Stereotactic Radiotherapy after Incomplete Transarterial (Chemo-) Embolization (TAE\TACE) versus Exclusive TAE or TACE for Treatment of Inoperable HCC: A Phase III Trial (NCT02323360)
, Elena Clerici 1, Davide Franceschini 1,*, Marco Badalamenti 1, Maria Ausilia Teriaca 1, Lorenza Rimassa 3,4, Vittorio Pedicini 5, Dario Poretti 5, Luigi Alessandro Solbiati 3,5, Guido Torzilli 3,6, Roberto Ceriani 7, Ana Lleo 3,7, Alessio Aghemo 3,7, Armando Santoro 3,4 and Marta Scorsetti 1,3Round 1
Reviewer 1 Report
# Overall Comments
Thank you for the opportunity to review this manuscript. The authors investigated SBRT After Incomplete TAE or TACE Versus Exclusive TAE or TACE For Treatment of Inoperable HCC. This report would be of value, though this study was terminated due to low accrual. I think the manuscript requires several minor revisions.
#Minor points
- The title did not appropriately reflect the study design, according to the clinicaltrials.gov page (https://clinicaltrials.gov/ct2/show/NCT02323360).
- I think that the authors did not mention that this study was terminated early because of slow enrollment in the abstract.
- As for toxicities, radiation-induced late toxicities may have been underestimated because of the short follow-up period, which should be discussed.
Author Response
- The title did not appropriately reflect the study design, according to the clinicaltrials.gov page (https://clinicaltrials.gov/ct2/show/NCT02323360).
The title was modified as required
- I think that the authors did not mention that this study was terminated early because of slow enrollment in the abstract.
This specification was added in the abstract
- As for toxicities, radiation-induced late toxicities may have been underestimated because of the short follow-up period, which should be discussed.
This specification was acknowledged in the discussion
Reviewer 2 Report
The authors reported results from a single institution randomized controlled trial that compared SBRT and TAE/TACE after detection of residual hepatocellular carcinoma following initial treatment with TAE/TACE. The study found a significant increase in local control rate (primary endpoint) and PFS that favored SBRT. Safety data were reported. However, the window for toxicity assessments was not specified. TACE was not performed according to conventional methodology (mixing chemotherapy with ethiodized oil followed by administration of embolic particles). The manuscript would benefit from several clarifications and revisions. Please see specific comments below.
Abstract.
1. Please report PFS and OS at 1 and 2 years for both SBRT and TAE/TACE arms.
Materials and Methods.
2. Please provide references for expected response rates to SBRT (85%) and TAE/TACE (40%) that were used for sample size calculation.
Results.
3. Please specify whether any of the target lesions had been treated with any modality other than TAE/TACE prior to randomization. How many times target lesions were treated with TAE/TACE prior to randomization?
4. What was the median longest diameter of the target tumor nodules?
5. Please describe how treatments were performed for patients with more than 1 lesion. Were the lesions targeted separately (multiple vessels targeted during TAE/TACE, multiple separate targets for SBRT), or were multiple lesions included in a single treatment zone?
6. For distant recurrence free survival, please describe median values and 95% CI for both groups, as well as p-value.
7. For overall survival, please describe median values and 95% CI for both groups, as well as p-value.
8. How many patients received a liver transplant?
9. Section 3.5 last sentence. What is meant by “prior locoregional treatment?” Please clarify.
10. Please specify whether any of the patients received repeat SBRT after progression.
11. Do the authors mean that patients received cytotoxic chemotherapy after progression? During the enrollment period, sorafenib (a tyrosine kinase inhibitor) was available. Do the authors mean that patients received sorafenib?
12. Section 3.7. What was the time window for toxicity assessment?
Discussion.
13. Please mention that TACE was not performed using conventional protocol involving mixture of epirubicin and ethiodized oil followed by particle administration. Rather, an unconventional method of administering particles and chemotherapy (please specify in the Methods whether chemotherapy was given before or after particle administration) was used. This should be listed as one of the study limitations.
Figure 1.
14. Since this was a single center study, why was stratification by center mentioned?
Author Response
- Please report PFS and OS at 1 and 2 years for both SBRT and TAE/TACE arms.
We added these data in the abstract and in the results sessions.
Materials and Methods.
- Please provide references for expected response rates to SBRT (85%) and TAE/TACE (40%) that were used for sample size calculation.
In Introduction and Discussion are reported references for response rate to TAE/TACE (ref 13,17,18,20, 21,24,25,26,36) and SBRT (ref. 26,27,28,29,30,31.35). These references were added in the Statistical Analysis paragraph.
Results.
- Please specify whether any of the target lesions had been treated with any modality other than TAE/TACE prior to randomization. How many times target lesions were treated with TAE/TACE prior to randomization?
We specified this data in the 3.1 session.
- What was the median longest diameter of the target tumor nodules?
The median dimension of longest diameter was 24.8 mm. We added this data in the 3.1 results session.
- Please describe how treatments were performed for patients with more than 1 lesion. Were the lesions targeted separately (multiple vessels targeted during TAE/TACE, multiple separate targets for SBRT), or were multiple lesions included in a single treatment zone?
For patients with multiple nodules, the lesions were targeted separately during TAE/TACE or SBRT. We added this sentence in the 3.1 session.
- For distant recurrence free survival, please describe median values and 95% CI for both groups, as well as p-value.
We added these data in the results session.
- For overall survival, please describe median values and 95% CI for both groups, as well as p-value.
We added these data in the results session.
- How many patients received a liver transplant?
Nobody. We specified this data in 3.1 session.
- Section 3.5 last sentence. What is meant by “prior locoregional treatment?” Please clarify.
The type of prior locoregional treatment were specified in the previous sentence of the same section 3.5 (“a prior aggressive locoregional management including surgery and/or RFA/PEI (median 47 versus 22 months, p = 0,007; HR 0,28 [CI95% 0,11-0,70])”.
- Please specify whether any of the patients received repeat SBRT after progression.
In the 3.6 results session, we specified that “At the event of progression (any site), 8 patients in the SBRT arm received a further TAE/TACE administration while 10 patients in the TAE/TACE arm received SBRT”. We specify in the same session that no patients received repeat SBRT after progression.
- Do the authors mean that patients received cytotoxic chemotherapy after progression? During the enrollment period, sorafenib (a tyrosine kinase inhibitor) was available. Do the authors mean that patients received sorafenib?
We replaced “chemotherapy” with “systemic therapy in 3.6 paragraph
- Section 3.7. What was the time window for toxicity assessment?
This specification was added in the section 3.7
Discussion.
- Please mention that TACE was not performed using conventional protocol involving mixture of epirubicin and ethiodized oil followed by particle administration. Rather, an unconventional method of administering particles and chemotherapy (please specify in the Methods whether chemotherapy was given before or after particle administration) was used. This should be listed as one of the study limitations.
It was a mistake, thanks. We performed conventional TACE using epirubicine mixed with iodized oil and followed by embolic particles administration. Incorrect sentence in session 2.7 was eliminated and the correct embolization procedure was better explaned in the same session.
Figure 1.
- Since this was a single center study, why was stratification by center mentioned?
Removed, since it was a mistake. thanks
