Keywords
Breast cancer - docetaxel - pneumonitis - steroids
Introduction
Docetaxel is a chemotherapeutic agent widely used in medical oncology practice. Pulmonary
toxicity in the form of interstitial pneumonitis has been associated with docetaxel
and reported when used for lung, breast, and prostate cancer.[1]
[2] Although rare, the identification of this complication is important as it has been
associated with up to 40% mortality in certain series.[3] We present a descriptive audit of patients with suspected docetaxel associated lung
injury from a single institute.
Methods
We reviewed the records 477 patients who received docetaxel over a 1 year period (June
2015 and 2016). Among these, patients who presented with respiratory symptoms within
4 weeks of administration of docetaxel were identified. After excluding patients with
overt signs of infection (fever, productive cough, and preexisting upper respiratory
symptoms) and those who had overt metastatic disease involving the lungs, we identified
eight patients (all 8 had breast cancer) with possible drug-induced lung injury. The
records of these were assessed for disease characteristics, details of chemotherapy,
clinical presentation, laboratory and radiological features, treatment details, and
outcomes.
Results
The indications for the use of docetaxel were breast cancer (n = 417, 87%), prostate cancer (n = 23, 5%), and lung cancer (n = 16, 3%). All patients received docetaxel 75 mg/m2 once in 3 weeks (with standard dose modifications for poor performance status/age/prior
toxicity). Patients received premedications including dexamethasone as per institutional
protocol and were continued on oral dexamethasone for three more days.
Clinical features
Among the 8 (1.7%) patients with possible docetaxel lung injury [Table 1], median age was 43 years (34–65 years). Four patients (50%) had metastatic disease
(none had lung/pleural metastasis). Two patients (25%) were on neoadjuvant chemotherapy,
and the other two (25%) were on adjuvant treatment. One patient had the preexisting
pulmonary disease (localized bronchiectasis). Four patients had received prior radiation
to the chest wall or dorsal spine as part of breast cancer treatment. One patient
received docetaxel in combination with cyclophosphamide (600 mg/m2), and the other 7 received it as a single agent. Co-administered medications included
pegylated granulocyte-colony-stimulating factor (n = 1) and zoledronic acid (n = 1).
Table 1
Characteristics of patients with suspected docetaxel-induced lung injury
|
Number
|
Age
|
Stage
|
Rx setting
|
Number of cyclesa
|
Number of daysb
|
Growth factorc
|
Prior RT
|
Major symptom
|
Grade of pneumonitis
|
In-patient duration (days)
|
Outcome
|
|
aNumber of cycles of docetaxel delivered before the occurrence of pulmonary toxicity;
bNumber of days which had elapsed from the last dose of the docetaxel before the occurrence
of pulmonary symptoms; cDuring the therapy with docetaxel. NACT - Neoadjuvant chemotherapy; RT - Radiation
therapy
|
|
1
|
38
|
III
|
NACT
|
3
|
18
|
No
|
Yes
|
Dyspnea
|
III
|
18
|
Resolution
|
|
2
|
65
|
IV
|
Palliative
|
3
|
23
|
No
|
No
|
Dyspnea
|
II
|
0
|
Resolution
|
|
3
|
42
|
III
|
NACT
|
3
|
28
|
No
|
No
|
Dyspnea
|
II
|
0
|
Resolution
|
|
4
|
40
|
IV
|
Palliative
|
4
|
17
|
No
|
Yes
|
Dyspnea
|
III
|
9
|
Resolution
|
|
5
|
55
|
III
|
Adjuvant
|
4
|
8
|
Yes
|
Yes
|
Dyspnea
|
III
|
8
|
Resolution
|
|
6
|
48
|
IV
|
Palliative
|
3
|
15
|
No
|
Yes
|
Cough
|
II
|
15
|
Resolution
|
|
7
|
36
|
II
|
NACT
|
3
|
12
|
No
|
Yes
|
Dyspnea
|
II
|
8
|
Resolution
|
|
8
|
45
|
IV
|
Palliative
|
3
|
15
|
No
|
No
|
Dyspnea
|
II
|
9
|
Resoluton
|
Median number of cycles before the onset of pneumonitis was 3 (3–4). The median time
from administration of the last dose was 16 days (8–28). The earliest occurrence of
the toxicity was in 8 days in a 55-year-old female who received a combination of cyclophosphamide
and docetaxel. Dyspnea was the most common presentation (n = 7) followed by cough (n = 1). None of the patients had a fever or pleuritic chest pain. All patients had
a documented normal systolic cardiac function as evaluated by echocardiography.
Radiological features
All patients underwent chest-X-ray at admission, and high resolution computed tomography
(CT) scan within 48 h of presentation [Figure 1]. All the patients presented with a pattern of diffuse interstitial pneumonitis.
Most of the patients had bilateral involvement with diffuse ground-glass haziness
and patchy parenchymal infiltrates with no site predominance. Diffuse peribronchiolar
thickening with mosaic attenuation of lung parenchyma in the involved segment was
the most common presentation [Figure 2]. One patient had mainly right-sided involvement more than left, and another patient
had associated minimal reactive pleural effusion. With treatment, all the patients
had a significant resolution of radiological abnormalities [Figure 3].
Figure 1: Pretreatment X-ray showing interstitial infiltrates involving mid and lower
zones (a) with significant resolution after treatment (b)
Figure 2: Pretreatment computed tomography scan - axial high resolution sections in
lung windows show diffuse perihilar groung glass haziness and peribronchial thickening
in bilateral mid zones (a-c). The same patient’s posttreatment corresponding high
resolution sections show marked resolution of the interstitial pneumonitis (d-f)
Figure 3: Pretreatment computed tomography scan - axial high resolution sections in
lung windows show diffuse perihilar groung glass haziness and peribronchial thickening
in bilateral mid zones (a and b). Posttreatment high resolution sections show significant
improvement in the interstitial pneumonitis with patchy residual ground glass haziness
(c)
Management and outcomes
Most (n = 6/8, 75%) required initial hospitalization. Three patients with CTCAE Grade 3 pneumonitis
required oxygen support. Bronchoscopy was done in six patients-no airway abnormalities,
inflammation, or secretions were noted in any of the studies. Bronchoalveolar fluid
(BAL) was negative for acid-fast bacillus and fungal stains in all six. Although there
was no fever, all the patients underwent workup for infectious causes and received
empiric broad-spectrum antibiotics considering the severity of the symptoms. Furthermore,
none of the patients were neutropenic. There was no response to antibiotics in any
of these patients and all of these patients had significant improvement in their symptoms
only after treatment with steroids.
All the patients were started oral prednisolone at a dose of 1 mg/kg and were tapered
over 2–3 weeks in responding patients. In all but the 3 patients requiring oxygen
support, prednisolone was started after 2–3 days of antibiotics and after CT scan
images were reviewed. High dose cotrimoxazole was used to cover pneumocystis in one
patient (based on radiological suspicion), which was discontinued after the negative
BAL. Two patients required early taper due to hyperglycemia and due to herpes Zoster
reactivation but remained symptom-free. In one patient, Tablet Pirfenidone was also
started as per the advice of the pulmonologist. The median duration of hospital stay
was 8.5 days (7–18 days). There was no recurrence of symptoms in any of the patients
during subsequent follow-up. Anti-cancer therapy was resumed wherever indicated, but
none were rechallenged with taxanes.
Discussion
Our audit identified a series of eight patients over a period of 1 year with possible
docetaxel-induced acute lung injury. Although this is a rare complication of a relatively
commonly used chemotherapeutic agent, it is well-recognized. The largest number of
cases with pneumonitis (18 cases) were reported in a series of patients with lung
cancer from Japan.[1] Although one may suspect the diagnosis based on clinicoradiological information,
the diagnosis of “docetaxel-induced pneumonitis” is a diagnosis of exclusion.[4] In our series, the timing of onset of symptoms, the interstitial pattern of infiltrates
and response to steroids were the strong pointers toward the diagnosis of drug-induced
lung injury. Although some patients did grow bacterial pathogens in the BAL fluid,
lack of fever, the absence of response to antibiotics and radiology suggestive of
an interstitial pattern of infiltration were all against a diagnosis of bacterial
pneumonitis. Furthermore, there was no evidence to suggest pneumocystis infection
after investigations including BAL.[5]
All our patients received 3 weekly cycles of docetaxel, and the overall incidence
was 1.7%. In the largest published series of docetaxel-related lung injury in patients
with lung cancer (n = 392) incidence was 4.6%.[1] However, more than two-third of patients in that series had preexisting lung abnormalities,
unlike our patients. Combination of cyclophosphamide with docetaxel producing pneumonitis
is also previously reported, and one of our patients had received this combination.
Apart from prexisting lung diseases, use of drugs like gemcitabine and radiation exposure
have also been associated with pneumonitis.[6]
[7] In most of the series, patients develop pneumonitis 2–3 weeks after chemotherapy.
However, there are case reports where this occurred as early as 3 days.[8] Most of the patients presented during second to the fourth cycle of docetaxel similar
to our report. However, it can be as early as one cycle and as late as nine cycles.[6] To make sure this rare complication is not related to any particular brand, we checked
the details of the batch number, brand and manufacturers which were different for
each patient.
Although the exact mechanism of lung injury is debatable, the most common pattern
of lung injury described is that of hypersensitivity pneumonitis.[9] Some studies have reported that bronchoscopy and bronchoalveolar lavage may give
some evidence to support the diagnosis of drug-induced pneumonitis based on lymphocytic
alveolitis, leukocytosis, and a low CD4/CD8 ratio.[4] Transbronchial lung biopsy may show nonspecific alveolar and interstitial edema
with mononuclear cellular infiltrate.[10]
Docetaxel-induced pneumonitis is a potentially serious complication with high mortality
rates.[6] In other reported cases also, prednisolone was the main drug used for treatment
along with other supportive measures, and many of them required ventilatory support.
In our series, all patients had a resolution of symptoms, and there was no mortality
which was possibly due to early institution of steroids based on the atypical radiological
findings. This is one of the largest series of possible docetaxel pneumonitis in patients
with breast cancer.
Conclusions
Docetaxel-induced lung injury is a rare but well-described complication commonest
form of presentation in interstitial pneumonitis. It is a diagnosis of exclusion and
high index of suspicion is required to identify this uncommon problem. It should be
considered as an important differential diagnosis in patients on docetaxel who presents
with respiratory distress. Early detection and appropriate treatment including steroids
are important to prevent mortality.
