Unexpected benefit from an ‘old’ metronomic chemotherapy regimen in advanced chordoma

Abstract

In this case report, we describe an older adult man affected by advanced chordoma progressing after treatment with cisplatin and imatinib. The patient was symptomatic for uncontrolled pain. We decided to treat the patient with metronomic cyclophosphamide, unexpectedly achieving long-lasting clinical and radiological benefit.

Background

This case is important as it shows the potential clinical benefit of metronomic chemotherapeutic regimens, that is, with continuous administration of low doses of drugs, in older patients affected by are cancer, such as chordoma.

Case presentation

Chordoma is a rare slow-growing tumour arising from notochord remnants most often in the skull base or sacrum in patients of all ages. There are no formally approved drugs in the advanced setting.¹ The tyrosine kinase imatinib has been often used in progressive cases,² while standard chemotherapy is considered poorly effective.¹ Here, we report the case of a 79-year-old man, with cardiac and renal comorbidities, with a pathological diagnosis of sacral chordoma from March 2013, when the patient first underwent surgery.

Treatment

In September 2015, after nine cycles of chemotherapy, pelvic MRI showed a local progressive disease. Therefore, a second-line treatment with imatinib 600 mg/d was started in October 2015, with a stable disease until February 2016. A pelvic MRI exhibited further painful local progression. Therefore, we prescribed an ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT scan to systemically characterise the disease, with the evidence of extensive primary pelvic disease. We decided to increase the imatinib dose to 800 mg/d. In June 2016, we observed a metabolic and morphological progressive disease of the left rib and further local pelvic progression. Considering the lack of further effective therapies, we continued imatinib 800 mg/d. After a brief interruption due to a low platelet count, imatinib 600 mg/d was reintroduced, with a good tolerability profile. In September 2016, the FDG PET-CT scan showed the progressive disease of the pelvic and rib lesions (maximum standardised uptake value (SUV_max) 5.2). We decided to continue the same treatment. In June 2017, the patient underwent antalgic radiotherapy on the ischial bone, due to localised pain classified as grade 8 of the Numerical Rating Scale (NRS), without clinical benefit.

In July 2017, the patient experimented further local progressive disease and progression of the rib metastasis (SUV_max 6.5) (figure 1A) with clinical worsening due to increased pain (NRS 9) (figure 1C). Therefore, we simultaneously started a third-line therapy with continuous low doses of (ie, metronomic schedule) of oral cyclophosphamide 50 mg/d plus prednisone 10 mg/d with concurrent palliative care to start intravenous opioids for bone pain control, after non-steroidal anti-inflammatory drugs failure.

Figure 1.

(A) PET-CT scan of July 2017; (B) PET-CT scan of November 2017 showing metabolic and dimensional partial response; (C) timeline of SUV_max and NRS, arrow points at the start of metronomic cyclophosphamide. NRS, Numerical Rating Scale; PET-CT, positron emission tomography CT; SUV_max, maximum standardised uptake value.

Outcome and follow-up

After a few weeks, the patient showed a significant clinical benefit, with rib and pelvic pain reduction (NRS 5) (figure 1C) and discontinuation of opioids. In November 2017, the first FDG PET scan evaluation during the third-line treatment showed a metabolic and morphological partial response (SUV_max 3.8) (figure 1B), with further benefit on bone pain (NRS 3) (figure 1C). In February 2018, the patient obtained an additional clinical benefit (NRS 1) (figure 1C), with an improvement in his quality of life. The last FDG PET-CT scan, in May 2018, showed stable disease. During his last visit in October, the patient showed persistent clinical benefit and refused to undergo further radiological evaluations.

Discussion

Metronomic chemotherapy is based on the frequent administration of conventional chemotherapeutic agents at very low doses to target both cancer cells and cancer-associated stromal cells, with minimal adverse effects and a lower chance of developing acquired drug resistance.³ Among drugs used with a metronomic schedule, cyclophosphamide in doses ranging from 50 to 100 mg/d associated with prednisone is a widely used alkylating agent studied in advanced prostate cancer,^{4 5} with clinical activity in some heavily pre-treated patients. Currently, oral cyclophosphamide is also used in the front line in some histological subtypes of sarcomas with tolerable toxicity, especially in older patients.⁶ An Italian randomised phase II clinical trial will soon assess the activity of metronomic cyclophosphamide or doxorubicin in elderly patients affected by advanced sarcomas (MetropolyS trial). Other metronomic chemotherapeutic regimens used in sarcoma patients include the combination of vinca alkaloids and methotrexate,⁷ or etoposide.⁸ We selected cyclophosphamide after imatinib progression, as early evidence supported the activity of imatinib in combination with cyclophosphamide in a subgroup of chordoma patients.⁹

To our knowledge, this is the first case reporting the use of metronomic cyclophosphamide in chordomas with the evidence of metabolic and morphological disease response and marked clinical benefit.

Learning points.

• Therapeutic options for chordomas and other rare cancers are limited.

• Older patients represent a particularly challenging population, as they often have significant comorbidities that restrict therapeutic choices.

• Metronomic chemotherapy with cyclophosphamide can provide long-lasting radiological response with significant clinical benefit in patients with chordoma.