Reviewer's report
Title:Interventionally implanted port catheter systems for hepatic arterial infusion
of chemotherapy in patients with primary liver cancer: A phase II-study.
Version: 1Date:13 February 2013
Reviewer: Robert Martin
Reviewer's report:
INTERVENTIONALLY IMPLANTED PORT CATHETER SYSTEM FOR
HEPATIC ARTERIAL INFUSION OF CHEMOTHERAPY IN PATIENTS
WITH LIVER CANCER: A PHASE II STUDY
By Sin, et al from the Charite University, Berlin
Dr. Sin and others present their single arm multi-histology phase II study of 70
patients who were treated with an interventionally placed hepatic arterial infusion
port. They enrolled 70 patients and presented a number of different success as
well dose-limiting toxicities. They identified a median treatment duration of 3.9
months and the most common reason for treatment discontinuation was disease
progression as well as chemotherapy-induced toxicity followed by device failure.
They report from these results that a hepatic arterial infusion catheter can be
safely applied to patients with primary liver tumors. This is an interesting
conclusion to the manuscript and Abstract with a number of key questions for the
authors.
1) Within the Background, unfortunately, the authors present some of their bias
and potentially outdated material to which they report that patients with
unresectable hepatocellular carcinoma as well intrahepatic cholangiocarcinoma
have a median survival of less than 12 months. It is well-established that
unresectable BCLC stage B hepatocellular carcinomas now have a median
survival closer to 19 or 20 months. In addition to that given the recent overall
survival benefit, albeit small but still a survival benefit in the medical oncologist’s
mind, intrahepatic cholangiocarcinoma is not felt to be chemo-resistant and is felt
to be quite active to the utilization of Cis-Gem regimen. Updating their
Background is necessary for any prospective reader to truly buy in to the
potential unmet problem that the authors are trying to present.
2) Also, within the Background the authors present a very biased view of the
potential benefits of the hepatic arterial infusion in the management of metastatic
colorectal cancer. There have been a number of negative studies, negative trials
and non-accruing trials that have made this therapy a very contentious subject
and a non-universally agreed upon method of utilization. Acknowledging that
there is a dramatic split in opinions is truly necessary when talking about
regionally delivered therapy to the liver.
3) Within the Methods the authors do not present a number of key factors that
are necessary for the reader to have a true understanding of the overall
methodology. First, the authors do not present any type of contraindications for
administering hepatic arterial infusion and/or placement. Specifically how do the
investigators manage patients who are jaundiced? Is it an absolute requirement
that biliary decompression would be performed? What is the actual hematologic
exclusion criteria for patients who are undergoing hepatic arterial therapy,
specifically related to their liver enzymes and more importantly their liver function
tests, specifically a total bilirubin? Insertion of these types of hematologic
exclusion criteria are necessary given the fact that we are dealing with systemic
chemotherapy.
4) In addition to that there is absolutely no discussion in regards to what if the
DSA angiogram shows significant amount of extrahepatic perfusion. How do the
authors manage a catheter that is potentially proximal to the GDA or because of
significant collateral vessels given that they are dealing with a more advanced
disease has significant extrahepatic perfusion? What are or what is the
angiographic exclusion for using a hepatic arterial infusion port even though the
catheter has been appropriately placed within the common hepatic artery?
5) Also within the Methods the authors provide no rationale and no published
data around three different dosages that the authors utilized. This is obviously
not a true phase II study given the fact that at least one of them had a dose
escalation so it falls under a potential phase I type of criteria. More importantly,
there is no data supporting any of these dosages that should be given
intra-arterially since a lot of these dosages are actually what is used systemically.
At least some form of rationale and published literature as to why these dosages
were utilized is of utmost importance to ensure that the prospective reader
understands this type of dosing schema.
6) Given that this is a reported phase II study or potentially phase I because of
the dose escalation, at minimum there should be some form of power
calculations that the authors should present. Currently, there is no power
calculation as to why 70 patients were appropriate.
7) Within the Results unfortunately the data is rudimentary or limited at best.
There is very limited to actually no specifics of the type of chemotherapy that the
patients have undergone prior to that. Given that this is a phase II study on
patients who have failed at least a first line or potentially second line therapy, far
greater transparency of this patient population is necessary to include type of
chemotherapy, extent of disease, location of disease, extent of target lesions that
are planned to be treated and extent of non-target lesions that are not obviously
going to be treated with the hepatic arterial infusion. This is of utmost importance
to both to demonstrate both safety but also simple patient selection.
8) Within the Results section the authors report implantation was successful in all
patients but yet do not define success. How do the authors specifically define
port implantation success?
9) Unfortunately the authors have been somewhat optimistic that a nearly 40%
dose-limiting toxicity and stoppage at less than or equal to three months of
therapy is indeed acceptable. This type of toxicity in a phase II study would
actually lead to potentially premature closure of the study and not meet accrual.
How the authors truly define acceptable is hard to delineate given the significant
toxicity that they are indeed presenting.
10)Given that the duration of treatment was quite short, 3.9 months, the authors
must present the extent of progression that caused treatment stoppage. This
degree of progression must be in the form of both target lesions that were treated
(did they progress?) as well as non-target lesions that were clearly not treated
that most likely being periportal lymph nodes or the lung. Significant amount of
transparency of the data is a significant limitation of this manuscript at this
present time.
11) Lastly is then related to the patient who died of severe gastrointestinal
hemorrhage or more importantly patients died within three months of their
catheter placement which must be deemed potentially related to the catheter.
Again, significant greater granularity and transparency of the data is of utmost
importance to truly believe what the authors are attempting to present.
12)Within the Discussion the authors glance over a number of hepatic arterial
infusion port manuscripts, specifically in both intrahepatic cholangiocarcinoma as
well as hepatocellular carcinoma which is a significant limitation of the
Discussion. Comparing hepatic arterial therapy specifically to Yttrium-90 or TACE
is I believe misguided given that there is no true comparison on technique as well
as drug delivery.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
No competing Interests
Reviewer's report
Title:Interventionally implanted port catheter systems for hepatic arterial infusion
of chemotherapy in patients with primary liver cancer: A phase II-study.
Version: 1Date:13 February 2013
Reviewer: Robert Martin
Reviewer's report:
INTERVENTIONALLY IMPLANTED PORT CATHETER SYSTEM FOR
HEPATIC ARTERIAL INFUSION OF CHEMOTHERAPY IN PATIENTS
WITH LIVER CANCER: A PHASE II STUDY
By Sin, et al from the Charite University, Berlin
Dr. Sin and others present their single arm multi-histology phase II study of 70
patients who were treated with an interventionally placed hepatic arterial infusion
port. They enrolled 70 patients and presented a number of different success as
well dose-limiting toxicities. They identified a median treatment duration of 3.9
months and the most common reason for treatment discontinuation was disease
progression as well as chemotherapy-induced toxicity followed by device failure.
They report from these results that a hepatic arterial infusion catheter can be
safely applied to patients with primary liver tumors. This is an interesting
conclusion to the manuscript and Abstract with a number of key questions for the
authors.
1) Within the Background, unfortunately, the authors present some of their bias
and potentially outdated material to which they report that patients with
unresectable hepatocellular carcinoma as well intrahepatic cholangiocarcinoma
have a median survival of less than 12 months. It is well-established that
unresectable BCLC stage B hepatocellular carcinomas now have a median
survival closer to 19 or 20 months. In addition to that given the recent overall
survival benefit, albeit small but still a survival benefit in the medical oncologist’s
mind, intrahepatic cholangiocarcinoma is not felt to be chemo-resistant and is felt
to be quite active to the utilization of Cis-Gem regimen. Updating their
Background is necessary for any prospective reader to truly buy in to the
potential unmet problem that the authors are trying to present.
2) Also, within the Background the authors present a very biased view of the
potential benefits of the hepatic arterial infusion in the management of metastatic
colorectal cancer. There have been a number of negative studies, negative trials
and non-accruing trials that have made this therapy a very contentious subject
and a non-universally agreed upon method of utilization. Acknowledging that
there is a dramatic split in opinions is truly necessary when talking about
regionally delivered therapy to the liver.
3) Within the Methods the authors do not present a number of key factors that
are necessary for the reader to have a true understanding of the overall
methodology. First, the authors do not present any type of contraindications for
administering hepatic arterial infusion and/or placement. Specifically how do the
investigators manage patients who are jaundiced? Is it an absolute requirement
that biliary decompression would be performed? What is the actual hematologic
exclusion criteria for patients who are undergoing hepatic arterial therapy,
specifically related to their liver enzymes and more importantly their liver function
tests, specifically a total bilirubin? Insertion of these types of hematologic
exclusion criteria are necessary given the fact that we are dealing with systemic
chemotherapy.
4) In addition to that there is absolutely no discussion in regards to what if the
DSA angiogram shows significant amount of extrahepatic perfusion. How do the
authors manage a catheter that is potentially proximal to the GDA or because of
significant collateral vessels given that they are dealing with a more advanced
disease has significant extrahepatic perfusion? What are or what is the
angiographic exclusion for using a hepatic arterial infusion port even though the
catheter has been appropriately placed within the common hepatic artery?
5) Also within the Methods the authors provide no rationale and no published
data around three different dosages that the authors utilized. This is obviously
not a true phase II study given the fact that at least one of them had a dose
escalation so it falls under a potential phase I type of criteria. More importantly,
there is no data supporting any of these dosages that should be given
intra-arterially since a lot of these dosages are actually what is used systemically.
At least some form of rationale and published literature as to why these dosages
were utilized is of utmost importance to ensure that the prospective reader
understands this type of dosing schema.
6) Given that this is a reported phase II study or potentially phase I because of
the dose escalation, at minimum there should be some form of power
calculations that the authors should present. Currently, there is no power
calculation as to why 70 patients were appropriate.
7) Within the Results unfortunately the data is rudimentary or limited at best.
There is very limited to actually no specifics of the type of chemotherapy that the
patients have undergone prior to that. Given that this is a phase II study on
patients who have failed at least a first line or potentially second line therapy, far
greater transparency of this patient population is necessary to include type of
chemotherapy, extent of disease, location of disease, extent of target lesions that
are planned to be treated and extent of non-target lesions that are not obviously
going to be treated with the hepatic arterial infusion. This is of utmost importance
to both to demonstrate both safety but also simple patient selection.
8) Within the Results section the authors report implantation was successful in all
patients but yet do not define success. How do the authors specifically define
port implantation success?
9) Unfortunately the authors have been somewhat optimistic that a nearly 40%
dose-limiting toxicity and stoppage at less than or equal to three months of
therapy is indeed acceptable. This type of toxicity in a phase II study would
actually lead to potentially premature closure of the study and not meet accrual.
How the authors truly define acceptable is hard to delineate given the significant
toxicity that they are indeed presenting.
10)Given that the duration of treatment was quite short, 3.9 months, the authors
must present the extent of progression that caused treatment stoppage. This
degree of progression must be in the form of both target lesions that were treated
(did they progress?) as well as non-target lesions that were clearly not treated
that most likely being periportal lymph nodes or the lung. Significant amount of
transparency of the data is a significant limitation of this manuscript at this
present time.
11) Lastly is then related to the patient who died of severe gastrointestinal
hemorrhage or more importantly patients died within three months of their
catheter placement which must be deemed potentially related to the catheter.
Again, significant greater granularity and transparency of the data is of utmost
importance to truly believe what the authors are attempting to present.
12)Within the Discussion the authors glance over a number of hepatic arterial
infusion port manuscripts, specifically in both intrahepatic cholangiocarcinoma as
well as hepatocellular carcinoma which is a significant limitation of the
Discussion. Comparing hepatic arterial therapy specifically to Yttrium-90 or TACE
is I believe misguided given that there is no true comparison on technique as well
as drug delivery.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
No competing Interests
Please review this paper.
user
Reviewer's report
Title:Interventionally implanted port catheter systems for hepatic arterial infusion
of chemotherapy in patients with primary liver cancer: A phase II-study.
Version: 1Date:13 February 2013
Reviewer: Robert Martin
Reviewer's report:
INTERVENTIONALLY IMPLANTED PORT CATHETER SYSTEM FOR
HEPATIC ARTERIAL INFUSION OF CHEMOTHERAPY IN PATIENTS
WITH LIVER CANCER: A PHASE II STUDY
By Sin, et al from the Charite University, Berlin
Dr. Sin and others present their single arm multi-histology phase II study of 70
patients who were treated with an interventionally placed hepatic arterial infusion
port. They enrolled 70 patients and presented a number of different success as
well dose-limiting toxicities. They identified a median treatment duration of 3.9
months and the most common reason for treatment discontinuation was disease
progression as well as chemotherapy-induced toxicity followed by device failure.
They report from these results that a hepatic arterial infusion catheter can be
safely applied to patients with primary liver tumors. This is an interesting
conclusion to the manuscript and Abstract with a number of key questions for the
authors.
1) Within the Background, unfortunately, the authors present some of their bias
and potentially outdated material to which they report that patients with
unresectable hepatocellular carcinoma as well intrahepatic cholangiocarcinoma
have a median survival of less than 12 months. It is well-established that
unresectable BCLC stage B hepatocellular carcinomas now have a median
survival closer to 19 or 20 months. In addition to that given the recent overall
survival benefit, albeit small but still a survival benefit in the medical oncologist’s
mind, intrahepatic cholangiocarcinoma is not felt to be chemo-resistant and is felt
to be quite active to the utilization of Cis-Gem regimen. Updating their
Background is necessary for any prospective reader to truly buy in to the
potential unmet problem that the authors are trying to present.
2) Also, within the Background the authors present a very biased view of the
potential benefits of the hepatic arterial infusion in the management of metastatic
colorectal cancer. There have been a number of negative studies, negative trials
and non-accruing trials that have made this therapy a very contentious subject
and a non-universally agreed upon method of utilization. Acknowledging that
there is a dramatic split in opinions is truly necessary when talking about
regionally delivered therapy to the liver.
3) Within the Methods the authors do not present a number of key factors that
are necessary for the reader to have a true understanding of the overall
methodology. First, the authors do not present any type of contraindications for
administering hepatic arterial infusion and/or placement. Specifically how do the
investigators manage patients who are jaundiced? Is it an absolute requirement
that biliary decompression would be performed? What is the actual hematologic
exclusion criteria for patients who are undergoing hepatic arterial therapy,
specifically related to their liver enzymes and more importantly their liver function
tests, specifically a total bilirubin? Insertion of these types of hematologic
exclusion criteria are necessary given the fact that we are dealing with systemic
chemotherapy.
4) In addition to that there is absolutely no discussion in regards to what if the
DSA angiogram shows significant amount of extrahepatic perfusion. How do the
authors manage a catheter that is potentially proximal to the GDA or because of
significant collateral vessels given that they are dealing with a more advanced
disease has significant extrahepatic perfusion? What are or what is the
angiographic exclusion for using a hepatic arterial infusion port even though the
catheter has been appropriately placed within the common hepatic artery?
5) Also within the Methods the authors provide no rationale and no published
data around three different dosages that the authors utilized. This is obviously
not a true phase II study given the fact that at least one of them had a dose
escalation so it falls under a potential phase I type of criteria. More importantly,
there is no data supporting any of these dosages that should be given
intra-arterially since a lot of these dosages are actually what is used systemically.
At least some form of rationale and published literature as to why these dosages
were utilized is of utmost importance to ensure that the prospective reader
understands this type of dosing schema.
6) Given that this is a reported phase II study or potentially phase I because of
the dose escalation, at minimum there should be some form of power
calculations that the authors should present. Currently, there is no power
calculation as to why 70 patients were appropriate.
7) Within the Results unfortunately the data is rudimentary or limited at best.
There is very limited to actually no specifics of the type of chemotherapy that the
patients have undergone prior to that. Given that this is a phase II study on
patients who have failed at least a first line or potentially second line therapy, far
greater transparency of this patient population is necessary to include type of
chemotherapy, extent of disease, location of disease, extent of target lesions that
are planned to be treated and extent of non-target lesions that are not obviously
going to be treated with the hepatic arterial infusion. This is of utmost importance
to both to demonstrate both safety but also simple patient selection.
8) Within the Results section the authors report implantation was successful in all
patients but yet do not define success. How do the authors specifically define
port implantation success?
9) Unfortunately the authors have been somewhat optimistic that a nearly 40%
dose-limiting toxicity and stoppage at less than or equal to three months of
therapy is indeed acceptable. This type of toxicity in a phase II study would
actually lead to potentially premature closure of the study and not meet accrual.
How the authors truly define acceptable is hard to delineate given the significant
toxicity that they are indeed presenting.
10)Given that the duration of treatment was quite short, 3.9 months, the authors
must present the extent of progression that caused treatment stoppage. This
degree of progression must be in the form of both target lesions that were treated
(did they progress?) as well as non-target lesions that were clearly not treated
that most likely being periportal lymph nodes or the lung. Significant amount of
transparency of the data is a significant limitation of this manuscript at this
present time.
11) Lastly is then related to the patient who died of severe gastrointestinal
hemorrhage or more importantly patients died within three months of their
catheter placement which must be deemed potentially related to the catheter.
Again, significant greater granularity and transparency of the data is of utmost
importance to truly believe what the authors are attempting to present.
12)Within the Discussion the authors glance over a number of hepatic arterial
infusion port manuscripts, specifically in both intrahepatic cholangiocarcinoma as
well as hepatocellular carcinoma which is a significant limitation of the
Discussion. Comparing hepatic arterial therapy specifically to Yttrium-90 or TACE
is I believe misguided given that there is no true comparison on technique as well
as drug delivery.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
No competing Interests
assistant