Severe rhabdomyolysis related to oxaliplatin adjuvant therapy for colorectal cancer

Abstract

Colorectal cancer is the third most common cancer in men and the second in women. The standard chemotherapy regiment in stage III colon cancer is based in oxaliplatin. The most common side effects include neutropenia, peripheral neuropathy, vomiting and diarrhoea. Rhabdomyolysis due to oxaliplatin is rare, and there are no established guidelines for managing this adverse event. This report describes a case of a 52-year-old man, with a resected stage III colon cancer that started postoperative adjuvant chemotherapy with capecitabine plus oxaliplatin. After the second cycle, the patient developed distal muscle pain and weakness, with a total inability to walk. Blood tests showed an elevated creatine kinase and renal injury. Severe drug-related rhabdomyolysis was diagnosed. The goal of this case report is to discuss the side effect of adjuvant chemotherapy, given its rarity and severity.

Background

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the world.^{1 2}

A significant number of patients are diagnosed at a localised stage, for whom surgical resection is possible.³ Several clinical trials demonstrated that postoperative adjuvant chemotherapy, for patients with node-positive/node-negative high-risk colon cancer, improved outcome and has become the standard of care.⁴ The combination of oxaliplatin with a fluoropyrimidine is the regiment that proved to be efficient in clinical trials and is the gold standard therapy.

Although in the vast majority of cases the side effects of this regimen are easy to manage, some of them occur in a small percentage of patients and must be diagnosed in a timely manner, because they can be life threatening.

This case reports a rare and severe side effect of a widely used and commonly well-tolerated adjuvant chemotherapy regimen.

Case presentation

A 52-year-old Caucasian man presented in 2016 symptoms of low abdominal pain and bowel habit change, with constipation and rectal pain, accompanied by rectal bleeding. He had no history of smoking, hypertension, dyslipidaemia, diabetes mellitus or renal disease and no relevant family history.

A laboratory study was made, including complete blood count, blood chemistry, coagulation profile and urinalysis. All were within normal value limits. The level of carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA 19.9) were normal (1.01 ng/mL and <0.6 U/mL, respectively). The colonoscopy revealed a stenotic tumour in rectosigmoid colon, at 14–16 cm from the anal margin. Biopsies from the tumour were made, and histology identified a poorly differentiated adenocarcinoma. In the CT scan, the tumour was located in the rectosigmoid transition with an extension of 6 cm. There was no evidence of adenopathies, liver or lung metastasis. The MRI revealed a stenosating segment of distal sigmoid colon, with 6.5 cm of longitudinal extension to the rectosigmoid transition. The infiltrative lesion began at 14 cm from the anal margin. Multiple adenopathies in the fat of the adjacent mesosigma and pericentimetric ganglionar formations in mesorectal fat were found.

The case was discussed by a multidisciplinary team, and it was decided to treat as a high-rectum/rectosigmoid transition tumour, with surgery as an initial approach. The patient underwent a high-anterior resection of rectosigmoid colon cancer without complications. The pathology report revealed a poorly differentiated ulcerated adenocarcinoma. The distal and proximal resection margins were clear, and no lymphatic, vascular or perineural invasion was found. Twenty-eight lymph nodes were retrieved, and two of them contained malignant cells. It was classified as a pT3 pN1 M0.

As a stage III CRC, the patient was proposed to adjuvant chemotherapy with capecitabine plus oxaliplatin (CAPOX) starting 5 weeks after surgery. The chosen regimen consisted in capecitabine (1000 mg/m2 orally twice daily) for 14 days and oxaliplatin (130 mg/m² intravenous infusion) on the first day of each cycle, with a periodicity of 3 weeks over 6 months (eight cycles).

In the first days of the first cycle, the patient reported some complaints of self-limited myalgias (grade 1). However, no laboratory abnormalities were found at this time. On the fifth day of the second cycle, he was admitted in the emergency department with myalgia (grade 2), malaise, weakness and inability to walk.

Investigations

The blood tests showed significant rhabdomyolysis, with elevated creatine kinase (CK) (8264 U/L) and hyperkalaemia 6.5 mEq/L, without ECG or gasometric alterations. Also presented were elevated lactate dehydrogenase and acute renal injury (creatinine 2.35 mg/dL). No urine alterations or myoglobinuria were found.

Renal ultrasonography was performed and excluded obstruction, and the acute renal injury was considered to be secondary to rhabdomyolysis.

Differential diagnosis

The patient denied similar previous episodes.

Probable causes of rhabdomyolysis were investigated, and the following were excluded: changes in body temperature; infections; excessive muscle activity; endocrine or electrolytic changes; muscular hypoperfusion due to a thrombotic event and mechanical trauma or compression. Considering potential pharmacological causes, the introduction of new drugs was excluded. Also considering the patient’s usual medication, only chemotherapy and antiemetics (dexamethasone and ondansetron on the first day of each cycle) were on the list.

The most probable and known causes of rhabdomyolysis were excluded. Given the patient’s treatment context, chemotherapy with oxaliplatin was considered to be the main cause of rhabdomyolysis.

Treatment

The main purpose of treating rhabdomyolysis is to reverse the specific cause of muscle injury, as well as prevent and treat its complications. Chemotherapy was stopped, and the patient was admitted to the medical oncology department. Intravascular volume expansion and antihyperkalaemia measures were performed. There was a progressive improvement of renal function and normalisation of CK levels. Haemodialysis was not necessary.

After 7 days, the patient returned home with normal CK values and renal function.

Outcome and follow-up

Despite laboratory improvement, he maintained complaints of weakness and myalgias, which resolved after 2 weeks. Then he completed adjuvant chemotherapy with capecitabine alone for six cycles more, with no toxicity.

After finishing treatment, the patient started clinical, laboratory and imagiological follow-up, without evidence of disease recurrence.

Discussion

In 2018, there will be an estimated 18.1 million new cancer cases and 9.6 million cancer deaths. CRC is the third most common worldwide, representing 10.2% of all new cases, and the second cause of cancer mortality, 9.2% of all cancer deaths.^{1 2}

The majority of patients with colon cancer are diagnosed at a localised stage, with the possibility of a surgical cure. Approximately half of them who undergo resection, particularly if node-positive disease, will relapse if no other treatment is performed.³Randomised clinical trials have demonstrated that adjuvant chemotherapy provides a significant disease-free survival benefit, reducing the recurrence rate and improving overall survival (OS). This benefit is more evident in stage III colon cancer.^{4 5} The standard regimen of adjuvant chemotherapy for stage III colon cancer is based on fluoropyrimidine and oxaliplatin. The Mosaic trial showed OS benefit with the addition of oxaliplatin to 5-fluorouracil/leucovorin (FOLFOX) in patients with stages II and III colon cancer.^{6 7} Some subsequent studies have also demonstrated the benefit of CAPOX and its non-inferiority compared with FOLFOX.^{8 9}

Since our patient was young and fit and had a stage III resected colon cancer, he was proposed to standard adjuvant treatment with CAPOX.

Oxaliplatin is a platinum-based chemotherapy drug, cell-cycle non-specific and is used for the treatment of CRC in combination with fluoropyrimidine.¹⁰ It also demonstrated efficacy in other gastrointestinal malignancies like gastric and pancreatic cancer. This drug undergoes a non-enzymatic conversion to active derivatives via displacement of the labile oxalate ligand. After activation, oxaliplatin binds preferentially to the cytosine and guanine bases of DNA, leading to cross-linking of DNA, thus inhibiting DNA synthesis and transcription.¹¹ The main dose-limiting toxicities are peripheral sensory neuropathy and haematological toxicity. There are other adverse events like allergic reactions, including acute laryngeal spasm, gastrointestinal toxicity, increase in transaminase or alkaline phosphatase levels and fatigue.¹²

In the reported case, myalgias appeared after the first cycle but were self-limited and mild. However, after the second cycle, severe rhabdomyolysis developed, with myalgias and acute renal injury. Other causes were excluded and, despite its rarity, considering the synchronous timing of chemotherapy initiation and symptom appearance, the event was admitted as a side effect of oxaliplatin.

Drug-related rhabdomyolysis due to oxaliplatin is rare and frequently severe.^{13 14} The mechanism of this adverse effect is not clear, and its incidence is unknown. There are few reported cases in the Asiatic population with metastatic disease, under palliative chemotherapy.

Maruoka et al reported a 73-year-old man with liver metastases of colon cancer, that a few hours after receiving oxaliplatin, he experienced proximal limb muscle pain and malaise, with elevated CK, dysphagia and respiratory distress due to laryngeal oedema. The rhabdomyolysis subsided for 112 days, and the colon cancer treatment had to be discontinued, which led to multiple peritoneal metastases and the death of the patient.¹³

There are also reported cases of rhabdomyolysis due to oxaliplatin in other types of cancers. Sato et al reported a case of a 76- year-old man, with liver metastasis of gastric cancer, who had rhabdomyolysis related to S-1 plus oxaliplatin therapy.¹⁴ Oxaliplatin also has other related less common side effect, like pulmonary toxicity.¹⁵

In this case, the patient recovered, and chemotherapy was resumed with capecitabine in monotherapy. He did not have subsequent toxicities, which reinforced the diagnostic of rhabdomyolysis secondary to oxaliplatin.

In summary, we report this clinical case to highlight the importance of being alert for small signs and/or symptoms that can sometimes go unnoticed but may indicate important and rare side effects of a drug. Although oxaliplatin is largely used in metastatic and adjuvant CRC and other malignancies, clinicians must remain vigilant for uncommon but potentially fatal side effects to carry out an early detection and adequate treatment of this complication.

Learning points.

• It’s important to keep in mind that all pharmacological therapies have potential side effects. Chemotherapy regimens have common side effects that are easier to identify and manage, but some other are rare and can put in risk patient’s life, if not quickly recognized.

• In CRC the CAPOX regimen is widely used and the most expected adverse effects are fatigue, nausea and vomiting, diarrhea, myelotoxicity, cardiotoxicity, hand-foot syndrome due to capecitabine, and peripheral neuropathy due to oxaliplatin.

• Rhabdomyolysis is a rare side effect of oxaliplatin and can be fatal. The real incidence and physiopathology are unknown and there are no established guidelines for its management.

• The aim of adjuvant chemotherapy is to decrease the likelihood of disease relapse. So, if there’s no evidence of active disease, the risk and the benefit from an adjuvant therapy should be balanced. For instance, it can be fatal for a healthy patient.

• The multidisciplinarity is also fundamental between oncologists and other medical specialties, since the effects due to chemotherapy are not always easy to recognize, and emergency services still remain one of the main support sites for oncological patients with acute complications.