Metastatic renal cell carcinoma (mRCC) is a disease with wide variation in clinical outcome between subsets of patients. Motzer et al., at the Memorial Sloan Kettering Cancer Center (MSKCC), were the first to stratify patients into favourable, intermediate and poor risk groups based on clinical criteria. More recently, Heng et al. have updated these and published the International Metastatic RCC Database Consortium (IMDC) criteria for a population treated with modern targeted therapies. Patients in the favourable risk category have a 2-year survival of over 75%, with some living for many years, indicating the possibility of indolent and/or highly treatment-responsive disease.
Prior to 2005, systemic therapy for mRCC was limited to cytokines, with modest efficacy in the majority of patients. Reports of indolent mRCC date back to the 1980s, with cases of spontaneous regression of metastatic disease also published . In 1988, Oliver et al. performed a prospective observational study of 73 patients with mRCC, and reported that 12 months after initiation of observation, the cancer remained stable in approximately 10% of the patients. Since then, it has been recognized that there is a small subset of patients with indolent mRCC that can be monitored for a prolonged period.
With seven new treatments approved for use in mRCC since 2005, current guidelines recognize first, second and possibly third-line treatment as standard [5–7]. Currently available therapies for mRCC are effective, but not curative, and are therefore given with palliative intent, aiming to optimize both life expectancy and quality of life. With careful supervision, these treatments are largely well tolerated; however, none are entirely free of toxicities or risk. In an era with widespread availability of effective systemic therapies, does observation remain a valid strategy for a subset of patients with mRCC?
The present review will examine the available evidence for an observation strategy in mRCC in the era of modern, effective therapeutic agents. Data for this review were compiled by searching PUBMED/MEDLINE and abstract databases from scientific meetings held by the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) up to March 2015 using the search terms: ‘observation’, ‘surveillance’, ‘advanced’, ‘metastatic’ and ‘renal cell carcinoma’. Only articles in English were considered.
RETROSPECTIVE STUDIES EVALUATING THE STRATEGY OF OBSERVATION IN METASTATIC RENAL CELL CARCINOMA
Several retrospective series have provided preliminary data supporting observation as a strategy for a subgroup of patients with mRCC and relatively low tumour burden (summarized in Table 1).
Fisher et al.[8▪] reported a cohort of 62 patients from two UK centres, in whom first-line systemic therapy was electively deferred due to asymptomatic or slowly progressive mRCC. All but one of the patients had favourable or intermediate risk disease as defined by Heng et al. In this carefully selected group, patients were observed for an average of 18.7 months [95% confidence interval (CI) 14.5–22 months] before receiving a variety of first-line systemic treatments. Median overall survival (OS), defined as the time from starting first-line systemic therapy to death, was 25.2 months (95% CI 11.6–23.2 months) in the full 62-patient cohort. The 39 patients who subsequently received sunitinib had a median OS of 17.4 months (95% CI 8.0–42.4 months) and a median progression-free survival (PFS) of 9 months (95% CI 8.1–9.9 months). This benefit is comparable to data from the pivotal phase III and expanded access trials of first-line sunitinib [14▪,15]. Analysis of factors that may identify patients with a longer time to progression was not undertaken. Thus, patients were observed for between 14 and 22 months, with no detectable adverse impact on their outcome.
Matsubara et al. reported a similar cohort of 29 patients with intermediate or favourable-risk mRCC in whom systemic treatment had been deferred due to patient preference, lack of symptoms or slow progression. Median PFS was 26.1 months, with median OS not yet reached; however, an impressive 48-month OS rate of 83.8% was reported. Multivariate analysis suggested that Karnofsky performance status (KPS) below 100%, presence of liver metastasis, time from diagnosis to active surveillance less than 1 year and neutrophilia were predictive factors for shorter time to progression.
A group from Cambridge, UK have reported outcomes of observation from a more heterogeneous cohort of patients with mRCC . de Velasco et al. identified 102 patients undergoing active surveillance, either for low-volume asymptomatic disease or due to coexistent comorbidities. The majority had not received prior therapy for mRCC; however, 19 patients had undergone surgery for oligometastatic disease, 13 had received radiation therapy and four patients had received biologic treatment. Median time on active surveillance for this cohort was 11 months (95% CI 8.8–13.1 months). OS was 39 months for the active surveillance cohort compared to 17 months for 158 patients treated at the same institution during the same time period with upfront systemic therapy. This difference must be interpreted with caution since this was a nonrandomized comparison with significant selection bias, but does support the assertion that a group of patients can be identified for which observation is an appropriate initial management strategy.
A South Korean retrospective series identified 58 patients with mRCC in whom initiation of systemic therapy was electively deferred . After a median follow-up of 31 months, the median time on observation was 12.4 months (95% CI 8.4–16.5 months) and the median OS was not reached. KPS below 100%, liver metastases and time from diagnosis to initiation of active surveillance for metastatic disease less than 12 months were all found to predict for shorter time to progression.
Recently, three Spanish oncology centres presented their collective experience of active surveillance in mRCC. Jove et al. identified 69 patients with favourable or intermediate-risk disease who had active surveillance as their initial therapeutic strategy from a total cohort of 277 diagnosed with mRCC during the defined period. Active surveillance was defined as a period of at least 6 months from first diagnosis of metastatic disease to initiation of systemic therapy. Median time on active surveillance was 14 months (95% CI 17.68–26.0 months). Median time on first-line systemic treatment, once initiated, was 6.63 months (95% CI 3.45–9.69 months) compared with 6.48 months (95% CI 4.89–8.06 months) for the 208 patients who had started immediate systemic therapy.
Despite their inevitable selection basis and other limitations, these retrospective series clearly demonstrate that in a subset of patients with low-volume asymptomatic disease, deferring systemic therapy appears safe and not to reduce duration of response to systemic therapy once it is initiated. In these carefully selected patients with good prognostic features, survival data are comparable and possibly superior to the published literature, likely reflecting the favourable biological characteristics associated with slowly progressive metastatic disease.
PROSPECTIVE STUDIES EVALUATING THE STRATEGY OF OBSERVATION IN METASTATIC RENAL CELL CARCINOMA
Prospective data evaluating this approach are limited. The phase III VEG105192 registration study of pazopanib provides some randomized data, suggesting that deferral of systemic therapy may not lead to inferior survival [16▪▪]. Patients in this study were stratified according to whether they were treatment-naïve or cytokine pretreated and randomized to pazopanib versus placebo. This study was conducted at a time when other approved targeted therapies, such as sunitinib, were not widely available in many parts of the world, hence the justification for the inclusion of treatment-naïve patients. Although the median PFS was significantly longer in the group treated with pazopanib upfront, there was no difference in OS even in this unselected group of patients deemed appropriate for systemic therapy, indicating that there was no survival detriment associated with deferring initiation of systemic therapy until radiological progression.
A recently presented prospective observational study has provided additional data supporting the deferral of systemic therapy for carefully selected patients with mRCC . Rini et al. reported a multicentre prospective cohort of 52 patients enrolled in a surveillance protocol, with the primary objective of assessing time to initiation of systemic treatment. Median time on observation was 14.1 months (95% CI 10.6–19.3 months), with estimated 12 and 24-month rates of continued surveillance of 58 and 33%, respectively. Exploratory analysis showed a significantly longer time on observation for patients with baseline tumour burden 1.5 cm or less versus greater than 1.5 cm (31.6 versus 13.8 months), although Heng risk group, or number or location of metastases, did not affect the duration of observation. Whilst it may be intuitive that patients with a very low disease burden can be observed for longer than those with a high disease burden, even the latter group achieved a clinically relevant duration of observation of greater than 12 months. Also, importantly, prospective assessment of anxiety and depression using standardized questionnaires did not show any change over the observation period.
The health economic impact of an initial surveillance strategy was analysed from a subset of patients in this study . Seventeen patients were matched by age, sex, Heng risk and length of follow-up to control patients with mRCC who received immediate systemic therapy. Excluding drug costs, a significant 45.4% decrease in direct aggregate costs was associated with initial observation compared with immediate systemic therapy.
HOW TO SELECT PATIENTS FOR DEFERRAL OF SYSTEMIC THERAPY?
Exploratory analyses from the reported series suggest that factors associated with shorter time to progression on observation include KPS below 100%, short time from diagnosis to metastatic disease, presence of liver metastasis and tumour burden above 1.5 cm [9–12]. Although these factors have not been prospectively validated, it is reasonable to propose that the ideal patients for enrolment onto a surveillance programme are asymptomatic patients with good performance status and a low burden of metastatic disease without liver involvement. It is, however, also worth noting that patients from these carefully selected cohorts who achieved shorter time on surveillance did not appear to suffer detrimental outcomes as a consequence. With advancements in molecular biology and cancer genomics, biomarkers that select patients with indolent disease may be identified. Until that time selection of appropriate patients is reliant on clinical factors.
SURVEILLANCE PROTOCOLS AND INITIATION OF SYSTEMIC THERAPY
In the prospective study conducted by Rini et al., patients were imaged at baseline, every 3 months in year 1, every 4 months in year 2 and then every 6 months. This protocol can be adjusted, with more frequent imaging for patients with asymptomatic but slowly progressive disease, whereas patients with prolonged disease stability may require less frequent imaging coupled with education about the need to present with new symptoms of concern to minimize the risk of a deterioration in performance status on observation. Initiation of systemic therapy would be recommended on symptomatic progression, acceleration in the pace of tumour progression on serial imaging or new organ involvement such as liver metastases.
IMPLICATIONS FOR CONTINUOUS VERSUS INTERRUPTED THERAPY
Observation may be considered not only as an initial management strategy but also as an interruption to first-line treatment. A retrospective series of 112 patients who had treatment breaks for any reason other than disease progression (toxicity, physician or patient choice) was reported by Mittal et al.. The median duration of first treatment break was 16.8 months, and some of these highly selected patients were able to have second or third treatment breaks.
An ongoing UK clinical trial is now prospectively comparing conventional continuous dosing of first-line sunitinib or pazopanib with a drug-free interval strategy (STAR: ISRCTN06473203) . The associated biomarker sub-studies may be an opportunity to prospectively evaluate prognostic biomarkers in the first-line treatment setting.
Emerging data from five retrospective series, one prospective cohort and a subgroup of a randomized phase III trial support the strategy of deferral of systemic therapy for selected patients with mRCC. Taken together, we believe these data constitute persuasive evidence for the inclusion of an observation strategy in mRCC treatment algorithms. Appropriate patients benefit from a period free from the toxicity of therapy without compromising the survival-prolonging benefit associated with future systemic treatment. Clinical criteria to split patients into favourable, intermediate and poor risk groups are well established; the typical patients selected for observation have good performance status, low tumour burden and an absence of liver metastasis. However, the current challenge is to understand the molecular heterogeneity of renal cancer, and to identify and prospectively validate both prognostic and predictive biomarkers. It is hoped that well designed studies with translational correlates will enable patients with indolent disease to be identified at diagnosis and recommended deferral of systemic therapy as an evidence-based approach.
Financial support and sponsorship
L.P. has received honoraria for consultancy from GSK, Novartis and Pfizer; lecture fees from Pfizer and travel expenses from GSK and Pfizer. D.M. has received honoraria for consultancy from Pfizer and travel expenses from Bayer. These honoraria and travel fees are all for work outside the scope of this submission.
M.M. has no conflicts of interest.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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