Outcomes of High-Dose Stereotactic Ablative Radiotherapy to All/Multiple Sites for Oligometastatic Renal Cell Cancer Patients

Round 1

Reviewer 1 Report

Dear Current Oncology, thank you for giving me the opportunity to review the manuscript “Outcomes of High-Dose Stereotactic Ablative Radiotherapy to All / Multiple Sites for Oligometastatic Renal Cell Cancer Patients”

In my opinion, despite the retrospective nature and the small number of patients enrolled, this work is further confirmation of the crucial role that ablative radiotherapy has in the setting of metastatic disease.

The results of this study are in fact similar with those obtained from important randomized studies in which the SABR was delivered concurrently with various systemic therapies and with radical intent against macroscopic metastatic disease, demonstrating a significant advantage on survival without a negative impact on patients' quality of life.

In any case, I kindly ask the authors to specify:

 -the range and the median value of the total volume irradiated;

- the criteria according to which some patients received SABR/pSABR only in some sites while others in all sites of metastatic disease;

- If  multiple site was treated with SABR / p-SABR concurrently or consecutively. If it was treated consecutively, were particular criteria used to decide a precise chronological order?

 I also suggest you:

- 10 patients treated with SABR/pSABR and anti PD1 are reported in the study. If some patients received SABR before failure of ICI, it would be interesting  the comparison on PFS and OS between these and those treated before the failure of TKIs (but only for patients who received SABR in some localizations of disease… Have you seen abscopal effect of radiation therapy combined with immune check point inhibitors?).

Kind regards.

Author Response

Response to Reviewer 1 Comments

Point 1: specify the range and the median value of the total volume irradiated

Response 1: We have checked all the targets for our cohort. The range and the median value of the total volume irradiated was 29.9 (0.9-966.1) cc. We have added this to the manuscript.

Point 2: specify the criteria according to which some patients received SABR/pSABR only in some sites while others in all sites of metastatic disease

Response 2: We have tried to irradiate all sites of metastatic diseases, but we did omit irradiation of pulmonary metsatasis in patients receiving immunotherapy, secondary to the concerns for the radiation-induced pneumonitis. We also omit irradiation of tiny lesion (less than 1 cm) in lungs or lymph node in some patients, secondary to uncertain etiology.  Therefore, we added the explanations to the revised manuscript: “Reasons for why some patients did not receive irradiation at all sites were discretions at treating physician regarding radiation or immunotherapy-related AEs such as pneumonitis, or uncertainty of malignancy on diagnosis, among others.”

Point 3: If multiple site was treated with SABR / p-SABR concurrently or consecutively. If it was treated consecutively, were particular criteria used to decide a precise chronological order?

Response 1: Since the number of irradiated sites were less than 5 and treatment at each site is not influenced by treatment at other sites, in our cohort, multiple sites were concurrently treated with SABR/p-SABR. For P-SABR, simultaneously integrated SABR boost was delivered first, as the surrounding tumor tissue would not shrink at the beginning and could serve as a spacer. Then, a conventional radiation plan was able to be administered to the whole tumor volume.

We have added the following to the revised manuscript: “Multiple sites were concurrently treated with SABR/p-SABR.”

Point 4: 10 patients treated with SABR/pSABR and anti PD1 are reported in the study. If some patients received SABR before failure of ICI, it would be interesting  the comparison on PFS and OS between these and those treated before the failure of TKIs (but only for patients who received SABR in some localizations of disease… Have you seen abscopal effect of radiation therapy combined with immune check point inhibitors?)

Response 1: Thank you for your comments. For the 10 patients treated with SABR/pSABR and immunotherapy, 9 patients received SABR before failure of immunotherapy, but 9 patients were treated concurrently with TKIs. As such, we could not conduct a comparison between these patients and those treated before failure of their TKIs or to evaluate the abscopal effect of radiation therapy since tumor shrinkage may have been caused by TKIs. Nevertheless, there is an increasing number of patients receiving triple combination therapy (i.e., radiotherapy, TKIs, and immunotherapy) at our institution, and the toxicities are acceptable. We may report the results for these patients later.

Reviewer 2 Report

In the manuscript it is suggested that the early use of high dose SABR to all mets may improve survival, which is not recommended in general at this moment. therefore this paper is interesting. I have a few questions and suggestions:

1.What is the definition of a large metastasis - where P-SABR is performed?

2. I was wondering what the a/b of RCC mets is - since the max BED for tumor is 217 Gy which is decribed on page 3?

3. Also I have some questions about the toxicity profile - is this acute or late toxicity? And maybe it is worthwhile to have the suggestion whether the toxicity is related to SABR or to systemic treatment. 

4. Can you think of an explanation that SABR works better before TKI failure - is it only a question of patient selection?

Author Response

Response to Reviewer 2 Comments

Point 1: 1.What is the definition of a large metastasis - where P-SABR is performed?

Response 1: The typial definition of large tumor is a maximal tumor size larger than 5 centimeters. However, regardless the tumor size, P-SABR is delivered to ablate the tumor that is close to adjacent normal organ, this approach is believed to protect normal tissues and to allow the higher dose to the whole tumor as much as possible. We have added this information to the manuscript.

Point 2: I was wondering what the a/b of RCC mets is - since the max BED for tumor is 217 Gy which is decribed on page 3?

Response 2:. BED was calculated using a linear quadratic model with alpha/beta = 3 Gy according to the published data [1-3]. As such, the BED for a dosing schedule of 50Gy/10Gy/5f was 217 Gy (alpha/beta = 3). We have added this information to the manuscript.

[1]   Franzese C, Franceschini D, Di Brina L, DʼAgostino GR, Navarria P, Comito T, et al. Role of Stereotactic Body Radiation Therapy for the Management of Oligometastatic Renal Cell Carcinoma. J Urol. 2019;201(1):70-5.

[2]   Jhaveri PM, Teh BS, Paulino AC, Blanco AI, Lo SS, Butler EB, et al. A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases. Acta oncologica (Stockholm, Sweden). 2012;51(5):584-8.

[3]   Nelson JW, Yoo DS, Sampson JH, Isaacs RE, Larrier NA, Marks LB, et al. Stereotactic body radiotherapy for lesions of the spine and paraspinal regions. International journal of radiation oncology, biology, physics. 2009;73(5):1369-75.

Point 3: Also I have some questions about the toxicity profile - is this acute or late toxicity? And maybe it is worthwhile to have the suggestion whether the toxicity is related to SABR or to systemic treatment. 

Response 3: The toxicities that we reported were related to radiation therapy. Since patients received systemic treatment concurrently with SABR, we used the Common Terminology Criteria for Adverse Events v4.0 to describe the toxicities. Please refer to Section 2.3. Endpoints on page 3.

Point 4: Can you think of an explanation that SABR works better before TKI failure - is it only a question of patient selection?

Response 4: Thank you very much for your comments. We think that there are several points to address when describing this issue: Based on the results from other studies, we believe that SABR before TKI failure or systemic therapies may bring better prognosis, as described in the Discussion section. In addition, an increasing number of studies have shown that earlier treatment intensification of metastasis (resistant clones) may improve survival. Finally some patients might not tolerate TKIs, therefore, SABR of metastasis is important before the discontinuation or dose reduction of TKIs that might lead to further tumor progression or spreading.