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Video: Stereotactic ablative body radiotherapy for inoperable primary kidney cancer

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Stereotactic ablative body radiotherapy for inoperable primary kidney cancer

Abstract

Objective

To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes.

Materials and Methods

This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan–Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size.

Results

Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1–2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4–5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001).

Conclusion

The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.

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Editorial: Stereotactic radiotherapy for primary renal cell carcinoma: time for larger-scale prospective studies

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A number of important trends in kidney cancer diagnosis have emerged in recent decades, including the increasing detection of renal tumours in older patients with more comorbidities. In the UK in 2012–2014, 50% of new cases were diagnosed in people aged 70 years and over. Whilst many of these lesions are incidental small renal masses suitable for active surveillance, the dilemma of how to manage the higher-risk lesion (rapid growth kinetics, larger size, symptomatic lesion) is increasingly encountered. Surgical management may pose an unacceptable risk of morbidity, mortality or dialysis, yet these patients may live long enough to experience the consequences of disease progression. Thermal ablation is an option for small cortical tumours (≤3 cm), but there are limitations for larger or centrally located tumours.

In this issue of BJUI, Siva and colleagues [1] report promising early efficacy and toxicity data using stereotactic ablative body radiotherapy (SABR) for the treatment of primary RCC in this difficult cohort. SABR is a non-invasive treatment that delivers very high doses of radiation over one to five outpatient sessions. It uses advanced motion management, radiation planning and image guidance techniques to ensure delivery of an ablative dose with millimetre precision. Survival benefits with stereotactic radiosurgery have been demonstrated in patients with solitary brain metastases [2], and SABR is now an accepted standard of care for patients with medically inoperable early-stage lung cancer [3]. Randomized phase III trials are currently under way, testing SABR against standard of care in primary prostate (clinicaltrials.gov ID NCT01584258) and liver cancer (NCT01730937) and in the oligometastatic setting (NCT02759783). Historically considered radio-resistant, both pre-clinical and clinical data now support the sensitivity of RCC to high-dose per fraction radiotherapy, as used in SABR [4].

The study by Siva and colleagues is one of the largest, early-phase, prospective studies of SABR for primary RCC to date, accruing 37 patients with cT1a–cT2a RCC not suitable for other therapies. Importantly, this was not a cohort of incidentally detected small renal masses. The majority (65%) of tumours were >4 cm (median 4.8 cm), were growing on surveillance or symptomatic, and were biopsy-proven. The inclusion of enlarging T1a tumours is not unreasonable. A recent analysis of patients with localized T1a kidney cancer from the Surveillance, Epidemiology and End Results (SEER) Medicare data reported an excess of kidney cancer deaths for non-surgically managed patients aged >75 years, highlighting how difficult it can be to find the right balance between active and expectant management in this group [5]. Indeed 11% of patients in the present study by Siva et al. developed distant metastases by 2 years.

In the present study, tumours <5 cm received a single 26-Gy fraction of SABR, whilst tumours >5 cm received 42 Gy over three fractions. Whilst acknowledging a number of uncertainties in modelling, this should equate to an equivalent biological dose in excess of 100 Gy. The authors found that delivering this SABR regimen was feasible and well tolerated with one grade 3 toxicity (transient fatigue) and no grade 4–5 toxicities. Most patients sustained only transient minor side effects (78%) or no treatment-related side effects (18%). The mean baseline estimated GFR was 55 mL/min, which decreased to 44 mL/min at 1 year, and was maintained for those with 2 years follow-up.

Similarly, short-term efficacy appears promising. With a median follow-up of 24 months, freedom from local progression at 2 years was 100%, with one patient subsequently progressing locally with concurrent distant metastases 28 months after treatment. Local progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. This is a pragmatic definition and takes into account the challenges in interpreting standard imaging after SABR and the difficulties in obtaining and interpreting repeat biopsies in this cohort. Similarly to the study by Sun et al. [6] it appears that stable or partial radiological responses will predominate in the early years after SABR and, unlike thermal ablation, changes in enhancement patterns can be very slow to evolve.

Longer-term follow-up is required to confirm these promising tumour control and nephron preservation rates, in addition to evaluating longer-term late effects. To that end, the present study has provided a platform for the authors to launch an international phase II clinical trial under the auspices of the TransTasman Radiation Oncology Group (TROG 15.03 FASTRACK, clinicaltrials.gov ID NCT02613819). Larger-scale prospective studies are essential to confirm the efficacy and safety of this non-invasive, nephron-sparing, ablative technique and provide further information to help refine patient selection and develop better biomarkers of response.

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David I. Pryor *† and Simon Wood†‡

 

*Department of Radiation Oncology, Princess Alexandra Hospital, Wooloongabba, †School of Medicine, University of Queensland, Brisbane, and ‡Department of Urology, Princess Alexandra Hospital, Wooloongabba, Qld, Australia

 

References

 

1 Siva S. Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int 2017; 120: 623–30
 

 

2 Andrews DW, Scott CB , Sperduto PW et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with  one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet (London, England) 2004; 363: 1665–72

3 Chang JY, Senan S, Paul MA et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015; 16: 630–7

 

4 De Meerleer G, Khoo V, Escudier B et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol 2014; 15: e170–7

 

5 Patel HD, Kates M, Pierorazio PM et al. Survival after diagnosis of localized T1a kidney cancer: current population-based practice of surgery and nonsurgical management. Urology 2014; 83: 126–32

 

6 Sun MR, Brook A, Powell MF et al. Effect of stereotactic body radiotherapy on the growth kinetics and enhancement pattern of primary renal tumors. AJR Am J Roentgenol 2016; 206: 544–53

 

Article of the Week: Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial

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Every week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial

 

Shankar Siva*,†, Daniel Pham*, Tomas Kron*,†, Mathias Bressel*, Jacqueline Lam*, Teng Han Tan*, Brent Chesson*, Mark Shaw*, Sarat Chander*, Suki Gill*,‡, Nicholas R. Brook§, Nathan Lawrentschuk*,, Declan G. Murphy*,† and Farshad Foroudi*,

 

*Peter MacCallum Cancer Centre, Melbourne, Vic., Australia, † Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic. Australia, ‡Sir Charles Gairdner Hospital, Nedlands Perth, WA, Australia, §Royal Adelaide Hospital, Adelaide, SA, Australia, and Olivia Newton John Cancer Centre, Heidelberg, Vic., Australia

 

Abstract

Objective

To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes.

Materials and Methods

This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan–Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size.

Results

Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1–2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4–5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001).

Conclusion

The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.

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April 2017 #urojc summary: Is SABR a viable therapeutic option for managing renal tumors in patients deemed unsuitable for surgery?

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saji_author-photo5April 2017 #urojc summary: Is SABR a viable therapeutic option for managing renal tumors in patients deemed unsuitable for surgery?

In April 2017, the International Twitter-based Urology Journal Club (@iurojc) #urojc reviewed an interesting recent article by Siva et. Al reporting their experience in a prospective cohort study utilizing Stereotactic Ablative Body Radiotherapy (SABR) on inoperable primary renal cell carcinomas. The article was made freely available courtesy of BJUI for the duration of the discussion (https://onlinelibrary.wiley.com/doi/10.1111/bju.13811/full). The journal club ran for 48 hours beginning on April 2nd at 21:00 UTC. The first author of the manuscript, Dr. Shankar Siva, a radiation oncologist at the Peter MacCallum Cancer Center joined the discussion using the Twitter handle @_ShankarSiva.

The study enrolled 37 total patients (T1a n=13, T1b n=23, and T2a n=1) due to one of three reasons: (1) deemed medically inoperable (n=28 Charlson Comorbidity >6), (2) high-risk group for surgery (n=11 high risk post-surgical dialysis), (3) refused surgery (n=1). The primary outcome measured was the successful delivery of radiotherapy. Secondary outcomes included (1) adverse events of radiotherapy, (2) local progression of the disease, (3) distant progression of the disease, and (4) overall survival.

@iurojc kicked things off with a starter question

There was immediate debate regarding the validity of treating patients with inoperable tumors using alternative modalities.

@PatrickKenneyMD cited a retrospective analysis by Kutikov et. al (@uretericbud) of the SEER database on competing causes of mortality in elderly patients with localized RCC. The study reported the 5-year probability of mortality from non-cancer related etiology to be 11% while the RCC related mortality probability was 4%. The authors of the paper encourage that management decisions for localized RCC in older patients should take into account competing causes of mortality. @DrewMoghanaki argued that many patients will still suffer from the sequelae of cancer progression that could be prevented by treating with non-surgical modalities such as SABR.
@_ShankarSiva chimed in

@uretericbud questioned the comparison of two discrepant neoplasms

@_ShankarSiva explained

From Belgium, an important point was made about the question itself.

While this conversation was occurring, a lively discussion on the utility of SABR compared to other established non-surgical modalities was taking place.

@_ShankarSiva replied

Next, @CanesDavid posed a question regarding the most frequent factors of surgical disqualification in the cohort

@benchallacombe noted a limitation of the study which led to a discussion of the utility of one of the four secondary outcomes of the study- local progression.

@nickbrookMD (co-author) cited an article by Crispen et. al that characterized the growth rate of untreated solid enhancing renal masses. @Rad_Nation proposed two follow-up studies that could be conducted.

Even if these studies are conducted, there is skepticism around whether Urologists will view SBRT as a viable alternative treatment modality for RCC.

@iurojc posed an important question. What should be the overall goal of the urologist? Is it to cure cancer by all means? Or perhaps to find a balance between quality of life and management of the disease? SBRT may play a crucial role in the latter situation.

To wrap things up, @iurojc asked a summary question.

The authors of the manuscript provided a response and their thoughts on what needs to be done next.

Thank you to everyone who participated in the April 2017 #urojc. Special thanks to the authors @_ShankarSiva and @nickbrookMD for joining in on the discussion and providing further insight to their work.

Akhil Saji is a third-year medical student at New York Medical College, Valhalla, NY.

Twitter @AkhilASaji

 

References

1. Siva, Shankar, et al. “Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial.” BJU international (2017)

2. Kutikov, Alexander, et al. “Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram.” Journal of Clinical Oncology 28.2 (2009): 311-317.

3. Crispen, Paul L., et al. “Predicting growth of solid renal masses under active surveillance.” Urologic Oncology: Seminars and Original Investigations. Vol. 26. No. 5. Elsevier, 2008

 

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