Chemotherapy dosing and toxicity in a patient with muscular dystrophy

Abstract

Background

Chemotherapy dosing has traditionally been based on a body surface area (BSA) calculation despite BSA dosing being problematic in a number of conditions, such as renal failure, liver failure, obesity, and sarcopenia. This case highlights another condition in which BSA dosing is problematic.

Case

A 57‐year‐old man with limb‐girdle muscular dystrophy presents with stage IIA inoperable squamous cell carcinoma of the lung. He is treated with chemotherapy and radiotherapy with curative intent but develops significant chemotherapy related toxicity affecting chemotherapy scheduling and dosing. Later, his cancer progresses, and he is commenced on palliative chemotherapy resulting in further significant chemotherapy toxicity.

Conclusion

Sarcopenia is known to increase risk of chemotherapy toxicity. This case postulates that changes in muscle mass seen in muscular dystrophy increases risk of chemotherapy toxicity, similar to sarcopenia.

1. INTRODUCTION

Chemotherapy dosing continues to be a challenge due to many agents having a narrow therapeutic range and significant toxicity. Chemotherapy dosing has traditionally been based on a body surface area (BSA) calculation despite there being known problems with BSA dosing in a number of conditions, such as renal failure, liver failure, obesity, and sarcopenia. This report documents toxicity associated with BSA dosing in a patient with limb‐girdle muscular dystrophy (LGMD) due to mutations in the CAPN3 gene, which codes for the CALPAIN 3 protein. Therefore, this report highlights another condition in which BSA dosing is problematic.

2. CASE

A 57‐year‐old male presented with haemoptysis and dyspnoea. Imaging with computed tomography and positron emission tomography revealed a 38 × 29‐mm mass in the right hilar region with endobronchial involvement, which was intensely FDG avid as well as multiple avid lymph nodes in right hilar and mediastinal regions but without evidence of disseminated disease. He underwent endobronchial ultrasound, which showed the right main bronchus to be compromised by the tumour. Patency of the right main bronchus was restored during endobronchial ultrasound. Biopsies confirmed a squamous cell carcinoma of the lung with disease present in 4R and 10R lymph nodes. He was staged as T3N2M0—stage IIA. Following multidisciplinary discussion of his case, a plan was made for definitive chemoradiotherapy. Primary resection or trimodality therapy was not pursued in part because the tumour involved the right main bronchus and bronchus intermedius, and the 4R lymph nodes were bulky on imaging.

His past medical history was significant for LGMD diagnosed at age 29 due to CAPN3 mutations. He mobilised with a wheelchair and lived independently but required daily assistance with activities of daily living. He performed regular upper body gym sessions. He did not require ventilation assistance. He was an ex‐smoker. He had T2N0 colorectal cancer treated with surgical resection with no adjuvant chemotherapy and an epithelial‐myoepithelial parotid tumour of low malignant potential resected followed by adjuvant radiotherapy. He also had resected left gynaecomastia and is awaiting surgery for right gynaecomastia. Other past medical history includes transient ischaemic attack and mild hypertension.

He commenced chemoradiotherapy with a plan for cisplatin 50 mg/m² days 1, 8, 29, and 36 with etoposide 50 mg/m² days 1 to 5 and 29 to 33 concurrently with radiotherapy 60Gy in 30 fractions. With a height of 178 cm and weight of 65 kg, he was dosed with actual body weight BSA (Mosteller calculation) of 1.79. His body mass index calculation is 20.5. Seven days into his treatment, he presented with febrile neutropenia with a neutrophil nadir of 0.61 × 10⁹/L on day 12 requiring admission and intravenous antibiotics. Accordingly, he missed his day 8 cisplatin. He then had a fall off his wheelchair resulting in fracture of C2 vertebral body and C3 and C4 spinous processes, which was treated conservatively. Chemotherapy on days 29 to 33 was given at a 25% dose reduction due to the neutropenia, and day 36 cisplatin was omitted as he was too unwell to receive treatment on that day.

Unfortunately, surveillance imaging 4 months after completion of treatment showed local disease progression in his right hilum plus an incidental pneumothorax. He was commenced on carboplatin AUC 5 day 1 and gemcitabine 1000 mg/m² days 1 and 8 of a 21‐day cycle. Carboplatin was dosed on actual body weight. He tolerated the first cycle with mild diarrhoea only, but the commencement of his second cycle was delayed due to myelosuppression with a platelet count of 22 × 10⁹/L and neutrophils of 0.33 × 10⁹/L from which it took 2 weeks to recover. He received a 20% dose reduction for cycles 2 and 3 due to his myelosuppression. At cycle 3 day 20, he was admitted with febrile neutropenia (neutrophil nadir of 0.55) and anaemia (haemoglobin nadir 57 g/L). Repeat imaging at this time showed a response to treatment, and he continued on single agent gemcitabine 1000 mg/m² days 1 and 8 of 21‐day cycle at a 20% dose reduction. After a further 3 cycles, he developed epistaxis with a platelet count of 27 × 10⁹/L, and he was switched to single agent docetaxel 75 mg/m² day 1 of 21‐day cycle at 50% dose reduction. On cycle 3 day 8, he was admitted with fever, hypotension, and diarrhoea and was diagnosed with severe chemotherapy induced colitis with no other cause found after extensive investigation. After a prolonged admission, he recovered and was discharged.

During this time, nivolumab became available, but the patient declined any further active treatment opting for best supportive care only.

3. DISCUSSION

Limb‐girdle muscular dystrophy refers to a heterogeneous group of muscular dystrophies characterised by weakness and atrophy of the proximal muscles leading to functional impairment. There are a number of subtypes of LGMD with different genetic and clinical features.1 Limb‐girdle muscular dystrophy due to CAPN3 mutation is also known as LGMD2A. This dystrophy is the most common LGMD and is characterised by weakness in the proximal muscles, scapular winging, calf hypertrophy, abdominal laxity, and age of onset about 10 to 30.1, 2 Diagnosis is mostly confirmed by genetic testing. No disease modifying treatment is currently available. Although several muscle groups show atrophy on clinical examination, some muscle groups (such as the lumbar muscles) may have radiological evidence of atrophy on magnetic resonance imaging but no clinical evidence of atrophy.3 A review conducted by the authors did not find any previous reports of chemotherapy dosing or toxicity in patients with muscular dystrophy.

Although there are many different definitions of sarcopenia and various methods to diagnosis, it is generally accepted that sarcopenia is a loss of skeletal muscle mass. Whilst loss of muscle mass is a normal function of ageing, it is also seen in many pathological conditions including muscular dystrophy and cancer. Cancer cachexia (of which sarcopenia is the predominant hallmark) is an important but underappreciated syndrome affecting up to 80% of patients and may be caused by insufficient nutritional intake (eg, due to nausea, alterations in taste, and dysphagia), increased metabolism, inflammation, or tumour/treatment related events (diarrhoea, anorexia, malabsorption, etc).4

Body surface area dosing has been a mainstay of chemotherapy dosing despite its limitations. Specifically, decreased skeletal muscle mass and sarcopenia have been associated with poor tolerance and increased toxicity from chemotherapy and tyrosine kinase inhibitors (eg, sunitinib, sorafenib, and vandetanib).5, 6, 7 Of all the reasons postulated for the relationship between sarcopenia and chemotherapy toxicity, the 2 most prominent are (1) altered pharmacokinetics in patients with sarcopenia—that is, sarcopenia is associated with higher plasma drug levels; and (2) sarcopenia reflects an underlying frail state (eg, cancer cachexia) in the patient rendering them more liable to toxicity independently of any other mechanism. Another purported mechanism is systemic inflammation in cancer, which may affect both pharmacokinesis and sarcopenia.8 Further, some chemotherapy agents are dosed based on renal function, which is often derived from serum creatinine levels. However, serum creatinine may overestimate renal function in sarcopenic patients leading to administration of toxic doses.

In contrast to BSA dosing in patients with decreased muscle mass, obese patients dosed at BSA using actual body weight do not experience high toxicity compared with normal weight patients.9, 10 However, more recently sarcopenic obesity (obesity in conjunction with low skeletal muscle mass) has been recognised as a predictor of both toxicity to chemotherapy and poor prognosis.11, 12 One hypothesis for the increased toxicity in sarcopenic obesity is the combination of higher doses of chemotherapy with reduced volume of distribution and reduced clearance by a depleted lean body mass.13 One study looked at the obesity paradox in patients with cancer and found that patients with sarcopenic obesity had a worse prognosis when compared with both (1) sarcopenic but nonobese patients and (2) obese but nonsarcopenic patients.14 In contrast, a recent review into sarcopenic obesity noted that whilst some studies showed a strong association between chemotherapy toxicity and sarcopenic obesity, others studies did not.13

While there are some similarities between the muscle loss seen in muscular dystrophy and that seen in sarcopenia,15 there are clear limitations in applying what we know about chemotherapy dosing in sarcopenia to patients with muscular dystrophy. One such limitation is that sarcopenia in cancer patients may reflect a more aggressive phenotype of cancer or other acquired premorbid conditions, which would not apply to patients with muscular dystrophy. Nevertheless, the data on chemotherapy dosing in sarcopenia are probably the closest we will get to understanding chemotherapy dosing in patients with muscular dystrophy. Development of chemotherapy dosing guidelines in patients with sarcopenia based on such data would be beneficial to clinicians.

4. CONCLUSION

This case highlights another problem with chemotherapy dosing by BSA. Oncology patients with decreased muscle mass have higher toxicity from chemotherapy and a poorer prognosis. Decreased muscle mass from muscular dystrophy may also increase risk of chemotherapy toxicity.

ETHICAL STATEMENT

Patient's written consent was obtained for publication of this case report.

As per the Research Ethics and Governance Unit of Fiona Stanley Hospital, no additional ethical review or approval was required for this study.

CONFLICT OF INTEREST

None

AUTHORS' CONTRIBUTIONS

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, C.L., D.T.R.; Methodology, C.L., DTR.; Investigation, C.L., D.T.R.; Writing ‐ Original Draft, C.L.; Writing ‐ Review & Editing, C.L., D.T.R.

Lomma C, Ransom D. Chemotherapy dosing and toxicity in a patient with muscular dystrophy. Cancer Reports. 2018;1:e1106. 10.1002/cnr2.1106