Prognostic Impact of Perioperative CA19-9 Levels in Patients with Resected Perihilar Cholangiocarcinoma

Round 1

Reviewer 1 Report

The manuscript by Lee at al. analyzes the prognostic value of perioperative CA19-9 changes in patients with resected pCCA. The data are of high interest for the care of patients with pCCA. The number of patients in the cohort is very high and the exclusion criteria were properly selected. The analysis and depiction of the data is of very high quality.

Especially the facts, that a high preoperative CA 19-9 levels is not associated with poor survival, if postoperative normalization occurs has been clearly demonstrated by the given data. Moreover, it is also of paramount interest, that postoperative normalization of CA 19-9 might guide the further postoperative treatment including adjuvant therapies, although these data need to be confirmed in further studies.

 

There are only some minor comments, which should be addressed:

Table 1: patient  numbers appears confusing and should be double-checked: sex ratio 52:32 (but only 82 patients in total not 84)

Table 3: why was liver resection type CBS used as reference (only two patients underwent CBS according to table 1 ?)

Patient group with preop. normal CA 19-9: This group is supposed to be a mixture of patients with early tumor stages (smaller tumors, high number of patients withpT1 and/or pN0 stage as shown in table 1) and patients with more advanced tumor stages, who are unable to express CA 19-9, i.e. half of the Lewis negative (a-/b-) patients.

I am not aware of the frequency of Lewis negative (a-/b-) patients in Korea, therefore this might be commented in the discussion. In theory,  in theory 5-30% of patients, which are Lewis negative (a-/b-) do not express CA 19-9, that would lead to approximately 32/114 = 30% (10 % of 322 = 32 ) of patients in the normal group, who are unable to express CA 19-9

If any data on Lewis negative (a-/b-) patients are available, it should be re-checked, if this might influence the predictive value of normal CA 19-9 prior to surgery.If theses data are not available or the prevalence in Korea is different, it should at least be discussed (see e.g. Kwon S, et al.. Lewis Antigen Phenotype and Survival of Patients With Pancreatic Cancer. Pancreas. 2020 Nov/Dec;49(10):1348-1354. doi: 10.1097/MPA.0000000000001687. PMID: 33122524. )

Author Response

The manuscript by Lee at al. analyzes the prognostic value of perioperative CA19-9 changes in patients with resected pCCA. The data are of high interest for the care of patients with pCCA. The number of patients in the cohort is very high and the exclusion criteria were properly selected. The analysis and depiction of the data is of very high quality.

Especially the facts, that a high preoperative CA 19-9 levels is not associated with poor survival, if postoperative normalization occurs has been clearly demonstrated by the given data. Moreover, it is also of paramount interest, that postoperative normalization of CA 19-9 might guide the further postoperative treatment including adjuvant therapies, although these data need to be confirmed in further studies.

There are only some minor comments, which should be addressed:

Table 1: patient  numbers appears confusing and should be double-checked: sex ratio 52:32 (but only 82 patients in total not 84)

-> As you mentioned, I corrected sex ratio to 52:30. (page4, Table1)

 

Table 3: why was liver resection type CBS used as reference (only two patients underwent CBS according to table 1 ?)

-> Major hepatectomy – defined as resection of three or more hepatic segments - including caudate lobe was considered firstly for the curative resection of Klatskin’s tumor in our center. However, due to other conditions (such as insufficient remnant liver volume, tumor extent, old age, poor general condition), central bisectionectomy(CBS) was performed in two patients for the purpose of liver parenchymal preserving surgery. The number of patients for each hepatic resection type is as follows except CBS; right or extended right hemihepatectomy (n=205), left or extended left hemihepatectomy (n=83), left trisectionectomy (n=19) and right trisectionectomy (n=13). CBS was involved to this study according to the definition of major hepatectomy and this number(n=2) don’t have a critical impact to analyze the outcome. Reference was changed to Right-side hemihepatectomy which has largest number of patients and re-analysis was done (Table 3).

 

Patient group with preop. normal CA 19-9: This group is supposed to be a mixture of patients with early tumor stages (smaller tumors, high number of patients withpT1 and/or pN0 stage as shown in table 1) and patients with more advanced tumor stages, who are unable to express CA 19-9, i.e. half of the Lewis negative (a-/b-) patients.

I am not aware of the frequency of Lewis negative (a-/b-) patients in Korea, therefore this might be commented in the discussion. In theory,  in theory 5-30% of patients, which are Lewis negative (a-/b-) do not express CA 19-9, that would lead to approximately 32/114 = 30% (10 % of 322 = 32 ) of patients in the normal group, who are unable to express CA 19-9

If any data on Lewis negative (a-/b-) patients are available, it should be re-checked, if this might influence the predictive value of normal CA 19-9 prior to surgery. If these data are not available or the prevalence in Korea is different, it should at least be discussed (see e.g. Kwon S, et al.. Lewis Antigen Phenotype and Survival of Patients With Pancreatic Cancer. Pancreas. 2020 Nov/Dec;49(10):1348-1354. doi: 10.1097/MPA.0000000000001687. PMID: 33122524. )

->In Korean patients with gastric cancer, approximately 10.5% (6/57 patients) have been reported to be homozygous Lewis genotype (le/le) which has neither the Le^a nor the Le^b antigen [8]. Based on the above reference, 11 patients (10.5% of 114) might be Lewis antigen-negative in normal CA19-9 group. Considering these false-negative patients, maximum sensitivity of CA19-9 would be approximately 90% and it should be considered when interpreting the results. 

There are several prior studies [1-4] supporting that Lewis antigen-negative [Le(a-b-)] individuals cannot produce CA19-9. On the other hands, there are some studies [5-7] that support that individuals with Le(a-b-) may still produce CA19-9 and their serum concentration of CA19-9 is clinically relevant. It is difficult to draw clear conclusion about Lewis antigen phenotype and CA19-9 secretion yet. Although we could not obtain information about Lewis antigen phenotype in this cohort, further research considering Lewis antigen could contribute to produce clear conclusion on this matter.

I really appreciate your comment, and I revised discussion section based on response to your question (page12, 320-332).

 

References>

1. Hidalgo M. Pancreatic cancer. N Engl JMed. 2010;362:1605–
2. Tempero MA, Uchida E, Takasaki H, et al. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Clin Cancer Res. 1987;47:5501–
3. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation Pancreas following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–
4. Berger AC, GarciaM Jr, Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008;26:5918–
5. Orntoft TF, Vestergaard EM, Holmes E, et al. Influence of Lewisalpha1-3/4-L-fucosyltransferase (FUT3) gene mutations on enzyme activity, erythrocyte phenotyping, and circulating tumor marker sialyl-Lewis a levels. J Biol Chem. 1996;271:32260–
6. Lamerz R. Role of tumour markers, cytogenetics. Ann Oncol. 1999;10(suppl 4):145–
7. Vestergaard EM, Hein HO, Meyer H, et al. Reference values and biological variation for tumor marker CA 19-9 in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis genotyping in a Caucasian population. Clin Chem. 1999;45:54–
8. Kim MJ, Kim HS, Song KS, Noh SH, Kim HG, Paik YK, et al. Altered expression of Lewis antigen on tissue and erythrocytes in gastric cancer patients. Yonsei Med J 2002;43:427-34

Author Response File: Author Response.docx

Reviewer 2 Report

Lee et al. present a retrospective study on the predictive capacity of perioperative CA 19-9 levels for patients who underwent surgery for resectable perihilar cholangiocarcinoma. They concluded that patients who experience a normalization of and patients who had a persistently normal CA 19-9 after surgery had more favorable outcomes than patients who did not achieve a normalization of the tumor marker. Furthermore, in the subgroup which did not normalize CA 19-9 postoperatively had significantly worse overall survival here with R1 resection compared to R0 resection.

1. It is customary to abbreviate perihilar cholangiocarcinoma as pCCA (PMID 32606456).
2. This study does not describe a protocol whereby patients who were diagnosed with resectable hilar cholangiocarcinoma were staged prior to surgery. The group of patients with normal pre- and postoperative CA 19-9 may comprise of patients who are Lewis antigen negative and therefore, are unable to secrete CA 19-9, leading to an underestimation of tumor biology (line 78).
3. The study included patients undergoing surgery with CA 19 9 > 1000 U/ml (Table 1), indicative of metastatic disease, which is why it would be helpful to know whether a standardized protocol was used to rule out metastasis prior to resection.
4. Furthermore, according to table 1, this CA 19-9 normalization or lack thereof did not predict recurrence rates which is a crucial outcome of cancer surgery (Table 1).
5. When stratified according to preoperative and postoperative CA 19-9 cut off levels, there was no difference in overall survival in the group where CA 19-9 change from high to low (28%) verses low to high CA 19-9 (30%) (Figure 2).
6. The authors should state which patients received adjuvant chemo or radiation therapy (Table 3). Indeed overall survival should be represented in the groups a) no adjuvant therapy b) adjuvant systemic chemotherapy c)adjuvant radiation therapy.
7. The type of adjuvant chemotherapy should be specified.
8. Was the CA 19-9 elevated in the presence of jaundice, how frequently did it decrease and by what magnitude did it decrease following biliary drainage?

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors have satisfactorily addressed the concerns raised by this reviewer.