Oligoprogressive Renal Cell Carcinoma Treated with Stereotactic Body Radiation Therapy Versus Switching to a New Systemic Therapy

Take Home Message

Stereotactic body radiotherapy achieves disease control comparable to switching systemic therapy, with no detrimental effect on survival in patients with metastatic renal cell carcinoma experiencing oligoprogression during systemic therapy. This strategy may preserve future therapeutic options.

Abstract

Purpose

The promising results of stereotactic body radiation therapy (SBRT) in achieving local control in various primary tumors and metastatic sites have prompted evaluation of its association with outcomes in patients with oligoprogressive metastatic renal cell carcinoma (mRCC) during systemic therapy (ST). This study aimed to describe and compare the clinical outcomes associated with SBRT versus switching ST in patients with oligoprogressive mRCC.

Methods

We conducted a single-center retrospective study of patients with mRCC and up to five oligoprogressive extracranial metastases during ST. Patients were categorized into two cohorts: those treated with SBRT without changing ST (group A) and those receiving a change in ST (group B). The primary endpoints were progression-free survival (PFS) and overall survival (OS).

Results

A total of 67 patients (group A: 31; group B: 36) treated between 2012 and 2022 were included. After a median follow-up of 46 mo (40 mo for patients alive at the last follow-up), the median PFS was 11 mo in group A and 10 mo in group B (p = 0.5), with 3-yr PFS rates of 19% and 27%, respectively. Median OS was 74 mo in group A and 41 mo in group B (p = 0.052), with 3-yr OS rates of 70% and 51%, respectively. These differences should be interpreted as observational findings rather than evidence of causality.

Conclusion

In this retrospective analysis of patients with oligoprogressive mRCC during ST, SBRT was observed to have similar PFS and OS compared with a strategy of switching to a new ST. These findings are exploratory and do not establish causal effects.

ADVANCING PRACTICE.

What does this study add?

This study adds real-world evidence that stereotactic body radiotherapy (SBRT) can be used to manage oligoprogressive metastatic renal cell carcinoma while continuing the same systemic therapy. SBRT achieved progression-free survival comparable to switching to a new systemic treatment, without a detrimental effect on overall survival. These findings suggest that SBRT may allow clinicians to delay changing systemic therapy and preserve subsequent treatment options in selected patients.

Clinical Relevance

This study suggests that, in selected patients with oligoprogressive metastatic renal cell carcinoma, SBRT to progressing lesions may achieve outcomes comparable to switching to a new systemic therapy, while potentially preserving later-line treatment options. Given the retrospective, single-center design and small sample size, these findings should be considered hypothesis-generating, but they support metastasis-directed therapy as a reasonable strategy in carefully selected patients with limited extracranial progression. Associate Editor: Maria Carmen Mir.

Patient Summary

In some patients with advanced kidney cancer, the disease may start growing again in only a few points. These areas can be treated with local radiotherapy. Our study observed similar survival outcomes in patients treated with local radiotherapy compared with those who switched to ST. This means radiotherapy can sometimes safely delay the need to switch treatments.

1. Introduction

Renal cell carcinoma (RCC) accounts for approximately 4% of all solid tumors, with incidence rising in recent years. The disease is more common in men than in women, and most diagnoses occur between the ages of 50 and 70 yr [1], [2]. About 30% of patients present with metastatic disease at diagnosis, and an additional 20–50% develop local or distant recurrence after primary surgery [3]. Prognosis in metastatic RCC (mRCC) remains poor, with a 5-yr survival rate of approximately 17% [4]. Metastatic disease is highly heterogeneous, ranging from indolent to rapidly progressive behavior. Though these differences have traditionally been attributed to histological subtypes, most commonly clear cell RCC (ccRCC; 70%), followed by papillary (10–15%), and chromophobe (5%) [5], recent studies highlight the role of underlying molecular characteristics [6].

Systemic therapy (ST) remains the standard of care for mRCC. Over the past decade, immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), used alone or in combination (ICI + ICI/ICI + TKI), have been associated with improved clinical outcomes [7]. Nevertheless, disease progression eventually occurs in most patients, with wide variation in its extent and speed.

The concept of oligoprogression, described by Guckenberger et al in the context of oligometastatic disease [8], refers to progression in a limited number of lesions, typically up to three to five, while the overall disease burden remains controlled. This pattern likely reflects clonal tumor heterogeneity and the emergence of focal acquired resistance during ST [9].

Traditionally, ST is changed at the time of progression. However, local ablative approaches such as surgery or stereotactic body radiotherapy (SBRT) have been used to treat sites of oligoprogression and may allow postponement of a new systemic line in selected patients. This strategy is already applied in certain solid tumors, including prostate cancer and non-small cell lung cancer [10], [11], [12]. Evidence in mRCC remains limited, although retrospective studies have reported encouraging outcomes [13], [14], [15]. For instance, in a single-center study of 44 patients with mRCC treated with SBRT to 74 oligoprogressive metastases, nearly 80% of patients remained on the same ST 2 yr after local treatment, with no grade 3–4 toxicities reported [16].

Based on our institutional experience, we conducted a retrospective study of patients with mRCC who developed up to five extracranial oligoprogressive metastases during ST. We evaluated associations between clinical outcomes in patients treated with SBRT while continuing ongoing ST versus those managed with a switch to a new ST. Given the retrospective and observational design, findings are exploratory and hypothesis-generating, and should not be interpreted as evidence of causality.

2. Materials and methods

2.1. Study population

We conducted a retrospective analysis of patients with mRCC treated at our institution between 2012 and 2022. Patients were identified based on documented oligoprogressive disease, defined as progression in up to five metastatic sites while receiving ST. For this analysis, patients were categorized into two groups according to the management strategy used at the time of oligoprogression: those who received SBRT delivered while continuing the same ST (group A), and those who switched to a new line of ST (group B). Patients were eligible for inclusion if they had a diagnosis of ccRCC or predominantly clear-cell histology, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria and an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at the time of progression.

Clinical data were retrospectively extracted from electronic medical records and radiotherapy planning archives. Collected variables included date of nephrectomy, disease stage at RCC diagnosis, date of metastatic disease diagnosis, date and site of oligoprogression, number of oligometastatic lesions, and type and line of ST at the time of progression. Treatment decisions, including SBRT administration, reflected routine clinical practice and were discussed within the institutional multidisciplinary oncologic team.

2.2. Endpoint and assessment

The study endpoints were progression-free survival (PFS) and overall survival (OS). PFS was calculated from the date of SBRT or switch of ST at the time of oligo-disease progression to the first documented clinical or radiological progression. Patients without evidence of disease progression were censored at the date of last follow-up. OS was calculated from the date of SBRT or switch of ST at the time of oligo-disease progression to death from any cause or last follow-up. Patients who were alive were censored at the date of last contact, as assessed either at the last clinical follow-up or through registry records. Clinical and radiological evaluation with computed tomography (CT) scan was performed every 3 mo after SBRT or switch of ST. Tumor response was categorized according to the European Organization for Research and Treatment of Cancer (EORTC)-RECIST 1.1 criteria.

2.3. Statistical analysis

Baseline characteristics were compared between patients treated with SBRT while continuing ST (group A) and those who switched to a new ST (group B). Categorical variables were analyzed using the chi-square or Fisher’s exact test, and continuous variables using the Wilcoxon rank-sum test.

PFS and OS were calculated from the date of SBRT or therapy switch. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test.

Univariable and multivariable Cox proportional hazards models were used to assess associations between clinical factors and outcomes. Treatment strategy was the primary variable of interest. Clinically relevant covariates selected a priori (age, ECOG performance status, number of progressive lesions, presence of bone metastases, and time to oligoprogression) were included to adjust for potential confounding. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported and interpreted descriptively.

As treatment allocation was not randomized but determined during multidisciplinary discussion, confounding by indication cannot be excluded. Therefore, results should be considered exploratory and hypothesis-generating.

All tests were two-sided, with statistical significance defined as p < 0.05.

3. Results

A total of 67 patients with mRCC were included in the analysis and treated between 2012 and 2022 (group A: 31; group B: 36). Baseline demographic and clinical characteristics are presented in Table 1. All patients developed extracranial oligoprogression during ongoing ST.

Table 1.

Patients’ characteristics for the whole population and according to the treatment group

	Population	Group A	Group B	p value
Patients’ number, n (%)	67	31 (47)	36 (53)
Age (yr), median (IQR)	67 (54–73)	65 (54–70)	68 (61–73)	0.11
ECOG PS, n (%)
0	55 (82)	20 (65)	35 (97)	<0.001
1	9 (13)	8 (26)	1 (2.8)
2	3 (4.5)	3 (10)	0
Time to oligoprogression (mo), median (IQR)	27 (15–69)	31 (15–69)	22 (17–41)	0.5
ST line at oligoprogression, n (%)
1	49 (73)	22 (71)	27 (75)	0.7a
2	12 (18)	5 (16)	7 (19)
3	5 (7.5)	3 (10)	2 (5.6)
4	1 (1.5)	1 (3.2)	0
ST at oligoprogression, n (%)
Sunitinib	32 (48)	16 (52)	16 (44)	0.8
Pazopanib	12 (18)	5 (16)	7 (20)
Others	23 (34)	10 (32)	13 (36)
Number of oligoprogression metastasis sites, n (%)
1	30 (46)	21 (68)	9 (25)	<0.001b
2	20 (30)	7 (22)	13 (36)
3–5	17 (25)	3 (9.6)	14 (39)

ECOG PS = Eastern Cooperative Oncology Group Performance Status; IQR = interquartile range; mo = months; ST = systemic therapy; yr = year.

The sum may not add to the total due to the round to the nearest decimal.

^aThe p value related to groups 0 versus 1–2.

^bThe p value related to groups 1 versus >1.

The median age was 65 yr in group A (interquartile range [IQR], 54–70 yr) and 68 yr in group B (IQR, 61–73 yr). The median time to oligoprogression, defined as the interval from the initiation of ST to the detection of new oligoprogressive lesions, was 31 mo (IQR, 15–69 mo) in group A and 22 mo (IQR, 17–41 mo) in group B.

At the time of oligoprogression, 73% of patients were on first-line ST (group A: 22; group B: 27), 18% on second-line, 7.3% on third-line, and 1.5% on fourth-line. The most commonly used agents were sunitinib (48%) and pazopanib (18%). ECOG performance status (PS) was 0 in 65% of patients in group A and 97% in group B; ECOG PS ≥1 was recorded as 36% and 2.7% in group A and B, respectively. The most frequent sites of oligoprogression were the lungs (42%), lymph nodes (28%), and bones (19%).

Among patients in group A, SBRT was delivered according to institutional standards in place during the study period. In most cases, the clinical target volume corresponded to the gross tumor volume defined on planning CT. For moving targets, such as lung lesions, four-dimensional CT simulation was used when available. Patients were generally immobilized in the supine position with thermoplastic devices. A planning target volume margin of 5–10 mm was commonly applied. Daily cone-beam CT image guidance before each fraction was documented for all SBRT treatments.

The median follow-up, calculated using the reverse Kaplan-Meier method, was 46 mo (IQR, 30.5–76.7 mo). Median PFS was 11 mo in group A and 10 mo in group B; no evidence of a difference in PFS between the two strategies was observed (p = 0.7).

The 3-yr PFS rates were 19% and 27% for group A and B, respectively (Fig. 1A-B).

Fig. 1.

Kaplan-Meier estimates of (A) progression-free survival (PFS) and (B) overall survival (OS) in patients with metastatic renal cell carcinoma and extracranial oligoprogression during systemic therapy, treated with SBRT while continuing the same systemic therapy or with a switch to a new systemic therapy. Numbers at risk are reported below the x-axis. SBRT = stereotactic body radiation therapy; ST = systemic therapy.

Median OS was 74 mo in group A and 41 mo in group B; although a numerical difference was observed, this did not reach statistical significance. The estimated 3-yr OS rates were 70% in group A and 51% in group B, with wide CIs and no statistically significant difference between groups (p = 0.07). In the overall population, the presence of bone metastases was associated with significantly worse OS. The 3-yr OS was 39% in patients with bone involvement compared with 65% in those without bone metastases (log-rank p = 0.01).

Within group A, ECOG PS was associated with OS. Patients with ECOG PS 0 had a 3-yr OS of 81% compared with 55% for those with ECOG PS ≥1 (log-rank p = 0.02; Table 2). The number of oligoprogressive lesions was not significantly associated with OS in group A. Patients with one or two lesions had a 3-yr OS of 66%, while those with three or more lesions had an estimated 3-yr OS of 100%; however, this estimate is based on a very small number of patients and should be interpreted as exploratory. No statistically significant association between bone oligometastases and OS was observed in group A, possibly reflecting limited statistical power within this subgroup.

Table 2.

PFS and OS for the whole population and according to the treatment group

		ALL
Variable	Category	3-yr PFS (%)	Log-rank p value	3-yr OS (%)	Log-rank p value
Group	A B	19 27	0.7	70 51	0.07
Performance status	0	26	0.08	63	0.2
	≥1	NA		50
Number of oligoPD lesions	1	18	0.3	56	0.2
	2	35		76
	≥3	13		50
Age HR (CI 95%)		1.01 (0.98–1.04)	0.6	1.02 (0.98–1.05)	0.4
GROUP A
Performance status	0	24	0.3	81	0.02
	≥1	NA		55
Number of oligoPD lesions	1–2 3+	21 0	0.1	66 100	0.4
Age HR (CI 95%)		1 (0.96–1.04)	0.9	0.99 (0.94–1.95)	0.8
GROUP B
Performance status	0	27	0.002	53	0.03
	≥1	0		0
Number of oligoPD lesions	1–2	31	0.3	60	0.3
	3+	16		38
Age HR (CI 95%)		1.02 (0.98–1.06)	0.4	1.02 (0.97–1.07)	0.4

CI = confidence interval; HR = hazard ratio; NA = not available; oligoPD = oligo progression disease; OS = overall survival; PFS = progression-free survival.

In group B, ECOG PS was strongly associated with both PFS and OS. Patients with ECOG PS 0 had a 3-yr PFS of 27%, whereas those with ECOG PS ≥1 had a 3-yr PFS of 0% (log-rank p = 0.002). Similarly, 3-yr OS was higher in patients with ECOG PS 0 compared with ECOG PS ≥1 (53% vs 0%, log-rank p = 0.03).

The number of oligoprogressive lesions was not significantly associated with PFS or OS in group B. Patients with one or two lesions had a 3-yr PFS of 31% and a 3-yr OS of 60%, compared with 16% and 38% in patients with three or more lesions (PFS log-rank p = 0.3; OS log-rank p = 0.3). Age was not associated with either PFS (HR 1.02, 95% CI 0.98–1.06; p = 0.4) or OS (HR 1.02, 95% CI 0.97–1.07; p = 0.4; Table 2).

A detrimental association between bone oligometastases and OS was also observed in group B, where the 3-yr OS was 25% in patients with bone involvement compared with 59% in those without bone metastases (log-rank p = 0.03).

In this retrospective analysis, SBRT for oligoprogressive disease was feasible and associated with the continuation of ongoing ST in selected patients. PS and bone metastases were associated with survival outcomes, while the number of lesions was not clearly associated; given the retrospective design and small sample size, these findings should be interpreted cautiously and considered hypothesis-generating, warranting prospective validation.

4. Discussion

In the era of personalized medicine, the concept of oligoprogression represents a challenge to the traditional approach to the management of metastatic cancer. It is critical to recognize that lines of STs are often limited and typically associated with shorter PFS and/or increased toxicity. In this context, the main objective of using a localized approach to oligoprogression is to postpone the introduction of alternative drugs, thus preserving therapeutic options for potential use at a later stage of the disease.

Although the available evidence remains limited, local therapies targeting oligoprogressive sites have been integrated into treatment strategies for several solid tumors. Prostate cancer (PC) represents a notable example, often exhibiting slow growth and oligoprogression following second-generation hormonal therapies. One of the studies with the longest follow-up, a post hoc analysis of two phase 1 clinical trials, demonstrated that SBRT achieved durable local control and was associated with continuation of ongoing ST in 38 patients with oligoprogressive metastatic castration-resistant PC [17]. At 3 yr, one-third of these patients remained progression-free, and two-thirds had not required a change in ST.

In our retrospective analysis of real-world management of patients with mRCC who developed oligoprogression in up to five metastatic sites during first-line or subsequent systemic treatments, patients treated with SBRT while continuing the same systemic regimen appeared to have PFS outcomes similar to those who switched to a new line of therapy. No clear differences in OS were observed, although the small sample size limits definitive conclusions.

The rationale for maintaining the same ST after local therapy in oligoprogressive mRCC relies on the assumption that the majority of the disease burden remains sensitive to ongoing treatment. Local therapy is intended to control resistant clones responsible for focal progression. Though the evidence supporting this strategy is still evolving [18], [19], [20], the approach aims to extend the overall duration of disease control by avoiding premature therapy escalation.

Similarly, Brain et al [14] assessed definitive radiotherapy as a strategy to postpone ST escalation (STE) in 72 patients with extracranial oligoprogressive mRCC. Their findings indicated that delaying STE did not compromise PFS or OS, suggesting that radiotherapy may be a feasible and safe option to defer therapeutic switching.

Moreover, in a prospective phase 2 study, Chueng et al [15] investigated SBRT in patients with International mRCC Database Consortium favorable or intermediate-risk mRCC who developed oligoprogression (≤5 progressing lesions) while receiving first- or second-line TKIs. Among 38 enrolled patients, the 1-yr local control rate was 93% (95% CI 71–98%), and median PFS after SBRT was 9.3 mo (95% CI 7.5–15.7). At 1 yr, 47% of patients had switched ST, with a median time to ST change of 12.6 mo (95% CI 9.6–17.4).

A summary of available evidence on local therapy for oligoprogressive mRCC is presented in Table 3.

Table 3.

Studies investigating the role of metastasis-directed local treatment in managing oligoprogressive mRCC

First author Study type	No. of patients	Metastatic site treated by LT (%)	No. Metastatic Site, n (%)	Systemic therapy (%)	Outcomes
Santini [13] Retrospective 2017	55	Lung (27) Bone (18) Contro. Kidney (17) Others (23)	NA	TKI (100)	mPFS 14 mOS 37
Meyer [22] Retrospective 2018	188	Brain (44) Bone (38) Visceral (22)	1 (41.5) 2 (36) ≥3 (22)	TKI (49.5) mTOR (3) No ST (34) Others (13)	mPFS 8.6 m mOS 23.2 m mTTs 10.5 m 1-yr LC 83%
Schoenhals [23] Retrospective 2021	36	Bone (46.5) Lung (14) Liver (12) Others (27.5)	1 (83) 2 (14) 3 (3)	TKI (70) ICI (20) mTOR (10)	mPFS 9.2 m mOS 43.4 m 1-yr LC 93%
Cheung [15] Phase 2 2021	38	Lung (37) Bone (21) Lymph node (12) Others (30)	1 (54) 2 (38) 3 (8)	TKI (100)	mPFS 9.3 m 2-yr LC 96% 2-yr OS 77%
De Brian [14] Retrospective 2022	72	Lung (49) Bone (49) Others (3)	NA	TKI (32) ICI (18) No ST (46) Others (4.0)	mPFS 12.1 mOS 60.8 1-yr LC 96%
Franzese [16] Retrospective 2022	44	Brain (35) Lung (28) Bone (13.5) Others (22)	1 (79) 2 (12) 3 (7) Others (2)	TKI (70) ICI (20)	mPFS 9.8 mOS 36.3 1-yr LC 96%

ICI = immune checkpoint inhibitors; LC = local control; LT= local treatment; m = month; mPFS = median progression-free survival; mOS = median overall survival; mRCC = metastatic renal cell carcinoma; mTOR = mammalian target of rapamycin; NA = not available; ST = systemic therapy; TKI = tyrosine kinase inhibitor; TTS = time to systemic therapy initiation; yr = year.

Current European and American guidelines acknowledge the potential role of local treatments for oligometastatic and oligoprogressive RCC [18], [19]. In clinical practice, management decisions for oligoprogressive mRCC take into account prior systemic treatments, anatomical sites of progression, patient characteristics, and the availability of subsequent therapeutic lines [21].

This study has several limitations, including its retrospective design, potential selection bias, and the relatively small sample size. The marked difference in time to oligoprogression between groups suggests biological heterogeneity and may limit causal interpretation, as patients with more indolent disease may have been preferentially managed with therapy switch. Nevertheless, our findings suggest that SBRT may represent a feasible management strategy in selected patients.

Prospective studies are required to determine causal effects, particularly in the context of modern STs combining ICIs and TKIs. Future prospective studies should incorporate predefined criteria for treatment selection, standardized assessment of confounders including comorbidity burden and tumor growth kinetics, and ideally randomized comparison between SBRT with continuation of ST versus early therapy switch.

5. Conclusions

SBRT for oligoprogressive lesions in mRCC was feasible and was associated with continuation of ongoing ST, with no apparent detrimental effect on short-term outcomes. Prospective studies are needed to confirm these findings and guide optimal patient selection.



Author contributions: Nadia Cordua had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.



Study concept and design: Cordua, Franzese.

Acquisition of data: Bertocchi, Lucchini, Aliprandi, Lo Faro, Cecchi, Di Cristina, Bertolini, Federico, Borea.

Analysis and interpretation of data: Franzese.

Drafting of the manuscript: Perrino, De Vincenzo, Cordua.

Critical revision of the manuscript for important intellectual content: Zucali, Scorsetti.

Statistical analysis: Giordano.

Obtaining funding: Zucali, Scorsetti.

Administrative, technical, or material support: None.

Supervision: Zucali, Scorsetti.

Other (specify): None.



Financial disclosures: Nadia Cordua certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.



Funding/Support and role of the sponsor: None.



Acknowledgments: The publication fee for this work was covered by the Italian Ministry of Health’s “Ricerca Corrente” funding to the IRCCS Humanitas Research Hospital.

Associate Editor: Maria Carmen Mir

Statistical Editor: Rod Dunn