NEWS & VIEWS GASTROINTESTINAL CANCER
Rationale for metronomic chemotherapy in phase III trials Robert S. Kerbel and Axel Grothey Refers to Simkins, L. H. et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet http://dx.doi.org/10.1016/ S0140-6736(14)62004-3 (2015)
Systemic therapy for the treatment of cancer has been dominated by the notion that ‘more is better’. Most chemotherapy agents, and many other cancer drugs, are administered at the maximum tolerated dose (MTD). In the case of chemotherapeutics, this commonly requires a drug-free break of 1–3 weeks between successive cycles to allow for recovery from the toxic effects of treatment inflicted on normal proliferating cells—such as bone marrow progenitors, which results in myelosuppression. Almost 15 years ago, a different concept on chemotherapy dosing and scheduling was proposed, based on preclinical studies,1,2 which was termed ‘metronomic’ chemotherapy.3 This term refers to the often daily, continuous administration of chemotherapy agents, which necessitates drug administration at doses lower than the MTD. Part of the rationale behind this alternative dosing approach is that the tumour would be under constant therapeutic pressure, but as the drug is used at a lower dose, it would also reduce the severity of the toxic effects of higher dose therapies. Initial preclinical results involving treatment of transplanted primary tumours showed surprisingly remarkable efficacy results that were subsequently confirmed in other models, such as spontaneous tumours in genetically engineered mouse models (GEMMs),4 and even in mice with advanced visceral metastatic disease.5 In a number of preclinical studies, superior efficacy of metronomic
chemotherapy over MTD-based chemotherapy was demonstrated, together with reduced toxicity.1–3 The antitumour effects of metronomic chemotherapy seem to involve several possible mechanisms, perhaps acting concurrently. These mechanisms include antiangiogenesis, stimulation of the immune system, and possibly direct tumour-cell targeting effects, including effects on cancer stem cells.3 In preclinical studies, combining metronomic chemotherapy regimens with targeted agents, especially antiangiogenic drugs, resulted in further enhancement of antitumour efficacy.1–4 It might be counterintuitive that lower doses of chemotherapy could actually be equally effective or more effective than MTDbased chemotherapy. In addition, determining the optimal dose for metronomic chemotherapy has, so far, been based on empiricism and not solid prospective evidence. Such factors have slowed the clinical development of metronomic chemotherapy. Although many phase II trials have shown encouraging results,3 confirmation of the clinical benefits of metronomic chemo therapy in large, well-controlled, randomized phase III trials has, until the recent publication of CAIRO3, been lacking. In the multicentre, phase III CAIRO3 trial, 6 bevacizumab plus metronomic capecitabine was assessed; no control arm of either capecitabine only or bevacizumab only was included.1–4
NATURE REVIEWS | CLINICAL ONCOLOGY
NPG
Investigational metronomic chemotherapy involves frequent, regularly spaced, long-term administration of a sub-maximum tolerated dose. The phase III CAIRO3 trial evaluated continuous metronomic oral capecitabine, with bevacizumab, as a maintenance treatment in patients with metastatic colorectal cancer; a benefit in progression-free survival compared with observation only was observed, highlighting that metronomic chemotherapy could be a less toxic and convenient therapy.
The Dutch Colorectal Cancer Group designed and undertook the CAIRO3 trial, in part, to evaluate the concept of metronomic chemotherapy and the impact that longer treatment duration might have on survival outcomes in patients with colo rectal cancer (CRC).6 In this study, patients with metastatic CRC first received six cycles of conventional induction therapy over 4.5 months, consisting of oxaliplatin given intravenously every 3 weeks, capecitabine taken orally at 1,000 mg/m2 twice daily for 2 weeks followed by a 1‑week break, and intravenous bevacizumab every 3 weeks at a dose of 7.5 mg/kg. Upon completion of this therapeutic regimen (called CAPOX‑B), patients who experienced clinical benefit (that is, stable disease, a partial response or a complete response) were randomized into two arms: observation only (no treatment) or treatment with a ‘maintenance’ regimen consisting of capecitabine and bevacizumab. Notably, in this maintenance setting, capecitabine was used at a dose and schedule that conforms to the definition of metronomic chemotherapy as it was taken continuously at a lower twice daily dose: 625 mg/m2. This schedule was designed to reduce the risk of adverse effects such as ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS hand-foot syndrome and diarrhoea, and to allow for prolonged treatment duration in combination with bevacizumab. Oxaliplatin was not included because of its known cumulative toxicity, such as neuropathy.
‘‘
…results of the CAIRO3 ... demonstrate that extending the duration of chemotherapy … improves survival outcomes
’’
The key rationale of the trial was to evaluate whether continuation of therapy consisting of a fluoropyrimidine and a VEGF inhibitor would lead to superior survival outcomes. The concept of ‘maintenance therapy’ is based on the idea that prolonged active antitumour treatment can be administered in a convenient way with limited adverse effects that do not compromise a patient’s quality of life (QoL), and is not associated with cumulative toxicities. The use of oral, lower dose daily capecitabine would seem ideal in this regard. Once the patients in either arm showed evidence of disease progression (progression-free survival‑1 or PFS‑1) patients were supposed to be re-treated with the original CAPOX‑B regimen until second tumour progression, assessed as PFS‑2, which constituted the primary end point of the trial; overall survival and QoL were also evaluated. The results showed a doubling of median PFS‑1, the secondary end point, from 4.1 months in the control arm to 8.5 months in the maintenance arm (hazard ratio [HR] 0.43, 95% CI 0.36–0.52; P
Rationale for metronomic chemotherapy in phase III trials Robert S. Kerbel and Axel Grothey Refers to Simkins, L. H. et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet http://dx.doi.org/10.1016/ S0140-6736(14)62004-3 (2015)
Systemic therapy for the treatment of cancer has been dominated by the notion that ‘more is better’. Most chemotherapy agents, and many other cancer drugs, are administered at the maximum tolerated dose (MTD). In the case of chemotherapeutics, this commonly requires a drug-free break of 1–3 weeks between successive cycles to allow for recovery from the toxic effects of treatment inflicted on normal proliferating cells—such as bone marrow progenitors, which results in myelosuppression. Almost 15 years ago, a different concept on chemotherapy dosing and scheduling was proposed, based on preclinical studies,1,2 which was termed ‘metronomic’ chemotherapy.3 This term refers to the often daily, continuous administration of chemotherapy agents, which necessitates drug administration at doses lower than the MTD. Part of the rationale behind this alternative dosing approach is that the tumour would be under constant therapeutic pressure, but as the drug is used at a lower dose, it would also reduce the severity of the toxic effects of higher dose therapies. Initial preclinical results involving treatment of transplanted primary tumours showed surprisingly remarkable efficacy results that were subsequently confirmed in other models, such as spontaneous tumours in genetically engineered mouse models (GEMMs),4 and even in mice with advanced visceral metastatic disease.5 In a number of preclinical studies, superior efficacy of metronomic
chemotherapy over MTD-based chemotherapy was demonstrated, together with reduced toxicity.1–3 The antitumour effects of metronomic chemotherapy seem to involve several possible mechanisms, perhaps acting concurrently. These mechanisms include antiangiogenesis, stimulation of the immune system, and possibly direct tumour-cell targeting effects, including effects on cancer stem cells.3 In preclinical studies, combining metronomic chemotherapy regimens with targeted agents, especially antiangiogenic drugs, resulted in further enhancement of antitumour efficacy.1–4 It might be counterintuitive that lower doses of chemotherapy could actually be equally effective or more effective than MTDbased chemotherapy. In addition, determining the optimal dose for metronomic chemotherapy has, so far, been based on empiricism and not solid prospective evidence. Such factors have slowed the clinical development of metronomic chemotherapy. Although many phase II trials have shown encouraging results,3 confirmation of the clinical benefits of metronomic chemo therapy in large, well-controlled, randomized phase III trials has, until the recent publication of CAIRO3, been lacking. In the multicentre, phase III CAIRO3 trial, 6 bevacizumab plus metronomic capecitabine was assessed; no control arm of either capecitabine only or bevacizumab only was included.1–4
NATURE REVIEWS | CLINICAL ONCOLOGY
NPG
Investigational metronomic chemotherapy involves frequent, regularly spaced, long-term administration of a sub-maximum tolerated dose. The phase III CAIRO3 trial evaluated continuous metronomic oral capecitabine, with bevacizumab, as a maintenance treatment in patients with metastatic colorectal cancer; a benefit in progression-free survival compared with observation only was observed, highlighting that metronomic chemotherapy could be a less toxic and convenient therapy.
The Dutch Colorectal Cancer Group designed and undertook the CAIRO3 trial, in part, to evaluate the concept of metronomic chemotherapy and the impact that longer treatment duration might have on survival outcomes in patients with colo rectal cancer (CRC).6 In this study, patients with metastatic CRC first received six cycles of conventional induction therapy over 4.5 months, consisting of oxaliplatin given intravenously every 3 weeks, capecitabine taken orally at 1,000 mg/m2 twice daily for 2 weeks followed by a 1‑week break, and intravenous bevacizumab every 3 weeks at a dose of 7.5 mg/kg. Upon completion of this therapeutic regimen (called CAPOX‑B), patients who experienced clinical benefit (that is, stable disease, a partial response or a complete response) were randomized into two arms: observation only (no treatment) or treatment with a ‘maintenance’ regimen consisting of capecitabine and bevacizumab. Notably, in this maintenance setting, capecitabine was used at a dose and schedule that conforms to the definition of metronomic chemotherapy as it was taken continuously at a lower twice daily dose: 625 mg/m2. This schedule was designed to reduce the risk of adverse effects such as ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS hand-foot syndrome and diarrhoea, and to allow for prolonged treatment duration in combination with bevacizumab. Oxaliplatin was not included because of its known cumulative toxicity, such as neuropathy.
‘‘
…results of the CAIRO3 ... demonstrate that extending the duration of chemotherapy … improves survival outcomes
’’
The key rationale of the trial was to evaluate whether continuation of therapy consisting of a fluoropyrimidine and a VEGF inhibitor would lead to superior survival outcomes. The concept of ‘maintenance therapy’ is based on the idea that prolonged active antitumour treatment can be administered in a convenient way with limited adverse effects that do not compromise a patient’s quality of life (QoL), and is not associated with cumulative toxicities. The use of oral, lower dose daily capecitabine would seem ideal in this regard. Once the patients in either arm showed evidence of disease progression (progression-free survival‑1 or PFS‑1) patients were supposed to be re-treated with the original CAPOX‑B regimen until second tumour progression, assessed as PFS‑2, which constituted the primary end point of the trial; overall survival and QoL were also evaluated. The results showed a doubling of median PFS‑1, the secondary end point, from 4.1 months in the control arm to 8.5 months in the maintenance arm (hazard ratio [HR] 0.43, 95% CI 0.36–0.52; P
