Abstract
Docetaxel is a chemotherapeutic agent commonly used against breast cancer, nonsmall cell lung cancer, gastric, prostate, head and neck cancer. Docetaxel- or taxane-induced interstitial lung disease (ILD) remains a relatively rare reported adverse event. Although rare, this complication remains an important event to identify and it carries a high mortality. We reported the case series of three patients who had pulmonary toxicity after docetaxel administration. Although literature has described patients progressing to respiratory failure and intubation, our patients responded well to steroid treatment and discontinued docetaxel administration.
Keywords: Docetaxel, Drug-induced pneumonitis, Taxane, Organizing pneumonia
Introduction
Docetaxel belongs to taxane class of chemotherapeutic agents, and it is commonly used against malignancies of breast, prostate, gastric carcinoma, head and neck, and nonsmall cell lung cancer. It has been included in many oncology guidelines including National Institute for Health and Care Excellence and European Society for Medical Oncology guidelines.1 The mechanism of action involves cellular mitosis inhibition by antagonizing the microtubule proteins disassembly.2 Major reported side effects of this drug include suppression of bone marrow, endocrine, gastroenterological, hepatic, neurological, and dermatological adverse effects. However docetaxel- or taxane-induced interstitial lung disease (ILD) remains a rare reported adverse event. Although this complication occurs in 1–5% of cases receiving docetaxel, yet it remains an important event that carries a high mortality that has been reported up to 40% in current available literature.3,4 We present a case series of three patients with docetaxel-induced lung injury from a tertiary care institute.
Case Report
Three female patients (Table 1) who were diagnosed cases of breast and endometrial carcinoma and were being managed with docetaxel for past 6–11 weeks complained of progressive breathlessness, fever, and dry cough. All patients had undergone 2D echocardiography and cardiac examination before starting the treatment. They had received four cycles of Epirubicin (an anthracycline) in standard doses with cyclophosphamide and other therapies. Thereafter, each patient received two to four cycles of docetaxel before symptom onset. Cumulative dose of docetaxel ranged from 220 mg to 440 mg. There was no past medical history of receiving taxanes earlier for any indication other than present chemotherapy schedule in all cases. Patient consent was obtained for images and inclusion in the study. The chest radiograph (Fig. 1) revealed multifocal consolidations in bilateral lungs. All patients had nonspecific interstitial pneumonia (NSIP)/organizing pneumonia (OP) pattern (Fig. 2, Fig. 3) on the high-resolution computed tomography (HRCT) of chest involving bilateral upper, middle, and lower zones. Spirometry could not be done in acute stage since all patients were on oxygen support at initial presentation and were not in a condition to perform spirometry maneuver.
Table 1.
Patient characteristics, taxane regimes, time correlations, radiological appearance, and outcome of the patients in the case series.
| Case 1 | Case 2 | Case 3 | |
|---|---|---|---|
| Age (years) | 60/F | 65/F | 67/F |
| Comorbidity | Nil | COPD | Hypothyroidism |
| ECOG score | PS-2 | PS-1 | PS-2 |
| Primary carcinoma diagnosis | Carcinoma breast right (operated) Stage T2N1M0 |
Carcinoma breast left (operated) Stage T3N2M0 |
Carcinoma endometrium (operated) Recurrent stage III |
| Taxane regime and number of cycles received | Docetaxel (2#) 110 mg Thrice weekly September 2021 to October 2021 |
Docetaxel (3#) 120 mg (1#)+ 110 mg (2#) Thrice weekly July 2021 to September 2021 |
Docetaxel (4#) 110 mg Thrice weekly June 2021 to August 2021 |
| Cumulative dose | 220 mg | 330 mg | 440 mg |
| Other agents given | Carboplatin (AUC 5)Trastuzumab 8 mg/kg load followed by 6 mg/kg thrice weekly | Cyclophoasphamide 600mg/m2 |
Carboplatin (AUC 5) |
| Symptom onset | 6 weeks | 8 weeks | 11 week |
| Time from the first dose (weeks) | |||
| Time from the final dose (weeks) | 1 week | 2 weeks | 2 weeks |
| HRCT and respiratory MDTM diagnosis | Nonspecific interstitial pneumonia (NSIP)/organizing | Organizing pneumonia | Organizing pneumonia |
| Follow-up imaging | Interval resolution (chest radiography in 8 weeks) | Interval resolution (Chest radiography in 12 weeks) | Interval resolution (HRCT in 08 weeks |
| HRCT/Chest X-ray | |||
| Force vital capacity (spirometry) after | 70% predicted | 66% predicted | 82% predicted |
Fig. 1.
Case 1: (a) Chest radiograph at initial presentation of case 1 showing bilateral taxane-induced lung injury and (b) chest radiograph after treatment with systemic steroids.
Fig. 2.
Case 2: (a) High-resolution computed tomography (HRCT) and (b) chest radiograph on presentation and (c) after treatment with systemic steroids.
Fig. 3.
Case 3: (a) High-resolution computed tomography (HRCT) at initial presentation and (b) HRCT chest after treatment with systemic steroids.
On a 6-min walk test (6MWT), all of them were not able to walk even 100 m and had significant desaturation. Arterial blood gas analysis revealed paO2 values of 66 mmHg, 60 mmHg, and 53 mmHg in cases 1, 2 and 3, respectively, with increased A-aDO2 gradient ranging from 33 to 45. Supplementary oxygen was required by all three patients to achieve oxygen saturation above 96% (with face masks/nasal prongs as per severity). Detailed investigations, which included full blood count, electrolyte sedimentation rate, C-reactive protein, throat swab reverse transcription polymerase chain reaction (RT-PCR) for swine flu and SARS-CoV-2, sputum for gram stain, pyogenic culture, fungal stain, fungal cultures, pneumocystis carinii pnuemonia (PCP) stain, acid-fast bacilli, serum pro-calcitonin ruled out the possibility of pulmonary infection. To rule out autoimmune etiology of ILD, rheumatoid factor and anti-nuclear antibodies were done, which were negative in all three cases. 2D echocardiography was normal in all patients, which was done to rule out pulmonary edema secondary to heart failure.
Since all the patients were having type 1 respiratory failure in acute stage with oxygen requirement, bronchoscopies were not offered. Bronchoalveolar lavage or lung biopsy in setting of such patients with respiratory distress could have led to undue complications. All patients were started on tablet Prednisolone at a dose of 1 mg/kg as per ideal body weight. Cases 1 and 3 improved after 4–6 weeks of steroids, while case 2 required slow tapering over 8 weeks. There was clinical response within days to weeks. All patients were successfully weaned off from oxygen after completion of treatment. In follow-up visit, all three patients could do 6MWT and showed no significant desaturation. Spirometry of cases 1 and 2 showed mild restriction, and in case 3, it was normal. Informed consent was obtained from all the above patients.
Discussion
Docetaxel is semisynthetic chemotherapeutic agent of taxane class. It acts by mechanism of depolymerizing cellular microtubules, which results in inhibition of protein, DNA, and RNA in cell mitosis. It also causes inhibition of angiogenesis and acts as a broad spectrum anticancer drug by influencing gene expression pathways and apoptosis pathways.2 Docetaxel-associated lung injury in the form of interstitial pneumonitis is although rare in occurrence, yet has been reported when the drug is used for lung, breast, prostate, and other cancers. Out of those cases receiving docetaxel for various cancers, approximately 1–5% can present with interstitial pneumonitis of varying severity (i.e. grade 3–4 according to Common Terminology Criteria for Adverse Events, version 5.3, 4, 5, 6 The pathology associated with docetaxel-induced lung injury can have different mechanisms. It can likely be due to type I and type IV hypersensitivity reactions to the offending drug.7 As a class, taxanes are known to cause cytotoxic T cells proliferation, which leads to hypersensitivity type of lung injury. It may also cause direct lung injury mediated by reactive oxygen metabolites. Other than the most common effects on lung in form interstitial pneumonitis, drug may also cause noncardiogenic pulmonary edema, peripheral edema, and pleural effusion due to capillary leakage syndrome. Hypersensitivity reaction may also manifest as stridor, wheezing, and angioedema.8 Interstitial lung injury commonly gives rise to an OP pattern on HRCT chest.9 NSIP pattern or overlap can also be seen. Hettiarachchi et al found OP as the most common pattern on HRCT chest; we also had two cases with OP and one case with overlap of OP and NSIP.3 Usual time of occurrence of pneumonitis is after two cycles of conventional dose. This toxicity has been found to be related more to the schedule rather than the dose of the drug. As per Chen et al, weekly schedule causes more pneumonitis and lower myelosuppression than the thrice weekly schedule.6 All our patients received thrice weekly schedule of docetaxel at doses of 75 mg/m2. Wang et al found that the mean timing of manifestation of toxicity on chest skiagram is approximately 10–20 days.4 In our cases, time for first dose was 06–11 weeks. Although apparent on clinicoradiological basis, the docetaxel-induced lung injury remains a diagnosis of exclusion with emphasis on ruling out infectious cause in cancer patient post chemotherapy. A sudden occurrence of cluster of docetaxel-induced ILD cases within a short timeframe in a institute needs consideration. A change of regime, pairing with other potential pneumotoxic agents, and change in constituents or quality of the formulation used could be possible issues requiring correction. The treatment of choice remains systemic glucocorticoid therapy along with other supportive care in selected patients in whom an infectious cause has been ruled out after screening cultures. The treatment includes prednisolone 40–60 mg/day with duration up to 2–3 weeks. Impending respiratory failure can be managed with 60–240 mg/day of prednisolone or equivalent along with a gradual tapering-off.4,10 The clinician should be alert and aware about the possibility of interstitial pneumonitis caused by docetaxel and should follow up patient for symptoms and clinical signs indicating development of this rare adverse event associated with high mortality.
Patients/ Guardians/ Participants consent
Patients informed consent was obtained.
Ethical clearance
Not Applicable.
Source of support
Nil.
Disclosure of competing interest
The authors have none to declare.
Acknowledgements
None.
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