PISCES: A Horoscope for First-Line Targeted Therapy of Metastatic Renal Cell Carcinoma

TO THE EDITOR: Escudier et al recently published a report of the PISCES (Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer) trial, which assessed treatment preferences for pazopanib versus sunitinib in newly diagnosed patients with metastatic clear cell renal cell carcinoma. We wish to congratulate the authors for the novelty of the study design. However, we are unsure whether the tested concept of a 10-week course of one targeted therapy followed by a 2-week washout and another 10-week period of a second targeted therapy (or vice versa) is of value, especially when treatment selection is made in a real-life clinical setting, where patients continue to receive therapy until disease progression or intolerable toxicity. The duration of therapy usually spans months or even years. Only occasionally is it administered for weeks (as in the study), for reasons such as early failure or unmanageable toxicity. The tolerability of targeted agents usually improves with time, and with dose and/or schedule adjustments. Moreover, the benefits of therapy, perceived toxicity, and patient acceptance of the targeted agent are also strongly affected by objective response rates. Under most circumstances, the efficacy is first assessed 12 weeks after the start of therapy. The relationship between efficacy, toxicity, tolerability, and the patient, as well as physician acceptance of this relationship, then determine whether treatment is pursued or abandoned. All of these processes are not realistically captured within the study design. Hence, the disconnect between the study design and the real-life clinical setting represents an important flaw. The study design also raises a concern with respect to short exposure time to two consecutive agents that are not administered with curative, but rather questionable, intent. Such exposure has unknown consequences and may induce resistance or other untoward effects when real-life treatment is needed to prevent life-threatening disease progression. The study design is actually reminiscent of studies where quality of life represents the main end point. There are settings in which such study design is appropriate, valid, and ethically acceptable, such as in patients with overactive bladder or benign prostate hyperplasia, where symptom relief represents the focal point of treatment and where drugs can be replaced or stopped without danger or consequence to patient survival. Conversely, we are concerned about the validity and appropriateness of the design of the study by Escudier et al in the context of a life-threatening disease, such as metastatic clear cell renal cell carcinoma, where short-term sequential use of two key agents is made without knowledge of its effect on further patient cancer control outcomes.

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