Programmed death-1 (PD-1) inhibitors can play an important role in the treatment of relapsed/refractory classical Hodgkin lymphoma (HL) patients in “real-world” settings.
“In HL patients who progress after prior cytotoxic therapy, immunotherapy in a real-world setting induces outcomes that are similar to in prior clinical trials,” Steven M. Bair, MD, of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, told MedPage Today. “For those who do progress, our study shows they can respond to conventional strategies, which could provide a bridge to transplant.”
Approximately 8,260 patients are diagnosed with HL in the United States each year, according to statistics from the Leukemia & Lymphoma Society. While HL is a highly curable malignancy, 20% of patients are not able to be cured with conventional treatments. PD-1 inhibition has resulted in impressive activity in the relapsed/refractory setting, leading to FDA approval of nivolumab in 2016 and pembrolizumab in 2017, but there has been limited information on experience with these agents in HL patients outside of clinical trials.
At the American Society of Hematology (ASH) annual meeting, Bair presented a multicenter, retrospective analysis of relapsed/refractory HL patients treated with PD-1 inhibitors in a real-world setting. The study included 42 patients, median age of 34, from seven centers in the United States. At diagnosis, 60% of the patients had stage III/IV disease, half had previously undergone an autologous stem cell transplant (SCT), and 7% had prior allogeneic SCT.
Patients received a median of four lines of therapy prior to the PD-1 inhibitor; 85% had ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)/AVD as frontline therapy, and 95% had brentuximab vendotin. Nivolumab was the initial PD-1 inhibitor; three-quarters of patients received a dose of 3 mg/kg every 2 weeks. Concurrent therapies with PD-1 inhibitors were used at some point in 19% of patients.
Almost two-thirds of patients (62%) achieved an overall response to nivolumab as assessed by the treating physician, with 45% achieving a complete response (CR). The median time to best response was 3 months.
At a median follow-up of 13 months at the time of the analysis, the median progression-free survival (PFS) and overall survival (OS) had not been reached. The 12-month OS rate was 96%, and the 12-month PFS rate was 65%. The median duration of therapy was 9 months. The median duration of response in patients with CR was 13 months, and for those in partial response, 9 months.
Dose delays occurred in one-third of patients — most commonly due to toxicity, non-adherence, and patient preference, Bair reported. Dose delays did not affect PFS: Half the patients discontinued the original PD-1 inhibitor, primarily due to disease progression. Four patients died — all due to disease progression.
Among the 40 patients for whom toxicity data were available, nearly half had toxicity attributed to the PD-1 inhibitor. The most common toxicities were hypothyroidism, rash, pneumonitis/dyspnea, and colitis. Toxicities resulting in drug discontinuation included encephalitis, colitis, and skin graft-versus-host disease. Toxicities were managed with systemic steroids, thyroid replacement, drug discontinuation, dose delay, or local steroid therapy. There were no treatment-related deaths.
In the 21 patients who discontinued PD-1 inhibitor therapy, two-thirds had subsequent systemic therapies and 12 were evaluable for response. A clinical benefit of systemic therapy was seen immediately after PD-1 inhibitor therapy in 75% of patients, with five responding to cytotoxic chemotherapies.
“Patients can respond after failing initial therapy,” Bair said. “The thought is that checkpoint inhibitors sensitize tumors to cytotoxic therapy.”
In another presentation at ASH17, French researchers hypothesized that anti-PD-1 therapy may increase sensitivity to chemotherapy given after anti-PD-1 therapy (sequential strategy) or in combination with anti-PD-1 therapy after an unsatisfactory response to immunotherapy (concomitant strategy). The retrospective analysis of 30 relapsed/refractory HL patients showed that patients with an unsatisfactory response or progressive disease with anti-PD-1 therapy had a new objective response with chemotherapy alone (61%) or chemotherapy in combination with anti-PD-1 therapy (90%). This response could make some patients eligible for allograft, the researchers suggested.
“This is the first multi-center retrospective analysis to describe the real-world experience with PD-1 inhibitors in HL patients in the United States. There was good concordance in a real-world setting with clinical trials in terms of overall response rate, survival, and the toxicity profile in general,” Bair said, noting that the patterns of discontinuation and dose delays did not affect outcomes.
“Systemic therapies after PD-1 inhibitor discontinuation appear to be active. Our results support the important role of PD-1 inhibitor therapy in relapsed/refractory HL and provide insight into practice patterns,” he continued. “When HL patients fail cytotoxic therapy, they have an option of salvage immunotherapy.”
Researchers are now exploring further regimens, sequences, and combinations with immunotherapy and cytotoxic therapy that could be a bridge to transplant, Bair noted. “We have a possible paradigm to treat HL that is progressing rapidly, and are also starting to see immunotherapy move into the frontline setting in HL.”
Doctors all over the world have been struggling to find the best possible treatment for cancer for decades. The Stanford University School of Medicine is now conducting a study for a new cancer vaccine.
What happened after that was amazing. They used 90 mice in the trial and they cured 87 successfully. Levy stated that they opted for just one injection of fairly tiny doses of two agents which stimulated the immune cells that already existed inside the tumor. The injection was so effective that even if the animal had other tumors in other parts of the body that weren’t being treated, even those were eliminated completely.
Science Translational Medicine published this study last month and the team is optimistic about the effectiveness of this drug on human patients. If all goes well, no patient will ever have to go through the debilitating side effects of chemotherapy.
According to Levy, the traditional methods of identifying immune targets specially for each tumor, having to activate all of the immune system or even the need for customizing the immune cells of a particular patient for a specific type of cancer, will become unnecessary because the two agents remove tumors from all parts of the body, even if they weren’t meant to treat those.
We might soon be seeing these agents used in cancer therapy. The team has permission to test one agent on humans and the second agent in many other medical trials.
A press release also revealed that the team has already recruited around 15 patients suffering from low-grade lymphoma. If it works on them, Dr. Levy is sure that they can use agents to treat various other tumors that occur.
The body does immediately being to reject any cancerous growths. The immune system and its cells, like T cells, are quick to spot the anomaly and remove it. However, as the tumor develops, it prevents the T cells from working.
This new study focuses on stimulating the T cells already present in the tumor by injecting the vaccine right into it. Dr. Levy is hopeful that as long as the T cells manage to get into the tumor, they can cure almost any variation of cancer using this method.
Large list of potentially targetable genes, but what about outcomes?
Interest is great in genomically informed targeted therapy, with the goal of identifying genomic alterations that (1) are drivers of tumor growth and progression in individual patients to individualize therapy; and (2) are targetable directly or indirectly with approved or investigational agents.
But should all women diagnosed with metastatic breast cancer undergo next-generation sequencing (NGS)? The question was debated by two experts at the most recent San Antonio Breast Cancer Symposium.
Yes, said Funda Meric-Bernstam, MD, chair of Breast Cancer Research at the University of Texas MD Anderson Cancer Center in Houston. Genomic testing should be part of the clinical management, and should be considered in all patients with metastatic breast cancer and adequate performance status who have an interest in clinical trials.
A large list of genes are potentially targetable in breast cancer, she said, pointing to PIK3CA, Akt, HER2, TRK and other rare alterations.
Several PI3K inhibitors are in clinical trials to target PIK3CA, with “emerging hope in upcoming inhibitors such as alpelisib in combination with fulvestrant” in PIK3CA-altered advanced breast cancer, she said. Activating Akt mutations, usually E17K, are most commonly found in hormone receptor-positive breast cancer. Objective responses have been elicited with the catalytic inhibitor AZD5363 as monotherapy in patients with estrogen receptor-positive AktE17K-mutant breast cancer and is now being studied in combination with fulvestrant. Ipatasertib, another Akt inhibitor, combined with paclitaxel in patients with PIK3 pathway aberrations increased progression-free survival to 9.0 months, compared with 4.9 months with paclitaxel alone in a phase II study.
HER2 is a proven genetic target, Meric-Bernstam said, noting that some patients who are HER2-negative on initial screening are subsequently found to be HER2-positive on NGS of another or newer sample. “We’re not sure if this is genomic evolution or heterogeneity or technical issues with the first testing, and we’re not as sure of the therapeutic sensitivity in this context, especially if it represents heterogeneity.”
If the tumor is HER2 amplified on NGS, validation is not needed to institute HER2-directed therapy. If the tumor is not amplified on NGS, the patient may still have a lower level of amplification or overexpression. “There’s a lot of enthusiasm about exploring HER2 mutations as a target.”
A few years ago, activating HER2 mutations were discovered in HER2-negative breast cancer. In a series of 5,605 women with breast cancer who underwent genomic profiling, 10.6% had HER2 amplifications, 2.4% had HER2 mutations, and 0.7% had co-occurring HER2 amplification and mutation, she continued. A few agents have already been approved in the HER space, with neratinib being the most prominent.
A very rare alteration found in several tumor types including breast cancer is TRK fusions. As presented at the 2017 ASCO annual meeting, in a phase I/II basket trial of patients with TRK (tropomyosin receptor kinase) fusions, almost all patients treated with the pan-TRK inhibitor larotrectinib had an objective response, which proved durable. Meric-Bernstam explained that TRK fusions are pathognomonic in secretory breast cancer, which constitutes less than 1% of breast cancers. “Because they are rare in breast cancer, I am not going to advocate for TRK fusion testing across the board for this reason, but if you do have a secretory breast cancer patient, please do TRK fusion testing.”
Not performing NGS means that patients with rare alterations cannot be entered into genotype-selected clinical trials, she argued.
ESR1, another current clinically relevant mutation, is rarely found in primary breast cancer but is commonly found in the metastatic setting. Evidence suggests that as ESR1 mutations accumulate with further treatment, there may be some value in retesting or performing liquid biopsy. An ESR1 mutation may affect the choice of therapy; an improved PFS was obtained with the use of fulvestrant compared with exemestane in breast cancer patients with ESR1 mutations, which was not the case in the patient who were ESR1 wild type.
Outcomes Not Altered, Potential Pitfalls Remain
The debater taking the other side at the symposium, Fabrice André, MD, of Gustave Roussy Cancer Center in Villejuif, France, said the key question is whether in the context of routine practice, NGS should be considered for detection of somatic mutations. At least as of yet, he said, no such rationale exists.
At present, no drug approved for use in the treatment of breast cancer requires a genomic test, he reminded listeners. “The reason is because the current way of interpreting DNA sequencing is not useful in metastatic breast cancers, and is potentially deleterious.”
Although NGS has been able to detect alterations in PIK3CA, Atk1, ERBB2, and ESR1 for which objective responses have been observed with the use of targeted therapy in early phase study, their detection did not improve outcome. Progression-free survival in these studies ranged from 5 to 8 months, which was not superior to standard of care. Further, these alterations can be detected by polymerase chain reaction (PCR) assays on circulating tumor DNA, which would be less expensive than NGS, he said.
In the case of sensitivity to PD-1 inhibitors such as pembrolizumab, accelerated approval of the agent was granted in those patients with microsatellite instability-high or mismatch repair-deficient solid tumors. The companion diagnostic for this purpose is immunohistochemistry or PCR, not NGS, said André. “Keep in mind that breast cancer with microsatellite instability is extremely rare — something like 1% and mostly in triple-negative breast cancer.”
The largest commercially available NGS panel can detect about 300 targetable genomic alterations. The issue here is that large gene panels report targetable alterations that are not relevant or for which the wrong drug may be recommended. Therefore, NGS reports can be deleterious because they recommend ineffective therapy and deny effective therapies, he said — one illustration of the wrong target, for example, is fibroblast growth factor receptor (FGFR)1/2 amplification for which an FGFR may be recommended. Nogova et al reported an objective response rate of 0% in patients with breast cancer and FGFR1/2 amplification.
Two large clinical trials in which large gene panels were used had efficacy as the primary endpoint, and in both cases, the targeted drugs matched to the genomic alteration detected by NGS failed to improve PFS.
Finally, said André, the reporting of large panels of genes leads to major ethical, regulatory, and financial issues that have not yet been sorted out. For example, in comparing results obtained from different NGS vendors, the overlap in genomic alterations is sometimes poor. Another pitfall is that somatic genetic testing in patients with advanced cancer may also detect previously unrecognized pathogenic germline variants.
Furthermore, he said, with genomic testing the likelihood of finding a drug matched to a genomic alteration is low. Although sequencing is inexpensive, it generates additional cost for biopsies and potentially the off-label use of expensive drugs.
In order to maintain their accreditation status with two major accrediting bodies, breast centers will need to implement a survivorship care plan (SCP). But to many, the more compelling reason to develop a survivorship care program is to continue to support patients in the aftermath of cancer and to help them manage the sometimes long-term effects of cancer treatment.
The impetus for this movement stems from the 2005 Institute of Medicine (IOM) report, “From Cancer Patient to Cancer Survivor: Lost in Transition,” that revealed some of the consequences of treatment, especially as treatments improve and patients experience a longer duration of survival.
“This is a partial list of the price of [breast cancer] survival: lymphedema, peripheral neuropathy, financial strain and bankruptcy, work loss of promotion, restricted performance and prolonged estrogen deprivation,” said Nathalie Johnson, MD, noting that 90% of breast cancer patients diagnosed at any stage survive five years or longer. Breast cancer survivors also may grapple with sexual dysfunction and marital strife.
At a daylong course on establishing a survivorship care program hosted by the American Society of Breast Surgeons, Dr. Johnson, medical director of the Legacy Cancer Institute, in Portland, Ore., and her colleagues described the importance of a survivorship care program, challenges to implementation, various program models and elements to consider when building a program.
“We have been trained to focus on the management of the disease, but this is our moment to start engaging patients to improve outcomes and survival and also to decrease the aftermath of treatment and increase our patients’ quality of lives,” Dr. Johnson said.
The most widely accepted definition of a survivor is any individual from the time of cancer diagnosis to the remaining balance of his/her life; given the collateral effect on people close to the survivor, a more recent definition includes family, friends and caregivers as part of the survivorship entity. The 2005 IOM report stressed a need for treatment summaries and identified four essential elements for survivorship care, said Leah Dietrich, MD, an oncologist in La Crosse, Wis., affiliated with the Gundersen Health System: “prevention of recurrent and new cancers; surveillance for metastases, recurrence and late-occurring long-term effects; intervention and the consequences of the cancer and its treatment; and coordination between specialists and primary care providers.”
An essential element of any survivorship care program is an SCP, a comprehensive summary of the care the patient received during treatment, and a follow-up plan developed with input from the patient, the primary care provider and the oncology provider. At a minimum, the IOM suggests the care plan should include diagnostic testing, tumor characteristics, the type of treatment the patient had, any toxicities the patient may have experienced, a list of other support services that were provided, contact information for the treating institutions and individual providers, and a key contact person who will coordinate the patient’s continuing care.
In addition, “the plan should address post-treatment surveillance, sexuality and fertility preservation, lymphedema management, risk reduction lifestyle and behavioral changes,” said Lisa Newman, MD, MPH, director of the Breast Oncology Program for the Henry Ford Health System, in Detroit.
“But more than simply using the document to list all these things, we hope the care provider will see that interaction of the patient receiving the document as an opportunity to educate the patient and be sure the patient truly understands how to incorporate all of the resources that are available to her or him as they move forward into the survivorship mode of their life.”
Challenges and Accreditation Status
Although the IOM provided some guidance on an SCP, it didn’t advise how an SCP and program should be implemented. Furthermore, there is a paucity of level 1 data on how to manage cancer survivors.
Referring to the National Cancer Institute’s guidelines, Jennifer Gass, MD, chief of surgery at Women and Infants Hospital, and director of Breast Fellowship at the Breast Health Center, in Providence, R.I., explained that in more than 1,000 articles on cancer survivorship, 65%, were observational, yielding level 0 evidence. “So most of what we’re relying on to guide us is expert opinion,” she said.
Also, it’s been difficult to determine whether the time and effort required of program directors to provide ongoing survivorship care are worth the necessary resources. Five randomized controlled trials failed to find a meaningful difference in outcomes, patient awareness and satisfaction between patients who received an SCP and those who did not. Nonetheless, the implementation of an SCP is required for breast programs to maintain their accreditation status with the Commission on Cancer (CoC) and the National Accreditation Program for Breast Centers (NAPBC).
The two accrediting bodies require accredited programs to deliver SCPs to eligible survivors within one year of diagnosis, or no later than 18 months for patients receiving long-term hormonal and targeted therapy. Although they initially differed in terms of deadline and proportion of eligible patients that need to receive SCPs, both the CoC and the NAPBC now require accredited centers to deliver SCPs to at least 50% of eligible patients by the end of 2018 and beyond, until further notice.
“Those of us who survey rarely find a breast center reaching 100% SCP delivery, and we often do not count them as deficient if they are working hard and/or have a lack of fiscal and/or human resources,” said Dr. Gass, who conducts surveys for the NAPBC. Critical to that agency is that every breast program has a leadership team that reviews the SCP annually, examines the methodology used to identify survivors, and evaluates the success rate of SCP delivery.
“They want to see that you’re doing that in your program leadership meeting minutes, and that you address it annually if not more often since it’s been such a difficult standard for centers to meet,” Dr. Gass said. She suggested that breast centers struggling to establish and distribute SCPs use their NAPBC survey results to lobby for resources.
Survivorship Care Program Models
Breast centers across the country vary greatly in their practice settings, patient populations and resources. There are many different models of survivorship care programs: from one-on-one consultations with a specialist, to referring patients to various resources, to multi-daylong clinics.
“In a consultative model, patients who have completed treatment have a one-time consultation with their oncology navigator, an advanced practitioner, a survivorship provider or in a survivorship clinic where a cancer treatment summary/survivorship care plan is developed. The patient is provided with tailored information and referrals to specialized services as needed, then returns to his or her oncologist or primary care physician for long-term care,” Dr. Dietrich said.
In a more longitudinal model, patients transition from their oncologist to a survivorship care clinic one to five years after completing therapy. The survivorship care clinic providers then deliver ongoing survivorship care.
“In all these models, we need to keep the patient at the center,” Dr. Dietrich said.
Coordination of the services program model may be useful in areas that have a lot of private practices around a hospital or community program, but few employed physicians or employed services. This model relies on access to services, such as physical therapy, nutritional services and psychological support, to which the patient can be referred.
“I think of this as a sort of virtual clinic,” Dr. Johnson said. “The upside is that patients can access the services they might need. The downside is that all the services are billed separately, so the patient will have more out-of-pocket expenses, which can be a barrier to access.”
In an oncology specialist–based care model, patients return to their oncologist to manage side effects of treatment and other issues.
“What is good for the patient is that this management is included in a standard visit, but the disadvantage is that it’s very disease focused,” Dr. Johnson said, noting that patients often need reinforcement to achieve and maintain healthy lifestyle changes. Also, patients with complex needs may need referral to someone who can manage problems, such as peripheral neuropathy or psychosocial issues.
In the primary care–based model, patients are returned to their PCPs, who may be more well suited to keep tabs on a patient’s overall health and wellness.
“It’s a good model if you can translate the information—teaching patients what their surveillance should be and possible side effects that should [lead them to] return to us to manage,” Dr. Johnson said. “It’s wonderful when the PCP picks up on something that doesn’t seem quite right and sends the patient back for appropriate care in the oncology system, but sometimes the nuances of recurrence are missed.”
The integrative care model, which involves collaboration with integrative care providers, is aimed at easing the patients’ way, providing care and appropriate referrals, and providing a layer of support for providers.
“Providers have only so much time. We have a medical oncologist who knows that some of us are better at dealing with anxious patients, so she sends them to us and knows they’ll get the help they need,” said Reza Antoszewska, ANP-C, a certified adult nurse practitioner with Legacy Good Samaritan Medical Center, in Portland, Ore.
The multidisciplinary clinic program (see sidebar, page 18), which involves variety of subspecialists, is an ideal model for patients with complex post-treatment issues or those with metastatic disease enduring ongoing treatment issues. Often dependent on funding and philanthropic support, this model is more well suited to large cancer programs.
“This kind of program is more expensive because you need more people to run it and a high volume of patients to sustain it,” Dr. Johnson said. “In smaller programs, the average patient will not need all the services a multidisciplinary clinic program would provide.”
The disease-specific model targets survivorship care on the type of cancer. It can work well for a range of practice sizes due to the high volume of breast cancer survivors, who account for 22% of all cancer survivors.
“In this model, you need a nurse practitioner or physician assistant who can see patients and bill for the service; referrals are sent to specialty services,” Dr. Johnson said. “This model can be sustainable for large and small practices, but it does keep the patient very focused on the disease and doesn’t incorporate much wellness, exercise and nutrition.”
There are a number of resources for breast centers to use in developing a survivorship care program. Dr. Dietrich’s practice found help in the George Washington University Cancer Institute and the American Society of Clinical Oncology. “These resources include tools to assess your clinical environment and what type of survivorship program would be best for you.” (See end of article for resources.)
Covering the Costs
What type of program works best will largely come down to the practice’s internal, external and collaborative resources, and what they can afford. “Most [hospital] administrators’ ears open when you talk about potentially losing accreditation, so that’s an opportunity to talk about various models,” Dr. Johnson said. “But we have to be fiscally responsible and look at what’s sustainable.”
For instance, physicians are the most expensive providers to direct a survivorship care clinic; they’re also not the only ones who can do so. “Nurse providers and physician assistants are an excellent resource and can bill for their services,” Dr. Johnson said. “Navigators are also essential, but you can’t bill for their services, so you have to look at how you can absorb that cost in other areas of your program.”
In general, most aspects of a survivorship care program are billable. Ms. Antoszewska advises getting to know your biller well. “They can provide a wealth of information,” she said.
Billing can be done by time or for assessment. Evaluation and management can be reported when more than half of a visit consists of counseling and care coordination. “Discussion of diagnostic results, prognosis, the risks and benefits of different treatments, instructions for those strategies, the importance of compliance, identification of symptoms, discussion of symptom management, and cancer prevention education and strategies—this is certainly reimbursable,” Ms. Antoszewska said.
In her practice, a typical visit also consists of a review of components of the patient’s diet, exercise, sleep, stressors and occupational concerns. In addition to evaluating social, physical, psychological, and spiritual or existential well-being, Ms. Antoszewska strives to help her patients connect the dots between those elements.
“Say, the relationship between family stress and how that affects their sleep, and the fact that if they were sleeping better they might feel more resilient and be better able to deal with family issues,” she said.
“The patients do love a robust survivorship care program, and it can really set your center apart,” she said.
A Few Resources for Developing a Survivorship Program
This resource from George Washington University has a wealth of information for those developing a survivorship program:
- The American Institute of Cancer Research offers great primary prevention information, including well-designed brochures, to help educate patients about ways to improve lifestyle to reduce the risk for future cancers:
- The National Comprehensive Cancer Network also provides useful information (a login is required):
- The CDC has a site with multiple resource links.
Two important immune-related AEs that are challenging diagnostically are pneumonitis and cardiac AEs. Pneumonitis of grade 3 or higher may develop in up to 2% of patients and requires a high level of suspicion, especially in patients with underlying lung disease. Cardiac immune-related AEs are non-specific in their manifestation and are likely under-reported. For both AEs, awareness is cardinal in early detection. Thus, the declared aim of SITC to keep the ICI AE guideline as a data source that is periodically updated is in keeping with the need of any health provider who treats cancer patients with ICI to familiarize themselves with these recommendations. Hopefully, this will be supplemented by prospective management data.
The Society for Immunotherapy of Cancer (SITC) has released new consensus recommendations on the recognition and clinical management of immune-related side effects from cancer immunotherapy.
The authors, members of the SITC Toxicity Management Working Group, noted that immunotherapy has become a pillar in the treatment of cancer, with clinical trials showing that checkpoint inhibitors can provide long-term benefit with generally manageable side effects. However, emerging patterns suggest that checkpoint inhibitors may cause unwanted side effects in a number of organ systems.
“We have, in a comprehensive fashion, organized thoughts on the proper screening, diagnosis, management, and handling of treatment interruptions or cessations with immune checkpoint inhibitors,” Igor Puzanov, MD, director of the Early Phase Clinical Trials Program and co-leader of the Cancer Center Support Grant Experimental Therapeutics Program at Roswell Park Cancer Institute in Buffalo, NY, told MedPage Today. “The recommendations provide an online reference point for practicing oncologists to find quick reference if they have a patient with a particular toxicity.”
New immunotherapy agents are being approved at a rapid pace, and patients have new treatment options, but “many of these agents have side effects we haven’t seen before. We’re seeing effects on the skin, lungs, gastrointestinal and endocrine systems, joints, heart and other organs, and some of these are only just beginning to be described,” he continued. “Clinicians need guidance on how to recognize early signs, how to treat adverse effects, and when to refer to a disease specialist.”
Puzanov is one of the four co-leaders of the multidisciplinary Working Group, which SITC convened to meet for a full-day workshop to develop the document to standardize the management of immune-related adverse events. Medical oncologists, surgeons, disease specialists, scientists, pharmacists, nurses, and others with relevant expertise met to develop guidance on managing adverse effects from immune checkpoint inhibitors.
The recommendations state that when caught early, most side effects from checkpoint inhibitors are mild to moderate and can be treated with drugs that temporarily suppress the immune system. “We focused on ensuring that clinicians recognize and know how to manage these emerging side effects so patients can continue to take advantage of the benefits of immunotherapy,” said Puzanov.
Serious and occasionally life-threatening immune-related adverse events have been reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by checkpoint inhibitor. Immunotherapy-related immune-related adverse events typically have a delayed onset and prolonged duration compared with adverse events from chemotherapy. Effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies, he said.
The recommendations follow an earlier effort by the European Society for Medical Oncology, which issued the first comprehensive Clinical Practice Guidelines for the management of toxicities from immunotherapy in May 2017. The SITC effort, however, is unique, Puzanov said, because it included representatives from pharmaceutical companies, who provided information derived from large databases of toxicities of immunotherapy.
“From the information in the databases, we also learned what we don’t have. We may ask about symptoms, but not recognize that fatigue or dyspnea may hide cardiac toxicity. A patient may actually have cardiomyopathy and be coded as [having] fatigue and dyspnea.” Puzanov noted that reports of fatal cardiac side effects from immune checkpoint inhibitors began appearing in the literature around 2016.
“Immune checkpoint inhibitors are coming to the community where practicing oncologists work. [Checkpoint inhibitors] have a different set of side effects than chemotherapy or targeted therapy. Physicians who treat cancer patients — hospitalists, emergency room physicians, and specialists — need to be aware of these side effects.”
For example, he noted, if a patient on chemotherapy develops shortness of breath and fever, the recommended treatment is antibiotics and supportive care. “If a patient on immunotherapy develops these symptoms, they could be due to cytokine storm, and the patient could develop pneumonitis. The patient may still develop pneumonia, but it may be pneumonitis. This can be confusing.”
Some side effects, like pneumonitis, come on early after immunotherapy, while others, like cardiac events, may come later. “Once we know the problem, we can properly treat the patient.”
Puzanov said he hopes clinicians will refer to the online consensus recommendations in real-time when they see patients: “If a patient presents with fever from immunotherapy, the clinician can look at the recommendations and decide whether this is an infection from the drug itself, and then start the patient on corticosteroids.”
The new recommendations are a “living document, and the plan is to update them accordingly as immune checkpoint inhibitors evolve and new drugs and combinations become available.
The next step for SITC is to issue a comprehensive handbook that provides more information on individual drugs and side effects with more references, he said, adding that SITC leaders will also be involved in the development of ASCO and NCCN guidelines.
“Immune checkpoint inhibitors are a whole new therapeutic ballgame,” said Puzanov. “They have changed the way we practice and treat cancer patients, but have also brought new challenges with novel toxicities. We need to conduct prospective trials with these agents to dig into the etiology of side effects. That will help us recognize which patients have the potential to develop toxicities at baseline when we give them immune checkpoint inhibitors.”
Jacqueline Smith was shocked when she received a stage III melanoma diagnosis at the young age of 21. As a black woman, she didn’t think it could happen to her. “Growing up, I learned that middle-aged, fair-skinned Caucasian women were at high risk for skin cancer,” Smith tells SELF. Smith, now 39, is a melanoma awareness advocate and public speaker who devotes much of her time to spreading knowledge of skin cancer risks, especially to other black women who may underestimate their chances of developing this potentially deadly disease.
Yes, black people can get skin cancer. What’s more, when they do, they’re much more likely to die from it.
“Skin cancer in [people] of color absolutely happens. It tends to be a perfect storm, which is why people who have darker skin and who develop skin cancer tend to have a much poorer prognosis,” dermatologist Brooke Jackson, M.D., who specializes in skin of color and owns a private practice in Durham, North Carolina, tells SELF.
A July 2016 study in the Journal of the American Academy of Dermatology found that of all racial groups, non-Hispanic black people had the lowest rates of melanoma diagnoses, but they were also the most likely to be diagnosed at a later stage.
The research pulled data from 96,953 patients given a melanoma diagnosis between 1992 and 2009. White people had the highest rate of skin cancer, with 45.8 diagnoses per 100,000 people, while black people had the lowest, with 1.35 diagnoses per 100,000 people. But despite the low incidence of melanoma in minority groups, these patients had significantly shorter survival rates than white patients.
According to the most recent data available from the American Cancer Society, the five-year melanoma survival rate is 93 percent for white people, but only 69 percent for their black counterparts.
There’s a whole host of complex reasons why black Americans are more likely to die from skin cancer than white Americans. To fully explore them, you first have to know a bit about what skin cancer really is.
Skin cancer happens when your skin cells grow abnormally and out of control. It’s the most common form of cancer in the United States.
Over 5 million people in the United States are diagnosed with skin cancer each year, according to the American Cancer Society’s 2017 report. The most common forms of this disease are basal cell carcinoma, squamous cell carcinoma, and melanoma.
Your skin’s outermost layer is called your epidermis, and it has three main types of cells, according to the American Cancer Society. The squamous cells in the outer part of your epidermis are flat and constantly slough off so new ones can take their place. Basal cells, which are deeper in the epidermis, divide to make new cells to replace the old squamous ones. Then there are melanocytes, which create melanin. It’s the brown pigment that, by making some people’s skin darker than others, allows for the human race to have such a beautifully diverse range in skin tones.
While everyone has a similar number of melanocytes, genetics determine how much of this pigment those cells actually make, according to the American Academy of Dermatology (AAD). The more melanin you have, the darker your skin.
The most prevalent types of skin cancer correspond with these different cells. Around 8 in 10 skin cancers in the United States are basal cell carcinomas, making this the most common form of this disease, according to the American Cancer Society. Basal cell carcinoma typically develops on areas most often exposed to the sun, like the head and neck, and grow slowly. They can present in a multitude of different ways, including as flat, firm, pale, or yellow areas, raised reddish patches, strange bumps, growths with raised edges, and open sores.
Squamous cell carcinoma, which makes up around 2 in 10 skin cancers, normally crops up on sun-exposed areas like the face, ears, neck, lips, and back of the hands, though it also sometimes shows up in the genital area. It often looks like a rough or scaly red patch, raised lump, open sore, or growth similar to a wart. Like basal cell carcinoma, it also grows slowly. The American Cancer Society estimates that these cancers kill around 2,000 people each year in the United States, although it’s hard to pinpoint the exact number of people who die from basal and squamous cell skin cancers annually because cancer registries don’t track them.
Melanoma, which starts in those pigment-providing melanocytes, can be much more lethal. “Melanoma isn’t the most common cancer, but we hear about it so often because it is the most deadly [skin cancer],” oncologist Michael K. Wong, M.D., Ph.D, a professor in the department of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, tells SELF. Melanoma only makes up around 1 percent of skin cancers, but it’s expected to kill around 9,320 people in the United States in 2018. Melanoma is more likely to be fatal because it’s aggressive and typically quicker to spread when left untreated than basal and squamous cell skin cancers.
Melanoma usually shows up as a new mole on your skin that may change in size, shape, or color. Experts use what’s known the ABCDE rule to summarize melanoma warning signs: Asymmetry that means the mole doesn’t look uniform all over, a strange border around the mole’s edge, uneven color, a diameter larger than around ¼ inch, and a mole that is evolving in shape, size, or color.
Melanoma most often appears on the chest and back in men and the legs in women, though it can really occur almost anywhere on your body, according to the American Cancer Society. The most common form is superficial spreading melanoma, according to the U.S. National Library of Medicine. (This is what Smith had.)
Black people are actually more susceptible to the least common subtype of the disease, known as acral lentiginous melanoma. This kind of melanoma shows up in unexpected places, like the palms of the hands, soles of the feet, and under the nails. This unexpected presentation causes it to fly under the radar, which is one reason why black people are more likely to be diagnosed with skin cancer at a later stage. Another reason: the damaging myths about black people being exempt from skin cancer.
There’s a dangerous, pervasive, and categorically inaccurate idea that melanin offers sufficient protection from the sun’s harmful UV rays.
Until she received her diagnosis, Smith says she believed that since she had dark skin, she didn’t need to protect herself from the sun. “I hear all too often that melanin is our natural sunscreen,” she says. She’s far from alone; a 2015 study in the Journal of the American Academy of Dermatology found that non-Hispanic black women were significantly less likely to regularly protect their face or other exposed areas with sunscreen than non-Hispanic white women. Overall, sunscreen use was lowest in people whose skin didn’t tend to burn. But your skin doesn’t need to actually burn in order for you to have skin damage—even a slight tan after sun exposure is a sign your skin has been injured, according to the Centers for Disease Control and Prevention (CDC).
The authors of the study, which was a nationally representative survey of 4,033 people, posited that people whose skin isn’t as sensitive to the sun may think they don’t need sun protection. While the study had its limitations, like relying on people’s self-reported sunscreen use, it points to what experts say is a commonly held belief. “The misperception is that melanin is universally protective and [dark-skinned people] do not need to wear sunscreen,” Dr. Jackson says.
It’s true that melanin does offer some protection from the sun by absorbing or deflecting harmful ultraviolet rays (invisible radiation from the sun that can damage the DNA of genes that control skin cell growth)—but it’s not enough to completely ward off the threat of skin cancer, no matter how dark your skin may be.
That’s why sunscreen—and people knowing they need it—is essential; it absorbs, reflects, or scatters sunlight to protect against UV rays, according to the CDC. The American Cancer Society suggests wearing a broad spectrum sunscreen (meaning it protects against both UVA and UVB rays) with SPF 30 or higher. Experts also recommend wearing accessories like hats and sunglasses, long-sleeved clothing in dark colors (or even with SPF), and trying to stay in the shade between 10:00 A.M. and 4:00 P.M. when UV rays are most intense.
But dutifully slathering on sunscreen and taking other protective measures isn’t enough to completely ward off skin cancer. In fact, the acral lentiginous melanoma that is more likely to affect black people can show up in areas that are rarely exposed to the sun, like the bottoms of the feet. No one knows precisely what causes non-UV related skin cancer to develop, Dr. Jackson explains, but potential factors include gene mutations, a family history of cancer or skin cancer, and various inherited syndromes that raise skin cancer risk, according to the American Cancer Society.
But make no mistake—the racial disparities in skin cancer survival rates are not solely based on insufficient information and sunscreen. There are many more factors at play.
Factors tied to lower socioeconomic status, like a lack of access to preventive screenings, absent or low-quality health insurance, and poor medical care can translate into worse health outcomes for people of color, according to the American Cancer Society’s 2016-2018 report on cancer in African Americans. And without insurance, skin cancer screenings are likely to be an afterthought. According to the United States Census Bureau’s 2016 report, all non-white populations had higher uninsurance rates than white people: 16 percent of Hispanic-origin people were uninsured, compared with 10.5 percent of black people, 7.6 percent of Asian people, and 6.3 percent of white people.
Even the toll of combatting discrimination and racism can affect health disparities, as chronic socioeconomic and race-related stress may contribute to poorer health outcomes, according to the American Psychological Association.
Even when someone is able to access medical treatment, health professionals aren’t immune from the misperception that black people don’t need to worry as much about skin cancer. “Sometimes people who evaluate you are of the belief, ‘Oh, you’ve got dark skin—we don’t have to worry about you,’” Dr. Jackson says. And unfortunately, this can lead to delayed diagnosis and treatment. “There’s definitely a correlation between delayed diagnosis and poor prognosis,” Dr. Jackson says.
This is a lot of heavy, disheartening information. But that doesn’t mean all hope is lost: Prevention and detection make it possible to survive skin cancer.
Melanoma, as deadly as it can be, is most survivable when it’s found and treated as soon as possible.
To catch any strange spots as soon as they pop up, Dr. Wong emphasizes the importance of checking your skin regularly for any new marks. Anything that gives you pause is worth flagging for your doctor, but that’s especially true if you’re a black woman and find spots in areas where acral lentiginous melanoma is most likely to develop. If you see an unexplained, persistent mark on the soles of your feet, under your nails, or on the palms of your hands, make an appointment with your dermatologist, Dr. Wong says, and get a second opinion if you don’t feel they’re taking you seriously. The right doctor will fully evaluate both your mark and medical history, then potentially decide to remove the spot for a biopsy, according to the Mayo Clinic.
If you do in fact have skin cancer, your treatment will depend on the type and stage of your disease. In the early stages, your doctor may be able to surgically remove the cancerous skin without any additional treatment, according to the Mayo Clinic. If your cancer has spread, though, it may also require radiation or chemotherapy.
Thanks to her diagnosis and treatment, Smith is alive, well, and determined to help others avoid the same fate.
After surgery, a clinical drug trial, and radiation, Smith’s cancer status is N.E.D., or “no evidence of disease.” She now works with the Melanoma Research Foundation, is a commissioner on Maryland’s Montgomery County Commission on Health, and has served on the District of Columbia Cancer Action Partnership. She plans to make her life’s work helping other cancer patients through research and advocacy.
“I would like people to realize melanoma is largely preventable,” Smith says. “Had I known I would develop melanoma, I would have diligently used sunscreen and made a better effort to shield myself from sun exposure. However, I am thankful for my life and health, the people I’ve met along the way, and my overall journey.”