Aortitis and aortic dissection after administration of pegfilgrastim during adjuvant chemotherapy for early breast cancer

Abstract

A 70 year-old woman on adjuvant chemotherapy for breast cancer developed acute aortitis after receiving pegfilgrastim. 12 days after pegfilgrastim administration, she presented to our hospital with fever and shoulder pain. White blood cell count and C-reactive protein were elevated. As the computed tomography scan revealed thickening of the walls of the aortic arch and surrounding arteries, we suspected granulocyte colony-stimulating factor-related aortitis. Although steroid treatment administered once improved the general condition, her symptoms and C-reactive protein worsened again. On increasing the steroid dose, her general condition recovered rapidly. On day 85, Stanford type A aortic dissection was incidentally detected by a follow-up computed tomography scan. Physicians should recognize these adverse events of filgrastim.

Introduction

Granulocyte colony-stimulating factor (G-CSF) is commonly used as a standard treatment for chemotherapy-related neutropenia in patients with various malignant tumors, and pegfilgrastim (peg-G), a long-acting G-CSF, has been recently used to prevent febrile neutropenia in patients undergoing intensive chemotherapy. Recently, acute aortitis and arteritis have been reported as rare side effects of G-CSF [1–12]. However, there is no clinical established treatment for G-CSF-related aortitis, although there are some reports that steroid therapy improved aortitis.

Here, we report a case in which acute aortitis developed after peg-G administration to prevent febrile neutropenia during chemotherapy and progressed to aortic dissection during steroid treatment.

Case report

A 70 year-old woman was diagnosed with early breast cancer and underwent breast conserving surgery with axillary dissection. She had rheumatoid arthritis and hypertension. Her rheumatoid arthritis was being followed up without medication.

As adjuvant chemotherapy for estrogen receptor-negative human epidermal growth factor 2-positive, T2N1M0 breast cancer, she was scheduled to receive EC (epirubicin + cyclophosphamide) regimen, followed by weekly paclitaxel with pertuzumab and trastuzumab. She received the EC regimen (epirubicin 100 mg/m² + cyclophosphamide 600 mg/m², every 3 week × 4 cycles) on day 1, and peg-G (3.6 mg) as primary prophylaxis for neutropenia on day 3. She developed pain around the right neck and shoulder on day 11, fever up to 38 ℃ on day 13, and presented to our hospital on day 15. She had normal blood pressure and heart rate, but laboratory tests revealed inflammation (white blood cells: 12,300/μL and C-reactive protein [CRP]:7.71 mg/dL). We suspected a bacterial infection and started levofloxacin for 3 days as empirical treatment. Despite the administration of antibiotics, her general condition did not improve, and the CRP increased to 16.73 mg/dL on day 17. Contrast enhanced-computed tomography (CT) revealed thickened walls of the right common carotid artery, brachiocephalic artery, and aortic arch (Fig. 1). Based on these findings, we suspected G-CSF-associated aortitis. She was treated with 25 mg/day of prednisolone (PSL) (0.5 mg/kg, every 24 h), according to the guidelines of aortitis (Takayasu’s disease). Although PSL treatment led to an improvement in her general condition and laboratory findings, she experienced chest pain, right-sided neck pain, and dyspnea on day 25, but the symptoms soon resolved. She developed atrial fibrillation along with re-elevation of WBC and CRP levels on day 28. D-dimer level was slightly elevated, but no cardiovascular abnormalities were detected, except for wall thickening of the ascending aorta on echocardiography. An antiarrhythmic drug was administered, and the PSL dose was increased to 40 mg/day. This resulted in a rapid improvement in her general condition and laboratory findings (Fig. 2).

Fig. 1.

Computed tomography (CT) scan revealed edema and thickening of the walls of the right common carotid artery (a), brachiocephalic artery, and the aortic arch (b) on day 17

Fig. 2.

Clinical course of the patient. Pegfilgrastim (peg-G) was administered on day 3. A computed tomography (CT) scan raised suspicion of peg-G-related aortitis on day 17; steroid treatment was initiated on day 18; chest and neck pain developed on day 25, and atrial fibrillation on day 28; increased steroid dose improved the general condition and laboratory parameters; a follow-up CT scan revealed Stanford type A aortic dissection on day 85. WBC, white blood cells; CRP, C-reactive protein; CT, computed tomography; PTX, paclitaxel; Pmab, pertuzumab; Tmab, trastuzumab

By day 50, the dose of PSL had been gradually tapered to 30 mg/day. The second cycle of the EC regimen and subsequent cycles was discontinued, and she received weekly paclitaxel combined with pertuzumab and trastuzumab, which do not require G-CSF to prevent febrile neutropenia.

On day 85, when the PSL dose was being tapered, a follow-up CT scan showed cavity formation in the right carotid artery and aortic arch, diagnosed as Stanford type A aortic dissection (Fig. 3). She was asymptomatic, with normal blood pressure (systolic BP 120–130 mmHg). She was treated with an antihypertensive without surgery. A follow-up CT scan revealed no enlargement of the affected aorta. She completed the steroid therapy on day 470 and is currently alive without recurrence of breast cancer or aortitis.

Fig. 3.

Follow-up computed tomography (CT) scan demonstrated cavity formation in the right carotid artery (a) and aortic arch (b) on day 85, confirming the diagnosis of Stanford type A aortic dissection

Discussion

We encountered a rare case of G-CSF-related thoracic aortitis and subsequent aortic dissection. This is only the second such case we found when we searched the PubMed database.

The use of peg-G in chemotherapy for breast cancer has increased as it decreases febrile neutropenia and helps to maintain the dose intensity of chemotherapy. However, large vessel vasculitis has been reported as a side effect of G-CSF. G-CSF stimulates the proliferation and differentiation of neutrophil precursors [1, 2]. Cytokine production is induced in this process, which may cause vasculitis and aortitis. However, the pathological association between G-CSF and aortitis is unclear.

Oshima et al. reported 16 cases of G-CSF-associated aortitis, of which 11 cases were associated with peg-G use in the Japanese Adverse Drug Event Report database [3]. The incidence of aortitis in patients who received G-CSF or peg-G in Japan was 0.47% and 1.58%, respectively. On the other hand, the United States Food and Drug Administration Adverse Event Reporting System reported that the frequency of G-CSF related aortitis was 0.0014%, which was lower than in Japan [3, 4].

Muzzana et al. and Hoshina et al. reviewed the literature from different perspectives on 52 and 49 cases of G-CSF-induced aortitis, respectively. Many cases overlapped in these two reports [5, 6]. In their reviews, the mean age was 60 years, and most patients were female (approximately 91%). All patients had cancer, and the most prevalent cancer type was breast cancer. Muzzana et al. reported that all patients underwent chemotherapy and that the most common drugs were variants of taxane (40%, 23 cases). The most frequent symptom was fever, which occurred at a median of 7 or 8 days after G-CSF administration, similar to that in febrile neutropenia. Regarding the type of G-CSF administered, peg-G was used in approximately 68% of patients. Hoshina et al. reported that most cases (89.8%) were diagnosed using CT scan, and most aortitis locations were the thoracic or thoracoabdominal aorta (71.4%). The period to remission was within 14 days in 44.9% of the cases. Hoshina H et al. also reported that steroids were administered to 59.2% of the patients; however, treatment efficacy was not significant.

Similar to our case, Sato et al. reported a case of G-CSF-induced aortitis resulting in Stanford type B thoracic dissection [7]. The patient was a 67-year-old Japanese woman who was administered peg-G for chemotherapy to target lung cancer; however, the chemotherapy regimen was not described. She developed general malaise and high fever on day 8 after administration of peg-G. CT scan detected bilateral common carotid arteritis and thoracic aortitis. Steroid therapy was performed shortly thereafter, and the symptoms improved. Incidentally, thoracic dissection was discovered using CT 36 days after G-CSF administration. The authors speculated that elevated IL-6 in their case might have played an important role in the pathogenesis, because IL-6 is reported to mediate the progression of aortic dissection in animal models [13]. Our case is similar to this case report in features such as type of G-CSF, time to onset, symptoms, patient background (normal blood pressure, no aneurysm), and incidental detection of thoracic dissection.

Based on our experience, we obtained new additional features of G-CSF-induced aortitis that developed into aortic dissection. Although Sato’s case report did not describe the chemotherapy regimen, our patient underwent EC. It has been previously reported that five cases of G-CSF-induced aortitis underwent an anthracycline regimen similar to our patient [8–12]. Moreover, Inoue et al. reported that EC regimen, but not G-CSF, induced aortitis in patients with advanced breast cancer [14]. Based on these reports and our experience, we suggest that both EC and peg-G may be associated with the development of G-CSF-induced aortitis resulting in aortic dissection.

Pain in the chest or back, is the most common symptom of acute aortic dissection occurring in over 90% of patients with acute aortic dissection [15, 16]. However, Sato’s case showed no remarkable symptoms of aortic dissection. In this case, the patient’s general condition and laboratory findings temporarily improved after PSL administration, but chest pain and neck pain appeared, followed by atrial fibrillation with re-elevation of WBC and CRP levels. In a retrospective review by cardiac surgeons, it was speculated that aortic dissection may have occurred when her condition worsened after the initial dose of steroid administration.

In conclusion, physicians should recognize that G-CSF-related aortitis has initial symptoms similar to those of febrile neutropenia and should carefully monitor the changes in symptoms and signs and follow-up by CT scan with the possibility of aortic dissection in mind after the onset of G-CSF-related aortitis.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by of the authors.

Informed consent

Informed consent was obtained from the patient in this case report.