1. Harrison, Michael R. MD

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The question comes up regularly in my practice: "Doc, do I really need to start therapy now? Can't we wait?"

renal cell carcinoma... - Click to enlarge in new windowrenal cell carcinoma. renal cell carcinoma
Michael R. Harrison,... - Click to enlarge in new windowMichael R. Harrison, MD. MICHAEL R. HARRISON, MD, is an Assistant Professor of Medicine, Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, N.C.

Metastatic renal cell carcinoma (mRCC) is a heterogeneous disease; there is a subpopulation of patients with relatively indolent biology and slow tumor growth. There is also the potential for substantial toxicity with all approved systemic therapies. So, when should we start systemic therapy in these patients?


If indolent disease is suspected, is it OK to wait a bit to gauge the growth rate of disease?


There is not much in the literature about deferring systemic therapy. My choice of the word "defer" is intentional: when we (the patient and I) make this choice, we are not saying that the patient will never get systemic therapy, we are just saying "not now." This phrasing distinguishes amongst those patients who are not candidates for systemic therapy (because of poor performance status, comorbidities, or other reasons) and those who may be offered best supportive care, or hospice, only.


Another important caveat is that we are really talking about those patients in whom disease is present, whether measurable or not. For patients who have had metastasectomy or other local therapy (i.e., SBRT), deferring systemic therapy is a different discussion in that this becomes a "pseudo-adjuvant" setting. That is, when all visible disease has been resected and/or treated, we're really talking about systemic therapy to prevent or delay reappearance of visible lesions.


We must also make a distinction between first-line, or systemic therapy-naive, patients and those who have been put into a complete remission (CR) or near-CR by systemic therapy. The mode of initial systemic therapy may also be important as we are seeing different recurrence patterns after VEGF receptor TKI discontinuation after response compared with immunotherapies (high dose IL-2, nivolumab). Finally, it is important to note that these patients are inherently difficult to study because they are, by definition, excluded from the clinical trials literature.


Research Overview

So what does the evidence tell us? Multiple retrospective studies in "first line" mRCC patients collectively suggest that:


* patients may defer systemic therapy for a year or more on average;


* these patients appear to have at least equivalent survival (and possibly, better) compared with patients treated with immediate systemic therapy;


* certain features may portend shorter time on until systemic therapy is required (i.e, poor MSKCC or Heng risk, short time from diagnosis to deferred systemic therapy, bone or liver metastases); and


* there is no decrement in the response rate to subsequent first-line systemic therapy.



These retrospective studies are limited by selection bias and the lack of patient-reported outcomes (PROs) and other correlates (J Cancer Res Clin Oncol 2014;140:1421-8, Clin Genitourin Cancer 2015 Jun;13:e159-66, J Clin Oncol 2015:suppl;abstr e15582, Eur J Cancer 2016:suppl 1, page e13; abstr AOS34).


The earliest prospective suggestion that deferred systemic therapy does not have an adverse effect on efficacy comes from a randomized discontinuation trial of sorafenib (J Clin Oncol 2006;24:2505-12). More recently, Rini et al reported at ASCO 2014 on a prospective observational study of mRCC patients with no prior systemic therapy, no disease-related symptoms, and measurable/evaluable disease (N=52) (Abstract 4520). The decision to start systemic therapy was at the treating physician's discretion. The median time on observation was 14.1 months and was longer in patients with <=3.0 versus >3 cm of disease (19.3 vs. 10.6 mos, p=.05). Interestingly, neither the Heng risk nor the location or number of metastatic sites was correlated with the length of observation. Observation also did not appear to reduce quality of life or increase anxiety/depression.


The ongoing prospective metastatic renal cell cancer (MaRCC) registry may allow unique opportunities to study rigorously the deferred systemic therapy population. In preliminary analysis and with relatively short follow up, over 40 percent of patients have had systemic therapy deferred as the initial decision upon enrollment (J Clin Oncol 34, 2016 (suppl; abstr e16084). MaRCC will describe the outcomes (i.e., OS, PFS), patterns of systemic therapy, reasons for physician decision-making, patient-reported outcomes, and health resource utilization across multiple treatment lines in the deferred systemic therapy population. Several interesting analyses may result.


Effective Tools

Tools such as the Quality-adjusted Time Without Symptoms or Toxicity (Q-TWIST), which combines survival time and quality of life to arrive at a single endpoint, could be used to evaluate quality-adjusted survival time on deferred systemic therapy compared with systemic therapy in patients with similar characteristics. Because deferred systemic therapy may be a more efficient use of resources, incorporating health resource utilization into Time Driven Activity-Based Costing (TDABC) or other models may be important. Q-TWIST and TDABC analyses may yield different results in the VEGFR TKI era compared with the dawning immunotherapy era.


Finally, because current prognostic models are lacking, collection of tissue and blood biomarkers might help with predicting an indolent disease course appropriate for deferred systemic therapy.


So, what do I tell the patient who poses the above question? I usually try to understand their unique reasons for wanting to defer systemic therapy. Then, I review with them their relevant disease characteristics. Next, I go through with them the above evidence regarding characteristics that may portend a short time on deferred systemic therapy. We come to a shared decision based on this discussion.


If there is a question of the growth rate of their disease, I may opt for repeat staging scans in 2 months (CT chest, abdomen, and pelvis) before making a final decision. Otherwise, I would typically surveil them with the schedule used in the Rini study: every 3 months for year 1, every 4 months for year 2, and then every 6 months.


Additionally, I counsel them that with any dramatic change in the growth rate of their disease or any new lesions, I am likely to recommend starting systemic therapy. In the era of precision medicine, our tools for managing deferred systemic therapy remain rudimentary.