Evaluation of a Comprehensive Skin Toxicity Program for Patients Treated With Epidermal Growth Factor Receptor Inhibitors at a Cancer Treatment Center

Key Points

Question

What is the association of a comprehensive skin toxicity program with adherence to prophylaxis guidelines for the prevention of epidermal growth factor receptor inhibitor (EGFRi)–associated cutaneous toxic effects at a tertiary cancer center?

Findings

This cohort study of 208 patients with cancer treated with EGFRi found that adherence to prophylaxis protocols for cutaneous EGFRi-associated toxicity significantly improved over time and was associated with a decreased need for rescue treatments and a lower incidence of EGFRi dose changes, coinciding with the integration of dermatologic care into traditional oncology care.

Meaning

Integrating dermatologic care into oncology practices may be associated with increased adherence to evidence-based prophylaxis protocols for rash and may raise awareness of appropriate treatment choices, which may minimize toxicity-associated chemotherapy interruptions.

Abstract

Importance

Up to 90% of patients treated with an epidermal growth factor receptor inhibitor (EGFRi) experience cutaneous toxic effects that are negatively associated with quality of life and lead to treatment interruptions. The Skin Toxicity Evaluation Protocol With Panitumumab trial found reduced incidence of skin toxicity and quality of life impairment with preemptive use of doxycycline hyclate, topical corticosteroids, moisturizers, and sunscreen, demonstrating the benefit of prophylactic treatment for skin toxicity.

Objective

To evaluate the association of a comprehensive skin toxicity program with adherence to prophylaxis guidelines for the prevention of EGFRi-associated cutaneous toxic effects.

Design, Setting, and Participants

A retrospective cohort study was conducted of all adult patients receiving at least 1 dose of cetuximab at the Dana-Farber Cancer Institute in the calendar year 2012 (2 years after publication of the Skin Toxicity Evaluation Protocol With Panitumumab) or the calendar year 2017 (2 years after full implementation of the Skin Toxicities from Anticancer Therapies program).

Main Outcomes and Measures

Primary outcomes were rate of preemptive rash treatment and selection of preemptive agents. Secondary outcomes were incidence of rash, rates of rescue treatments, rates of cetuximab dose changes or interruptions, and overall survival at 2 years.

Results

There were 118 patients (85 men; median age, 62.4 years [range, 23.5-91.7 years]) treated with cetuximab in 2012 and 90 patients (70 men; median age, 62.5 years [range, 30.7-90.5 years]) treated with cetuximab in 2017; 11 patients (9%) in 2012 and 31 patients (34%) in 2017 were treated at Dana-Farber Cancer Institute affiliate sites. At cetuximab treatment initiation, 29 patients (25%) in 2012 and 42 patients (47%) in 2017 were prophylactically treated for skin toxicity (P < .001). From 2012 to 2017, preemptive tetracycline use (13 of 29 [45%] to 30 of 42 [71%]; P = .02) and topical corticosteroid use (2 of 29 [7%] to 24 of 42 [57%]; P < .001) increased and topical antibiotic use (23 of 29 [79%] to 18 of 42 [43%]; P = .002) decreased. There was no significant difference in incidence of rash by prophylaxis status. Patients prescribed prophylactic treatment were 94% less likely to require a first rescue treatment for rash (adjusted odds ratio, 0.06; 95% CI, 0.02-0.16; P < .001), 74% less likely to require a second rescue treatment for rash (adjusted odds ratio, 0.26; 95% CI, 0.08-0.83; P = .02), and 79% less likely to experience a cetuximab dose change or interruption (adjusted odds ratio, 0.21; 95% CI, 0.06-0.81; P = .02) than patients not prescribed prophylactic treatment, adjusting for treatment site and year.

Conclusions and Relevance

Dermatologists can add value to oncology care by raising awareness of appropriate treatment options and increasing adherence to evidence-based prophylaxis protocols for EGFRi-associated rash, which is associated with decreased interventions and toxicity-associated chemotherapy interruptions.

This cohort study evaluates the association of a comprehensive skin toxicity program for patients with cancer with adherence to prophylaxis guidelines for the prevention of epidermal growth factor receptor inhibitor–associated cutaneous toxic effects at the Dana-Farber Cancer Institute.

Introduction

Cetuximab is an epidermal growth factor receptor inhibitor (EGFRi) demonstrating significant survival benefit in metastatic colorectal and head and neck cancer.^1,2 However, 90% of patients who receive EGFRi treatment experience cutaneous toxicities, such as papulopustular or acneiform eruptions, xerosis, pruritus, and paronychia.³ These dermatologic adverse events may be associated with quality of life impairment, increased infection risk, and EGFRi dose modification, interruptions, or discontinuation.^4,5,6,7 Interruption of EGFRi treatments secondary to dermatologic adverse events may be detrimental to overall survival; survival is significantly improved in patients experiencing at least a grade 2 acneiform rash compared with patients experiencing a less severe or no rash.^2,8

The benefits of preemptive rash treatment are well established.^9,10,11 The Skin Toxicity Evaluation Protocol With Panitumumab (STEPP) trial demonstrated improved quality of life and a 50% reduction in the incidence of grade 2 or greater rash in patients treated with preemptive doxycycline hyclate, topical corticosteroids, moisturizers, and sunscreen,⁹ prompting practice guidelines for the prevention and management of EGFRi-associated cutaneous toxicity.^12,13 Prophylactic hydrocortisone acetate, 1%, with moisturizer, sunscreen, and minocycline hydrochloride or doxycycline hyclate, 100 mg, twice daily are recommended for the first 6 weeks of EGFRi therapy.¹² Because the papulopustular eruption is inflammatory in nature,¹⁴ medium-potency or high-potency topical corticosteroids are recommended for treatment after the development of a rash.¹² Awareness of and adherence to these guidelines among oncology clinicians are thus far poorly understood.

In 2014, the department of dermatology at the Dana-Farber/Brigham and Women’s Cancer Center established its program in Skin Toxicities from Anticancer Therapies (STAT) at the main campus, providing urgent and follow-up dermatologic care for oncology patients with dermatologic adverse events. In its first full year of implementation (2014-2015), the STAT program comprised numerous clinical practice interventions and educational initiatives (Box).

Box. Components of the STAT Program (2014-2015).

Clinical Interventions

• Colocalization of 9 oncodermatologists within head and neck, genitourinary, and cutaneous oncology clinics during 7 of 10 sessions per week

• Establishment of urgent access slots in oncodermatology clinics during 10 of 10 sessions per week

Education Initiatives

• Monthly educational skin toxicity case conferences

• Five 1-hour lectures delivered to thoracic oncologists, head and neck oncologists, nurse practitioners, physician assistants, and research nurses

Tools Developed

• Smart phrases embedded in the electronic medical record outlining management of dermatologic adverse events

• Patient-facing teaching sheets describing expected skin toxic effects and approach to management

Between 2014 and 2017, these initiatives were implemented solely at the main campus of the Dana-Farber Cancer Institute (DFCI) in Boston, Massachusetts. The DFCI also has 4 satellite locations in Brighton, Massachusetts; Milford, Massachusetts; South Weymouth, Massachusetts; and Londonderry, New Hampshire, where these interventions were not implemented. Patients at the satellite locations are treated by staff oncologists specific to each site but have access to the same oncologic therapies, interventions, and clinical trials offered at the main campus. There is minimal intersite mobility among patients or oncologic clinicians, and there are no known differences in disease characteristics between patients treated at satellite locations and those treated at the main campus. This study assessed adherence to evidence-based prophylaxis protocols for EGFRi-associated rash as well as for outcomes associated with prophylaxis at DFCI’s main campus and satellites 2 years before and after the STAT program was established at the DFCI main campus.

Methods

Study Design

The DFCI’s electronic pharmacy database was queried for all adult patients receiving at least 1 dose of cetuximab in 2012 or 2017 at any DFCI location. Cetuximab was selected owing to its intravenous administration and consistency of treatment documentation; 2012 represents 2 years after publication of the STEPP protocol, and 2017 represents 2 years after full implementation of the STAT program. The study was approved by the Partners Human Research Committee. Patient consent was waived by the Partners Institutional Review Board committee because no patients were contacted for this minimal-risk, retrospective cohort study and all protected health information was kept secure by the researchers.

Data Collection

A retrospective medical record review was completed December 31, 2018, for the 2012 cohort and July 28, 2019, for the 2017 cohort. Data on demographic characteristics, disease characteristics, oncologic and prophylaxis regimens, and treatment location were recorded. Primary outcomes were rates of prophylactic rash treatment and prophylactic agent selection. Secondary outcomes included the incidence of rash, the rates of first and second rescue treatments, the rate of cetuximab dose changes or interruptions, and overall survival at 2 years. Prophylactic treatments were defined as agents prescribed at cetuximab initiation prior to rash development. First and second rescue treatments were defined as the first and second additional unique prescriptions given to treat EGFRi-associated rash or manage symptoms after documented development of rash. Categories of treatment agents captured through prescriptions include oral tetracyclines, topical antibiotics, and topical corticosteroids. Supportive care (moisturizer and sunscreen) was captured from documentation of counseling in progress notes.

Statistical Analysis

Prophylaxis rate by year and treatment site, prophylactic agent selection by year, incidence of rash, rates of first and second rescue treatments, and rate of cetuximab dose changes or interruptions by prophylaxis status were compared using t tests. Three separate multivariable logistic regression models defined the adjusted odds ratios with 95% CIs for the presence of first rescue treatment, second rescue treatment, and cetuximab dose changes or interruptions with respect to prophylaxis status, adjusting for year and treatment site. Cox proportional hazards regression ratios defined overall survival at 2 years for colorectal and head and neck cancer by prophylaxis status. Statistical testing was 2-sided, and the results were deemed statistically significant at P < .05. Analyses were performed with Stata/SE, version 15.1 (StataCorp LLC).

Results

Cohort Characteristics

There were 118 patients (85 men; median age, 62.4 years [range, 23.5-91.7 years]) who received cetuximab in 2012 and 90 patients (70 men; median age, 62.5 years [range, 30.7-90.5 years]) who received cetuximab in 2017; 11 patients (9%) in 2012 and 31 patients (34%) in 2017 were treated at DFCI satellite locations. Primary tumors were colorectal tumors (2012, 67 [57%]; 2017, 43 [48%]), head and neck tumors (2012, 43 [36%]; 2017, 34 [38%]), and cutaneous squamous cell carcinoma (2012, 5 [4%]; 2017, 10 [11%]). Most patients had stage IV disease at cetuximab treatment initiation, with no significant difference by treatment site (colorectal: 90% [74 of 82] at the main campus vs 96% [27 of 28] at satellite locations; P = .30; head and neck: 64% [43 of 67] at the main campus vs 70% [7 of 10] at satellite locations; P = .72). The median duration of cetuximab treatment was 78 days (range, 1-2101 days) in 2012 and 66 days (range, 1-2105 days) in 2017. There were 98 patients (83%) in 2012 and 73 patients (81%) in 2017 who received systemic corticosteroids within their oncologic regimens. The demographic characteristics of patients, the disease characteristics, and concurrent oncologic treatments are summarized in the Table.

Table. Data on Demographic Characteristics, Disease Characteristics, and Oncologic Regimens.

Characteristic	Patients, No. (%)		P value
	2012 (n = 118)	2017 (n = 90)
Sex
Male	85 (72)	70 (78)	.35
Female	33 (28)	20 (22)
Vital status
Alive	18 (15)	35 (39)	<.001
Dead	100 (85)	55 (61)
Age, y
Mean	61.3 (11.5)	62.6 (13.1)	.62
Median (range)	62.4 (23.5-91.7)	62.5 (30.7-90.5)
Race/ethnicity
Asian	1 (1)	1 (1)	.81
Black or African American	5 (4)	3 (3)
Hispanic or Latino	9 (8)	4 (4)
White	99 (84)	79 (88)
Other or unknown	5 (4)	6 (7)
Cancer type
Colorectal	67 (57)	43 (48)	.23
Head and neck	43 (36)	34 (38)
Cutaneous squamous cell carcinoma	5 (4)	10 (11)
Other gastrointestinal malignant neoplasm	3 (3)	3 (3)
Cancer stage
II	8 (7)	6 (7)	.84
III	12 (10)	7 (8)
IV	98 (83)	77 (86)
Cetuximab therapy
First line	25 (22)	21 (23)	.71
Second or later line	93 (79)	69 (77)
Duration, d
Mean	146.4 (222.4)	156.0 (262.4)	.34
Median (range)	78 (1-2101)	66 (1-2105)
Concurrent chemotherapy
Multi-agent chemotherapy regimen	96 (81)	60 (67)	.02
Single-agent cetuximab	22 (19)	30 (33)
Concurrent radiotherapy
Radiotherapy	15 (13)	13 (14)	.72
No radiotherapy	103 (87)	77 (86)
Concurrent corticosteroids
Oral	94 (80)	66 (73)	.33
Intravenous	4 (3)	7 (8)
None	20 (17)	17 (19)
Treatment location
DFCI main campus	107 (91)	59 (66)	<.001
DFCI affiliate site	11 (9)	31 (34)

Abbreviation: DFCI, Dana-Farber Cancer Institute.

Primary Outcomes

At cetuximab treatment initiation, 29 patients (25%) received prophylactic treatment of rash in 2012, and 42 patients (47%) received prophylactic treatment of rash in 2017 (P < .001) (Figure 1A). Stratified by treatment location, the increase in prophylaxis occurred primarily at the main campus (from 25% [27 of 107] in 2012 to 58% [34 of 59] in 2017; P < .001), with no significant increase in the satellite locations (from 18% [2 of 11] in 2012 to 26% [8 of 31] in 2017; P = .62). In 2017 alone, the prophylaxis rate was significantly higher at the main campus than at the satellite locations (58% [34 of 59] vs 26% [8 of 31]; P = .004).

Figure 1. Rates of Prophylactic Treatment, Selection of Treatment Agents, and Rates of Rescue Treatments and Cetuximab Dose Changes/Interruptions.

A, Rate of rash prophylaxis by year and treatment site. B, Selection of treatment agents for rash prophylaxis by year. C, Rescue treatments and cetuximab dose changes by prophylaxis status. DFCI indicates Dana-Farber Cancer Institute. The lines extending into and beyond the bars indicate 95% CIs.

^aSignificant at P < .05.

^bSignificant at P < .001.

From 2012 to 2017, preemptive tetracycline use (45% [13 of 29] to 71% [30 of 42]; P = .02) and topical corticosteroid use (7% [2 of 29] to 57% [24 of 42]; P < .001) increased, and topical antibiotic use (79% [23 of 29] to 43% [18 of 42]; P = .002) decreased (Figure 1B). There was no significant difference in sunscreen or moisturizer use from 2012 to 2017 (17% [5 of 29] to 12% [5 of 42]; P = .53). Stratified by treatment location, both the increase in preemptive topical corticosteroid use (from 7% [2 of 27] in 2012 to 68% [23 of 34] in 2017; P < .001) and the decrease in preemptive topical antibiotic use (from 78% [21 of 27] in 2012 to 41% [14 of 34] in 2017; P = .004) were found to occur primarily at the main campus, with no significant change at the satellite locations (topical corticosteroids: from 0% [0 of 2] in 2012 to 12% [1 of 8] in 2017 [P = .65]; topical antibiotics: from 100% [2 of 2] in 2012 to 50% [4 of 8] in 2017 [P = .24]). The tetracyclines prescribed were either minocycline or doxycycline, consistent with guidelines. The topical antibiotics prescribed included clindamycin hydrochloride and metronidazole hydrochloride. The most commonly prescribed topical corticosteroid was triamcinolone acetonide, 0.1%, followed by hydrocortisone acetate, 2.5%, desonide, 0.05%, hydrocortisone acetate, 1%, clobetasol propionate, 0.05%, and betamethasone acetate, 0.05%.

Secondary Outcomes

Most study patients had grade 1 rash (60% [71 of 118] in 2012 and 66% [59 of 90] in 2017). With regard to more severe rashes, there were no study patients with grade 4 rash, 5 patients (6% [5 of 90] of the 2017 cohort) with grade 3 rash, and 21 patients (11% [13 of 118] in 2012 and 9% [8 of 90] in 2017) with grade 2 rash. There was no significant difference in the incidence of rash (82% [58 of 71] vs 72% [98 of 137]; P = .11) or severity (grade 1, 83% [48 of 58] vs 84% [82 of 98] [P = .88]; grade ≥2, 17% [10 of 58] vs 16% [16 of 98]; P = .88) between patients prescribed prophylactic treatment and patients not prescribed prophylaxis. After the development of rash, the proportions of patients needing a first rescue treatment (45% [26 of 58] vs 93% [91 of 98]; P < .001) and a second rescue treatment (7% [4 of 58] vs 23% [23 of 98]; P = .008) were significantly lower among patients prescribed prophylactic treatment compared with patients not prescribed prophylaxis (Figure 1C). There was an insignificant increase in the number of patients formally referred to dermatology for EGFRi-associated rash between 2012 and 2017 (from 8% [7 of 84] to 17% [12 of 72]; P = .07).

Furthermore, patients prescribed prophylactic treatment had significantly lower rates of cetuximab dose changes or interruptions compared with patients not prescribed prophylactic treatment (5% [3 of 58] vs 19% [19 of 98]; P = .01). Patients prescribed prophylaxis were 94% less likely to require a first rescue treatment for rash (adjusted odds ratio, 0.06; 95% CI, 0.02-0.16; P < .001), 74% less likely to require a second rescue treatment for rash (adjusted odds ratio, 0.26; 95% CI, 0.08-0.83; P = .02), and 79% less likely to experience a cetuximab dose change or interruption (adjusted odds ratio, 0.21; 95% CI, 0.06-0.81; P = .02) compared with patients not prescribed prophylaxis.

There was a nonsignificant increase in rash-associated cetuximab dose changes or interruptions from 2012 to 2017 overall (11% [9 of 84] to 18% [13 of 72]; P = .19), with much of the increase occurring at the satellite locations (from 17% [1 of 6] in 2012 to 32% [8 of 25] in 2017; P = .46). No patients had cetuximab withheld or stopped prematurely secondary to rash at the main campus in 2017, whereas 6 patients had cetuximab withheld or stopped prematurely secondary to rash at the main campus in 2012. There was no significant difference in overall survival at 2 years by prophylaxis status for colorectal (hazard ratio, 0.725; 95% CI, 0.466-1.129; P = .15) or head and neck cancer (hazard ratio, 1.264; 95% CI, 0.621-2.573; P = .53), adjusting for race/ethnicity, age, and cancer stage (Figure 2A and B).

Figure 2. Kaplan-Meier Curves for Overall Survival by Prophylaxis Status at 24 Months.

A, Overall survival for colorectal cancer at 24 months. B, Overall survival for head and neck cancer at 24 months. HR indicates hazard ratio.

Discussion

This study evaluated adherence to evidence-based prophylaxis protocols for EGFRi-associated rash at an urban cancer center and its community-based satellite locations before and after implementation of a comprehensive skin toxicity program at the main campus. There was a significant increase in the prophylaxis rate in 2017 compared with 2012; this increase occurred primarily at the main campus rather than at the satellite locations. Prophylactic agent selection also improved from 2012 to 2017 in accordance with published guidelines. Increased oral tetracycline and topical corticosteroid use with corresponding decreased topical antibiotic use was seen, consistent with guidelines based on the knowledge that EGFRi-associated rashes are inflammatory processes distinct from acne.^12,14 Similar to the increase in the prophylaxis rate, much of the improvement in agent selection also occurred at the main campus rather than at the satellite locations.

Prophylactic rash treatment was also associated with a significantly decreased likelihood of needing rescue treatments after the development of a rash as well as a significantly decreased likelihood of experiencing cetuximab dose changes or interruptions. We did not find a decreased incidence of rash with prophylaxis, which was demonstrated previously for rashes of grade 2 severity and above.^9,10,11 Whereas 10% to 20% of patients may develop grade 3 or 4 rashes while taking cetuximab,³ our study observed no patients with grade 4 rash, 5 patients (6% of the 2017 cohort) with grade 3 rash, and 21 total patients (11% in 2012 and 9% in 2017) with grade 2 rash. This lower incidence of severe rash may be associated with concurrent systemic corticosteroid use within cetuximab-based oncologic regimens, as observed in 82% of patients. Given the documentation inconsistencies and Common Terminology Criteria for Adverse Events updates in 2017,¹⁵ the rates of first and second rescue treatments were used as proxies for rash severity. Although not directly associated with rash grade, we considered the need for additional prescriptions to treat EGFRi-associated rash to be clinically significant.

Notably, prophylaxis rates remained low in 2017 (47% of the entire 2017 cohort and 58% of the 2017 main campus cohort), highlighting an important opportunity for continued improvement given the demonstrated benefits of prophylaxis. Lack of survival difference by prophylaxis status, as previously demonstrated,^9,16 provides additional support that these antitoxicity interventions may not be negatively associated with EGFRi antitumor activity.

Overall, we demonstrated that the integration of dermatologists into oncology care through institution-wide initiatives is associated with increased prophylaxis rates for EGFRi-associated skin toxicity and improved prophylactic treatment selection. Furthermore, we showed that the benefits associated with prophylaxis for EGFRi-associated rash included fewer rescue treatments and dose changes or interruptions to EGFRi anticancer therapy. Although it is possible that experience over time improved guideline adherence for EGFRi-associated rash prevention and management, the rates and patterns of prophylaxis in 2012 (2 years after guideline publication and 8 years after cetuximab’s initial US Food and Drug Administration approval) were still inconsistent with guidelines and improved only after STAT implementation. Lack of significant improvement at the satellite locations by 2017 further supports the finding that STAT implementation, rather than just increased experience with time, was associated with improving care.

Anticipating the need for increased access to dermatologic expertise in the community setting, STAT has had a greater presence in the satellite locations since 2017 through conferences and shared education tools. We suspect that these educational initiatives may be more critical in settings in which oncologists are generalists rather than focusing on a single disease; oncologists specializing in a specific malignant neoplasm are better positioned to keep up with diverse toxicity-associated guidelines than those who treat many cancers. Further study is required to determine the association of the implementation of the remote components of STAT with guideline adherence and the generalizability to the greater oncology community, where physical access to oncodermatologists may be limited.¹⁷

Limitations

This study has some limitations, including its retrospective design and potential bias from incomplete documentation. Also, the findings from our single-institution study may not be generalizable to other institutions or the greater oncology community.

Conclusions

Nevertheless, the results of this study highlight the value of integrating dermatologic care and education into oncology centers by increasing adherence to evidence-based prophylaxis protocols for rash and appropriate treatment agent selection, which may minimize toxicity-associated chemotherapy interruptions and improve quality of life.