Cox proportional hazards regression analysis
Of the various clinicopathological prognostic factors under study,
univariate Cox regression analysis illustrated that FIGO stages IB3,
IIA2 and IIIC, LVSI (+), lymph node metastasis, parametrial invasion,
surgical margins positive, depth of stromal invasion, tumour size of>4
cm and chemoradiotherapy (P ˂0.001) were associated with a lower
5-year DFS and OS (Table 2).
There was no evidence for a relationship with patient age, histologic
type, clinical symptoms or surgical delay time.At a median (IQR)
follow-up of 58 (47-75) months, 70 patients (8.75%) had recurrence, and
65 (8.13%) died during the study period.
The association between delayed surgery and survival outcome was
confirmed by Cox analysis. Remarkably, a longer waiting period (longer
wait time group) was not associated with poorer outcomes in terms of
either OS or DFS. In the whole cohort, a longer wait time was not
statistically associated with DFS (5-year rates of 91.5% versus 90.9%,
HR 0.99, 95% CI 0.62~1.59, P =0.98; Fig. 2A) or
OS (5-year rates of 92.9% versus 90.8%, HR 0.68, 95% CI
0.42~1.10, P =0.11; Fig. 2B) when compared to a
shorter wait time. In multivariable
Cox regression analyses, with adjustment for sex, FIGO stage and
histology, the surgical delay time was also not associated with DFS (HR
0.90, 95% CI 0.56~1.45, P =0.662; Table 3, Model
I) or OS (HR 0.62, 95% CI 0.38~1.02, P =0.060;
Table 3, Model I). This association remained unchanged after adjusting
for age, FIGO stage, histology, nodal status, clinicopathological
characteristics, postoperative therapy, and clinical symptoms (Table 3,
model III).
In addition, when wait time was considered a continuous variable, there
was no association with DFS (HR per additional wait week 0.997, 95% CI
0.98~1.01, P = 0.655) or OS (HR per additional wait week
0.984, 95% CI 0.97~1.00, P=0.079) (Table 3).
To test the robustness of our
findings, we performed several sensitivity analyses.
In a sensitivity analysis, cases were limited to LVSI (+).
There were 30 (14.3%, 30/210)
recurrences and 29 (13.8%, 29/210) deaths during the follow-up (median,
60 months). We found similar associations between surgical wait time and
5-year DFS (82.8%, HR 1.62, 95% CI 0.76~3.46, P=0.213)
and OS (85.3%, HR 0.87, 95% CI 0.42~1.8, P=0.706)
(Fig. 3).
Sensitivity analysis
In a sensitivity analysis, cases were limited to tumours ≤4 cm. There
were both 20 (3.86%, 20/518) recurrences and deaths during the
follow-up (median, 60 months). We found similar associations between
surgical wait time and DFS (96.5%, HR 1.13, 95% CI
0.45~2.82, P=0.798) and OS (95.8%, HR 0.81, 95% CI
0.33~2.01, P=0.652) (Fig. S2).
However, in patients with a tumour size>4 cm, the survival outcome was
worse in those with a wait time < 12 weeks, although there was
no significant difference in DFS and OS between the two groups (Fig.
S3). We considered that this might
be due to rapid tumour growth, irregular vaginal bleeding or contact
bleeding and other typical clinical symptoms, resulting in earlier
medical treatment and shorter waiting times for patients.
4. Discussion
4.1 Main findings and
interpretation
Since December 2019, the outbreak of coronavirus disease 2019 (COVID-19)
has seriously affected the lives and health of people around the world.
Millions of people even die, greatly affecting the timely diagnosis and
treatment of other diseases, especially cancer2,3, 13-15.
During the COVID-19 epidemic in China, many patients with early clinical
symptoms of cervical cancer were managed and centralized quarantine
procedures for a long time, resulting in delayed diagnosis and
treatment. Thus, it is likely that there are a number of patients in
whom surgery for early cervical cancer is being postponed.
Consequently, patients and their
families are subjected to tremendous psychological burdens, such as
varying degrees of anxiety, worry and panic. For the current COVID-19
pandemic, data examining the outcome of surgical delay time for cervical
cancer patients are of utmost importance.
We defined the surgical delay time as
the time from the onset of typical
clinical symptoms to surgery, which differs from published studies. In
China, a large proportion of cervical cancer patients are likely to
receive appropriate treatment quickly once they are diagnosed.
However, cervical cancer screening
is not timely and sufficient in northwestern China. There may be
a prolonged period from symptom onset to the first medical visit and
surgical treatment. Focus of
research should determine the longest acceptable surgical delay time
before the patient outcomes are adversely affected rather than examining
whether surgical delay affects patient outcomes at all.
To our knowledge, this study is the first to specifically examine
whether delayed surgery may be a risk factor for poor postoperative
outcomes in patients with early cervical cancer in the Chinese
population. The main finding of the current study is that approximately
half of the patients waited more than three months for surgery, and a
12-week wait time for radical hysterectomy was not associated with
reduced OS and DFS in the long term.
In our study, Kaplan–Meier survival
analysis showed that a longer wait time was not associated with 5-year
DFS or OS, which was similar to previous findings. A retrospective study
from the National Cancer Database examining 2732 cases of only stage IA
cervical cancer showed that the 4.5-year OS rate was 95.0% and that a
longer hysterectomy wait time was not associated with all-cause
mortality risk7.
However, another study results indicated that
a waiting time longer than 8 weeks was associated with poorer after
5-year survival (HR 3.4, 95% CI 1.3~9.2,P =0.021) in FIGO stages IA2 or IB1 cervical cancer patients,
although OS showed no significant difference between short (≤8 weeks)
and long (>8 weeks) wait times12.
These
contrasting results are probably because all cervical cancer patients in
our study and the Kulisara et al.
study7-11 had
early-stage disease in which prognosis is generally good after radical
hysterectomy.
A logical theory to explain our findings is that cervical cancer tumours
develop slowly in the early stages, and therefore delaying surgical
therapy for a short period of time may not have an influence on
oncologic prognosis10, 17.
This is based on the finding that
disease progression is uncommon among women whose pregnancy has been
disrupted by early-stage cervical cancer and that afflicted patients
frequently postpone delivery to allow for foetal development throughout
pregnancy without jeopardizing mortality5.
4.2 Strengths and limitations
Due to time limitations, the DFS and OS 5 years after surgery are still
unclear and require long-term follow-up. Our study also found that LVSI,
lymph node metastasis, tumour size and depth of invasion were
independent prognostic indicators of 5-year DFS and OS. Our findings
have many important implications for future practice.
It is suggested that patients with
early cervical cancer should have a medical visit as soon as possible
after the onset of clinical symptoms and receive radical hysterectomy
within 12 weeks.
During the
current COVID-19 epidemic, taking “containment” measures is merely a
temporary stopgap. A short delay time did not increase the poor outcome
of patients with early cervical cancer.
5. Conclusion
In conclusion, our study
suggests that a delay time of 12 weeks from the onset of typical
clinical symptoms to radical hysterectomy may not increase the risk of
long-term disease recurrence and poor survival in patients with
early-stage cervical cancer. This
information partly supports the recent suggestion to consider
postponement of surgery for 6~8 weeks for the management
of early cervical cancer during the COVID-19 pandemic. During the
COVID-19 pandemic, delayed surgery has not resulted in serious outcomes,
and thus, patients should not be overly anxious, irritable or worried.