Is there any evidence for prophylactic doxycycline upfront with patients starting cetuximab or panitumumab (to prevent rash)?

Comment by InpharmD Researcher

While overall evidence evaluating the role of prophylactic doxycycline in preventing EGFR inhibitor (cetuximab or panitumumab)-induced rash is limited, one phase II open-label randomized trial reported pre-emptive doxycycline (100 mg BID), along with skin moisturizer and topical hydrocortisone, effectively reduced incidence of ≥ grade 2 skin toxicity compared to reactive treatment. Despite conflicting findings among observational studies, expert opinion advises administration of systemic antibiotics (either doxycycline or minocycline) during the first 6-8 weeks of cetuximab or panitumumab therapy. Further investigation is required to elucidate the optimal use of doxycycline, focusing on select patient population and duration of therapy.

Background

A 2018 review aimed to provide preventative recommendations, from an infectious disease perspective, for cancer patients who received therapies targeting cell surface receptors and associated signaling pathways. Among various therapeutic agents, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) are known to cause secondary skin and soft tissue infection in cases of severe papulopustular rash. To prevent such complications, systemic antibiotics with doxycycline or minocycline are suggested as prophylactic modality. A referenced 2016 meta-analysis assessed the efficacy of prophylactic antibiotics in patients with solid tumors treated with EGFR inhibitors, in particular in terms of severity and duration of skin toxicity. Of 13 included trials (N= 1,073), 6 involved monoclonal antibodies cetuximab or panitumumab. In all cases, the prophylactic antibiotics used for treatment were tetracyclines (tetracycline in 3 studies, doxycycline in 4 studies, and minocycline in 6 studies), with doxycycline commonly given as 100 mg PO BID for at least 4 weeks. Overall, patients in the prophylactic antibiotic arms had a significantly lower risk of developing a skin rash (odds ratio [OR] 0.53; 95% confidence interval [CI] 0.39 to 0.72; p<0.01), and moderate-to-severe toxicities (Grade 2-4) were reduced by nearly 70% (OR 0.32; 95% CI 0.19 to 0.55; p<0.01) in 12 trials. However, subgroup analysis based on type of antibiotics did not reveal doxycycline explicitly to be associated with a significant reduction in all-grade analysis (OR 0.64, p= 0.09 and 0.25, p<0.01), yet minocycline did in skin rash of both all and worst grades (OR 0.53, p= 0.01 and 0.30, p= 0.01). As minocycline outperformed doxycycline in terms of skin rash of all grades, it may be preferred in patients with acneiform skin rash, whereas in a metastatic setting, doxycycline should be considered, given its more favorable safety profile and fewer drug interactions with cytotoxic agents. The mixed nature of included trials, both randomized and observational, and the lack of information on duration, timing of onset, and side effects associated with systemic antibiotics, may limit the findings. Nevertheless, results from available randomized controlled trials suggest the administration of systemic antibiotics (e.g., doxycycline 100 mg Q12H or minocycline 100 mg daily) for the first 6 to 8 weeks. [1], [2]

References:

[1] Aguilar-Company J, Fernández-Ruiz M, García-Campelo R, Garrido-Castro AC, Ruiz-Camps I. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Cell surface receptors and associated signaling pathways). Clin Microbiol Infect. 2018;24 Suppl 2:S41-S52. doi:10.1016/j.cmi.2017.12.027
[2] Petrelli F, Borgonovo K, Cabiddu M, et al. Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis. Br J Dermatol. 2016;175(6):1166-1174. doi:10.1111/bjd.14756
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any evidence for prophylactic doxycycline upfront with patients starting cetuximab or panitumumab (to prevent rash)?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-3 for your response.

 

Skin Toxicity Evaluation Protocol With Panitumumab (STEPP), a Phase II, Open-Label, Randomized Trial Evaluating the Impact of a Pre-Emptive Skin Treatment Regimen on Skin Toxicities and Quality of Life in Patients With Metastatic Colorectal Cancer

Design

Phase II, open-label, randomized trial

N= 95

Objective

 To examine differences between pre-emptive and reactive skin treatment for specific skin toxicities in patients with refractory metastatic colorectal cancer (mCRC) for any epidermal growth factor receptor (EGFR) inhibitor

Study Groups

Pre-emptive (n= 48)

Reactive (n= 47)

Inclusion Criteria

 Age 18 years or older with metastatic adenocarcinoma of the colon or rectum with at least one unidimensional measurable lesion ≥ 20 mm (using magnetic resonance imaging or computed tomography [CT] scan) or ≥ 10 mm (using a spiral CT scan) that could not be cured by surgical resection; had disease progressoin or unacceptable toxicity with first-line treatment containing fluoropyrimidine and oxaliplatin-based chemotherapy with or without bevacizumab for mCRC; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; adequate hematologic, renal, metabolic, and hepatic function

Exclusion Criteria

 Irinotecan treatment, anti-EGFR therapy or vaccine treatment for mCRC, incidence of pulmonary embolism, deep vein thrombosis, or any other significant thromboembolic event within 8 weeks before randomization

Methods

Patients were randomized 1:1 to receive pre-emptive skin treatment using skin moisturizer or sunscreen during anytime of the treatment, 1% hydrocortisone cream applied topically at bedtime, and doxycycline 100 mg BID; or reactive treatment after skin toxicity develops which consisted of any treatments the investigator deemed necessary for the management of emergent skin toxicity and could be adminsitered at any time during weeks 1 to 6. Pre-emptive treatment was initiated one day before administration of the first panitumumab dose and continued through weeks 1 to 6. The chemotherapy regimen consisted of panitumumab 6 mg/kg every 2 weeks with FOLFIRI chemotherapy at 9 mg/kg every 3 weeks with irinotecan chemotherapy.

Duration

 Follow-up: 7 weeks

Outcome Measures

 Primary: incidence of protocol-specified ≥ grade 2 skin toxicities during the 6-week treatment period

Baseline Characteristics

  

Pre-emptive (n= 48)

Reactive (n= 47)

  

Age, years, median [range]

 60 [24-84] 61 [40-86]  

Male

 67% 55%  

ECOG performance

0

1

2

 

71%

25%

4%

 

64%

36%

0

  

Primary tumor type

Colon

Rectal

 

71%

29%

 

60%

40%

  

No. of metastatic sites

1

> 1

 

38%

63%

 

36%

64%

  

Patients receiving chemotherapy

Every 2 weeks

Every 3 weeks

 

58%

42%

 

57%

43%

  

Results

Endpoint

Pre-emptive (n= 48)

Reactive (n= 47)

Odds ratio (95% confidence interval [CI])

Patients with grade 2 or higher skin toxicity

14 (29%)

29 (62%)

0.3 (0.1 to 0.6)

Grade 2 toxicity

Grade 3 toxicity

11 (23%)

3 (6%)

19 (40%)

10 (21%)

  

Adverse Events

All patients experienced at least one adverse event.

Grade 3 or higher adverse events: 60% in the preemptive group; 81% in the reactive group.

Study Author Conclusions

The preemptive skin treatment regimen was well tolerated. The incidence of specific ≥ grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the preemptive group compared with the reactive group. Patients in the preemptive group reported less quality of life impairment than patients in the reactive group.

InpharmD Researcher Critique

 The lack of blinding could introduce bias, thereby influencing the evaluation of skin toxicities and quality of life. Although the study compared pre-emptive and reactive treatment approaches, there was no control group that received no treatment or a placebo.



References:

Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(8):1351-1357. doi:10.1200/JCO.2008.21.7828

 

Doxycycline for prevention of erlotinib-induced rash in patients with non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial

Design

Randomized, open-label, prospective, phase II trial

N= 147

Objective

 To evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer (NSCLC)

Study Groups

Doxycycline (n= 73)

Control (n= 74)

Inclusion Criteria

Age 18 years or older, histologically or cytologically confirmed inoperable locally advanced or metastatic (stage IIIB/IV) NSCLC, failed first-line platinum-based chemotherapy, measurable disease according to Response Evaluation Criteria in Solid Tumors, Eastern Cooperative Oncology Group (ECOG) performance status less than 2, adequate organ function and an estimated life expectancy of 12 weeks or longer

Exclusion Criteria

Small-cell bronchogenic cancer or neuroendocrine tumors; a history of other active malignancy within the last 5 years; no prior chemotherapy for advanced NSCLC; a history of clinically significant cardiovascular, eye, or gastrointestinal disease; rash of any etiology at study entry; previous treatment with an EGFR inhibitor; hypersensitivity to erlotinib treatment; current use of cyclines; history of allergic reactions to tetracyclines

Methods

Patients were randomized (1:1) to receive erlotinib 150 mg/day per PO plus doxycycline 100 mg/day per PO for 4-12 months per the investigator's discretion; or erlotinib alone. A clinically relevant rash was determined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] criteria that a rash involving less than 50% of the body surface area with symptoms is a grade 2, involving greater than or equal to 50% of the body surface area with symptoms is a grade 3, and a more generalized, exfoliative rash is a grade 4.

Duration

 Max follow-up: 13.5 months

Outcome Measures

 Doxycycline efficacy on skin lesions induced by erlotinib during the first 4 months of treatment

Baseline Characteristics

  

Doxycycline (n= 73)

Control (n= 74)

  

Age, years

 64 64  

Female

34% 32%  

ECOG performance status

0

1

2

 

45%

37%

18%

 

37%

50%

13%

  

WHO histology

Epidermoid carcinoma

Adenocarcinoma

Bronchoalveolar carcinoma

Large-cell carcinoma

Other

 

23%

69%

1%

4%

3%

 

24%

68%

1%

5%

1%

  

Disease stage at inclusion

Nonresectable stage IIIB

Stage IV

Stage IIIA

 

15%

82%

3%

 

15%

85%

0

  

Best response of first-line chemotherapy

Complete response/partial response

Stable disease

Progression

Not done

 

37%

33%

27%

3%

 

45%

35%

20%

0

  

Results

Endpoint

Doxycycline (n= 73)

Control (n= 74)

p-value

Patients with at least 1 onset of folliculitis

52 (71%)

59 (81%)

0.18

Time between first dose of erlotinib and onset of folliculitis, days (95% confidence interval [CI])

14 (13 to 22)

13 (8 to 16)

0.14

Duration of folliculitis, days (standard deviation [SD])

60 (36)

61 (34)

 -- 

Patients with other skin lesions

Patients with xerosis

Patients with paronychia

29

27

5

31

30

6

0.003

0.002

0.55

Adverse Events

Almost all patients in both the doxycycline and control arms experienced treatment-emergent adverse events (TEAEs), mainly folliculitis, diarrhea, and xerosis.

Doxycycline-related TEAEs were mostly gastrointestinal issues. 

Serious TEAEs occurred in about 25-32% of patients in both arms, mostly due to general physical health deterioration.

Four patients in each arm withdrew due to AEs considered related to erlotinib.

Study Author Conclusions

 Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity. 

InpharmD Researcher Critique

The study's findings may have been influenced by the exclusion of individuals with more severe illnesses. The open-label design may further introduce bias in the study's results due to preconceived notions or expectations about the treatment, possibly made sensitive from their recurrent NSCLC status.



References:

Deplanque G, Gervais R, Vergnenegre A, et al. Doxycycline for prevention of erlotinib-induced rash in patients with non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial. J Am Acad Dermatol. 2016;74(6):1077-1085. doi:10.1016/j.jaad.2016.01.019

 

Systemic Doxycycline for Pre-emptive Treatment of Anti-EGFR-related Skin Toxicity in Patients with Metastatic Colorectal Cancer Receiving First-line Panitumumab-based Therapy: A Post Hoc Analysis of the Valentino Study

Design

Post hoc analysis of Valentino study (multicenter, randomized, open-label phase II trial)

N= 226

Objective

To assess the safety and efficacy of the administration of pre-emptive doxycycline prophylaxis for anti-EGFR-related skin toxicity

Study Groups

Pre-emptive prophylaxis (n= 143)

No prophylaxis (n= 83)

Inclusion Criteria

Patients enrolled in the Valentino study that received at least 1 cycle of study treatment

Exclusion Criteria

Patients not receiving the study treatment

Methods

Valentino study was designed to evaluate the non-inferiority in terms of progression-free survival (PFS) of maintenance with single-agent panitumumab versus panitumumab plus 5-fluorouracil/leucovorin (5-FU/LV) after a 4-month induction with panitumumab plus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer (mCRC) in the first line of treatment. The trial showed that maintenance with single-agent panitumumab was inferior to panitumumab plus 5-FU/LV, though with a slightly reduced toxicity burden. 

The pre-emptive therapy of skin toxicity was recommended by the study protocol in order to decrease the incidence of grade ≥ 3 skin rash according to the literature. Such treatment should have been administered from cycle 1 day 1 of study treatment and consisted in skin moisturizer applied to the face, hands, feet, neck, back, and chest daily in the morning and topical steroids at bedtime; sunscreen applied to exposed skin areas before going outdoors; and doxycycline 100mg daily for 1 week starting from day 1 of cycle 1 and then every other cycle.

Duration

Treatment: 7 months (range 0–35) in the overall trial population, 6 months (range 0–35) in patients who received the pre-emptive prophylaxis for anti-EGFR class-specific toxicity, and 7 months (range 0–25) in patients who did not receive the pre-emptive prophylaxis

Outcome Measures

Primary: differential incidence of treatment-related and panitumumab-related adverse events (AEs) in patients stratified according to the administration of the pre-emptive antibiotic prophylaxis for anti-EGFR class-specific toxicity

Secondary: duration of treatment, the occurrence of treatment delays and dose reductions of panitumumab, PFS and overall survival (OS)

Baseline Characteristics

  

Pre-emptive prophylaxis (n = 143)

No prophylaxis (n = 83)

  

Age, years, median [IQR]

 64 (55-70) 63 (54-70)  

Female

32% 35%  

ECOG performance status

0

1

 

73%

27% 

 

73%

27% 

  

Prior adjuvant treatment

 18%  11%  

Primary tumor resected

 64% 63%  

Liver-limited disease

 33% 40%  
Synchronous metastases 76% 82%  

BRAF status

Wild-type

Mutated

 

97%

3%

 

94%

6%

  

Abbreviations: ECOG= Eastern Cooperative Oncology Group; IQR= interquartile range

Results

Endpoint

Pre-emptive prophylaxis (n = 143)

No prophylaxis (n = 83)

p-value

Overall treatment-related toxicity

Any grade: 142 (99%) 

Grade 1/2: 140 (98%)

Grade 3/4: 104 (73%)

Any grade: 81 (98%)

Grade 1/2: 81 (98%)

Grade 3/4: 57 (69%)

Any grade: 0.556

Grade 3/4: 0.544

Panitumumab-related AE

Skin rash

Any grade: 116 (81%)

Grade 1/2: 77 (54%)

Grade 3/4: 39 (27%)

Any grade: 75 (90%)

Grade 1/2: 54 (65%)

Grade 3/4: 21 (25%)

Any grade: 0.085

Grade 3/4: 0.876
Dry skin

Any grade: 17 (12%)

Grade 1/2: 17 (12%)

Grade 3/4: 0

Any grade: 19 (23%)

Grade 1/2: 19 (23%)

Grade 3/4: 0

Any grade: 0.058

Grade 3/4: N/A
Paronychia

Any grade: 23 (16%)

Grade 1/2: 21 (15%)

Grade 3/4: 2 (1%)

Any grade: 13 (16%)

Grade 1/2: 12 (14%)

Grade 3/4: 1 (1%)

Any grade: 1.000

Grade 3/4: 1.000
Hypomagnesemia

Any grade: 60 (42%)

Grade 1/2: 58 (41%)

Grade 3/4: 2 (1%)

Any grade: 27 (33%)

Grade 1/2: 24 (29%)

Grade 3/4: 3 (4%)

Any grade: 0.202

Grade 3/4: 0.359
Conjunctivitis

Any grade: 23 (16%)

Grade 1/2: 21 (15%)

Grade 3/4: 2 (1%)

Any grade: 18 (22%)

Grade 1/2: 17 (20%)

Grade 3/4: 1 (1%)

Any grade: 0.371

Grade 3/4: 1.000
No significant differences in terms of treatment duration, treatment delays or dose reductions, PFS, and OS were observed in the two sub-populations. 

Study Author Conclusions

The adequate management of anti-EGFR-related skin toxicity is fundamental to optimize the outcome of mCRC patients, balancing the survival benefit with patients’ quality of life, especially in the first-line setting. 

InpharmD Researcher Critique

The study's main limitations include its retrospective nature, potential biases, and small sample size, which could affect the significance of primary endpoint results. Subpopulations based on skin toxicity prophylaxis were non-randomly defined, and the open-label design may bias adverse event assessment. Incomplete compliance with prophylactic measures also affects the outcomes. Despite these biases, this analysis sheds light on pre-emptive prophylaxis in maintenance treatment for mCRC, distinct from prior trials.



References:

Raimondi A, Corallo S, Lonardi S, et al. Systemic doxycycline for pre-emptive treatment of anti-EGFR-related skin toxicity in patients with metastatic colorectal cancer receiving first-line panitumumab-based therapy: a post hoc analysis of the Valentino study. Support Care Cancer. 2021;29(7):3971-3980. doi:10.1007/s00520-020-05972-2