Consolidation Chemotherapy Rather than Induction Chemotherapy Can Prolong the Survival Rate of Inoperable Esophageal Cancer Patients Who Received Concurrent Chemoradiotherapy

Round 1

Reviewer 1 Report

In this retrospective study, the authors evaluated the survival rate and toxicity of esophageal squamous cell carcinoma patients receiving either Concurrent chemoradiotherapy (CRT) alone (standard treatment for inoperable esophageal cancers) or CRT in combination with induction chemotherapy (IC) or consolidation chemotherapy (CCT). The authors concluded that the addition of CT to chemoradiotherapy has significant prognostic advantages for inoperable EC patients. These are interesting and clinically relevant results that will need further validation, though not necessary for the scope of this study. I need the authors to address and incorporate the following points in the manuscript:

-line 40- Please explain RTOG 85-01 in one line indicating it involved chemotherapy. At the moment, it is unclear what was given in combination with radiation therapy.

-line 44- Induction chemotherapy(IC) and consolidation chemotherapy (CCT) in combination with concurrent chemoradiotherapy have been in clinical use or trials for any other cancer type apart from the esophageal, which the authors reported?

-line 62- Please highlight your perspective in the discussion on why CCT did not improve the disease control rate (DCR) (p=0.384) and the objective response rate ORR (p=0.393), though it significantly improved OS(p<0.001) and PFS(p=0.003)?

-What do the authors think about the potential role of surgery in combination with chemoradiotherapy in esophageal cancer? Are there any reports out there explaining the same?

-Please include some references from the year 2022.

Author Response

Dear reviewer:Thank you for your constructive comments on my manuscript. I really appreciate all your comments and suggestions! For your suggestions, we have carefully considered them and made the following corrections.

 

Point 1-line 40- Please explain RTOG 85-01 in one line indicating it involved chemotherapy. At the moment, it is unclear what was given in combination with radiation therapy.

We have changed the original sentence:

-line 43-The RTOG 85-01 trial reported a significantly higher five-year survival rate for EC patients who received concurrent radiotherapy with cisplatin and fluorouracil than for those treated with radiotherapy alone(26%vs0%).

 

Point 2-line 44- Induction chemotherapy (IC) and consolidation chemotherapy (CCT) in combination with concurrent chemoradiotherapy have been in clinical use or trials for any other cancer type apart from the esophageal, which the authors reported?

IC and CCT have been used in cancers other than esophageal cancer, but here I am referring to esophageal cancer. I’m sorry for not expressing clearly. We have made the following changes:

-line 49-Therefore, induction chemotherapy (IC) and consolidation chemotherapy (CCT) have been used in combination with concurrent chemoradiotherapy to improve survival outcomes of patients with esophageal cancer.

 

Point 3-line 62- Please highlight your perspective in the discussion on why CCT did not improve the disease control rate (DCR) (p=0.384) and the objective response rate ORR (p=0.393), though it significantly improved OS(p<0.001) and PFS(p=0.003)?

The findings come from a Meta analysis of 11 articles. After reviewing the literature, we find that the meta-analysis results of DCR and ORR were obtained from 368 patients from 3 studies. The sample size is small and there is a certain heterogeneity. Thus, we consider the reliability to be low. A larger sample size may provide a different result.

On the contrary, the positive results of OS and PFS were respectively obtained from 2008 patients in 11 studies and 1111 patients from 6 studies. In particular, there was no obvious heterogeneity among the 11 studies on OS, so the results were more convincing to some extent. We consider the reason why CCT improve OS of EC patients may be that CCT further cleared tumor cells in the blood and reduced distant metastasis. As a result, the lives of patients can be prolonged.

We have added our views in the discussion (line 184-191)：A recent meta-analysis of 11 articles shows that although CCT did not improve the disease control rate (DCR) (p=0.384) and the objective response rate ORR (p=0.393), it significantly improved OS(p<0.001) and PFS(p=0.003). The DCR and ORR were de-rived from 368 patients in 3 studies, whereas OS and PFS were respectively obtained from 2008 patients in 11 studies and 1111 patients in 6 studies. We consider the results of the meta-analysis of DCR and ORR are doubtful because of the small sample size and heterogeneity. The positive results of OS and PFS may be due to the fact that CCT further removed tumor cells from the blood and reduced distant metastases.

 

Point 4-What do the authors think about the potential role of surgery in combination with chemoradiotherapy in esophageal cancer? Are there any reports out there explaining the same?

1. Preoperative neoadjuvant chemoradiotherapy combined with surgery

• For resectable esophageal cancer, preoperative neoadjuvant chemoradiotherapy combined with surgery is effective and safe. The CROSS study reported that neoadjuvant chemoradiotherapy combined with surgery significantly improved R0 resection rate (92% vs 69%, P= 0.001) and 5-year overall survival rate (47% vs 34%, P=0.003) compared with surgery alone for resectable esophageal cancer. Local area control (P<0.0001) and distant disease control (P=0.004) are also improved significantly. No significant differences in the occurrence of complications were found between the two treatment groups (DOI: 1056/NEJMoa1112088; DOI: 10.1016/S1470-2045(15)00040-6). The 10-year results of the 2021 CROSS update of neoadjuvant chemoradiotherapy combined with surgery for esophageal cancer confirmed the long-term survival benefit of this treatment modality (DOI: 10.1200/JCO.20.03614).

2. Salvage surgery after chemoradiotherapy

• Salvage surgery is a treatment option that can overcome locoregional failure in patients with recurrent or persistent disease after definitive chemoradiotherapy. In a retrospective study, the 3-year OS rate of 48.7% and 5-year OS rate of 41.7% in ESCC patients who relapsed after definitive chemoradiotherapy were obtained after rescue surgery, which provided acceptable short-term and long-term results （DOI：1245/s10434-022-11802-y）.

3. Surgery and postoperative chemoradiotherapy

• Postoperative radiotherapy combined with chemotherapy is also a feasible and powerful treatment. For patients with R0 resection, NCCN guidelines do not recommend treatment other than regular follow-up, but postoperative chemoradiotherapy for esophageal cancer has been attempted considering the poor OS rate in patients who have undergone resection alone. In view of the local and systemic treatment that can be achieved by concurrent chemoradiotherapy, we believe that prophylactic chemoradiotherapy after surgery is beneficial for patients with locally advanced esophageal cancer regardless of R0 resection. The single-arm phase II trial of LI H et al. confirmed the efficacy and safety of postoperative prophylactic chemoradiotherapy, but large studies are still needed to provide evidence and select suitable populations. (DOI: 3389/fonc.2022.900443)

In addition, for patients with esophageal cancer recurrence after surgery, if they cannot be operated again, rescue chemoradiotherapy is a powerful treatment. Zhang C et al. reported that the 3-year survival rate of patients with local lymph node recurrence after esophagectomy was 36.7% after RT or CRT, and the toxic effects were controllable (DOI: 10.3389/fonc.2021.638521) Studies have also demonstrated the survival benefits of salvage surgery (DOI: 10.1016/j.ejso.2008.02.014).

Our study discusses the treatment of locally advanced inoperable esophageal cancer, and according to your comments, we have added surgery-related content in the introduction (line 36-39)：Early esophageal cancer is mainly treated by surgery. For operable locally advanced esophageal cancer, the CROSS study identified the standard modality of treatment for neoadjuvant chemoradiotherapy combined with surgery.

 

Point 5-Please include some references from the year 2022.

We searched the 2022 literature on PubMed and found not many articles related to our study. We supplement this in the manuscript (line 204)：Additionally, a study published in 2022 compared the efficacy and safety of IC+CRT, IC+CRT+CCT and CRT+CCT for the first time, suggesting that IC+CRT+CCT may also be a new treatment mode that can be tried.

In addition, we have also added literature that was previously ignored (line 195)：Hopefully, a prospective, randomized, controlled phase III trial comparing CRT plus CCT with CRT alone for locally advanced esophageal cancer is currently underway and we look forward to its results.

 

After careful consideration, we have made the above modifications. In addition, some language expression and format problems has been further revised. We reviewed the references and removed the less relevant content. All revisions to the manuscript have been marked up using the “Track Changes” function of MS Word.Thank you for taking the time to review! Looking forward to your comments!

Reviewer 2 Report

Thanks for the opportunity to review the manuscript by Xia et al. "Consolidation chemotherapy rather than Induction Chemotherapy can prolong the survival rate of inoperable esophageal cancer patients who received concurrent chemotherapy". The authors are well versed and recognized in the subject matter, as evidenced by relevant prior publications.  I would prefer the publication of the manuscript after after some points have been processed:

Title: Please adjust the title with a shorter and comprehesive title

Introduction: Please insert spaces between the words and the corresponding acronyms.

Discussion: line 150 delete space, 152 the same. In line 157 to write "my" is uncommon in research articles, please change the sentence. In the complete discussion section are several punctuation errors, missing spaces, and personally inked comments. This destroys the good scientific aspect that the manuscript has until the discussion. Please change the discussion part into four major sections: 1. what is new in your study, 2. what say the literature, 3. limitations, 4. conclusion

Author Response

Dear reviewer:Thank you for your constructive comments on my manuscript. I really appreciate all your comments and suggestions! For your suggestions, we have carefully considered them and made the following corrections.

Title: Please adjust the title with a shorter and comprehensive title

We worked out some new titles such as “Induction chemotherapy or consolidation therapy combined with concurrent chemoradiotherapy versus chemoradiotherapy alone in the treatment of inoperable esophageal cancer”. However, we consider the original title maybe the best one because it both covers the key words and highlights the outcomes of our study. In the meanwhile, the lengths of original title and the new titles are about the same. If you have better idea, please let us know. We will definitely consider it carefully.

Introduction: Please insert spaces between the words and the corresponding acronyms.

We have corrected the formatting problem you mentioned.

Discussion: line 150 delete space, 152 the same. In line 157 to write "my" is uncommon in research articles, please change the sentence. In the complete discussion section are several punctuation errors, missing spaces, and personally linked comments. This destroys the good scientific aspect that the manuscript has until the discussion. Please change the discussion part into four major sections: 1. what is new in your study, 2. what say the literature, 3. limitations, 4. Conclusion

We have corrected the spacing and punctuation issues.

Four parts of the discussion have been refined:

1. At the end of paragraph 1, we call out the innovations of this study (line160):To the best of our knowledge, this is the first clinical study that reports the outcomes and safety of IC+CRT, CRT, and CRT+CCT in patients with patients with locally advanced inoperable ESCC.
2. In paragraphs 2 to 4 we present our research results and discussion.
3. The limitations are modified and located in paragraphs 5 (line213):This study had several limitations. First, the study is retrospective and it was conducted in a single institution. Second, the sample size is not very large. Third, in-duction and consolidation chemotherapy were performed in two cycles in this paper so the treatment of other cycles was not investigated.
4. Since the discussion is long, we have separated the conclusion from the discussion (line217): Our research proves that for patients with inoperable esophageal squamous cell carcinoma, 2 cycles of IC before CRT do not prolong their survival, while 2 cycles of CCT after CRT can improve OS significantly and safely. Our conclusion requires to be supported by further large prospective studies.

 

After careful consideration, we have made the above modifications. Language expression and format problems has been further revised. All revisions to the manuscript have been marked up using the “Track Changes” function of MS Word. Thank you for taking the time to review! Looking forward to your comments! 

Round 2

Reviewer 1 Report

The authors have addressed my points satisfactorily, and the manuscript can now be considered for publication! 

Reviewer 2 Report

Thanks, to the authors. The revision has improved the maunscript of the article. I recommend the publication of the article "Consolidation chemotherapy rather than Induction chemotherapy can prolong the survival rate of inoperable esophageal cancer patients who received concurrent chemoradiotherapy" now.