PD-1 Inhibitor Maintenance Therapy Combined Iodine-125 Seed Implantation Successfully Salvage Recurrent Cervical Cancer after CCRT: A Case Report
and Ping Jiang 2,*Round 1
Reviewer 1 Report
This is a very interesting case report. Please describe the following two points.
1. Please show the immunohistochemistry results of PD-L1 in biopsy specimens.
2. Please explain toripalimab in the Discussion session.
Author Response
1. Please show the immunohistochemistry results of PD-L1 in biopsy specimens.
Response:
The patient refused genetic testing of PD-L1 in biopsy specimens, due to genetic testing is expensive for this patietnt's family.
2. Please explain toripalimab in the Discussion session.
Response:
Thank you for your advise, I explained Toripalimab in the Discussion session. Pages 6 of 8, Line 238-245
Reviewer 2 Report
In this article, the authors report a case of a patient with cervical cancer that recurred five months after adjuvant chemotherapy and concurrent chemoradiotherapy. The disease prognosis after interstitial implantation brachytherapy (IIB) was determined and the patient underwent radioactive 125I-seed implantation combined with PD-1 inhibitor treatment. The patient exhibited a partial response after seed implantation. The manuscript is straightforward, well written, and concise and has clear results within the scope of a case report. Definitely deserves to be published and is a valuable contribution to the “Current Oncology” journal. Some minor flaws need to be addressed before publication.
Minor points:
[1] “1. Introduction”, Pages 1 and 2 of 8, Line 47:
The occurrence of cervical cancer is far from understood, which involves numerous factors and more explorations are required for the mechanisms and more treatment of cervical cancer. Within this context, selective targeting of angiogenic kinases by tyrosine kinase inhibitors may represent a novel therapeutic tool, but its use alone or in combination with chemotherapy is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Along with the immune checkpoint programmed cell death 1 (PD-1), T-lymphocyte–associated molecule-4 (CTLA-4) inhibitors have been of considerable interest. Patients with incurable advanced/metastatic disease should also be considered for clinical trials of novel targeted agents. Please, incorporate this updated information at the end of the introduction section, based on the following reference.
[2] “4. Discussion”, Page 4 of 8, Lines 136-139:
“Systemic chemotherapy is basically palliative and can be performed in conjunction with surgery or radiotherapy. However, it has no significant benefit to survival, which is still less than 12 months for most patients [3, 11].”
At that point, please do report the retrospective review of patients with cervical cancer, treated at the Royal Marsden Hospital between 2004 and 2014. This was the first reported series of patients treated at large proportion with second-line systemic treatment for recurrent or metastatic cervical cancer. In this retrospective series, 70% of women treated with systemic therapy for recurrent or metastatic cervical cancer subsequently received second-line therapy with an ORR of 13.2%, a median PFS of 3.2 months and a median OS of 9.3 months. Higher response rates were observed with either platinum-, taxane- or anti-angiogenic-based therapy.
[3] “4. Discussion”, Page 5 of 8, Lines 195-197:
“Radiotherapy exerts its cytotoxic mitotic effects on tumor cells through DNA damage. In the past, it was viewed as an immunosuppressant [43, 44].”
At that point, please make a comment on the unique mechanism of action of PARP inhibitors, which is the sensitizing effect to DNA-damaging treatments, such as the radiotherapy is. Veliparib potentiates the effect of fractionated radiation through its impairment of both single- and double strand breaks repair pathways.
Recommended reference: Boussios S, et al. Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach. Invest New Drugs. 2020;38:181-193.
Author Response
Minor points:
[1] “1. Introduction”, Pages 1 and 2 of 8, Line 47:
The occurrence of cervical cancer is far from understood, which involves numerous factors and more explorations are required for the mechanisms and more treatment of cervical cancer. Within this context, selective targeting of angiogenic kinases by tyrosine kinase inhibitors may represent a novel therapeutic tool, but its use alone or in combination with chemotherapy is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Along with the immune checkpoint programmed cell death 1 (PD-1), T-lymphocyte–associated molecule-4 (CTLA-4) inhibitors have been of considerable interest. Patients with incurable advanced/metastatic disease should also be considered for clinical trials of novel targeted agents. Please, incorporate this updated information at the end of the introduction section, based on the following reference.
Response:
thank you for your advise, I incorporated your updated information into Introduction section. Targeted therapy, PARP inhibitor, and immune checkpoint inhibitor were mentioned in separately paragraphs. Pages 2 of 8, Line 45~51; Pages 2 of 8, Line 52~55; Pages 2 of 8, Line 56~63
[2] “4. Discussion”, Page 4 of 8, Lines 136-139:
“Systemic chemotherapy is basically palliative and can be performed in conjunction with surgery or radiotherapy. However, it has no significant benefit to survival, which is still less than 12 months for most patients [3, 11].”
At that point, please do report the retrospective review of patients with cervical cancer, treated at the Royal Marsden Hospital between 2004 and 2014. This was the first reported series of patients treated at large proportion with second-line systemic treatment for recurrent or metastatic cervical cancer. In this retrospective series, 70% of women treated with systemic therapy for recurrent or metastatic cervical cancer subsequently received second-line therapy with an ORR of 13.2%, a median PFS of 3.2 months and a median OS of 9.3 months. Higher response rates were observed with either platinum-, taxane- or anti-angiogenic-based therapy.
Response:
thank you for your advise, I added the results from "McLachlan J, Boussios S, Okines A, Glaessgen D, Bodlar S, Kalaitzaki R, et al. The Impact of Systemic Therapy Beyond First-line Treatment for Advanced Cervical Cancer. Clinical oncology (Royal College of Radiologists (Great Britain)). 2017;29:153-60.10.1016/j.clon.2016.10.002". Thank you very much for mentioned the study, which presented improtant prognosis information about recurrent cervical cancer and emphasized the significant value of exploration innovative treatment strategy. Pages 5 of 8, Line 177~181
[3] “4. Discussion”, Page 5 of 8, Lines 195-197:
“Radiotherapy exerts its cytotoxic mitotic effects on tumor cells through DNA damage. In the past, it was viewed as an immunosuppressant [43, 44].”
At that point, please make a comment on the unique mechanism of action of PARP inhibitors, which is the sensitizing effect to DNA-damaging treatments, such as the radiotherapy is. Veliparib potentiates the effect of fractionated radiation through its impairment of both single- and double strand breaks repair pathways.
Recommended reference: Boussios S, et al. Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach. Invest New Drugs. 2020;38:181-193.
Response:
I added concise comment about PARP inhibitors at the end of disscussion. Pages 6 of 8, Line 270~277
Reviewer 3 Report
The authors attempted to show the efficacy of radioactive 125I-seed implantation combined with PD-1 inhibitor treatment in a woman with recurrent cervical cancer. Recently a randomized clinical trial has shown the efficacy of pembrolizumab for women with persistent, recurrent, or metastatic cervical cancer. In this study, about 20% of complete response was observed in the pembrolizumab group.
I'm sorry to say, the reviewer thinks this case is not a rare case and not worth being published in a high impacted journal.
Author Response
Response:
Thank you for consider my manuscript. We presented this case because some preclinical studies from several different groups have reported substantial in-creases in locoregional tumour control and systemic disease control when radiation is combined with checkpoint blockade immunotherapy. Our previous study indicated that 3D-PNCT assisted RISI is a promising therapy for patient with recurrent patient, the 2-years LC rate were about 80%. Howerver, distant metastatic lead majority of PFS failure, meanwhile D90<130Gy would lead to significant poor LC. Therefore, we assumed that the combination of 3D-PNCT assisted RISI and PD-1 inhibitor would reduce distant metastatic and improve LC for patient with D90<130Gy. The hypothesis based on PD-1 inhibitor was a effective therapy for recurrent/Persistent/metastatic cervical cancer and radiotherapy will induce the immunomodulatory effects through the tumor microenvironment and upregulation of the inflammatory cascade. In general, we assumed taht PD-1 inhibitor eliminate potential distant metastatic and sensitizing the effect of radiotherapy.
Round 2
Reviewer 3 Report
The authors revised the manuscript according to the reviewers' comments.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
