Research Review: February 2021

And, as we in clinical oncology know: cancer still happened. Our patients received difficult news through face masks and video screens. They experienced changes in care delivery, with different chemotherapies, surgeries, and schedules than usual in order to keep patients and providers as safe as possible during the pandemic. They debated between fears of exposure to the SARS-CoV-2 virus in medical clinics and risking cancer relapse by staying away. They navigated the fear of dying from COVID-19 on top of the fear of dying from cancer.

Perhaps no group of patients with cancer has more psychosocial stressors than those diagnosed as adolescents and young adults (AYAs). These patients (defined by the National Cancer Institute as those 15 to 39 years old) are also navigating life stressors like developing autonomy and identity, education and vocational attainment, marriage, starting a family, parenting, caregiving, and—frankly—living. For these reasons, this group has high risks of poor psychosocial outcomes.¹ Compared to their peers, they are more likely to have ongoing mental health problems (including death by suicide), less likely to get married, less likely to have a job, less likely to be paid as well if they have a job, less likely to have children, and more likely to have ongoing poor health-related quality of life.

With all that in mind, 2020 surprised me. 2020 was the year that confirmed my faith in AYA resilience.

I have been studying resilience for over a decade. When I started my career as a pediatric oncologist, I noticed the stressors of AYA patients and wondered if we were missing a critical opportunity: rather than wait for (and belatedly try to fix) poor outcomes, what would happen if we introduced concepts like resilience training to buffer the negative impacts of cancer and its treatments?

Over hundreds of hours of interviews with AYAs with cancer, we learned that their perceptions of resilience aligned with psychological theory: Resilience is a process of harnessing resources to sustain well-being in the face of adversity.² Those “resilience resources” tend to be the same in adversities as variable as cancer, natural disaster, poverty (and pandemics). They include three categories:

• Individual resources: personal characteristics and skills, community resources
• Social support networks and communities; and
• Existential resources: the quest for meaning and purpose.

Which resources work best for whom and in which circumstances is variable, although once people identify their preferences, they tend to return to the same resources again and again.

The most commonly endorsed AYA resilience resources included skills in stress-management, goal-setting, reframing negative thoughts, and benefit-finding.³ We translated each of these resources into a reproducible, bedside coaching program called “Promoting Resilience in Stress Management” (PRISM), and then tested PRISM in feasibility, acceptability,⁴ and phase 2 randomized clinical studies.⁵ Compared to AYAs who received usual oncology care, those who received PRISM reported higher self-perceived resilience, hope, and cancer-related quality of life, and lower psychological distress.^5,6 At the start of 2020, we were busy testing PRISM in phase 3 clinical trials. When COVID-19 hit, the world (including our research) paused. We halted enrollment and waited for the return-to-normalcy. Perhaps like our very AYAs who realize only after the fact that life is not “on pause” and will never be the same after cancer, we quickly learned that our research plans would be irrevocably changed, too. It was time be research-resilient.

By the summer of 2020, we had converted PRISM to a virtual (Zoom-delivered) coaching program supported by a digital app. AYA patients loved it. “PRISM at my fingertips!” one exclaimed. Another commented on the “new normal” of Zoom. Seasoned coaching staff reported that patients seemed more—not less—engaged by video. “They always shared what was hard, but now they seem to find comfort in the screen.” We also noticed increased willingness and eagerness to practice resilience skills. “It seems pretty important these days,” said one patient. Another said that gratitude came easier; being able to “stay in school” because the whole world had gone remote made cancer less lonely.

Now, in early 2021, I realize my patients taught me something: there is always change—sometimes hard, sometimes manageable. And there is always time—to heal, to learn, to adapt, and to grow. Resilience is not static, and it is not manifest by some sudden ability to thrive. Indeed, “getting through” (that time where we can only put one foot in front of the other) is a first, critical phase of resilience. Feeling uncertain, afraid, and exhausted is part of that phase, and all those feelings are normal. The second phase of resilience is when we begin to do the sometimes new and always deliberate work of “harnessing resources.” Here, we acknowledge the hard, recognize what is in our control (and what is not), and lean into change. The last phase of resilience is when we “look back and learn.” It is when we reflect, crystallize what we did, and recognize who we have become.

These phases are not linear; we constantly flow between and across them. While we are exhausted and “getting through,” we may also start “harnessing resources” by considering what we have done in tough times before. We may also begin to consider how this adversity will change us. While we are deliberately “harnessing resources,” we may start to identify new purpose by “looking back and learning.”

The power of resilience is in its perpetual motion. Moving through and around these phases buffers us from the next adversity, whether we know it or not. It is a skill that can be refined and strengthened. Think of it this way: having cancer as an AYA is always hard, but there are moments when patients reflect and say, “I did that,” and more, “now I know I can do something hard again.” As we strengthen our metaphorical resilience muscle, we come to better understand our strengths, limitations, and opportunities for growth.

What does this mean for us now, in early 2021? Probably nothing but clarity. People have been navigating adversity for millennia. Although some seem to do it with more observable grace and skill than others, most keep going, despite their exhaustion. We have no choice but to be resilient. Today, after a year that changed the world, I have confidence and hope. We learned to be resilient in the time of COVID-19. We can, and will, be resilient again.

References

1. Bleyer A. Young adult oncology: the patients and their survival challenges. CA Cancer J Clin. 2007;57(4):242-255.
2. Southwick SM, Bonanno GA, Masten AS, Panter-Brick C, Yehuda R. Resilience definitions, theory, and challenges: interdisciplinary perspectives. Eur J Psychotraumatol. 2014;5.
3. Rosenberg AR, Yi-Frazier JP, Wharton C, Gordon K, Jones B. Contributors and inhibitors of resilience among adolescents and young adults with cancer. J Adolesc Young Adult Oncol. 2014;3(4):185-193.
4. Rosenberg AR, Yi-Frazier JP, Eaton L, et al. Promoting resilience in stress management: a pilot study of a novel resilience-promoting intervention for adolescents and young adults with serious illness. J Pediatr Psychol. 2015;40(9):992-999.
5. Rosenberg AR, Bradford MC, McCauley E, et al. Promoting resilience in adolescents and young adults with cancer: Results from the PRISM randomized controlled trial. Cancer. 2018;124(19):3909-3917.
6. Rosenberg AR, Bradford MC, Barton KS, et al. Hope and benefit finding: Results from the PRISM randomized controlled trial. Pediatr Blood Cancer. 2019;66(1):e27485.

However, one common and challenging side effect of earlier diagnosis/treatment for CRC is oxaliplatin-induced peripheral neuropathy (OIPN), which may be long-lasting or permanent and, in the case of younger patients, means the prospect of living with these conditions for many years. Patients with OIPN often experience numbness, tingling, and pain in their extremities, with severity ranging from mild to severe. Problems can vary from loss of ability to dress oneself and participate in hobbies to disabilities affecting mobility and/or occupation. Younger patients may be more severely impacted if they are unable to work, provide for their families, or reach life goals, all of which significantly affect quality of life. During oxaliplatin treatment, 85% of individuals experience OIPN severe enough to require dose modification,³ which may impact survival outcomes.

Prevention/reduction of the side-effect burden of potentially life-saving treatment, such as OIPN, is therefore an urgent priority. Current methods for addressing the serious, debilitating side effects of OIPN are limited to dose reduction/delay or stopping treatment altogether, all of which compromise the efficacy of treatment. Duloxetine has demonstrated effectiveness in the treatment of OIPN, including reduction of associated chronic pain),⁴ and for multiple painful conditions including diabetic neuropathy and fibromyalgia. Pre-clinical trials in animals have also demonstrated duloxetine’s effectiveness in preventing OIPN.

In May 2020, the Alliance for Clinical Trials in Oncology opened research study A221805—Duloxetine to Prevent Oxaliplatin-induced Chemotherapy-induced Peripheral Neuropathy—led by principal investigator Ellen M. Lavoie Smith, PhD, MSN, RN, AOCN^®, FAAN. This randomized, double-blinded, placebo-controlled clinical trial is testing the effectiveness of duloxetine in preventing the potentially chronic and disabling side effects of OIPN. Participants are adults with Stage II or low-risk Stage III colorectal cancer who will undergo surgery followed by 3 months of oxaliplatin-based adjuvant chemotherapy (CAPOX 4 cycles or FOLFOX 6 cycles), a mainstay treatment for CRC that causes acute and persistent oxaliplatin-induced peripheral neuropathy.

A221805 is a phase 2 to phase 3 trial designed to determine if one of two duloxetine doses (30 mg or 60 mg), when compared to placebo, might prevent OIPN (phase 2. If duloxetine appears to be more effective than placebo in the phase 2 trial, the most promising dose (30 mg or 60 mg) will be compared to placebo (phase 3) to assess duloxetine’s effectiveness for preventing OIPN sensory symptoms and chronic neuropathic pain. Study drug is taken from start of chemotherapy treatment to one month after chemotherapy completion, followed by one week of tapering off the drug. Patients are followed for 18 months to measure both acute and chronic symptoms.

Duloxetine’s safety profile has been extensively studied in those with fibromyalgia, depression, and musculoskeletal pain. Because of an FDA black box warning about an increased risk of suicidal thinking/behavior in children, adolescents, and young adults, patients under the age of 25 are not eligible for this study. Other cautions include a risk of increased bleeding and a note to avoid ingestion of alcohol. Potential drug interactions may occur with CYP1A2 or CYP2D6 inhibitors, so they should be avoided.

Neuropathy symptoms, including numbness, tingling, and pain, are most accurately described by those who experience them—the patients. Therefore, patient-reported outcome (PRO) surveys were incorporated into this study as a critically important component of data collection. Because the sensory symptoms of OIPN can be both acute and chronic, PRO surveys are used for serial measurement of symptoms for 18 months after oxaliplatin treatment. To facilitate the use of PROs, participants are offered and encouraged to utilize the iMedidata Rave Patient Cloud ePRO App on a smartphone or tablet for electronic (ePRO) surveys, which participants can easily complete on their device in a variety of settings. This free app reminds participants when their surveys are due, and securely sends responses directly to the database. Paper booklets are available for participants who do not have the necessary electronic device or WiFi access.

A primary objective of A221805 is to determine the effectiveness of duloxetine to prevent OIPN sensory symptoms and chronic neuropathic pain. Currently the only methods of addressing these symptoms are oxaliplatin dose reduction/delay or treatment cessation; however, these interventions compromise treatment efficacy. If duloxetine is found to be effective in mitigating these symptoms, the benefits would be two-fold: 1) dose reductions/delays or treatment cessation may be avoided, thereby improving treatment efficacy, and 2) the burden of long-term side effects of OIPN, including disability and diminished quality of life, could be lightened.

References

1. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average‐risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J. 2018;68:250-281. 
2. Rex DK, Boland CR, Dominitz JA, et al. Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. J Gastroenterol. 2017;153(1):307-323. Available at https://doi.org/10.1053/j.gastro.2017.05.013
3. Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol. 2014:23(10):997-1005.
4. Smith EML, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309(13):1359-1367.

The National Cancer Institute defines AYA patients as between the ages of 15 and 39. This covers a wide span of chronological age as well as life stage, circumstances, achievements, and aspirations. Diversity defines this population—while some 29 year olds will have more in common with those in their early 20’s, others will feel more connected to those in their late 30’s.

One thing that AYAs often do have in common, regardless of age, is the feeling that they are not getting all the information they need, or the “whole story.” A recent example of this came up during a support group for women under age 40 with Stage IV breast cancer that I facilitate. I was explaining palliative care and a participant asked, “Why are the doctors keeping palliative care from me?” The patient felt she would benefit from this information, while the physician’s perspective was, “I don’t want the patient to think I’ve given up hope.” Through facilitated peer group support, not only can AYA patients connect with others at similar stages in life, but also the patient’s voice can help us to better understand unmet needs.

When speaking with new residents and nurses about AYA patients, I recommend that in meeting with patients under age 40, at a minimum, they discuss:

• Fertility—Just as AYAs deserve an expert in cancer care, they also deserve an expert in fertility care. Be prepared to provide patients with referral information.
• Peer support—Have information and resources to support AYAs and connect them with others in a similar life situation.
• Decision makers—AYAs may be in non-traditional relationships. If there is a crisis who will their decision maker be?

Engaging with AYA patients requires flexibility, openness, and a willingness to be innovative. At Providence Cancer Institute, I specialize in working with children who have a parent with cancer. It’s believed that 24% of patients getting treatment for cancer have kids aged 18 or younger at home. That is one-quarter of our patient population. When physicians are talking to these patients about their treatment options, how many may be thinking: “How am I going to pay my rent? How am I going to tell my kids? What about my job?” Engaging psychosocial support along the cancer care continuum helps identify barriers, as does rescreening for distress when there is a change in care.

Time pressures, finances, and life responsibilities are known barriers to clinical trial participation for AYAs. Any time we ask a patient to do something more that requires time away from work, there is potential financial impact. One thing we do not do well with in cancer care is being flexible with our treatment options. In presenting on building and improving quality psychosocial care for AYA patients, Karen Fasciano, PsyD, Senior Psychologist and Young Adult Program Director at the Dana-Farber Cancer Institute, has stressed the importance of innovation and engagement for this patient population.

This is especially the case with clinical trials, which are by nature rigid. With the AYA population in particular, but for others as well, non-traditional jobs may mean that to participate they need a little different schedule or more flexibility. When you’re asking someone to come in weekly to get blood draws, that impacts their finances. Making clinical trials more accessible for AYAs (and others) requires stepping back from the protocol and asking: Is there a way to add a little more flexibility so that participation in the study would be feasible for AYA patients?

At my cancer center, research nurses are heavily involved in clinical trial recruitment. A physician may present the trial option to the patient, but the research nurse explains all the ins and outs of the study. With this approach, patients feel like they have more time to ask questions and get answers.

Another step we’ve taken is to include young adults on our cancer center’s patient advisory board. This empowers AYAs to share their lived experience of care at our institution, allowing us to listen and learn.

Finally, a strategy cancer programs may want to consider is developing an AYA patient navigator position. This would not be a volunteer role— with training, it could be a position for a former patient or peer supporter who has been through cancer treatment and may have participated in a clinical trial.

Resources

Davis LE, Janeway KA, Weiss AR, et al. Clinical trial enrollment of adolescents and young adults with sarcoma. Cancer. 2017;123(18):343-3440. This commentary that lays out needed changes to realize increased enrollment of AYAs in sarcoma clinical trials.

Freyer DR, Seibel NL. The clinical trials gap for adolescents and young adults with cancer: recent progress and conceptual framework for continued research. Curr Pediatr Rep. 2015;3(2):137-145. This article includes a Clinical Trial Pathway to Enrollment. Each step in the pathway is multi-faceted. In conclusion, the authors write the path starts with “having clinical trials focused on cancers relevant to this age group that are available, accessible, effectively presented, and ultimately acceptable to an eligible patient. Addressing all of these will require continued research in areas as diverse as cancer biology and therapeutic decision-making, involving institutions ranging from NCI to community-based hospitals.”

Isack A, Santana VM, Russo C, Klosky JL, Fasciano K, et al. Communication regarding therapeutic clinical trial enrollment between oncologists and adolescents and young adults with cancer. J Adolesc Young Adult Oncol. 2020 Oct;9(5):608-612. Authors surveyed 193 AYA patients and reviewed medical records of informed consent discussions. Survey results showed that many respondents were unable to “accurately report” if they’d been offered a clinical trial. Of respondents on clinical trials, more than one-quarter did not recall being enrolled. Authors offer several suggestions for approaching clinical trial conversations with AYAs.

National Cancer Policy Forum. Board on Health Care Services; A Livestrong and Institute of Medicine Workshop; Institute of Medicine. Identifying and Addressing the Needs of Adolescents and Young Adults with Cancer. 2014. National Academies Press: Washington, DC.

Roth M, Mittal N, Saha A, Freyer DR. The Children's Oncology Group Adolescent and Young Adult Responsible Investigator Network: A New Model for Addressing Site-Level Factors Impacting Clinical Trial Enrollment. J Adolesc Young Adult Oncol. 2020;9(4):522-527. This report outlines multiple site-level barriers to AYA clinical trial enrollment identified by the COG AYA Responsible Investigator Network and describes a novel model for developing and integrating solutions via a nationally coordinated strategy. Site-level barriers fell into four main areas: lack of available trial; poor communication between pediatric and medical oncology; logistical barriers to access; and need for leadership support.

Smith AW, Keegan T, Hamilton A, et al. Understanding care and outcomes in adolescents and young adults with cancer: A review of the AYA HOPE study. Pediatr Blood Cancer. 2018;Oct 7: e27486. This review of the 10-year NCI-supported AYA Hope Study that recruited patients diagnosed at ages 15 to 39 with germ cell, Hodgkin and non‐Hodgkin lymphoma, acute lymphoblastic leukemia, and sarcoma from SEER cancer registries into the first multicenter U.S. population‐based study of medical care, physical, and mental health outcomes for AYAs with cancer. The authors write: “Review of the 17 published manuscripts showed low awareness of clinical trials and substantial impact of cancer on financial burden, education and work, relationships and family planning, and physical and mental health. It highlights the feasibility of a longitudinal population‐based study and key lessons learned for research on AYAs with cancer in and beyond the United States.”