Potential of Alkalization Therapy for the Management of Metastatic Pancreatic Cancer: A Retrospective Study

Round 1

Reviewer 1 Report

Abstract

1. Please mention in your abstract that the OS difference was not statistically significant.

Introduction

1.       Please provide reference for the “rapidly increasing incidence” statement.

2.       Please add references to other statements made in the introduction.

3.       Please briefly mention how this study is different to the retrospective case control study which was done by your group on the same subject population.

Methodology

1.       Please clarify whether pancreatic cancer meant only pancreatic adenocarcinoma?

2.       Previous study by your group (Reference 10) also included patients within the same study period, were these patients distinct from the patients included in your current study?

3.       Please clearly mention the inclusion and exclusion criteria – were patients with hypertension, congestive heart failure, renal failure, and electrolyte abnormalities, who could be adversely affected by the alkalinization therapy excluded?

4.       Please clarify whether the study was approved by the institute’s IRB?

5.       How was the sample size calculated?

6.       Patients with metastatic cancers who are frailer or with lower performance status might not be able to adhere to the diet protocol and therapy auto selecting them into the lower urine pH group, how was this taken into consideration in the study design?

7.       Were all the deaths due to cancer? Or some other underlying comorbidity?

8.       Were data abstractors blind to the hypothesis?

Results

1.       Please add a table comparing the baseline characteristics such as age, sex, performance status, comorbidity, type of chemotherapy or no chemotherapy, prior surgery etc. of the patient population in the three groups you are comparing. This is because it is not clear from the study whether the difference in OS was due to alkalinization or due to differences in the population.

2.       Please add the p value for the comparison between the three groups.

3.       What was the median follow-up in the total population and the three subgroups?

Discussion

1.                   Please reference studies that support the concept that giving alkalinization therapy translates to alkaline pH in the TME, there are mouse model experiments which show that.

2.                   Please mention that the differences in the survival in the groups compared were not statistically significant.

1. Please revise the manuscript preferable with help from a native speaker.

Author Response

Reviewer 1

Thank you for your valuable comments and suggestions regarding our manuscript. Below are our point-by-point responses to how each comment was addressed. Please also see the revised manuscript with tracked changes.

Abstract

1. Please mention in your abstract that the OS difference was not statistically significant.

Response:

We appreciate your valuable comment. In accordance with your suggestion, we demonstrated that there was no statistically significant difference in OS by providing the p-value, as follows. (page 1, lines 28-31)

“Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH (p = 0.0639).”

Introduction

1. Please provide reference for the “rapidly increasing incidence” statement.
2. Please add references to other statements made in the introduction.

Response:

In accordance with your comments, we have cited the following additional references.

Added references (For comment 1)

(1) Klein, A. P. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021, 18 (7), 493-502. DOI: 10.1038/s41575-021-00457-x.

Added references (For comment 2)

(3) Park, W.; Chawla, A.; O'Reilly, E. M. Pancreatic cancer: A Review. JAMA 2021, 326 (9), 851-862. DOI: 10.1001/jama.2021.13027.

(4) Schnelldorfer, T.; Ware, A. L.; Sarr, M. G.; Smyrk, T. C.; Zhang, L.; Qin, R.; Gullerud, R. E.; Donohue, J. H.; Nagorney, D. M.; Farnell, M. B. Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible? Ann Surg 2008, 247 (3), 456-462. DOI: 10.1097/SLA.0b013e3181613142.

(5) Tanaka, J.; Nakagawa, T.; Harada, K.; Morizane, C.; Tanaka, H.; Shiba, S.; Ohba, A.; Hijioka, S.; Takai, E.; Yachida, S.; et al. Efficient and accurate KRAS genotyping using digital PCR combined with melting curve analysis for ctDNA from pancreatic cancer patients. Sci Rep 2023, 13 (1), 3039. DOI: 10.1038/s41598-023-30131-y.

(6) Okusaka, T.; Furuse, J. Recent advances in chemotherapy for pancreatic cancer: evidence from Japan and recommendations in guidelines. J Gastroenterol 2020, 55 (4), 369-382. DOI: 10.1007/s00535-020-01666-y.

(7) Okusaka, T.; Nakamura, M.; Yoshida, M.; Kitano, M.; Ito, Y.; Mizuno, N.; Hanada, K.; Ozaka, M.; Morizane, C.; Takeyama, Y.; et al. Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis. Int J Clin Oncol 2023, 28 (4), 493-511. DOI: 10.1007/s10147-023-02317-x.

3. Please briefly mention how this study is different to the retrospective case control study which was done by your group on the same subject population.

 Response:

Our previous study included not only patients with metastatic pancreatic adenocarcinoma, but also those with relapse, whereas we excluded patients with relapse in this study. Furthermore, we increased the number of patients to analyze, and compared them by categorizing them into 3 groups based on their mean urine pH, which is another difference from the previous study. We have added this information to the Introduction section of the revised manuscript, as follows. (page 2, lines 81-86)

 “Similar to a previous study that included patients with metastatic and re-current pancreatic adenocarcinoma, we focused on a cohort of patients with stage 4 metastatic pancreatic adenocarcinoma, and re-examined the efficacy of ”alkalization therapy“, a nonsurgical treatment that has shown favorable outcomes at our clinic for various solid tumors. Furthermore, we investigated the effect of urine pH levels on prognosis improvement by grouping the patients into 3 categories based on their urine pH values.”

Methodology

1. Please clarify whether pancreatic cancer meant only pancreatic adenocarcinoma? 

Response:

This study only analyzed patients with pancreatic adenocarcinoma, and patients with Intraductal Papillary Mucinous Neoplasm and neuroendocrine tumors were excluded from the study. We have added this information to the revised manuscript, as follows. (page 2, lines 89-90)

 “This study was a retrospective analysis performed to assess the potential effects of “alkalization therapy” on patients with stage 4 metastatic pancreatic adenocarcinoma.” 

2. Previous study by your group (Reference 10) also included patients within the same study period, were these patients distinct from the patients included in your current study?

 Response:

As you pointed out, the patients from reference 10 (reference 16 in the revised manuscript) were included in this study. To make this point clear, we have also added this information to the revised manuscript, as follows. (page 3, lines 104-105)

“The study population included 25 patients from our previous study [16] .”

3. Please clearly mention the inclusion and exclusion criteria – were patients with hypertension, congestive heart failure, renal failure, and electrolyte abnormalities, who could be adversely affected by the alkalinization therapy excluded?

Response:

The indication for alkalization therapy was determined by the attending physician, but as shown in Table 1, which was created in response to the reviewer’s comment regarding the Results section, all of the subjects in this study were outpatients with a performance status of 0 to 1, and there were no patients who needed to be excluded owing to comorbidities. We have added this information to the revised manuscript, as follows. (page 3, lines 104-105)

“All of the patients were outpatients (Performance Status 0-1), and underwent alkalization therapy as shown in Table 1.”

4. Please clarify whether the study was approved by the institute’s IRB?

Response:

Our study was approved by our Institutional Review Board, as stated in the manuscript after the Conclusion section, as follows. (page 10, lines 315-318)

“The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Japan Chapter of the American College of Chest Physicians, and has been registered with UMIN Clinical Trials under registration number UMIN000052333 (date of approval: September 21, 2023)”

5. How was the sample size calculated?

Response:

This study was a retrospective study, and we included all patients with stage 4 metastatic pancreatic cancer who were treated at our clinic between January 2011 and April 2022

6. Patients with metastatic cancers who are frailer or with lower performance status might not be able to adhere to the diet protocol and therapy auto selecting them into the lower urine pH group, how was this taken into consideration in the study design?

Response:

The patients evaluated in this study had a performance status of 0 to 1, and could visit the outpatient clinic where we were able to measure their urine pH, so there was no one who could not receive alkalization therapy guidance owing to their condition. To make this point clear, we have added the following explanation to the text, which overlaps with the part corrected for comment 3 above. (page 4, lines 139-141)

“All of the patients were outpatients (performance status (PS): 0–1), and underwent “alkalization therapy”, as shown in Table 1.” 

7. Were all the deaths due to cancer? Or some other underlying comorbidity?

Response:

Of the 63 deaths, only 1 was owing to head trauma after a fall. The other 62 deaths were owing to the primary disease. We added this information to the revised manuscript, as follows. (page 7, lines 177-178)

“Of the 63 deaths, only 1 was owing to head trauma after a fall. The other 62 deaths were owing to the primary disease.”

8. Were data abstractors blind to the hypothesis?

Response:

The individuals who extracted the data were not blinded, but the data extractors and data analyzers were different individuals.

Results

1. Please add a table comparing the baseline characteristics such as age, sex, performance status, comorbidity, type of chemotherapy or no chemotherapy, prior surgery etc. of the patient population in the three groups you are comparing. This is because it is not clear from the study whether the difference in OS was due to alkalinization or due to differences in the population.

Response:

We agree that this is a very important point. If the patients’ basic background characteristics are unclear, it is not clear whether the difference in OS is owing to the alkalization therapy or differences in characteristics among the groups. In accordance with your comment, we created Table 1 to show the patients’ background characteristics, and changed the text as follows. As a side note, none of the patients had surgery, and no data on the complications of chemotherapy or alkalization therapy were collected in this study. (page 4, lines 139-148)

“All of the patients were outpatients (performance status (PS): 0–1), and underwent “alkalization therapy”, as shown in Table 1. The median age of the patients assessed was in the 60s for all 3 groups, and there were slightly more men in all groups. Few patients in Groups 2 and 3 had a prior history of malignancy and underwent radiotherapy for pancreatic cancer. The PS was slightly less favorable in Group 1 than in the other groups. First-line chemotherapy regimens were mostly gemcitabine hydrochloride + nab-paclitaxel combination therapy (GEM+nabPTX) or folinic acid, fluorouracil, irinotecan oxaliplatin therapy (FOLFIRINOX) in Group 1, whereas they were more diverse in Groups 2 and 3. Moreover, there were more patients who did not receive any chemotherapy in Group 3.”

In addition, we have added an explanation about the effects of chemotherapy on OS to the Discussion section of the revised manuscript, as follows. (page 9, lines 292-295)

“Although this study was limited to patients with stage 4 pancreatic cancer with distant metastasis, there may be a need to adjust for background factors, such as sex, location of metastasis, types of chemotherapy regimens, and other concurrent treatments.”

2. Please add the p value for the comparison between the three groups.

Response:

We have added the p-value among the 3 groups to the text, as follows. (page 6, lines 163-164)

 “Despite not reaching statistical significance, there was a discernible trend, i.e., higher urine pH correlated with extended OS (p = 0.0639).” 

3. What was the median follow-up in the total population and the three subgroups?

 Response:

The analysis was conducted on 2023/09/30, and the patients were assessed from 2011/1/1 to 2022/4/30. Hence, even the patients who were included most recently have undergone at least 1 year and 5 months of follow-up. To make this clear, we have added the following to the revised manuscript. (page 3, line 116)

 “Data were analyzed on September 30, 2023.”

Discussion 

1. Please reference studies that support the concept that giving alkalinization therapy translates to alkaline pH in the TME, there are mouse model experiments which show that.

Response:

We think this is a very important point. We have added this information to the text, and cited a reference of a study using mouse models, as follows. (page 8, lines 221-224)

“A previous study focused on the TME in mouse models of end-stage pancreatic cancer, which showed that oral administration of sodium potassium citrate increased HCO3− concentration in blood, HCO3− concentration and pH in urine, and neutralized the tumor extracellular pH [13].”

Added reference

(13) Ando, H.; Eshima, K.; Ishida, T. Neutralization of Acidic Tumor Microenvironment (TME) with Daily Oral Dosing of Sodium Potassium Citrate (K/Na Citrate) Increases Therapeutic Effect of Anti-cancer Agent in Pancreatic Cancer Xenograft Mice Model. Biol Pharm Bull 2021, 44 (2), 266-270. DOI: 10.1248/bpb.b20-00825.

2. Please mention that the differences in the survival in the groups compared were not statistically significant.

Response:

We have added that the differences in the survival of the groups compared were not statistically significant, as follows, and also added a new reference. Although we did not find a statistical difference, we think that the results we obtained are important. (page 9, lines 272-276)

“ By comparing the median OS of the 3 groups divided by average urine pH levels, i.e., a pH of 7.5 or higher, 6.5 or higher but less than 7.5, and less than 6.5, we observed that longer patient survival depended on a higher average urine pH, which suggested that despite the absence of a statistical difference (p = 0.0639) [41], there was a correlation between average urine pH and the achievement of the objective of “alkalization therapy” .”

 Added reference

(41) Amrhein, V.; Greenland, S.; McShane, B. Scientists rise up against statistical significance. Nature 2019, 567 (7748), 305-307. DOI: 10.1038/d41586-019-00857-9.

Reviewer 2 Report

In the present article titled “Potential of alkalization therapy for the management of metastatic pancreatic cancer: a retrospective study” the authors reported a retrospective analysis performed to assess  the effects of “alkalization therapy” on patients with metastatic pancreatic cancer.

Alkalization therapy significantly increase urine pH in patients and correlate with favorable cancer treatment outcomes.

Overall, the manuscript is well written, even if some minor stylistic revisions should be made.

 The reference list is quite up to date.

The manuscript is clear and scientific data in the draft are  presented in a well-structured manner.

I think this article is acceptable for publication in Cancers.

Author Response

Reviewer 2

Thank you for your valuable comments and suggestion regarding our manuscript. Below are our point-by-point responses to how we addressed each comment. Please also see the revised manuscript with tracked changes. 

1. The alkalinisation diet is based on fruits and vegetables. Do the authors have some information on whether they derived from organic or intensive agriculture and whether the difference source might reflect a different effectiveness in term of OS. A recent paper emphasized a very important difference in this sense (Logozzi M, Di Raimo R, Mizzoni D, Fais S. Nanovesicles from Organic Agriculture-Derived Fruits and Vegetables: Characterization and Functional Antioxidant Content. Int J Mol Sci. 2021 Jul 29;22(15):8170. doi: 10.3390/ijms22158170. PMID: 34360936; PMCID: PMC8347793).

 Response:

We appreciate your valuable comment. We actually do not have such information. The paper you introduced is very interesting, and we understand how vital this perspective is. Nevertheless, in practice, the patients who come to the clinic are diverse, with various preferences and opinions, and some of them struggle even to modify their diet slightly. In the future, we would like to aim to augment the treatment effects by advising the patients to eat organic vegetables, but we expect that it will be difficult, so we would like to proceed gradually. 

2. There are very few pre-clinical and clinical studies investigating the role of either Antiacidic compounds (i.e. proton pump inhibitors) and other strategy of alkalinisation (a mix of carbonates and bicarbonates, alkaline water) to counteract cancer alone or in combination with chemotherapy. On one hand this reviewer believe that the authors should include and comment this literature. On the other hand could be interesting to know whether there is difference between patients receiving proton pump inhibitors as gastroprotective agents or not. The literature include: 

• Astigiano S, Puglisi A, Mastracci L, Fais S, Barbieri O. Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice. J Enzyme Inhib Med Chem. 2017 Dec;32(1):363-368. doi: 10.1080/14756366.2016.1252760. PMID: 28095711; PMCID: PMC6009900.

3. Related to point 2 there are some retrospective trials that support the use of proton pump inhibitors in either cancer prevention and combination therapies, including : 

• Chen CH, Lee CZ, Lin YC, Kao LT, Lin HC. Negative Association of Proton Pump Inhibitors With Subsequent Development of Breast Cancer: A Nationwide Population-Based Study. J Clin Pharmacol. 2019 Mar;59(3):350-355. doi: 10.1002/jcph.1329. Epub 2018 Oct 17. PMID: 30329162. 

• Ding DC, Sung FC, Chen W, Wang JH, Lin SZ. Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: A population-based cohort study. Breast J. 2020 Mar;26(3):474-478. doi: 10.1111/tbj.13519. Epub 2019 Sep 2. PMID: 31478297. 

• Papagerakis S, Bellile E, Peterson LA, Pliakas M, Balaskas K, Selman S, Hanauer D, Taylor JM, Duffy S, Wolf G. Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma. Cancer Prev Res (Phila). 2014 Dec;7(12):1258-69. doi: 10.1158/1940-6207.CAPR-14-0002. PMID: 25468899; PMCID: PMC4372797.

 Response:

We are grateful for your insightful comments. We acknowledge that there are other alkalization strategies for alkalization therapy that we could use at our clinic, and we realized that we missed including a discussion on this point in the original manuscript. We have discussed the study of the paper you suggested, as well as cited some additional references in the revised manuscript, as follows. (page 8, lines 224-242)

“In addition, we should also consider the other ideas of “alkalization therapy” that have been proposed to date. The use of proton pump inhibitors (PPIs) to alkalize the TME has been attracting attention. It has been observed that PPI prevents tumor cells from ac-quiring resistance to cytotoxic anticancer drugs, and induces the apoptosis of tumors in animal models and cultured cells of malignant melanoma, adenocarcinoma, and malignant lymphoma [31-33]. Furthermore, in a large retrospective observational study that investigated the association between PPI exposure and breast cancer incidence, patients diagnosed with breast cancer had 25% less exposure to PPIs compared with the matched control group (95% CI = 0.72–0.78) [34], and in a prospective cohort study that compared the incidence of breast cancer between PPI users and non-users, the adjusted hazard ratio for PPI users was 0.32 (95% CI = 0.20–0.49) [35], with both studies concluding that PPI intake may reduce the risk of breast cancer. In a randomized controlled trial study using PPI as an alkalizing agent, it has been reported that PPI was combined with chemotherapy in patients with metastatic breast cancer, and antitumor effects were obtained [36]. In addition to PPIs, in a study using water with added alkalizing agent, it has been reported that the progression of prostate cancer in the transgenic adenocarcinoma of the mouse prostate mouse model was suppressed by drinking alkaline water [37]. Similarly, there is also a report that alkaline water significantly inhibited tumor growth in a mouse model of malignant melanoma [38].”

Additional references:

(31) Luciani, F.; Spada, M.; De Milito, A.; Molinari, A.; Rivoltini, L.; Montinaro, A.; Marra, M.; Lugini, L.; Logozzi, M.; Lozupone, F.; et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 2004, 96 (22), 1702-1713. DOI: 10.1093/jnci/djh305.

(32) De Milito, A.; Iessi, E.; Logozzi, M.; Lozupone, F.; Spada, M.; Marino, M. L.; Federici, C.; Perdicchio, M.; Matarrese, P.; Lugini, L.; et al. Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 2007, 67 (11), 5408-5417. DOI: 10.1158/0008-5472.CAN-06-4095.

(33) De Milito, A.; Canese, R.; Marino, M. L.; Borghi, M.; Iero, M.; Villa, A.; Venturi, G.; Lozupone, F.; Iessi, E.; Logozzi, M.; et al. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 2010, 127 (1), 207-219. DOI: 10.1002/ijc.25009.

(34) Chen, C. H.; Lee, C. Z.; Lin, Y. C.; Kao, L. T.; Lin, H. C. Negative Association of proton pump inhibitors with subsequent development of breast cancer: A nationwide population-based study. J Clin Pharmacol 2019, 59 (3), 350-355. DOI: 10.1002/jcph.1329.

(35) Ding, D. C.; Sung, F. C.; Chen, W.; Wang, J. H.; Lin, S. Z. Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: A population-based cohort study. Breast J 2020, 26 (3), 474-478. DOI: 10.1111/tbj.13519.

(36) Wang, B. Y.; Zhang, J.; Wang, J. L.; Sun, S.; Wang, Z. H.; Wang, L. P.; Zhang, Q. L.; Lv, F. F.; Cao, E. Y.; Shao, Z. M.; et al. Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J Exp Clin Cancer Res 2015, 34 (1), 85. DOI: 10.1186/s13046-015-0194-x.

(37) Astigiano, S.; Puglisi, A.; Mastracci, L.; Fais, S.; Barbieri, O. Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice. J Enzyme Inhib Med Chem 2017, 32 (1), 363-368. DOI: 10.1080/14756366.2016.1252760.

(38) Azzarito, T.; Lugini, L.; Spugnini, E. P.; Canese, R.; Gugliotta, A.; Fidanza, S.; Fais, S. Effect of Modified Alkaline supplementation on syngenic melanoma growth in CB57/BL mice. PLoS One 2016, 11 (7), e0159763. DOI: 10.1371/journal.pone.0159763. 

4. Lastly I would like the authors will discuss a new paradigm for future cancer therapies that will target the microenvironment instead of the tumor cells.

Response:

Thank you again for evaluating our manuscript. Introducing a new paradigm shift requires courage, and we are confident and motivated as a group to have your sympathy. We have also added the following sentences to the text. (page 9, lines 277-282)

“This remarkable result suggests that, in the treatment of malignant tumors, although targeting the behavior and genetic mutations of tumor cells is certainly important, alkalizing and modifying the TME can amplify the antitumor effects of standard treatments. Furthermore, the TME can also act as a sufficient therapeutic target itself, and hence “alkalization therapy” is a promising treatment method that is gentle to the patient’s body, does not cost much, and is expected to lead to a paradigm shift.”

Reviewer 3 Report

Potential of alkalization therapy for the management of meta- 2 static pancreatic cancer: a retrospective study . by Masahide Isowa,  et al

In this retrospective study the authors show that patients with  pancreatic cancer receiving a mix of alkaline diet (based mostly on fruits and vegetables) and alkalinizing agents (i.e. sodium bicarbonate and citric acid), in combination with standard chemotherapy, underwent a significant increase in overall survival. The clinical follow up was also based on the measure of urine pH and the most amazing results were obtained in patients showing a urine pH 7.5 or more that more than doubled the OS as compared to patients showing a lower or frankly acidic pH.

This may represent a milestone study between the very few reports that we can find in the current and past literature. I have in fact some suggestions to improve this study but I very favourable the its publication.

1.     The alkalinisation diet is based on fruits and vegetables. Do the authors have some information on whether they derived from organic or intensive agriculture and whether the difference source might reflect a different effectiveness in term of OS. A recent paper emphasized a very important difference in this sense (Logozzi M, Di Raimo R, Mizzoni D, Fais S. Nanovesicles from Organic Agriculture-Derived Fruits and Vegetables: Characterization and Functional Antioxidant Content. Int J Mol Sci. 2021 Jul 29;22(15):8170. doi: 10.3390/ijms22158170. PMID: 34360936; PMCID: PMC8347793).  

2.     There are very few pre-clinical and clinical studies investigating  the role of either Antiacidic compounds (i.e. proton pump inhibitors) and other strategy of alkalinisation (a mix of carbonates and bicarbonates, alkaline water) to counteract cancer alone or in combination with chemotherapy. On one hand this reviewer believe that the authors should include and comment this literature. On the other hand could be interesting to know whether there is difference between patients receiving proton pump inhibitors as gastroprotective agents or not. The literature include:

·      

·       Astigiano S, Puglisi A, Mastracci L, Fais S, Barbieri O. Systemic alkalinisation delays prostate cancer cell progression in TRAMP mice. J Enzyme Inhib Med Chem. 2017 Dec;32(1):363-368. doi: 10.1080/14756366.2016.1252760. PMID: 28095711; PMCID: PMC6009900.

3.     Related to point 2 there are some retrospective trials that support the use of proton pump inhibitors in either cancer prevention and combination therapies, including :

·       Chen CH, Lee CZ, Lin YC, Kao LT, Lin HC. Negative Association of Proton Pump Inhibitors With Subsequent Development of Breast Cancer: A Nationwide Population-Based Study. J Clin Pharmacol. 2019 Mar;59(3):350-355. doi: 10.1002/jcph.1329. Epub 2018 Oct 17. PMID: 30329162.

·       Ding DC, Sung FC, Chen W, Wang JH, Lin SZ. Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: A population-based cohort study. Breast J. 2020 Mar;26(3):474-478. doi: 10.1111/tbj.13519. Epub 2019 Sep 2. PMID: 31478297.

·       Papagerakis S, Bellile E, Peterson LA, Pliakas M, Balaskas K, Selman S, Hanauer D, Taylor JM, Duffy S, Wolf G. Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma. Cancer Prev Res (Phila). 2014 Dec;7(12):1258-69. doi: 10.1158/1940-6207.CAPR-14-0002. PMID: 25468899; PMCID: PMC4372797.

4.     Lastly I would like the authors will discuss a new paradigm for future cancer therapies that will target the microenvironment instead of the tumor cells.

All in all while the study is very interesting and intriguing I suggest to implement it with further literature and new analysis as suggested above

the english needs some careful revision

Author Response

In the present article titled “Potential of alkalization therapy for the management of metastatic pancreatic cancer: a retrospective study” the authors reported a retrospective analysis performed to assess the effects of “alkalization therapy” on patients with metastatic pancreatic cancer.

Alkalization therapy significantly increase urine pH in patients and correlate with favorable cancer treatment outcomes.

Overall, the manuscript is well written, even if some minor stylistic revisions should be made.

The reference list is quite up to date.

The manuscript is clear and scientific data in the draft are presented in a well-structured manner.

I think this article is acceptable for publication in Cancers.

Reviewer 3

Response:

We are grateful for your assessment. We plan to incorporate the feedback of the other reviewers and improve the quality of our paper.

Round 2

Reviewer 1 Report

Thank you for making the changes.

Minor revision to remove typos and minor grammatical errors.

Reviewer 3 Report

now it appears suitable for publicaation

probably some minor editing is needed