullary adenocarcinoma at the conference and gave attendees an overview of these new recommendations. Here are some highlights from the first version of these guidelines:
- Histologic subtyping of tumors is important, and this guides treatment.
- Genetic evaluation (to identify inherited mutations) and molecular profiling of the tumor are important, as these also inform treatment selection, especially in the metastatic setting.
- Chemotherapy is based on specific subtype: for the intestinal subtype, clinicians should follow the NCCN Guidelines for Colon Cancer; for the pancreaticobiliary subtype, they should follow the NCCN Guidelines for Hepatobiliary Cancers.
- Workup of clinically suspicious ampullary neoplasms initially follows the pancreatic protocol, with esophagogastroduodenoscopy and colonoscopy as indicated.
- For localized disease, patients can proceed to surgery or can be considered for neoadjuvant systemic therapy, particularly if patients are at high risk.
- If a neoadjuvant regimen is utilized, the pathologic analysis should include a tumor regression score.
- Given the association between ampullary carcinoma and colon carcinoma, it is important that patients undergo appropriate colon cancer screening as per standard guidelines.
Colorectal Cancer Screening
“The first and most significant change in our guidelines was a lowering of the initial screening age for average-risk individuals from 50 to 45. The second biggest change is to extend the surveillance period from what was 5 to 7 years to 10 years now for patients with only one to two small tubular adenomas.”
—Reid M. Ness, MD, MPH
Reid M. Ness, MD, MPH
The NCCN Guidelines on Colorectal Cancer Screening reflect significant changes that will spare some patients unnecessary interventions and, in other cases, facilitate earlier detection of colorectal cancer. The updated recommendations were presented at the NCCN 2022 Annual Conference by Reid M. Ness, MD, MPH, Assistant Professor of Medicine at Vanderbilt-Ingram Cancer Center, Nashville.
The changes to the guidelines pertain primarily to the age at which screening is initiated and to surveillance intervals that are dependent on findings on the index colonoscopy. They include:
- For average-risk individuals, lowering the initial screening age from 50 to 45
- For persons with a first-degree relative with colorectal cancer, initiating colonoscopy beginning at age 40, or 10 years before the earliest diagnosis of colorectal cancer in the family, with surveillance at least every 5 years
- For adults whose first-degree relatives have had advanced adenomas or advanced sessile serrated polyps at any age, initiating screening at age 40, or 10 years before the earliest diagnosis of colorectal cancer in the family
- For persons with second- and third-degree relatives with colorectal cancer, initiating screening at 45, as their risk is comparable to persons with no adenomas
- For patients with one or two small tubular adenomas, extending the surveillance period from what was 5 to 7 years to 10 years now
- Shortening the time to the first surveillance exam to 6 months following resection of large adenomas or sessile serrated polyps that have unfavorable characteristics or were removed piecemeal
- Shortening the time to first surveillance to 1 year for patients found to have at least 10 adenomas or sessile serrated polyps at a single colonoscopy.
Dr. Ness explained that the impetus for lowering the initial screening age is based on well publicized trends in colorectal cancer incidence since the implementation of colorectal cancer screening in 1980. Over time, there has been a 40% reduction in colorectal cancer incidence but a rising incidence of the cancer in adults under age 50. Some screening experts argued that the cost of earlier screening would result in “unacceptably high” absolute costs, he said. “Despite these concerns, our committee felt that the cost-to-benefit trade-off was acceptable,” he said, further noting that all national colorectal cancer screening guidelines have now been “brought into accord.”
Locoregional Management of Early-Stage Breast Cancer
“For clinically N0 patients with one to two positive sentinel nodes after upfront surgery, we should be moving away from using nomogram estimations of additional nodal risk to support performing axillary dissection, since axillary radiation provides similar therapeutic outcomes with significantly less lymphedema. Instead, we should be shifting our thought process toward considering axillary radiation for all eligible patients in whom dissection is not needed for additional treatment considerations.”
—Meena S. Moran, MD
Meena S. Moran, MD
A. Marilyn Leitch, MD
The updated NCCN Guidelines for the locoregional management of early-stage breast cancer contain numerous new recommendations, especially for radiotherapy. These were presented by Meena S. Moran, MD, Professor of Therapeutic Radiology at Yale School of Medicine and Chief of the Yale Breast Radiotherapy Program for the Yale New Haven Hospital Health Care System, and A. Marilyn Leitch, MD, Professor of Surgical Oncology and the S.T. Harris Family Distinguished Chair in Breast Surgery at the University of Texas Southwestern Simmons Comprehensive Cancer Center, Dallas.
The following are the key changes for early-stage breast cancer:
- Recommendations for axillary staging have been separated for patients who undergo breast-conserving surgery vs those who undergo mastectomy, creating two individual pathways.
- For node-negative (N0) disease, internal mammary nodal irradiation should be considered when patients have centrally or medially located tumors.
- Radiotherapy recommendations for node-positive patients were also modified to reflect the benefit of whole-breast radiotherapy with inclusion of any portion of the undissected axilla at risk, with or without a boost to the tumor bed.
- Management of positive sentinel nodes after mastectomy and sentinel node biopsy remains controversial. The NCCN has omitted the inclusion axillary lymph node dissection for patients with clinically N0 T1/T2 tumors and no more than two positive nodes on sentinel lymph node biopsy for whom postmastectomy radiotherapy is planned. (The previous version stated that if a sentinel node–positive patient did not meet ACOSOG Z0011 criteria, axillary lymph node dissection was required.) Also, after mastectomy, in patients who were initially clinically N0 but are pathologically node-positive on sentinel lymph node biopsy and do not undergo axillary lymph node dissection, radiotherapy should include the undissected axilla at risk, with or without coverage of the other regional nodal basins.
- The section on neoadjuvant therapy underwent major reformatting. The assessment of complete vs partial response has been replaced with the assessment of the ability to undergo breast-conserving surgery.
- For patients with clinically or pathologically node-positive disease receiving neoadjuvant therapy and who have not undergone axillary lymph node dissection, radiation should cover the entire axilla, regardless of whether a pathologic complete response was achieved in the nodes.
- For patients with positive nodes after neoadjuvant therapy, the radiation field should cover any portion of the undissected axilla; for those who are clinically node-negative and remain pathologically node-negative following sentinel lymph node biopsy, radiation is not necessary after mastectomy.
- Repeat sentinel lymph node biopsy can be considered for patients with a local breast recurrence after breast-conserving surgery or after mastectomy.
- Specifics regarding the delivery of radiation and its sequencing with systemic therapy agents were updated.
HER2-Negative Breast Cancer
“These BRCA1/2 mutations are not frequent, but if you find these patients, a PARP [poly (ADP-ribose) polymerase] inhibitor may be something to consider. We can now make the case that more patients should be getting genetic testing.”
—William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
The systemic treatment of HER2-negative breast cancer is largely governed by whether the patient is hormone receptor–positive or –negative. In the past several years, the treatment landscape was essentially revolutionized by the emergence of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the hormone receptor–positive subset and by immunotherapy for patients with hormone receptor–negative, HER2-negative tumors. In contrast, the more recent advances have been tweaks that help escalate treatment where necessary and de-escalate it whenever possible.
Some of these small but important changes to the guidelines were reviewed at the conference by William J. Gradishar, MD, FACP, FASCO, Chief of the Division of Hematology and Oncology and the Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine and Director of Robert H. Lurie Comprehensive Cancer Center’s Maggie Daley Center for Women’s Cancer Care, Chicago.
The NCCN Guidelines for HER2-Negative Breast Cancer, focusing on systemic therapy, include the following updates:
- For HER2-negative, hormone receptor–positive, BRCA-mutated early breast cancer, adjuvant olaparib (with endocrine therapy) can be considered in patients with residual disease.
- For HER2-negative, hormone receptor–positive early breast cancer with high-risk characteristics, 2 years of adjuvant abemaciclib can be considered in conjunction with endocrine therapy.
- For triple-negative early breast cancer with high-risk characteristics, adjuvant pembrolizumab is a preferred option (following neoadjuvant pembrolizumab).
- For patients with triple-negative breast cancer and residual disease after neoadjuvant therapy, capecitabine can be useful as maintenance.
- For HER2-positive early breast cancer, adjuvant therapies listed as useful in certain circumstances include neratinib, paclitaxel/trastuzumab/pertuzumab, and ado-trastuzumab emtansine.
- For locally recurrent or metastatic HER2-negative disease, paclitaxel plus bevacizumab has been removed as an option.
- For locally recurrent or metastatic HER2-positive disease, a new second-line option, cited as “preferred,” is fam-trastuzumab deruxtecan-nxki. This drug can also be considered as first-line therapy in select patients.
Vaccination for Patients With Cancer and Cancer Survivors
“Patients with cancer are vulnerable to infection while under active treatment, as chemotherapy, radiation therapy, and immune-altering therapies can lead to neutropenia, lymphopenia, and altered immune competence. Immune deficits can persist for months or even years after treatment.”
—Maria Alma Rodriguez, MD
Maria Alma Rodriguez, MD
Maria Alma Rodriguez, MD, Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, detailed the appropriate immunization practices in these highly susceptible populations. Here are the key additions and updates to the NCCN Guidelines for Survivorship regarding immunizations and infections:
For all cancer survivors:
- Human papillomavirus (HPV) vaccine is now recommended for adults up to age 26, and not recommended after age 45.
- Hepatitis B vaccine indication has been expanded to include adults up to age 60.
- COVID-19 vaccine was added.
If some special circumstance or risk factor is present:
- Pneumococcal vaccine is recommended in immunocompromised survivors at least 19 years old.
- Herpes zoster vaccine may now be considered in survivors at least 19 years old who are or will be immune-deficient or immunosuppressed as a result of disease or therapy.
For survivors who underwent cellular therapy:
- Hepatitis A vaccine and COVID-19 vaccinations were added.
- Pneumococcal vaccine recommendations for dosing and timing were revised: one dose of the 20-valent or one dose of the 15-valent pneumococcal conjugate vaccine followed by one dose of the 23-valent pneumococcal polysaccharide vaccine at least 1 year later is recommended.
- The herpes zoster vaccine may now be considered in cellular therapy survivors at least 19 years old.
For all other survivors:
- Pneumococcal vaccine recommendations for dosing and timing have been revised: one dose of the 20-valent or one dose of the 15-valent pneumococcal conjugate vaccine followed by one dose of the 23-valent pneumococcal polysaccharide vaccine at least 1 year later is recommended.
- Hepatitis B vaccine and COVID-19 vaccines were added.
- The herpes zoster vaccine may now be considered in survivors who are at least 19 years old and who are or will be immune-deficient or immunosuppressed as a result of disease or therapy.
The commonly used live attenuated varicella vaccine (single or combined with the measles, mumps, and rubella [MMR] vaccine) is now contraindicated or to be used with caution in actively immunocompromised survivors themselves and their close contacts. Moreover, the guideline states that all live virus vaccines are contraindicated in patients with cancer and immunocompromised survivors and should be avoided as possible.
Multiple Myeloma
“A key factor in selecting therapy for multiple myeloma is whether the patient is refractory to lenalidomide.”
—Shaji K. Kumar, MD
Shaji K. Kumar, MD
Multiple new treatments have been approved for multiple myeloma in the past few years, but their optimal use is still being explored. As patients become refractory to one, then another, what is the proper sequencing? These and other questions were addressed by Shaji K. Kumar, MD, the Mark and Judy Mullins Professor of Hematologic Malignancies at the Mayo Clinic Cancer Center, Rochester, Minnesota.
Dr. Kumar indicated the following are the latest additions to the NCCN Guidelines for Multiple Myeloma:
- A new section on the management of venous thromboembolism was added. The management algorithm includes a risk-stratification scoring system (based on the IMPEDE or SAVED models) that allows for the personalization of thromboprophylaxis.
- The guidelines for relapsed disease were reorganized by early relapse (1–3 prior therapies) and late relapse (> 3 prior therapies).
For early relapse, there are new preferred options:
- Isatuximab-irfc, carfilzomib, and dexamethasone (category 1)
- Daratumumab, pomalidomide, and dexamethasone (category 1).
For previously treated patients:
- Ciltacabtagene autoleucel was added as an option for patients with at least four prior therapies that include an anti-CD38 antibody, a proteasome inhibitor and an immunomodulatory drug.
- For early relapse, selinexor, carfilzomib, plus dexamethasone was added as useful in certain circumstances; panobinostat with carfilzomib or lenalidomide plus dexamethasone was removed.
- Daratumumab, carfilzomib, lenalidomide, plus dexamethasone was added as useful in certain circumstances.
For primary treatment in transplant candidates:
- Daratumumab, carfilzomib, lenalidomide, plus dexamethasone was added as useful in certain circumstances.
For primary treatment in nontransplant patients:
- Bortezomib, lenalidomide, and dexamethasone (VRD-lite) was added as option for frail patients.
- Ixazomib became a new option for maintenance.
Relapsed/Refractory Indolent B-Cell Lymphomas
“Tazemetostat is a good option in patients who are elderly or those who do not have bulky or rapidly progressive disease, particularly those with wild-type EZH2 who may do well with responding or stable disease for a period of time.”
—Ann S. LaCasce, MD, MMSc
Ann S. LaCasce, MD, MMSc
Ariela Noy, MD
The NCCN Guidelines for B-Cell Lymphomas—in particular the indolent subtypes follicular and marginal zone lymphomas—underwent no major revisions in the past year. However, the panel made a few changes in systemic therapy for relapsed or refractory disease. These revisions were discussed at the conference by Ann S. LaCasce, MD, MMSc, and Ariela Noy, MD. Dr. LaCasce is Director of the Dana-Farber/Mass General Brigham Fellowship in Hematology/Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston. Dr. Noy is an Attending and Professor of Medicine at Memorial Sloan Kettering Cancer Center and Weill Medical College, New York.
The NCCN Guidelines now state:
- In follicular lymphoma, as a third or subsequent line of treatment, the EZH2 inhibitor tazemetostat is now an option in the elderly or unfit patient.
- In marginal zone lymphoma, Bruton’s tyrosine kinase inhibitors, lenalidomide and rituximab, and chemoimmunotherapy regimens are now “preferred” options for the second or subsequent line of therapy.
- In marginal zone lymphoma, the PI3K inhibitor umbralisib, previously a “preferred” drug in the second line and beyond, has been withdrawn by the manufacturer.
- The PI3K inhibitors idelalisib and duvelisib were removed as recommended regimens in the second-line or later treatment for follicular lymphoma and as third-line and later treatment for marginal zone lymphoma.
Cancer Screening and Surveillance Testing for Older Adult Cancer Survivors
“For cancer screening, the benefits are pretty clear. We’re looking for a lower risk of death from cancer, as well as diagnosis of cancer at an earlier stage, leading to less intensive treatments. But what are the harms? They include false-positive tests, unnecessary biopsies, incidental findings—which are more common with imaging modalities for screening—and overdiagnosis.”
—Nancy L. Keating, MD, MPH
Nancy L. Keating, MD, MPH
With regard to both cancer screening and surveillance testing in older adult cancer survivors, the recently updated NCCN Guidelines for Older Adult Oncology aim to avoid excessive screening and overdiagnosis. The recommendations take into account factors such as life expectancy, health status, and patients’ goals and values as well as individual benefit vs harm. These changes were presented by Nancy L. Keating, MD, MPH, Professor of Health Care Policy and Medicine at Harvard Medical School and a physician at Dana-Farber/Brigham and Women’s Cancer Center, Boston.
In terms of cancer screening for adult cancer survivors, the NCCN Guidelines for Older Adult Oncology incorporate life expectancy and the patient’s fitness and desire for further anticancer treatment in its recommendations:
- For patients with a life expectancy less than 10 years, discontinue routine cancer screening, as these patients are unlikely to benefit.
- For patients with a life expectancy of at least 10 years, assess the patient’s goals and values: are they consistent with the desire for anticancer treatment if cancer is detected? If no, stop cancer screening.
- If yes, is the patient’s health status such that anticancer treatment would be appropriate? If no, stop cancer screening
- If yes, and the patient is fit enough, engage in shared decision-making about risk vs benefit:
- Benefits are likely to exceed harms of screening if the patient’s risk of cancer is higher than average or life expectancy is longer.
- Benefits are unlikely to exceed harms of screening if comorbid illness increases harms associated with screening or cancer treatment, or if the patient’s risk of cancer is low.
The NCCN Guidelines approach routine surveillance testing for older adult cancer survivors with no evidence of disease in a similar fashion:
- If the patient’s life expectancy is less than 5 years, the patient is unlikely to benefit from routine surveillance testing; the recommendation is to stop routine surveillance in the absence of symptoms or exam findings.
- If the patient’s life expectancy is at least 5 years, assess the patient’s goals and values and follow the same cancer screening guidelines for adult cancer survivors.
“Here, the life expectancy cutoff is 5 years, because of the concern that patients who’ve had a history of cancer might actually be at higher risk of a cancer recurrence, so surveillance testing might be beneficial,” Dr. Keating noted. “If life expectancy is less than 5 years, patients are unlikely to benefit from surveillance testing for finding a recurrence or a new cancer, but if life expectancy is more than 5 years, then a discussion with the patient about goals and values is important.”
DISCLOSURE: Dr. Behrman, Dr. Ness, Dr. Moran, Dr. Keating, Dr. LaCasce, Dr. Noy, and Dr. Rodriguez reported no conflicts of interest. Dr. Leitch has consulted for AstraZeneca and Puma Biotechnology. Dr. Gradishar has served as a consultant or advisor to Genentech/Roche, AstraZeneca, MacroGenics, Seattle Genetics, and Merck. Dr. Kumar disclosed financial relationships with AbbVie, Amgen, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Regeneron, Roche, Sanofi-Aventis, and Takeda Pharmaceuticals North America.
