Abstract
Background/Aim: Palbociclib is an FDA-approved cyclin-dependent kinase inhibitor for the treatment of advanced breast cancer. Limited information is available regarding the toxicity of palbociclib and concurrent radiation therapy. Case Report: Herein, we report a case of esophageal toxicity in a patient treated with palbociclib and radiation therapy. A 63-year-old woman was treated with palbociclib followed by palliative radiation therapy. The patient presented three days after completing radiation therapy with severe odynophagia, and dysphagia and was found to have grade 2-3 esophageal ulcers. Palbociclib and radiation therapy was held on admission, and a resolution of her symptoms and improvement in her oral intake was noted at which time she was restarted on palbociclib with no further radiation treatment. Conclusion: Caution is advised when patients are undergoing concurrent palbociclib and even low-dose palliative radiation treatment. In these patients, providers should maintain a high index of suspicion for toxicities such as dermatitis or mucositis.
- Mucositis
- palbociclib
- chemotherapy
- palliative
- radiation therapy
- Ibrance
- chemoradiation
Palbociclib (Ibrance) belongs to a relatively new class of chemotherapy agents approved for the treatment of breast carcinoma. As a selective inhibitor of the cyclin-dependent kinases (CDK) 4 and 6, palbociclib was the first drug of its class to be approved.
CDK 4/6 inhibitors prevent the formation of the cyclin D-CDK4/6 complex. The cyclin D-CDK4/6 complex is necessary for phosphorylation of the retinoblastoma (Rb) protein, which allows for the progression of the cell cycle past the restriction (R1/2) checkpoint in the G0 phase of the cell cycle. As such, CDK 4/6 inhibitors arrest cells in the G0 phase and prevent the cell cycle from entering the G1 phase.
The drug received full approval in March 2017 from the Food and Drug Administration (FDA) for the treatment of estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor 2-negative (HER2−), advanced or metastatic breast cancer. Clinical trials have shown that although this combination significantly slows the progression of advanced cancer no significant improvements in overall survival times was noted (1).
In September 2019, the FDA released a safety announcement for the potential of life-threatening interstitial lung disease and pneumonitis in patients receiving CDK 4/6 inhibitors (2). Furthermore, data are limited on the safety of its use with concurrent radiation therapy. A limited body of work continues to describe the adverse effects of concurrent radiation therapy (RT) and palbociclib treatment. We present a case of a patient with metastatic breast cancer who received palliative radiation while on palbociclib and developed gastritis.
Case Report
The patient is a 67-year-old post-menopausal woman, who, at the age of 63, was diagnosed with Stage IIA pT2N0M0 ER+/PR+/HER2-left breast intraductal carcinoma in situ, which was treated with lumpectomy followed by chemoradiation therapy and tamoxifen. Subsequently, at age 65, she was found to have calcifications in her right breast on a surveillance mammogram, with subsequent biopsy revealing an ER+/PR+/HER2− ductal carcinoma in situ. A CT of the abdomen and pelvis revealed a 2-cm lucent lesion in T10 and a 4-cm lucent lesion in the right ilium. A follow-up bone scan revealed moderate heterogeneous uptake in the T10 vertebral body and right posterior ilium and bone biopsy confirmed metastasis. The patient was started on palbociclib (125 mg orally daily for 21 days) and letrozole (2.5 mg PO daily). Three weeks after beginning palbociclib the patient received palliative radiation to T10 (2,000 Gy in five fractions over six days) (Figure 1) and the right iliac crest (2,000 Gy in five fractions over six days), four days thereafter the patient presented to the emergency room with complaints of odynophagia and dysphagia to solids and liquids, dyspepsia, and non-bilious hematemesis for the past five days. Esophagogastroduodenoscopy (EGD) was done which revealed severe ulcerative esophagitis in the distal third of the esophagus along with gastritis (Figures 2 and 3). Strictures were also present in the distal third of the esophagus. Multiple biopsies were obtained which revealed reactive squamous mucosa inflammation along with multiple ulcerations in the esophagus, stomach, and duodenum (Figures 4 and 5).
Palbociclib was held on admission and the patient was started on IV pantoprazole and a clear liquid diet. On day 4 of admission, she was able to tolerate a soft diet. She was restarted on letrozole and discharged home with gastroenterology (GI) and oncology follow-up. One month after discharge, the patient was seen in the oncology clinic. She continued to tolerate a diet and reported significant improvement in odynophagia and dysphagia. At which point she was restarted on palbociclib (125 mg orally daily for 21 days), without any additional radiation treatment. Two months after discharge, EGD was repeated and revealed significant improvement in esophagitis and gastritis.
Conclusion
The cytotoxic effects of radiation are dose-dependent and generally rise as the dose of radiation increases. Palliative radiotherapy, which generally delivers 8 Gy in 1 fraction, 20 Gy in 4 fractions, or 30 Gy in 10 fractions has been shown to have minimal side-effects (3). The benefits of a single 8 Gy fraction include patient convenience and potentially lower acute toxicity, however, there is potential that single fractionation schemes may require a higher retreatment rate compared to fractionated palliative regimens (4). Additionally, randomized trials comparing single versus multiple fraction palliative radiotherapy regimens have shown non-inferiority of a single fraction versus multiple fraction treatments in an intention to treat analysis, however, did not appear non-inferior in the per-protocol analysis (5). Thus, physicians must weigh each case individually to determine the best paradigm for treatment. The rate of acute toxicity following 20 Gy is generally very low, Rades et al. compared multiple fractionations and only reported Grade 1-2 acute toxicity overall (6).
There is limited literature investigating the concurrent use of RT and palbociclib. Multiple authors have reported increased acute radiation toxicity following concurrent radiation and palbociclib therapy. Messer et al. reported a case of dermatitis necessitating hospitalization and following concurrent RT and palbociclib (7). Further, Kalash et al. reported a case series of patients who developed dramatic pulmonary fibrosis secondary to combination therapy (2), resulting in a U.S. FDA safety communication release. High-grade hematological toxicity was also noted by Ippolito et al. in a patient treated with concomitant treatment of CDK4/6 and radiotherapy (8). Finally, Kawamoto et al. reported severe enterocolitis after combined palbociclib and palliative (9). Chang-Lung et al. describe a potential intestinal radioprotection effect in mice model when mice pretreated with palbociclib receive single-fraction RT (10). However, they go on to report treatment with palbociclib before and during fractioned RT exacerbated acute radiation toxicity.
Despite the growing body of literature of acute radiation toxicity with concurrent RT, it remains poorly understood. Fortunately, clinical trials are underway to address the safety of radiation therapy and concurrent palbociclib (NCT03691493, NCT03709680).
In the case of our patient, the degree of esophagitis (grade 2-3) exceeds what is normally expected in patients receiving similar levels of radiation without concurrent palbociclib (11). Of note, the potential for palbociclib itself to cause gastrointestinal (GI) intestinal symptoms exists, with the manufacturer reporting GI symptoms in up to 30% of patients. However, these symptoms are generally limited to nausea, vomiting, diarrhea, and stomatitis. Moreover, the manufacturer only reports a 1% risk of grade 3 mucosal toxicity. Given this evidence, while the possibility of the esophagitis solely being caused by palbociclib remains, we believe it to be highly unlikely. Further, four weeks after discharge, the patient was restarted on palbociclib without radiation therapy, which she tolerated without recurrence of symptoms. This offers increased support for our theory that our patient's presentation is the result of concurrent RT and palbociclib therapy.
The potential to develop acute toxicities (mucositis/dermatitis/stomatitis) with RT may be increased when combined with palbociclib. As a result, caution is advised when patients are undergoing concurrent palbociclib and radiation treatment.
Acknowledgements
The Authors would like to thank the Department of Medicine and the Department of Radiation Oncology at Rutgers New Jersey Medical School for their assistance in the development of this manuscript. The primary author would also like to thank his friends and family in New Jersey and Pakistan for their continued support and guidance.
Footnotes
Authors' Contributions
Umair M. Nasir contributed to the conception, development, literature review, drafting and revision of the article. Alexander M. Mozeika contributed to the drafting and revision of the article along with literature review. Bruce Haffty, Mutlay Sayan and Imraan Jan contributed to the revision of the article as well as calculating dosage of radiation and location of radiation treatment. Noel Kowal contributed to pathology figures and figure explanations. Sushil Ahlawat Kowal contributed with EGD figures and figure explanations. Neil Kothari contributed to drafting and revision of the article.
Conflicts of Interest
The Authors confirm that they have no conflicts of interest to disclose.
- Received July 5, 2020.
- Revision received July 22, 2020.
- Accepted July 23, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved