Is There a Place for Adjuvant Chemotherapy in the Treatment of Locally Advanced Cervical Cancer?

Round 1

Reviewer 1 Report

In the current manuscript, the authors touched on an important topic. They explained the aim of the current study and the limitations of randomized studies evaluating the role of adjuvant chemotherapy after concurrent chemoradiotherapy in patients with locally advanced cervical cancer detailly. This is a pertinent study.

Author Response

In the current manuscript, the authors touched on an important topic. They explained the aim of the current study and the limitations of randomized studies evaluating the role of adjuvant chemotherapy after concurrent chemoradiotherapy in patients with locally advanced cervical cancer detailly. This is a pertinent study.

 

Response: Thank you for your dedicated time and the acceptance of our manuscript without any change.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors are to be complemented with the fact that they keep the discussion on adjuvant chemotherapy for cervical cancer ongoing.  However, in my opinion the statement that " After gathering all the evidence from previous RCTs and the OUTBACK trial, as well as from other previous studies and clinical knowledge from other cancer types, there is only one definite conclusion, which is the absolute need for further research regarding ACT in order to optimally treat LACC", seems to much biased. The by far largest trial is negative for OS, recruitment of which was done by international collaboration. Three smaller studies are also negative. The authors are to be complemented on discussing weaknesses and strenghts of the trials that they discussed., However, I do miss the same depth of discussion on the radiotherapy parameters. CRT is the basis of the treatment of LACC, and information on whether there was brachytherapy involved or dose or which method of image guided RT was used is also essential. furthermore, although they mention it,  the authors may stress some more that in the study by Duenas Gonzalez , the chemotherapy used concomitantly is different from standard CRt and may be this could be part of the explanation why that study was positive. 

Although I am glad that the authors state that innovation on cervical cancer deserves more attention from the scientific and financial community than it receives, the comparison with breast cancer is too extensive and Table 3 actually distracts from the primary objective of the manuscript. Suggest to delete.

 

As a comment on this sentence:"  When designing new regimens for the successful treatment of LACC, we must take into consideration patient and disease specificities, treatment cost and feasibility, due to the fact that the majority of cases of CC are diagnosed in undeveloped countries.".. page 10 line 424, basis of  improvement of outcome is  the availability of an effective strategy, and thus far, this has not been proven for adjuvant chemotherapy. 

Finally, as the authors state that a new trial should be developed, I think it would add if they give some more details, for example on geographical area that the patients need to be included. 

 

 

Author Response

The authors are to be complemented with the fact that they keep the discussion on adjuvant chemotherapy for cervical cancer ongoing. 

 

[1] However, in my opinion the statement that " After gathering all the evidence from previous RCTs and the OUTBACK trial, as well as from other previous studies and clinical knowledge from other cancer types, there is only one definite conclusion, which is the absolute need for further research regarding ACT in order to optimally treat LACC", seems to much biased.

 

Response: Thank you for your dedicated time and revision. Thank you for this observation and we agree that it could be misinterpreted but our intention was not to be solely and exclusively. Hence, we have deleted it and reform it, lines 527-528.

 

Now, the text of that part of conclusions states:

“Moreover, there is absolute need for further research in order to optimally define position of ACT in the treatment of LACC.“

 

[2] The by far largest trial is negative for OS, recruitment of which was done by international collaboration. Three smaller studies are also negative. The authors are to be complemented on discussing weaknesses and strenghts of the trials that they discussed. However, I do miss the same depth of discussion on the radiotherapy parameters. CRT is the basis of the treatment of LACC, and information on whether there was brachytherapy involved or dose or which method of image guided RT was used is also essential.

 

Response: Thank you for the constructive suggestion with which we absolutely agree. Hence, we have incorporated the important parts regarding RT and BCT in the manuscript under previous trials for all RCTs, lines 135-142; 157-165; 180-183; 199-201.

 

Now, the text of that part of results states:

Lines 135-142

„All patients received the same dose of RT, 50.4 Gy to the entire pelvic region in 28 fractions of 1.8 Gy/d, 5 days a week, over the 6 weeks of chemotherapy. Furthermore, after completion of CCRT majority of patients (93%) underwent low- or intermediate-dose rate brachytherapy (BCT) with cesium-137. A BCT dose of 30 to 35 Gy was delivered to point A to result in a cumulative dose of 80 to 85 Gy combining XRT and BCT andcumulative XRT and BCT dose to point B (the pelvic wall) was 55 to 65 Gy. The ACT arm has started with adjuvant chemotherapy two weeks after BCT [13].“

 

Lines 157-165

„Patients have received conventional RT which consisted of external RT and BCT. External RT was given to the whole pelvis in dose of 40–50 Gy with a midline shield to give the pelvic lymph nodes a dose of up to 50 Gy. A parametrium dose of up to 60–66 Gy was added to the involved side, depending on the extent of parametrial involvement. While BCT was given either high or medium dose rate, according to the standard in each center. The high dose rate was 700–750 cGy at point A; two times per week for 2 weeks (four applications). The medium dose rate was a single application of 2,500– 2,800 cGy to point A or two applications of 1,400–1,750 cGy to point A. The total dose at point A was 68–80 Gy.“

 

Lines 180-183

„RT comprised of external irradiation to the whole pelvis of 41.4–50.4 Gy in 23–28 fractions plus high-dose rate (HDR) BCT (30–35 Gy in 6–7 fractions) to point A, together with a parametrial boost.“

 

Lines 199-201

„While RT comprised of 45–50.4 Gy given in 25–28 fractions, 1.8–2 Gy/day, 5 days a week and patients had high-dose rate BCT 6.0-7.5 Gy for 3-4 fractions.“

 

[3] furthermore, although they mention it, the authors may stress some more that in the study by Duenas Gonzalez, the chemotherapy used concomitantly is different from standard CRt and may be this could be part of the explanation why that study was positive.

 

Response: Thank you for the helpful and constructive input. In order to stress out the importance of different chemotherapies received concomitantly with RT, we have rephrased the initial text of the manuscript under previous trials, lines 142-149.

 

Now, the text of that part of results states:

„In addition to this regimen of RT and BCT, ACT arm also received the combination chemotherapy (cisplatin and gemcitabine) concomitantly with RT, unlike CCRT arm which received only monocisplatin concomitantly. Consequently, in this study patients from ACT arm received different, combinational chemotherapy concomitantly with RT, as well as adjuvantly resulting in difficulties to define or measure impact of both of them on the final OS results. Higher toxicity rate of the combinational chemotherapy could have caused the difference in the discontinuation rate between these two study arms.“

 

[4] Although I am glad that the authors state that innovation on cervical cancer deserves more attention from the scientific and financial community than it receives, the comparison with breast cancer is too extensive and Table 3 actually distracts from the primary objective of the manuscript. Suggest to delete.

 

Response: Thank you for the valuable observation. As suggested we have deleted the Table 3 and part of text comparing LACC with breast cancer.

 

[5] As a comment on this sentence:"When designing new regimens for the successful treatment of LACC, we must take into consideration patient and disease specificities, treatment cost and feasibility, due to the fact that the majority of cases of CC are diagnosed in undeveloped countries.".. page 10 line 424, basis of improvement of outcome is  the availability of an effective strategy, and thus far, this has not been proven for adjuvant chemotherapy.

 

Response: Thank you for the constructive and helpful comment. In order to emphasize our first intention, we have introduced a sentence of explanation that only with good foundation and treatment strategy we can assess validity of adjuvant chemotherapy in countries with lower socioeconomic background, lines 453-457.

 

Now, the text of that part of future directions states:

„Furthermore, novel RCTs with properly designed, widely applicable, treatment strategy for assesment of adjuvant chemotherapy, should be carried out in regions from which majority of targeted population of patients come from, such as countries with lower income and socioeconomic status.“

 

[6] Finally, as the authors state that a new trial should be developed, I think it would add if they give some more details, for example on geographical area that the patients need to be included.

 

Response: Thank you for this observation. As suggested, we have clarified our initial explanation for new trials, mentioning that new RCTs should be properly designed so that they can be carried out in countries with highest incidence of LACC, which are countries with lower socioeconomic background, as mentioned above, lines 453-457.

Round 2

Reviewer 2 Report

The authors adapted the manuscript accordingly to previous comments and included the radiotherapy details 

In the conclusion, lines 531-533, the authors defined their message nicely,  "conclusion is that its results should not represent the final verdict and close the subject of 531 ACT in LACC. Moreover, there is absolute need for further research in order to optimally 532 define position of ACT in the treatment of LACC."

But in the abstract, the wording is still too strong: Lines 31-33" After gathering all the evidence from previous RCTs and the OUTBACK trial, as well  as from other previous studies and clinical knowledge from other cancer types, there is only one 32 definite conclusion, which is the absolute need for further research regarding ACT in order to optimally treat LACC"

 

 

Author Response

Thank you once again for your dedicated time and valuable comments.

Thank you also for this observation. We have missed to rephrase the sentence in the abstract and now we have adjusted it according to your suggestion, lines 31-32.

Now, the text of the abstract states:

"In conclusion, there is absolute need for further research in order to optimally define position of ACT in the treatment of LACC."