Mikel Ross, MSN, RN, AGNP-BC
Mario E. Lacouture, MD
Does evidence of the effectiveness and safety of scalp cooling to reduce hair loss among women being treated for breast cancer mean that scalp cooling is a new standard of care? “I would suggest that it is,” stated Mikel Ross, MSN, RN, AGNP-BC, of the Breast Medicine Service, Memorial Sloan Kettering Cancer Center (MSK), New York, at the 2018 Lynn Sage Breast Cancer Symposium hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.1
“Certainly, the data and the evidence have evolved over the past 40 to 50 years and continue to demonstrate that it is efficacious—not perfect, but better than doing nothing,” he said. “It does have the potential to enhance quality of life,” he added, and patients frequently request scalp cooling.
Decades of data allow clinicians to “set expectations” for hair preservation based on the type of chemotherapy a patient is receiving. Moreover, the evidence allays safety concerns by showing that scalp cooling has not been associated with an increased risk of scalp metastases or reduced survival, Mr. Ross said. Bolstering the case for considering scalp cooling to be a new standard of care, he cited an editorial in JAMA2 commenting on two 2017 studies3,4 showing “scalp cooling was associated with prevention of significant hair loss in approximately 50% of women” and calling scalp cooling an intervention whose “time has come.”
‘Hair Matters’
“Hair matters,” Mr. Ross asserted—so much so, he noted, that patients with breast cancer who are concerned about hair loss may try to negotiate receiving chemotherapy that is perhaps less effective but also less likely to result in significant hair loss.
[Chemotherapy-related hair loss] is really something that affects patients’ quality of life.— Mario E. Lacouture, MD
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“It is really something that affects patients’ quality of life and may even impact their livelihood,” Mario E. Lacouture, MD, Director of the MSK Oncodermatology Program, reminded symposium participants, primarily physicians.5 “The increased survival in breast cancer to unprecedented levels in the past few decades has now resulted in patients being able to focus on the psychosocial consequences of their treatment.”
40 Years of Data
There are two basic modalities of scalp cooling, Mr. Ross noted: “gel caps, which are kept cold with dry ice brought by the patient—a kind of patient-directed intervention—and the machine-based systems, with cooling caps attached by a hose to a freestanding cooling unit.” Two such systems have been approved by the U.S. Food and Drug Administration (FDA): Dignitana, in December 2015, and Paxman, in April 2017.
Scalp cooling is a significant step forward in meeting the goal of hair preservation while being able to deliver chemotherapy.— Mikel Ross, MSN, RN, AGNP-BC
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An efficacy review with 40 years of data encompassing 65 clinical trials that included more than 5,000 study subjects, resulting in 85 different abstracts and publications, showed “the bottom line was if you ‘cooled,’ you did better than if you did not cool, in terms of keeping your hair,” Mr. Ross said. “We see great variability in terms of the percentage of hair preservation success. Most studies reported approximately 50% success.” The separate studies of the two scalp-cooling systems “give us greater insight into what to expect” and how to set reasonable expectations for patients.
In the Dignitana trial,3 among 101 women with stage I or II breast cancer who used scalp cooling and 16 who did not, the overall rate of success (defined as 50% or greater hair retention 4 weeks after completion of treatment) was 66% in a cohort of primarily docetaxel-plus-cyclophosphamide recipients. “Contrast that to those who did not cool, whose failure rate was 100%,” Mr. Ross said. The results show “scalp cooling is a significant step forward in meeting the goal of hair preservation while being able to deliver chemotherapy,” he commented.
In the Paxman Trial,4 among 95 women with stage I or II breast cancer who used scalp cooling and 47 who did not, the overall rate of success (using Common Terminology Criteria for Adverse Events) with blind evaluation by a clinician was “roughly a 50-50 split” (50.5% success vs 49.5% failure), Mr. Ross reported. For women receiving taxane-based chemotherapy, the success rate was 66%, the same as the Dignitana trial, but for the nearly one-third receiving anthracycline-based therapy, it was, “as you would have expected, much less”—around 22%, he noted. These results help inform discussion and set patient expectations with patients, he said. “Success rates with anthracycline therapy are lower but certainly better than if you do nothing, which yields a 100% failure rate.”
Endocrine Therapy–Induced Alopecia
“There have been anecdotal reports of patients losing a lot of their hair with tamoxifen or aromatase inhibitors,” Dr. Lacouture noted, including a report that aromatase inhibitors induce male pattern hair loss.6-8
A meta-analysis of data from 13,415 patients who had received endocrine treatments and 6,015 patients who served as controls found “the incidence of all-grade alopecia ranged from 0% to 25%, with an overall incidence of 4.4%.”6 Dr. Lacouture said the overall incidence “was likely underreported.”
“The highest incidence of all-grade alopecia was observed in patients treated with tamoxifen in a phase II trial (25.4%); similarly, the overall incidence of grade 2 alopecia by meta-analysis was highest with tamoxifen (6.4%),” according to the meta-analysis. “The overall relative risk of alopecia in comparison with placebo was 12.88 (P < .001), with selective estrogen receptor modulators having the highest risk.”
The authors concluded that the long-term use of endocrine-based cancer therapies and their findings about alopecia “are critical for pretherapy counseling, the identification of risk factors, and the development of interventions that could enhance adherence and mitigate this psychosocially difficult event.”
A study to assess the impact of endocrine therapy–induced alopecia on quality of life7 found “most of these patients had mild alopecia, but the impact on quality of life was almost as significant as if they had lost all of their hair,” Dr. Lacouture reported.
Adding CDK4/6 inhibitors
Two pivotal studies have shown that by adding a cyclin-dependent kinase (CDK) 4/6 inhibitor such as palbociclib (Ibrance) or ribociclib (Kisqali) to an aromatase inhibitor, “you double the incidence of alopecia,” Dr. Lacouture said. In one study, all-grade alopecia increased from 15.8% with letrozole plus placebo to 32.9% with letrozole and palbociclib.9 In the other study, all-grade alopecia increased from 15.5% with letrozole plus placebo to 33.2% with letrozole and ribociclib.10
There is a significantly greater impact on quality of life in patients treated with CDK4/6 inhibitors plus aromatase inhibitors than in patients who have aromatase inhibitor–induced alopecia.— Mario E. Lacouture, MD
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“There is a significantly greater impact on quality of life in patients treated with CDK4/6 inhibitors plus aromatase inhibitors than in patients who have aromatase inhibitor–induced alopecia. Moving forward, it will become even more important to address this issue in these patients,” Dr. Lacouture said.
“We are hoping to define the incidence of these untoward events in these patients by conducting the CHANCE Study: Chemotherapy-Induced Hair, Aging, and Nail Sequelae in Breast Cancer–Early Stage.” Patients are being followed for 3 years, starting at the beginning of their therapy. A total of 300 will receive cytotoxic agents—200 on tamoxifen or an aromatase inhibitor and 100 serving as controls.
Of 138 patients who have completed their primary chemotherapy, about 60% have persistent hair loss, 35% have madarosis (loss of the eyelashes), and 4% have hirsutism. “Surprisingly, up to 70% of chemotherapy-naive patients have some degree of alopecia with tamoxifen,” Dr. Lacouture said, “and up to 55% of chemotherapy-naive patients on aromatase inhibitors have some degree of alopecia—much higher than we were anticipating.”
Safety Issues
Safety concerns regarding scalp cooling, Mr. Ross noted, center on scalp metastases and the concern that cooling might “help preserve a cancer cell that will set up shop later in a distant organ and compromise that patient’s overall survival.”
Two reports cited by Mr. Ross found the rate of scalp metastases to be approximately 1%. A systematic review of 3 studies involving more than 50,000 patients followed for 2.2 to 9 years found about a 1% rate of scalp metastases with or without scalp cooling.11 A meta-analysis of data on 1,959 patients who used scalp cooling and 1,238 who did not12 found the incidence of scalp metastases to be “under the 1% mark, but most importantly, the P value is not statistically significant, so there has not been demonstrated a statistical difference in the rate of scalp metastases, based on whether a person cools or does not cool,” Mr. Ross said.
“Overall survival, of course, is our gold standard, and this would also provide an insight into the question of whether there are cancer cells that seed the visceral organs or the bone as a result of this practice,” Mr. Ross added. A retrospective review of 533 patients who used scalp cooling and 817 who did not, followed for 6 to 8 years, found the number of events comparable (107 vs 199), with the hazard ratios comparable (0.89 vs 1.0) and not statistically significant.13
Mr. Ross noted that both the Dignitana and Paxman trial protocols included a requirement to collect safety data for 5 years of follow-up, “but to date, there has been no demonstrated difference between cohorts based on the practice of scalp cooling.”
Beyond Breast Cancer
“In July 2017, the FDA approved scalp cooling for all solid tumors with some exceptions,” Mr. Ross said. Following this approval, “MSK launched its program for all solid tumors, available to patients at all of our sites.” About 200 patients have enrolled since the start of machine cooling—45% with breast cancer, 45% with gynecologic cancers, and 10% with other tumors—and it has been used with about 2,000 chemotherapy infusions.
Nationwide, scalp cooling grows by about 20 to 30 sites every month, and there are now “well beyond 200,” Mr. Ross said. For those who might be considering starting a scalp-cooling program at their institution, “implementation is a bit of a challenge, but it can be done,” Mr. Ross advised. “One of the biggest barriers remains financial reimbursement.”
The FDA lists several disease-related contraindications for scalp cooling, with the caveat that they may not apply in the palliative setting. “We have taken the position that for someone who is in a palliative setting, as long as they have been well advised of the risks and benefits of this intervention, we are supportive of their decision,” Mr. Ross noted.
The disease-related contraindications include hematologic malignancies, central nervous system disease (primary or metastatic), head and neck cancer, squamous cell lung cancer, small cell lung cancer, skin cancers, tumors associated with metastases in transit, bone marrow ablation, and prior or planned skull irradiation. Cold-related contraindications are cold sensitivity, cold agglutinin disease, cryoglobulinemia, cryoglobulinemia, cryofibrinogenemia, and cold urticaria.
Beyond Scalp Cooling
Cooling devices have also been used to prevent or reduce other side effects of cancer treatment, such as paronychia, which can occur in up to 80% of patients receiving taxanes, and hand-and-foot neuropathy.
Dr. Lacouture cited a study published in 2005, which “did not receive the attention I believe it should have.” It assessed the effectiveness of a frozen gel glove in reducing nail and skin toxicities among 45 patients receiving docetaxel alone or in combination with chemotherapy.14 Patients wore a frozen glove on the right hand, with the left hand acting as the control. “The severity of the nail toxicities was reduced 4-fold, from 51% in the ungloved hands to 11% in the gloved hands,” and all of them were grade 1, Dr. Lacouture reported. “Based on these observations,” he added, “patients [at MSK] receiving taxanes for breast cancer have their hands cooled with a gel-type device.”
Overall survival, of course, is our gold standard, and this would also provide an insight into the question of whether there are cancer cells that seed the visceral organs or the bone as a result of [scalp cooling].— Mikel Ross, MSN, RN, AGNP-BC
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In a more recent study among 40 patients with breast cancer who wore cold gel packs on both their hands and feet on their dominant side during taxane therapy, “the tactile sensitivity of hands and feet was reduced by more than 60%,” Dr. Lacouture said, from 80.6% on the control side to 27.8% on the cooled side.15 Sensitivity to warmth was also decreased 4-fold when the patients had their hands cooled, from 32.4% to 8.8%. “This provided more -encouragement to use the nail-cooling method to prevent not only nail toxicities, but more importantly, the neuropathy,” he added.
“The use of these gel packs or gloves is not very easy, logistically. You have to keep them in a special freezer or have the patients bring them in dry ice,” Dr. Lacouture pointed out. In an MSK study, “we decided to use just bags of ice. So, it would be something that everyone would be able to use anywhere.” Although patients who put their hands on the ice had reduced neuropathy, “the difference was not significant, probably due to the small number of patients,” he said (19 in the cryotherapy group, 20 in the control group). “But, interestingly, all of these patients reported less neuropathy compared to historic controls.”
The plans are to repeat the latter study with a larger number of patients. “I do believe there is a signal here for using these ice bags to prevent taxane-induced neuropathy. They would be easy to use anywhere,” Dr. Lacouture said. ■
DISCLOSURE: Mr. Ross has financial relationships with Pfizer and Paxman Scalp Cooling Systems. Dr. Lacouture is a consultant/speaker with Legacy Healthcare Services, Adgero Biopharmaceuticals, Amryt Pharma, Celldex Therapeutics, Debiopharm, Galderma Research and Development, Johnson & Johnson, Novocure, Lindi Skin, Merck Sharp & Dohme, Helsinn Healthcare SA, Janssen Research & Development, Menlo Therapeutics, Novartis Pharmaceuticals, F. Hoffmann-La Roche, AbbVie, Boehringer Ingelheim, Allergan, Amgen, E.R. Squibb & SonsEMD Serono Inc, AstraZeneca, Genentech, Leo Pharma, Seattle Genetics, Bayer, Manner SAS, Lutris, Pierre Fabre, Paxman Coolers, Adjucare, Dignitana, Biotechspert, Teva Mexico, Parexel, OnQuality Pharmaceuticals, Novartis, and Takeda Millennium; and receives research funding from Berg, Bristol-Myers Squibb, Lutris, Paxman, Novocure, US Biotest, and Veloce.
REFERENCES
2. Hershman DL: Scalp cooling to prevent chemotherapy-induced alopecia: The time has come. JAMA 317:587-588, 2017.
3. Rugo HS, Klein P, Melin SA, et al: Association between use of a scalp cooling device and alopecia after chemotherapy for breast cancer. JAMA 317:606-614, 2017.
4. Nangia J, Wang T, Osborne C, et al: Effect of a scalp cooling device on alopecia in women undergoing chemotherapy for breast cancer: The SCALP randomized clinical trial. JAMA 317:596-605, 2017.
6. Saggar V1, Wu S, Dickler MN, et al: Alopecia with endocrine therapies in patients with cancer. Oncologist 18:1126-1134, 2013.
7. Freites-Martinez A, Shapiro J, Chan D, et al: Endocrine therapy-induced alopecia in patients with breast cancer. JAMA Dermatol 154:670-675, 2018.
8. Rossi A, Iorio A, Scali E, et al: Aromatase inhibitors induce ‘male pattern hair loss’ in women? Ann Oncol 24:1710-1711, 2013.
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10. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 375:1738-1748, 2016.
11. Ross M, Fischer-Cartlidge E: Scalp cooling: A literature review of efficacy, safety, and tolerability for chemotherapy-induced alopecia. Clin J Oncol Nurs 21:226-233, 2017.
12. Rugo HS, Melin SA, Voigt J: Scalp cooling with adjuvant/neoadjuvant chemotherapy for breast cancer and the risk of scalp metastases: Systematic review and meta-analysis. Breast Cancer Res Treat 163:199-205, 2017.
13. Lemieux J, Provencher L, Perron L, et al: No effect of scalp cooling on survival among women with breast cancer. Breast Cancer Res Treat 149:263-268, 2015.
14. Scotté F, Tourani JM, Banu E, et al: Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. J Clin Oncol 23:4424-4429, 2005.
15. Hanai A, Ishiguro H, Sozu T, et al: Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy: Prospective self-controlled trial. J Natl Cancer Inst 110:141-148, 2018.
