The Impact of COVID-19 on the Diagnosis and Treatment of Lung Cancer at a Canadian Academic Center: A Retrospective Chart Review

Round 1

Reviewer 1 Report

General comment:

Thank you very much for sharing your work and  your COVID-19 experience with us. It is such an interesting work, which shows a slightly divergent tendency from all the previously published papers since, despite the major impact detected, it hasn’t ben as huge as many other authors have communicated.

In general, it’s a quite complete work, but maybe  the surgical treatment has been a little forgotten. Let’s not forget it’s a paramount part of the whole NSCLC, and we should also study and remember it as so.

Indeed, one aspect that hasn’t been considered and should be studied is the type of surgery performed during the pandemic period. Such as you wrote, there were less hours of operating rooms, as also less surgeons, so surgeries could have had  the tendency to turn into simplier ones, (maybe avoiding great ressections and performing –for example- wedge ressecions), or maybe avoiding more complex patients. It is a very important part of the lung cancer patient treatment and has barely been explained.

Introduction/Discussion:

As I previously said, despite the important role of surgery in the NSCLC treatment, it has been barely mentioned in the introduction and discussion. It has been studied the effects of COVID-19 in lung cancer surgery during 2020, but it hasn’t been mentioned nor referred, for example, these two papers:

• Lieven P Depypere , Niccolò Daddi , Michael R Gooseman, Hasan F Batirel, Alessandro Brunelli. The impact of coronavirus disease 2019 on the practice of thoracic oncology surgery: a survey of members of the European Society of Thoracic Surgeons (ESTS). Eur J Cardiothorac Surg. 2020 Oct 1;58(4):752-762. doi: 10.1093/ejcts/ezaa284.
• Néstor J Martínez-Hernández, Usue Caballero Silva, Alberto Cabañero Sánchez, José Luis Campo-Cañaveral de la Cruz, Andrés Obeso Carillo, José Ramón Jarabo Sarceda, Sebastián Sevilla López, Ángel Cilleruelo Ramos, José Luis Recuero Díaz, Sergi Call, Felipe Couñago, Florentino Hernando Trancho, On Behalf Of The Scientific Committee Of The Spanish Thoracic Surgery Society. Effect of COVID-19 on Thoracic Oncology Surgery in Spain: A Spanish Thoracic Surgery Society (SECT) Survey. Cancers. 2021 Jun 9;13(12):2897. doi: 10.3390/cancers13122897.

Line 95:

You speak about waiting times “from existing  guidelines”, but which guidelines are those? You should reference them.

Statistical Analysis:

There is a mistake, since the template has been copied (it should be erased). Besides, statistical analysis itself is not complete; it hasn’t even been referred which test it was used to determinate the p-value.

References:

There is a line jump between 10th and 11th

Author Response

Response to Reviewer 1 Comments

Response to Reviewer 1 Comments

We appreciate the careful review and constructive suggestions. It is our belief that the manuscript is substantially improved after making the suggested edits. 
Below are our responses. The revision has been developed in consultation with all coauthors, and each author has given approval to the final form of this revision. 

Point 1.  In general, it’s a quite complete work, but maybe the surgical treatment has been a little forgotten. Let’s not forget it’s a paramount part of the whole NSCLC, and we should also study and remember it as so.
Response: We agree that surgical treatment was not described in the details. However, the aim of the study was to identify the changes in wait time and ability to provide the standard of care in the time of pandemic. We added some description of surgical treatment on lines 158-160: The most common type of surgery was VATS lobectomy: 27/46 (58%) in 2019 and 16/26 (62%) in 2020, followed by wedge resection: 18 (38%) in 2019) vs 10 (38%) in 2020. One patient had a pneumonectomy in 2019. No statistical difference was observed. 

Point 2. Indeed, one aspect that hasn’t been considered and should be studied is the type of surgery performed during the pandemic period. Such as you wrote, there were less hours of operating rooms, as also less surgeons, so surgeries could have had  the tendency to turn into simpler ones, (maybe avoiding great resections and performing –for example- wedge resections), or maybe avoiding more complex patients. It is a very important part of the lung cancer patient treatment and has barely been explained.
Response: Sure, this is important point and manuscript is amended to state (lines 174-176): Please see point 1

Point 3. As I previously said, despite the important role of surgery in the NSCLC treatment, it has been barely mentioned in the introduction and discussion. It has been studied the effects of COVID-19 in lung cancer surgery during 2020, but it hasn’t been mentioned nor referred, for example, these two papers:
Response:  Both articles are cited on line 220 and 223 (ref#15 and 19) 

Point 4. You speak about waiting times “from existing guidelines”, but which guidelines are those? You should reference them.
Response:  The guidelines are listed in table 1and references added in the table and line 95

Point 5. There is a mistake, since the template has been copied (it should be erased). Besides, statistical analysis itself is not complete; it hasn’t even been referred which test it was used to determinate the p-value.
Response: corrected and statistical test has been added on lines 110-111

Point 6. There is a line jump between 10th and 11th
Response: bibliography is corrected

Reviewer 2 Report

The Authors present a retrospective analysis on the effect of COVID-19 on lung cancer diagnosis and treatment. The study design is appropriate, with the expected limitations of a retrospective single Institution analysis which should be adequately explained and underlined. 

In my opinion, there are some issues that deserve attention before the manuscript can be considered worthy of publication.

• In the background of the article I would suggest to cite and discuss the biggest study to date on the effect of COVID-19 on patients with thoracic malignancies: Garassino MC, Whisenant JG, Huang LC, et al. TERAVOLT investigators. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. Lancet Oncol. 2020 Jul;21(7):914-922. doi: 10.1016/S1470-2045(20)30314-4.
• Similarly, a thorough review of clinical practice guidelines for management of patients during the COVID-19 pandemic can be discussed: Zaniboni A, Ghidini M, Grossi F, et al. A Review of Clinical Practice Guidelines and Treatment Recommendations for Cancer Care in the COVID-19 Pandemic. Cancers (Basel). 2020 Aug 29;12(9):2452. doi: 10.3390/cancers12092452. PMID: 32872421.
• Lines 133-134: "Remaining cases did not have pathological confirmation of lung cancer either due to patient age and comorbidity or refusal of biopsy". However, no details on patients' comorbidities are reported in the patients' characteristics. 
• Table 2. The percentage of patients with locoregional disease is quite low, especially considering the proportion of patients with early stage disease. It would be better to provide a TNM stage classification. 
• There is no difference between patients receiving FDT and PT considering the two study periods. This is rather important, considering that the drop in the number of patients diagnosed with lung cancer can be due to several random reasons, however the fact that there was no difference in disease stage and intent of oncologic treatment implies that there has been no substantial difference in the management of these patients.
• In referral to the previous points, an evaluation of survival and/or disease outcomes would help to interprete the results
• Lines 146-147: the Authors state that: "Treatment patterns revealed a significant increase in the utilization of radiosurgery as the first definitive treatment". For which disease stage(s)? Was the intent curative? Infact, not all pulmonary lesions can be treated with definitive radiosurgery: please explain better. 
• The use of targeted therapy increased from 27% in 2019 to 31% in 2020. This is nonsense, please consider to state that the number of targeted therapies has not significantly changed.
• Line 192: "This could be related to a decline in screening of cancers during the pandemic". However, there is no codified lung cancer screening. Do the Authors mean that patients with previous diagnosis of lung cancer may have disattended correct follow up schedules? Please, rephrase. 
• Lines 209-211: "Many institutions have changed the treatment plan in order to minimize the risk of patient exposure. We observed 18% (37% in 2020 vs 19% in 2019) increase in radiosurgery and a 7% (25 in 2020 vs 32 in 2019) decrease in surgical resections during the pandemic". Again, please specify the patients population for which you have considered that radiosurgery is superimposable to radical surgery.
• Lines 216-218: "This decline in surgery is partially due to patients preferring to receive radiosurgery rather than surgery to minimize their hospital stay and decrease their risk of getting COVID-19 infection". I do not reckon that patients' preference might overcome medical indications for treatment, otherwise you consider a special population of patients in which you can considered radiosurgery superimposable to radical surgery. Moreover, radiosurgery implies that patients access to hospital, therefore exposing them to the riesk of COVID-19.
• Lines 238-241: "It is worth mentioning that patients need to come to the hospital for their systemic chemotherapy, which could explain why so many patients did not meet the target time, compared to targeted therapy. This finding is also consistent with a study conducted by Fujita’s team that found that adding immunotherapy to standard chemo therapy causes a longer delay during COVID-19 era". This part is not clear, please clarify.

Author Response

Response to Reviewer 2 comments

We appreciate the careful review and constructive suggestions. It is our belief that the manuscript is substantially improved after making the suggested edits. 
Below are our responses. The revision has been developed in consultation with all coauthors, and each author has given approval to the final form of this revision. 

Point 1.  The Authors present a retrospective analysis on the effect of COVID-19 on lung cancer diagnosis and treatment. The study design is appropriate, with the expected limitations of a retrospective single Institution analysis which should be adequately explained and underlined. 

Response: paragraph is amended and the title has been added to paragraph. 

Point 2. 

In the background of the article I would suggest to cite and discuss the biggest study to date on the effect of COVID-19 on patients with thoracic malignancies: Garassino MC, Whisenant JG, Huang LC, et al. TERAVOLT investigators. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. Lancet Oncol. 2020 Jul;21(7):914-922. doi: 10.1016/S1470-2045(20)30314-4.

Response: The reference is introduced in the introduction and cited on line 40-42 .

Point 3. 

Similarly, a thorough review of clinical practice guidelines for management of patients during the COVID-19 pandemic can be discussed: Zaniboni A, Ghidini M, Grossi F, et al. A Review of Clinical Practice Guidelines and Treatment Recommendations for Cancer Care in the COVID-19 Pandemic. Cancers (Basel). 2020 Aug 29;12(9):2452. doi: 10.3390/cancers12092452. PMID: 32872421.

Response: The suggested manuscript sited in the discussion line 210-213

 

Point 4.

Lines 133-134: "Remaining cases did not have pathological confirmation of lung cancer either due to patient age and comorbidity or refusal of biopsy". However, no details on patients' comorbidities are reported in the patients' characteristics. 

Response: The sentence is deleted

Point 5.

Table 2. The percentage of patients with locoregional disease is quite low, especially considering the proportion of patients with early stage disease. It would be better to provide a TNM stage classification. 

Response: The prevalence of locoregional stage lung cancer (3A-3C) is in concordance with the literature. According to  Canadian Cancer Statistics it ranges between 15-20%. The TNM staging was added in the table for clarification. 

Point 6.

There is no difference between patients receiving FDT and PT considering the two study periods. This is rather important, considering that the drop in the number of patients diagnosed with lung cancer can be due to several random reasons, however the fact that there was no difference in disease stage and intent of oncologic treatment implies that there has been no substantial difference in the management of these patients.

Response: This is very important point, thank you for bringing it up. We pointed this out in the discussion, lines 197-198: Despite the pandemic, we were able to deliver definitive treatment (FDT) to the same number of patients (85% in 2019 vs 82% in 2020).

Point 7

In referral to the previous points, an evaluation of survival and/or disease outcomes would help to interpret the results

Response: As mentioned above the aim of the study is wait time and the trajectory of care. The survival is beyond the scope of this project. In addition the data is not mature enough to draw the conclusion.

Point 8

Lines 146-147: the Authors state that: "Treatment patterns revealed a significant increase in the utilization of radiosurgery as the first definitive treatment". For which disease stage(s)? Was the intent curative? Infact, not all pulmonary lesions can be treated with definitive radiosurgery: please explain better. 

Response: It is clarified that the treatment of early stage disease with curative intent, line 138 and 218

Point 9.

Line 192: "This could be related to a decline in screening of cancers during the pandemic". However, there is no codified lung cancer screening. Do the Authors mean that patients with previous diagnosis of lung cancer may have disattended correct follow up schedules? Please, rephrase. 

Response: The sentence is rephrased (lines 187-189): Fear related to contracting COVID-19, quarantining, and stay-at-home orders has caused patients to be more apprehensive to seek care for emergent issues [1].

Point 10

Lines 209-211: "Many institutions have changed the treatment plan in order to minimize the risk of patient exposure. We observed 18% (37% in 2020 vs 19% in 2019) increase in radiosurgery and a 7% (25 in 2020 vs 32 in 2019) decrease in surgical resections during the pandemic". Again, please specify the patients population for which you have considered that radiosurgery is superimposable to radical surgery.

Response: Answered in point 8

Point 11.

Lines 216-218: "This decline in surgery is partially due to patients preferring to receive radiosurgery rather than surgery to minimize their hospital stay and decrease their risk of getting COVID-19 infection". I do not reckon that patients' preference might overcome medical indications for treatment, otherwise you consider a special population of patients in which you can considered radiosurgery superimposable to radical surgery. Moreover, radiosurgery implies that patients access to hospital, therefore exposing them to the risk of COVID-19.

Response: Sentence rephrased: As a result of prioritization of available treatments, we observed 18% (37% in 2020 vs 19% in 2019) increase in radiosurgery given with the curative intent to early stage disease and a 7% (25% in 2020 vs 32% in 2019) decrease in surgical resections during the pandemic. Overall in the province of Quebec an 18% decrease in lung cancer surgeries was observed during the pandemic compared to 2019 [2]. This decline in surgery is partially due to reduced operating room hours, the lack of medical staff and long waiting list. When radiosurgery offered as an alternative to surgery few patients preferred to receive radiosurgery rather than surgery to minimize their hospital stay and decrease their risk of getting COVID-19 infection.

Point 12.

Lines 238-241: "It is worth mentioning that patients need to come to the hospital for their systemic chemotherapy, which could explain why so many patients did not meet the target time, compared to targeted therapy. This finding is also consistent with a study conducted by Fujita’s team that found that adding immunotherapy to standard chemo therapy causes a longer delay during COVID-19 era". This part is not clear, please clarify.

Response: paragraph is amended for clarification:   Hospital staff shortage and increased workload of those continued to work in cancer care and patients’ recurrent visit to the hospital might explain the delay of systemic chemotherapy. Fujita and colleagues reported delay in systemic chemotherapy compared to targeted treatment in lung cancer patients. They also found that adding immunotherapy to standard chemotherapy causes a longer delay during COVID-19 era [3].

Round 2

Reviewer 1 Report

Dear authors: Every point has been properly corrected.

Congratulations!!