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Rethinking end-points for bone-targeted therapy in advanced cancer

European Journal of Cancer, August 2016, Pages 105 - 109

Abstract

The principal objective for any medical therapy is to improve either the duration of life and/or its quality. Metastases in bone can lead to clinically defined events termed skeletal-related events (SREs) which are a quantifiable measure of skeletal morbidity. Avoidance and/or delay of SREs have become the principal objective in trials exploring the efficacy of bone-targeted therapy in patients with skeletal metastases. Despite reductions in the frequency or rate of SRE occurrence, trials of bone-targeted therapy have failed to show any effect on either progression-free or overall survival when compared with placebo or other bone-targeting agents. Similarly, trials of bone-targeted therapy have not shown consistent effects on quality of life. The validity of SRE-based primary outcome measures in cancer clinical trials is therefore, questionable. More novel end-point selection for trials of bone-targeted therapy seems warranted. Composite measures comprising occurrence of symptomatic skeletal events and patient reported outcomes may be an effective solution and warrants further investigation.

Highlights

  • Bone-targeted therapy for bone metastases reduces the frequency of skeletal events.
  • However, this treatment does not affect survival or overall quality of life.
  • The use of skeletal events as primary end-points in cancer trials is questionable.
  • Composite end-points comprising survival and patient reported outcomes warrant further study.

Keywords: End-points, Clinical trials, Bone metastases, Bisphosphonates, Denosumab, Solid tumours.

The principal objective for any medical therapy is to improve either the duration of life and/or its quality [1] and [2]. These objectives are even more important when providing palliative treatment to cancer patients. Bone is a common site of metastasis in many cancers including breast, prostate, non-small cell lung cancers and multiple myeloma. These metastases can induce a deregulation of bone formation (osteoblast function) and resorption (osteoclast function) resulting in increasing bone destruction.

Metastases in bone can lead to the development of skeletal-related events (SREs), clinically defined events comprising the need for radiation or surgery to bone, pathologic fractures, spinal cord compression, and hypercalcaemia. In addition to being a quantifiable measure of skeletal morbidity, the development of SREs in general, and pathological fractures specifically, have been shown to be associated with worse survival [3]. Avoidance and/or delay of SREs has therefore become the principal objective in trials exploring the efficacy of bone-targeted therapy in patients with skeletal metastases.

Since the 1990s, a large number of phase III clinical trials have explored the role of both bisphosphonates and denosumab as treatment for bone metastases. These trials have led to the regulatory approval of these agents in this setting. Over time, the choice of primary end-point in these trials has changed. Initially, trials were designed to observe a quantitative change in the proportion of patients suffering from SREs. Later trials, especially those exploring denosumab have utilised time-to-event end-points such as time to first SRE. More recently, focus has shifted to symptomatic skeletal events (SSEs) [4]. However, there has been little validation of these end-points as adequate surrogates for either survival or quality of life (QoL).

In contrast to data in early stage breast cancer [5], bone-targeted therapy has not been shown to have any anti-cancer effect in patients with metastatic solid cancers. Despite reductions in the frequency or rate of SRE occurrence, individual trials exploring bone-targeted therapy have failed to show any effect on either progression-free or overall survival when compared with placebo or other bone-targeting agents. Meta-regression analysis comprising all trials reporting on both frequency of SREs and overall survival showed that there was no significant association between reduction in the risk of SRE and the hazards of death (R = –0.36, p = 0.32, see Fig. 1A). Consequently, it can be assumed that avoidance of SREs through use of bone-targeted therapy is not prognostic. The occurrence of SREs likely represents poor systemic cancer control and SRE avoidance through the use of bone-targeted therapy rather than systemic anti-cancer therapy is likely of questionable benefit from a survival perspective.

gr1

Fig. 1 Meta-regression analysis exploring the association between (A) reduction in risk of skeletal-related events (SREs) and hazard ratio for overall survival (OS) and (B) reduction in risk of SREs and risk of improvement in quality of life. The diagonal line is the fitted weighted linear regression line. The size of the circle is relative to the sample size of the study. QoL, quality of life.

Similarly, individual trials of bone-targeted therapy have not shown consistent effects on overall QoL; some trials showed no effect on QoL [6] and [7], and of those where effect was seen, methodologic limitations such as effect of multiplicity made interpretation difficult [8]. Bone-targeted therapy is not an entirely benign treatment. Intravenous infusion of amino-bisphosphonates can be associated with fever, myalgias and musculoskeletal pain, while all bone-targeted agents can cause electrolyte alterations (especially to calcium, magnesium and phosphate). A rare, but highly morbid toxicity of bone-targeted therapy is osteonecrosis of the jaw, which requires meticulous follow-up of dentition and oral hygiene in patients receiving these drugs. An additional concern of the long-term use of bone-targeted therapy is microfractures, which can lead to reduced skeletal integrity [9]. All these side-effects need to be balanced by the potential effect of avoidance of morbidity of SREs.

Measuring QoL can be difficult due to a relatively high variability of many common QoL tools [10]. Clinical trials of bone-targeted therapy have utilised different QoL tools and end-points making pooling of data difficult. Most trials focused on pain scales such as the brief pain inventory [11]. However, the most frequent reporting of overall QoL has been using generic QoL tools such as FACT-G [12] and exploring clinically significant (≥5 point) improvement in scores. Meta-regression analysis comprising all trials reporting these end-points showed that there was no significant association between reduction in the risk of SRE and improvement in QoL. However, only three studies contributed data to this analysis which may explain why statistical significance was not observed despite a relatively high correlation between reduction in the risk of SRE and improvement in QoL (R = –0.71, p = 0.50, see Fig. 1B).

In view of the above, it would appear that change to the frequency of SRE occurrence with bone-targeted therapy is not an adequate surrogate for either survival or QoL. Therefore, the validity of SRE-based primary outcome measures in bone-targeted therapy trials is questionable. As such, more novel end-point selection for trials of bone-targeted therapy seems warranted.

The validation of surrogate end-points in oncology is complex and controversial [13] and [14]. While measurement of intermediate end-points is easier and allows for smaller sample sizes of clinical trials, identification of adequate surrogacy with definitive outcomes such as QoL or survival remains elusive in many settings [15]. However, despite this, there has been little progress in the development novel, validated and practical end-points that truly reflect either the patient experience or the benefit of bone-targeted therapy. The use of composite end-points has been suggested as one method which may allow for the inclusion of clinically relevant outcomes into an end-point whose use in large clinical trials would be feasible [16].

The use of composite end-points in branches of medicine such as cardiology is prevalent [17] and [18]. Such end-points have also been used successfully in oncology. The initial registration study for gemcitabine in advanced pancreatic cancer utilised a composite primary end-point [19] of pain (analgesic consumption and pain intensity), performance status, and weight. More recently, a composite end-point comprising survival, disease progression and deterioration of symptoms was used as a secondary end-point in the AXIS trial, a phase III clinical trials comparing axitinib to sorafenib for metastatic renal cell carcinoma [20]. Results of the AXIS trial showed that compared to progression-free survival (a non-validated end-point in renal cell carcinoma), there was dilution of effect for the composite end-point, however, statistical significance was retained. These data suggest feasibility of the use of such composite end-points in large cancer clinical trials.

The use of such composite end-points in studies of bone-targeted therapy appears to have merit. Such an end-point could comprise of a SRE-related measure such as occurrence of SRE or time to first SRE as well as a validated QoL measure which may be a generic QoL tool or a bone-specific measure. The development and validation of such an end-point will have some challenges including optimal choice of the SRE end-point. Some SREs are symptomatic while others may be identified incidentally. They also differ significantly in impact; palliative radiation to a painful rib metastasis is considered equivalent to spinal cord compression despite substantially less morbidity. Both clinical trials and population-based observation studies show that the most common type of SRE is the receipt of radiation to bone [21] and [22]. The need for radiation to bone can be subjective and recommendations for such therapy may be based on identification of asymptomatic imaging findings rather than symptomatic deterioration. Focus on SSEs has drawn attention and has been shown to be a dynamic measure of the efficacy of bone-targeted therapy [4]. Inclusion of SSEs rather than SREs may result in a greater association with improved QoL outcomes. SREs often occur at initial diagnosis [23] of metastatic disease. However, beyond diagnosis, in the era of effective anti-cancer therapy in many solid tumours, SREs are increasing occurring towards the end of life [24]. This may make time-to-event analyses such as time to first SRE more challenging. Finally, it would be important to decide on whether each element in the composite end-point should be weighted similarly or whether a greater weight should be applied to the QoL component. Once these challenges have been overcome, such end-points would need to undergo statistical and then clinical validation.

The delivery of affordable, high quality, evidence-based healthcare is a major issue affecting all countries including those with high income [25]. Translation of data from clinical trials to clinical practice is already compromised by the efficacy-effectiveness gap with data showing that in many scenarios routine use of drugs is associated with lesser benefit and greater toxicity compared to data from clinical trials [26]. Additionally, reduced generalisability relating to the increasing use of exclusion criteria in clinical trials is also described [27]. Consequently, the use of clinically meaningful end-points is crucial to the efficient delivery of cancer care. The use of end-points comprising SREs alone does not appear to be valid for clinical trials of bone-targeted agents. As such, novel end-points are urgently needed in this setting. Composite measures comprising occurrence of SSEs and patient reported outcomes may be an effective solution and warrants further investigation.

Conflict of interest statement

The authors declare no relevant conflicts of interest.

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Footnotes

a Department of Medical Oncology, Hospital Álvaro Cunqueiro- Estructura Organizativa de Xestión Integrada (EOXI) of Vigo, Spain

b Division of Medical Oncology, The Ottawa Hospital, and University of Ottawa, Ottawa, Canada

c Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada

d Department of Medicine, University of Toronto, Toronto, Canada

Corresponding author: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Ave, 5-124, Toronto, ON M5G 2M9, Canada. Tel.: +1 416 946 4501x5181; fax: +1 416 946 4563.


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