Title: A novel Silva pattern-based model for precisely predicting recurrence in intermediate-
risk cervical adenocarcinoma patients
Version: 2 Date: 27 Jun 2022
Reviewer's report:
The article aims to establish a Silva-based model to predict recurrence specific for the
intermediate-risk AC patients and guide adjuvant therapy.
The research analyzed 345 AC patients that were classified according to Silva pattern, their
clinicopathological data and survival outcomes were assessed. Among them, 254 patients with
only intermediate-risk factors were identified, and this population was analyzed to propose the
model.
The article is about a relevant topic and is well written. Some suggestions and clarification of
the methodological approach could improve the paper.
1. Study population: all cases were treated with radical Hysterectomy? Clarify the inclusion
criteria.
2. Histopathological reviews: clarify the specimens used for the Silva patterns. Surgical
(hysterectomy) specimens, LEEP, and/or biopsies?
3. Please clarify the criteria for the surgical approach: laparoscopy vs laparotomy (page 11 line
221)
4. PG 11 line 224- The patient with Silva pattern A the recurred and died after 3y? The recurrence
analysis for the model calculations considered 3y interval or all the data?
5. Page 7 lines 135-138: The primary outcomes were 3-year recurrence-free survival (RFS) and
3-year OS. RFS was defined as the interval from the initial cervical cancer diagnosis to the first
finding of any recurrence or the last follow-up. OS was defined as the interval from the initial
diagnosis to cervical cancer-related death or the last follow-up. Only for the first 3y? As on page
9 lines 179-180: The median follow-up time was 102 (36-168) months. Please clarify the time
interval.
6. Supl Table 1: 58.6% of the patients received adjuvant therapy. Please clarify the criteria and
if all patients with risk factors received the treatment.
7. Supl Table 2: 49.2% of the patients received adjuvant therapy- please clarify the criteria. Is
there any patient that had the criteria and did not receive the treatment? If so was excluded? This
data is important because is directly related to RFS and OS.
8. Page 12 lines230-232 Where is the data shown? How was it calculated? Pattern A vs Pattern
B+C? Referring to RFS? OS?
9. Table 2: The title refers to univariate and multivariate analysis: multivariate analysis was not
shown.
10. Table 2: RFS and Overall survivor was calculated considering all data or 3y interval?
11. Table 3: Significant intermediate-risk factors: This data refers to which population? (n=345
or n=254?) The HR was calculated according to RFS? OS? Please clarify.
12. In the multivariate Cox analysis only DSI>2/3 was statistically significant - discuss this
finding.
13. Table S2: How the HR was calculated? According to RFS? OS?
14. Table S2: Surgical approach: No n=234/yes n=20- please clarify the data
15. Witch pathological criteria were used to classify mild and substantial LVSI?
16. The performance of the models was only analyzed considering RFS? Is there any data
regarding the models that were tested according to OS?
17. Supplementary Table 7: this is the two-factor model, please correct all the lines other than
the first one. (If the data is according to this analysis, if not correct the Title of the table)
18. Supplementary Table 3: All the options that included DSI were relevant, as this is the most
important factor in the multivariate Cox analysis it is important to address the subject.
19. Supplementary Table 3: Although slightly superior to Sedlis Criteria, only the Silva C +>3cm
+ DSI>2/3 had an HR superior in the univariate analysis, discuss the topic and the relation to
the log-rank test analysis.
20. Page 14 line 284: The results showed that, despite being inferior to the four-factor models,
most three-factor or two-factor models were better than the Sedlis criteria. From my point of
view, some were better but not most of them.
21. There is no Supplementary Table 4 and Table 6. Please correct the number or insert the tables.
The research is relevant and focuses on an important topic of cervical cancer treatment. I
recommend a review of the paper with attention to methodological limitations and needs for
clarification.
Proceed with caution in the conclusions as:
The results showed that, despite being inferior to the four-factor models, most three-factor or
two-factor models were better than the Sedlis criteria (page 14 lines 283-287);
or
We established Silva pattern-based models with potential recurrence prediction value in 254
intermediate-risk AC patients, including 12 four-factor models, 30 three-factor models and 16
two-factor models. (3) Notably, compared with the conventional Sedlis criteria, the four-factor
model, which includes any three of four intermediate-risk factors (Silva C, #3 cm, DSI >2/3, and
>mild LVSI), exhibited better recurrence prediction performance and surpassed the other three-
factor and two-factor models. (4) Specifically, in the best model (any three of the four factors:
Silva C, #3 cm, DSI >2/3, and >mild LVSI), we further constructed various combinations and
found that the model exhibited the best discriminating ability for recurrence when patients met
the three factors of Silva C, #3 cm, and DSI >2/3.(pages 14-15)
Those conclusions are not definitive as the paper analyzed only 3y RFS. There is no evaluation
regarding OS or long-term follow-up, it is precipitated to suggest that these findings are enough
to substitute Sedlis criteria in the clinical practice.