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Metronomics during palliative care in paediatric oncology? For sure! But handle me with care

Following the article entitled Metronomic therapy can increase quality of life during paediatric palliative cancer care, but careful patient selection is essential by Porkholm published in Acta Paediatr 2016 the editors have asked us to write an acompgnying short editorial piece.

Metronomic chemotherapy (MC) is low-dose chemotherapy that is administered frequently and without extended drug-free breaks [1]. In clinical practice, MC is often combined with drugs that were not originally developed as anticancer agents – drug repositioning – in multidrug regimens that are known as metronomics [2]. These regimens can exert potent anti-angiogenic, pro-immune and direct anticancer effects that can lead to disease control, even in patients with refractory tumours. Metronomics has been actively used in both adult and paediatric oncology in various settings and reports suggest that it usually induces low levels of toxicity [1]. This makes it an ideal a priori strategy for palliative care where tumour control needs to be obtained with minimum toxicity.

The study by Porkholm et al. [3] in this issue of Acta Paediatrica is of interest in this context. The authors used an oral combination of daily thalidomide, etoposide and celecoxib to treat 17 patients with different types of tumours in a palliative care setting. The median overall survival was 6.2 months and the 24-month survival rate was 18%, with two patients showing stable disease at the end of the follow-up period. This confirmed that metronomics was capable of contributing to the control of refractory diseases in a small, but significant, proportion of patients. Meanwhile, the Lansky scores increased significantly during treatment and 35% of the patients experienced a transient improvement in their clinical status. However, it is noteworthy that grade III-IV adverse events occurred in 76% of patients and there were two treatment-related infectious deaths.

This very small cohort of heterogeneous patients has accurately highlighted both the promising activity and the potential caveats and risks, associated with metronomics in the palliative care setting. As previously reported in several paediatric metronomic studies and case series, this strategy can indeed help to control disease progression, sometimes for extended periods of time [4-7]. In a palliative care context, long-term survivors generate numerous questions. Should the treatment be stopped or not and, if so, should this be after one or two years or when the treatment becomes too toxic? Should the treatment be stopped gradually or suddenly? What should patients be told in terms of their prognosis when the disease is controlled for a long period of time? Should the palliative approach be continued, even if it means that the child and/or his parents face an ever-present threat that prevents them getting on with their lives? Should the conversation be switched to the notion of a cure once the patient has undergone a long enough follow-up period and, if so, how long is long enough?

Aside from these challenging questions, which remain unanswered for now, the major issue raised by the Porkholm et al. study [3] lies in the unexpectedly high toxicity of treatment. A single drug administered in a metronomic fashion is usually well tolerated and only generates mild toxicity. Nevertheless, metronomic regimens usually combine several drugs and this sometimes leads to highly complex multidrug protocols [5], resulting in an increased risk of toxicity, both in terms of frequency and severity. The authors suggest that patients should be carefully selected. Indeed, it is important to pay attention to a number of factors when prescribing a metronomic treatment, including the weight of previous treatments, such as the number of lines of chemotherapy and type of treatment, previous bone marrow involvement and the time interval since the last line of treatment. This approach avoids unacceptable toxicity, which can outweigh the clinical benefits in terms of survival and control of tumour-related symptoms. But clinicians also need to design protocols very carefully to avoid overlapping toxicity profiles between the agents incorporated in the combinatorial treatment. Relying on drug repositioning broadens the number of agents that can be rationally added to MC [8], but managing a good balance between safety and activity can still be achieved [4-7]. Indeed, Fousseyni et al. [7] designed a simple metronomic treatment for frail patients or patients with refractory and/or relapsing disease in low-income and middle-income country settings that led to long-lasting control of the tumours in some patients, together with good tolerance. Interestingly, the answer to whether metronomics can be better than the best supportive care might come from yet another middle-income country, India. A randomised trial comparing best supportive care versus the four-drug metronomic regimen developed by Kieran et al. [4] has been established in New Delhi (NCT01858571). While its results might not be directly transferable to a high-income country setting, it could be the first demonstration that metronomics can indeed produce better results than just best supportive care for paediatric patients in palliative settings.

Lastly, the concept of metronomics should not be restricted to palliative care. Historically, it has been used as maintenance treatment for children with acute lymphoblastic leukaemia and it is also currently being evaluated for instance in rhabdomyosarcoma patients ((NCT00643565), which would potentially broaden the scope of its clinical applications. MC can also cure patients with refractory diseases, such as large cell anaplastic lymphoma [9] or low-grade glioma [10], and can be combined with targeted agents or immune therapies [1]. With regard to anticancer therapy, accurate selection criteria are critical to define which patients are most likely to benefit from metronomics. This must include features related to the individual patient and the clinical context and the choice of cytotoxic drugs and doses. Future studies will need to seek reliable biomarkers and apply computational pharmacology tools [11] so that metronomics can reach its full potential in both adult and paediatric oncology.

1 André N, Carré M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol 2014; 11: 413–31.

2 André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013; 14: e239–48.C

3 Porkholm M, Toiviainen-Salo S, Seuri R, Lönnqvist T, Vepsäläinen K, Saarinen-Pihkala UM, et al. Metronomic therapy can increase quality of life during paediatric palliative cancer care, but careful patient selection is essential. Acta Paediatr 2016; 105: 946–51.

4 Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas CA, et al. A feasibility trial of antiangiogenic (metronomic) chemotherapy in paediatric patients with recurrent or progressive cancer. J Paediatr Haematol Oncol 2005; 27: 573–81.

5 Peyrl A, Chocholous M, Kieran MW, Azizi AA, Prucker C, Czech T, et al. Anti-angiogenic metronomic therapy for children with recurrent embryonal brain tumours. Paediatr Blood Cancer 2012; 59: 511–7.

6 André N, Abed S, Orbach D, Alla CA, Padovani L, Pasquier E, et al. Pilot study of a paediatric metronomic 4-drug regimen. Oncotarget 2011; 2: 960–5.

7 Fousseyni T, Diawara M, Pasquier E, André N. Children treated with metronomic chemotherapy in a low-income country: METRO-MALI-01. J Paediatr Haematol Oncol 2011; 33: 31–4.

8 Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology—patient and health systems opportunities Nat Rev Clin Oncol 2015; 12: 732–42.

9 Brugières L, Pacquement H, Le Deley MC, Leverger G, Lutz P, Paillard C, et al. Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol 2009; 27: 5056–61.

10 Bouffet E, Jakacki R, Goldman S, Hargrave D, Hawkins C, Shroff M, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol 2012; 30: 1358–63.

11 Barbolosi D, Ciccolini J, Lacarelle B, Barlesi F, André N. Computational oncology – mathematical modelling of drug regimens for precision medicine. Nat Rev Clin Oncol 2016; 13: 242–54.