Keywords docetaxel - toxic epidermal necrolysis - breast cancer - case report
Introduction
Docetaxel is derived from the needles Taxus baccata (European yew tree). It binds to microtubules and enhances tubulin polymerization
leads to inhibition of mitosis and cell division. Reported cutaneous toxicities include
alopecia, hypersensitivity with skin rash, pigmentation, onycholysis, palmar–plantar
erythrodysesthesia, cutaneous lupus, and erythema multiforme. In our case, patient
developed toxic epidermal necrolysis (TEN) following administration of docetaxel,
which is a rare side effect of docetaxel.
Case Report
A 39-year-old woman was diagnosed with metastatic breast cancer (liver and lung metastasis).
She was on palliative chemotherapy docetaxel 75 mg/m2 with trastuzumab (8 mg/kg in first cycle followed by 6 mg/kg in consecutive cycles)
on a 3-weekly schedule. She tolerated two cycles of planned therapy. Nine days after
third cycle of docetaxel and trastuzumab on August, 08, 2021, she presented with complaints
of blisters that later ruptured with excoriation of skin over both hands, feet and
back, oral mucositis with difficulty in swallowing, sticky eyelids with conjunctival
redness, multiple episodes of vomiting, loose motions, shortness of breath, and low-grade
intermittent fever.
On examination, her Eastern Cooperative Oncology Group performance status was 4, pulse
rate 125/min, feeble, rhythmic, normovolumic, hypotension (90/60 mm Hg), tachypnea
(respiratory rate >21/min), afebrile, saturation of peripheral oxygen 80%, and Grade
III oral mucositis. Dermatological examination showed extensive erythematous desquamation
with ruptured blisters involving skin of hands, lips, feet, vulva, perianal region,
and lower back involving more than 30% of body surface was noted with mucosal involvement
([Fig. 1 ]). Crepitations was present in both lower zones of lung. Patient was admitted in
intensive care unit. Laboratory evaluation showed hemoglobin of 9.4 g/dL (11–14),
total leukocyte count 32.27 × 109 /L (4–10 × 109 ) with 82% neutrophils, 11% lymphocytes, 7% monocytes, and platelets of 2.84 lakh/mm3 , creatinine 1.1 mg/dL (0.5–1.5 mg/dL), and blood urea 102 mg/dL (15–40 mg/dL). Bilirubin
of 4.11 mg/dL (0.5–1.5 mg/dL), serum glutamic oxaloacetic transaminase 54 U/L (0–40
U/L) and serum glutamic-pyruvic transaminase 40 U/L (0–45 U/L), random blood sugar
164 mg/dL, pH 7.20 (7.35–7.45), bicarbonate 16 mEq/L (22–26 mEq/L) and rest other
investigations were within normal limits. Chest X-ray showed dense homogenous opacity
in left hemithorax obscuring left costophrenic angle suggestive of left-sided pleural
effusion.
Fig. 1 (a) Photograph of erythematous bullous eruptions over feet. (b) Photograph of hand
with skin excoriation with erythema after rupture bullous lesion. (c) Both eyelid
skin excoriation. (d) Conjunctival hemorrhage. (e) Mucosal lesion of lips and tongue.
Punch biopsy taken from the lesions on the left forearm and left medial foot, on hematoxylin-eosin-stained
specimen, light microscopy features suggested TEN ([Fig. 2 ]). Diagnosis of docetaxel-induced TEN was confirmed and managed with intravenous
fluids, vasopressors, steroids, antibiotics, and total parenteral nutrition with hypothermia
prevention. Secondary infection control and skin care were instituted. Unfortunately,
patient died on the sixth day of hospitalization.
Fig. 2 Biopsy images and pathology report: microscopic examination of the skin (hematoxylin
and eosin stain) was performed. The punch biopsies from the edges of both lesions
(left forearm and left medial foot) show similar morphologic features (1) orthokeratosis
of epidermis, (2) follicular plugging, (3) subcorneal separation and small vesicle
formation, (4) basal vacuolar changes, (5) superficial dermis shows perivascular lymphoplasmacytic
infiltrate, (6) papillary dermis shows mild edematous changes, and (7) interstitium
shows increased mast cells. The histologic features are consistent with toxic epidermal
necrolysis/Stevens–Johnson's syndrome.
Discussion
Docetaxel a microtubule inhibitor got first approved in 1996 for the treatment of
metastatic breast cancer patients who relapsed after anthracycline-based chemotherapy.[1 ]
[2 ]
Side effects of docetaxel include neutropenia, anemia, thrombocytopenia, and minor
rash to severe anaphylaxis reactions, which are reversible on stopping treatment.
In literature, various skin reactions reported includes maculopapular drug rash, alopecia,
nail hyperpigmentation and destruction, onycholysis, palmar–plantar erythrodysesthesia,
cutaneous lupus and scleroderma,[3 ] photolichenoid eruption,[4 ] erythema multiforme major,[5 ] and persistent serpentine supravenous hyperpigmented eruption.[6 ]
Only a few cases of life-threatening TEN-like adverse reaction due to docetaxel have
been reported till date.
As per Gell and Coombs system,[7 ] docetaxel causes delayed onset T-cell-mediated type IVc hypersensitivity reaction,
and can occur days to weeks after exposure.
Immunophenotype study of lymphocytes in blister fluid of TEN lesions suggested a cell-mediated
cytotoxic reaction against keratinocytes leading to apoptosis.[8 ] Further studies showed that cytotoxic T cells are drug specific, human leukocyte
antigen (HLA) class I restricted, and directed against the native form of the drug
rather than against a reactive metabolite.[8 ]
[9 ]
[10 ]
[11 ] Drugs directly bind to major histocompatibility complex class I and the T cell receptor
leading to stimulation the immune system, clonal expansion of drug-specific cytotoxic
T cells, killing of keratinocytes via release of soluble death mediators, including
granulysin.[12 ]
Drugs directly bind to the HLA class I peptide pouch,[13 ] and change the repertoire of peptides recognized as foreign[14 ] and make the HLA–drug complex recognized as foreign.
Medications are most common cause for TEN. TEN involves sloughing of more than 30%
of the body surface area. It starts with malaise, fever, and involvement of mucous
membranes in nearly all cases.[15 ] Toxic epidermal necrosis is distinguished from Stevens–Johnson's syndrome (SJS)
by severity and percentage of involvement of body surface area.
The skin lesions, that is, erythematous macules, patches, and almost 50% of cases
start with erythema lead to full-thickness epidermal necrosis and skin resembles that
of extensive thermal injury as seen in our patient. TEN is a potential life-threatening
adverse reaction with risk for complications such as secondary infections, dehydration
renal, gastrointestinal involvement, and finally scarring with cosmetic and functional
problems.
Anticancer medications reported to cause severe cutaneous adverse reactions (SJS and
TEN), alkylating agents (treosulfan, chlorambucil, temozolomide, procarbazine), plant
alkaloids (paclitaxel, docetaxel, etoposide), anthracyclines (doxorubicin), antimetabolites
(methotrexate, cytarabine, fludarabine, gemcitabine), antitumor antibiotics (bleomycin),
epidermal growth factor receptor inhibitor (afatinib, cetuximab, panitumumab), immune
checkpoint inhibitors (nivolumab, pembrolizumab), etc.
Prevention of adverse effects can be with premedication, which can be started from
a day before infusion up to 5 days. Once TEN is established, management involves multispecialty
supportive care with critical care, skin specialist, plastic surgery, nutrition specialist
and infectious disease physicians involved in fluid and electrolyte management, wound
care, nutritional support, and treatment of superinfection. Data regarding use of
corticosteroids are mixed, as their use may increase risk of sepsis in TEN.[16 ]
The Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) prognostic
scoring system is applied to rapidly evaluate individual patient on admission. Overall
mortality rates of 25 to 35% have been seen with TEN using SCORTEN prognostic scoring
system which is used to determine prognosis on days 1 and 3 of hospitalization.[17 ]
Mortality rate (%) as follows:
0 to 1 = 3.2% (confidence interval [CI]: 0.1–16.7)
2 = 12.1% (CI: 5.4–22.5)
3 = 35.3% (CI: 19.8–53.5)
4 = 58.3% (CI: 36.6–77.9)
≥ 5 = > 90% (CI: 55.5–99.8)
The SCORTEN score in our case was 5, which suggests > 90% risk of mortality. The occurrence
of TEN after third cycle of docetaxel-based therapy in our case should caution us
toward the rarity and unpredictability of this toxic reaction ([Table 1 ]).
Table 1
Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN)
Risk factors
Score
Patient
0
1
Age
< 40 y
≥ 40 y
39 y
Associated cancer
No
Yes
Breast cancer
Heart rate
< 120
> 120
125 beats/min
Detached or compromised body surface area
< 10%
≥ 10%
>30% of body surface area
Serum blood urea nitrogen
≤ 28 mg/dL (10 mmol/L)
> 28 mg/dL (10 mmol/L)
102 mg/dL
Serum bicarbonate
≥ 20 mEq/dL (≥ 20 mmol/L)
< 20 mEq/dL (≥ 20 mmol/L)
16 mEq/dL
Serum glucose
≤ 250 mg/dL (≤ 13.88 mmol/L)
> 250 mg/dL (≤ 13.88 mmol/L)
164 mg/dL
SCORTEN score 5
Conclusion
Docetaxel-induced TEN is a rare but fatal complication. Early recognition and intensive
management with supportive care by team of specialist can limit this life-threatening
complication of a commonly used cytotoxic drug in cancer management.
