Radiation-Induced Oropharyngeal Squamous Cell Carcinoma: Case Report and Review of the Literature

Round 1

Reviewer 1 Report

In the article Radiation-Induced oropharyngeal squamous cell carcinoma: case report and review of the literature, Giannini et al. addresses an interesting topic, second primary radiation induced oropharyngeal cancer, presenting a case diagnosed 13 years after irradiation 13 of a nasopharyngeal carcinoma in a young female patient. In fact, it is not a rare case but a favorable response to preoperative immunotherapy, a treatment that made surgery feasible for radio-induced cancer within safety margins. The case presentation includes 5 figures summarizing endoscopic, imaging and surgical/pathological data. Even if the case is presented rigorously and clearly, in the discussion part I would have included more data related to re-irradiation options/side effects, but also data related to possible synergistic effects between irradiation, chemotherapy and therapy with immune checkpoint inhibitors with references/arguments from the fundamental research to support the hypothesis of the benefit of ICI in the second primary even after a long time from radio-chemotherapy for the primary tumor. I believe that deepening these aspects would add value to the article and provide scientific support for the use of preoperative immunotherapy in cases of radioinduced cancers. Also, if possible, I would attach images from the initial treatment plan highlighting the doses received by the region where the radioinduced cancer developed, in the context of the data presented for radiation induced sarcoma vs squamous carcinoma.

Author Response

Thank you for your comments.

“..I would have included more data related to re-irradiation options/side effects”

We implemented the discussion as follows (lines 232-238):

For RISCC, re-irradiation could lead to serious complications and severe late toxicity, such as osteoradionecrosis, fibrosis, severe dysphagia and fatal bleeding, could reduce the survival advantages [28]. No specific studies on re-irradiation for RISCC can be found in literature. Retrospective data on patients with RISCC of the tongue after RT for NPC show that the survival rate of patients not receiving surgery was lower than that of the surgically treated group [12].

“..but also data related to possible synergistic effects between irradiation, chemotherapy and therapy with immune checkpoint inhibitors with references/arguments from the fundamental research to support the hypothesis of the benefit of ICI in the second primary even after a long time from radio-chemotherapy for the primary tumor. I believe that deepening these aspects would add value to the article and provide scientific support for the use of preoperative immunotherapy in cases of radioinduced cancers.”

Currently, available data (either prospective or retrospective) neither support nor limit the use of immune checkpoint inhibitors in RISCC patients. However, some considerations on the potential synergy of chemotherapy and immunotherapy in inducing a clinical and pathologic response were added to the discussion (lines 253-261):

Currently, available data (either prospective or retrospective) neither support nor limit the use of immune checkpoint inhibitors in RISCC patients. The patient under study was diagnosed with a locally advanced oropharyngeal SCC with clinical evidence of regional lymph node involvement. There is increasing evidence that pre-operative immunotherapy (i.e., the combination of anti-CTLA4 ipilimumab plus anti-PD1 nivolumab)induces major responses on primary tumors but not on regional nodes, as shown in the IMCISION clinical trial [31]. Therefore, we cannot exclude that the absence of lymph node involvement (pN0) observed after surgery may have been influenced by the synergy between chemotherapy and pembrolizumab.

“..I would attach images from the initial treatment plan highlighting the doses received by the region where the radioinduced cancer developed, in the context of the data presented for radiation induced sarcoma vs squamous carcinoma.”

An Image showing the initial treatment plan has been added in the text (Figure 8).

Reviewer 2 Report

In this manuscript, the authors describe a case of radiation related squamous cell carcinoma of head and neck who received neo-adjuvant chemoimmunotherapy followed by surgery. I have the following suggestions for the authors to further improve the manuscript:

1.       I would recommend including histologic/pathologic slide, with one slide depicting the PD-L1 staining.

2.       In case description, please specify which assay was utilized for PD-L1 evaluation

3.       Please provide the update on the patient, particularly how long has the follow up continued since first diagnosis of RT induced malignancy, and update on how the patient is doing at lat follow up

4.       Minor grammatical/spelling error, eg.

a.       Section: detailed case description, line 66 “seeked” should be changed to “sought”

b.       Line 91, ipisilateral is duplicated

Minor revisions are needed in the manuscript. Would recommend changing to shorter sentences in some instances as well, such as line 138-142 should be split into two or three sentences, one for each period mentioned. 

Author Response

1. I would recommend including histologic/pathologic slide, with one slide depicting the PD-L1 staining.

We provided to add a figure showing the PD-L1 staining (figure 6).

2. In case description, please specify which assay was utilized for PD-L1 evaluation

We specified the assay utilized in the in lines 94-101:

Programmed death-ligand 1 (PD-L1) immunohistochemistry was performed on 3-μm-thick formalin fixed, paraffin embedded (FFPE) sections with the 22C3 PharmDx assay (mouse monoclonal primary anti-PD-L1 antibody, Dako, Carpinteria, CA, USA) on the Autostainer Link 48 (Agilent Technologies, Santa Clara, CA, USA). Immunostains were evaluated by an expert head and neck pathologists, and the combined positive sore (CPS), defined as the number of PD-L1-positive tumour cells, lymphocytes and macrophages divided by the total number of viable tumour cells, multiplied by 100, was determined following reccomendations.

3. Please provide the update on the patient, particularly how long has the follow up continued since first diagnosis of RT induced malignancy, and update on how the patient is doing at last follow up.

We provided to implement the text with the update of the patient status at last follow-up (lines 163-167):

Manteinance immunotherapy started 40 days after surgery. Currently the patient has completed 3 cycles of pembrolizumab (200mg flat dose). Patient is in good general conditions (Estern Cooperative Oncology Group Performance Status: 1). Exclusive oral feeding is adequate, with stable body weight, and no clinical evidence of cancer relapse was found at last clinical examination (103 days after surgery).

We also added a picture taken during last clinical examination, showing surgical outcomes (figure 7). We hope that it would be appreciated.

4. Minor grammatical/spelling error, eg.

1. Section: detailed case description, line 66 “seeked” should be changed to “sought”

1. Line 91, ipsilateral is duplicated

Minor revisions are needed in the manuscript. Would recommend changing to shorter sentences in some instances as well, such as line 138-142 should be split into two or three sentences, one for each period mentioned.

We provided to correct minor spelling errors and split the sentence 138-142 as suggested.