Review for 10.1186/s12876-022-02204-1 (2022)

Reviewer’s report
Title: 
A prospective, multicenter, open-label, single-arm clinical trial design to
evaluate the safety and efficacy of 90Y resin microspheres for the treatment of
unresectable HCC: the DOORwaY90 (Duration Of Objective Response with
arterial Ytrrium-90) study
Version: 
0 
Date: 
28 Dec 2021
Reviewer's report:
ABSTRACT
Modifications to the abstract to reflect the comments to the body of the
manuscript.
"The results of this trial should help refine the potential benefits of SIRT with 90
Y resin
microspheres as first-line therapy for unresectable HCC."
Comment: This is presented as a safety and efficacy study. Determination of
Y90 as first-line therapy would need a comparison to standard of care (surgery if
eligible, or best systemic therapy if not eligible for surgery). Not sure the
investigators can claim that this trial will determine appropriateness of resin Y90
as first-line therapy for HCC. The discussion sentence therefore should be
modified.
BACKGROUND
Comment: SIRT is a term used by SIRTEX and therefore has commercial
implications. This reviewer suggests avoiding the term SIRT and simply use
"radioembolization" (also, the use of the whole word "radioembolization" is
preferable over the abbreviation "RE").
The authors state: "SIRT does not induce complete vascular occlusion". This is
only true if the embolic load is small and the vascular capacitance is large. Given
that resin spheres have a lower specific activity and somewhat larger particle size
compared to glass microspheres, the embolic effect is clearly greater for resin, a
fact that interventionalists with experience using both devices know. The
investigators should clarify that using the so-called 3-day FLEXdose, which
minimizes embolic effect by increasing the sphere specific activity, is potentially
capable of having a non-embolic or minimally embolic effect. Such clarification
sends a clear message to Y90 users.
METHODS/DESIGN
"7) assessment of long-term toxicity"
Comment: The authors are to be commended for paying attention to the long-
term effects, which is a weakness of many radiation therapy studies. However, it
can bring out the dangers of the proposed dosimetry methodology, as discussed
below.
"For safety considerations, ≥33% of the total liver volume (body surface area-
based) must be disease free and not treated with 90Y [15]."
Comment: Reference 15 is not part of the radioembolization literature, yet the
authors refence this publication to justify the above statement. The stated percent
value may be appropriate for surgical resection candidates, but this is clearly a
series of patients who are not surgical resection candidates. This is an invalid
extrapolation because the tolerance for liver loss is vastly different between those
who qualify for resection and those who do not.
As currently designed, this investigation allows exposure of 66% of the liver to
Y90 in a Child C and/or ALBI 2 patient. This reviewer considers it outright
dangerous in this group of patients. 
The safe percent of treated liver in those
with certain degrees of liver deterioration is far less than 66%.
A recent publication that pertains specifically to HCC and radioembolization
(Biochemical Safety of Ablative Yttrium-90 Radioembolization for
Hepatocellular Carcinoma as a Function of Percent Liver Treated. 
De la Garza-
Ramos. J Hepatocell Carcinoma. 2021 Jul 30;8:861-870. doi:
10.2147/JHC.S319215. eCollection 2021. PMID: 34368021) provides a safety
framework that the investigators are urged to take into consideration. The
percent liver treated when using ablative radiation doses MUST take into
consideration the liver condition, and therefore the percent liver volume exposed
MUST be adjusted accordingly. Importantly, this recent publication includes a
larger population than the investigation under review intends to accrue, so it
should be given much attention.
The medical community has great interest in proving the safety and efficacy of
radioembolization, but the fastest way to truncate its potential is to show
excessive toxicity. Radiation exposure to too much liver will, without a doubt,
negatively impact SAE's and the overall survival. The investigators chose co-
primary endpoints overall response rate and duration of response, but the entire
oncology community will be looking at the overall survival to compare to
systemic therapies. Poor patient selection causing excessive toxicity and a poor
survival will destroy the credibility of radioembolization as an important therapy
for HCC. This reviewer finds it alarming that an important trial like this one can
have a counterproductive effect that can be avoided with a completely re-thought
patient selection process.
"Exclusion Criteria (Table 1)"
Comment: The trial design excludes patients that are eligible for percutaneous
ablation. The investigators are urged to reconsider this exclusion criterion. The
available evidence for ablative radioembolization suggests that sub-
lobar/segmental Y90 is a suitable substitute for percutaneous ablation. The
accrual success of the trial will be greatly enhanced by allowing inclusion of
patients that could be percutaneously ablated. This reviewer sees not scientific or
ethical reason why a patient should receive percutaneous ablation over ablative
radioembolization based on our current knowledge.
"Treatment plan Dosimetry
3D volumetric software is used to segment…."
Comment: Please clarify which imaging is used for the volume calculation. If
available, it should be cone-beam CT at the time of angiography. Need to specify
if volumetrics are obtained only using the MAA SPECT, or if fusion with formal
CT scan or MRI is to be used. This is unclear in the manuscript.
"Treatment plan dosimetry constraints
TLV is calculated based on the method of Vauthey…"
Comment: This reviewer can't understand why the investigators would use BSA
to calculate TLV. This is a very inaccurate method. Importantly, this
investigation's methodology includes imaging-based segmentation, which easily
and quickly can provide accurate total liver volume for each individual patient.
Use of BSA makes no sense given its inaccuracy and the plans for calculation of
actual liver/tumor volumes using segmentation software.
"If the 90Y treatment-spared liver volume is ≥33% but <40% of the TLVBSA,
the dose to the perfused normal liver parenchyma will be limited to <150 Gy. If
the 90Y treatment-spared liver volume is ≥40% of the TLVBSA, there will be no
upper limit to the dose allowed to the perfused normal liver parenchyma."
Comment: As indicated previously, this reviewer disagrees vehemently with this
methodology because it is potentially dangerous in patients with Child C class
and/or ALBI 2 scores. The danger will not be apparent in the early follow up but
will become more and more obvious after 6 months. I agree with the
investigators that CTCAE toxicities should be evaluated at 3 and 6 monhts. This
is to a large extent a safety study, therefore much care should be given to
avoiding a patient population that Y90 practitioners know is likely to have
adverse events.
"Tumor mean dose (Dtumor) constraints: the planned mean dose to the tumor
must be in the range of 150 to 400 Gy. In the unlikely event that the planned
mean dose to the total tumor compartment cannot exceed 150 Gy, the patient is
considered a screening failure."
Comment: The acceptable safety of radiation doses over 400 Gy given to sub-
lobar liver volumes is apparent in the current Y90 literature. Not sure why the
investigators are limiting the tumor dose. The radiation dose WITHIN the tumor
is not a limiting factor. The dose to the surrounding liver parenchyma is.
Therefore, if a dose limit is established it should be for the normal surrounding
liver and not the tumor itself. Given that beta radiation travels such a short
distance the INTRA-TUMORAL dose can considerably greater than 400 Gy
without increasing risks. To facilitate accrual, I would suggest to the
investigators NOT to consider these patients screening failures but would
emphasize that the exposure to normal parenchyma must be better thought out to
minimize radiation toxicity and to minimize loss of liver function. 
"SIRT procedure"
Comment: The investigators should clarify how they intend to handle sphere
deliveries that could result in vascular stasis. This reviewer understands that
vascular stasis is less of a problem now compared to the past, but sublobar
administrations potentially can be limited by vascular stasis given the smaller
liver volumes targeted. What will happen if such situation is encountered? Also,
the investigators should keep track of cases where tumor dose was estimated to
be <100 Gy and see if it correlates at all with sphere delivery issues such as
stasis.
"Outcomes"
Comment: Overall response rate is an appropriate endpoint. 
The use of "duration of response" can be debated. A similar commonly used
endpoint is time-to-progression, which will facilitate comparison with other
publications that report the more widely used TTP. Importantly, patients with
HCC are cirrhotic in 90%, so progression of disease must be categorized
depending on where it occurs. If it occurs within the treatment field it should be
considered an "in-radiation field" progression, in contrast to an "out-of-radiation
field" progression. The former is a direct reflection of the treatment effect,
whereas the latter reflects the natural history of HCC multi-focality. This will
allow a clearer and more fair assessment of the Y90 treatment itself. Measuring
outcomes on the basis of overall recurrence is an inadequate assessment of loco-
regional therapies such as percutaneous ablation, and so it should be for Y90.
"Secondary endpoints include toxicity, quality of life, resection and transplant."
Comment: The absence of survival analysis is a glaring gap. Not sure why the
investigators are avoiding this metric, but it is obviously necessary. This
reviewer suspects that avoidance of survival as an endpoint has to do with the
historical failure in showing survival benefit in old resin Y90 trials, but I believe
this only makes this investigation suspicious. This reviewer again points out that
the inclusion/exclusion criteria as written endanger many patients. Rather than
risking a trial with poor survival I would suggest going back to the drawing
board, improving the protocol, and working on showing that high quality
radioembolization actually does have a positive impact on survival metrics.
"Intent-to-treat"
Comment: I agree with the investigators that to be fair to radioembolization the
intent-to-treat principle should be applied AFTER determining eligibility with
the preliminary angiographic /MAA workup. 
DISCUSSION
"However, because of differences in the size, distribution, and specific activity
of glass and resin microspheres, dosimetry findings cannot be translated from
one product to the other, and therefore, the DOORwaY90 trial is needed to
provide information on the impact of personalized dosimetry on the efficacy of
90Y resin microspheres."
Comment: Agreed. However, the methodology should be far more careful with
excessive parenchymal exposure.
"As SIRT is a locoregional therapy, assessment of local disease control is a more
relevant measure of effectiveness than overall survival."
Comment: This reviewer finds this statement technically correct, but the reality
of clinical practice is more complex. To the patient the two most important
outcomes are quality of life and life expectancy (an opinion shared by most
clinicians). This trial appropriately addresses the quality-of-life questions. Not
addressing survival will cast a shadow of doubt on the trial results. The
investigators' statement that local disease control is more relevant than overall
survival is difficult to accept. That is why this reviewer proposes a more nuanced
data analysis, utilizing TTP categorized by in-field and out-of-field progression,
which will allow analysis of survival with consideration to non-Y90 factors,
such as multifocal HCC development, as well as the usual categorization by
tumor stage and liver functional condition/degree of compromise. A surgical
resection trial (another loco-regional therapy) without analysis of survival would
be unthinkable. Why would this trial be any different?
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
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from apparent manipulation?
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