This study aimed to evaluate the effect of waiting time, from diagnosis to initiation of definitive concurrent chemoradiation (CCRT), on overall survival in cervical cancer patients.
Patients with cervical cancer who were treated with definitive CCRT between 2000 and 2017 were retrospectively reviewed. Time from initial pathological diagnosis to definitive CCRT was analyzed both as a continuous variable (per day) and as a categorical variable in two groups (group 1 ≤ median, group 2 > median). Patients with a waiting time of more than 60 days were excluded.
The median waiting time was 14 days (0–60). There were differences between group 1 and group 2 in age and chemotherapy regimens. However, no significant difference was found in the International Federation of Gynecology and Obstetrics stage, cell type, or the number of cycles of chemotherapy received during CCRT. A longer waiting time was associated with poorer overall survival on the Kaplan-Meier curve (group 1 vs. group 2, p=0.042). On multivariate analysis, intervals as either a continuous variable (hazard ratio [HR], 1.023; 95% confidence interval [CI], 1.006 to 1.040; p=0.007) or a categorical variable (HR, 1.513; 95% CI, 1.073 to 2.134; p=0.018), FIGO stage, cell type, and the number of cycles of chemotherapy received during CCRT were significant independent prognostic factors for overall survival.
A shorter waiting time from pathological diagnosis to definitive CCRT showed benefit on overall survival. Our findings suggest that an effort to minimize waiting times should be recommended in cervical cancer patients who are candidates for CCRT.
Approximately 570,000 cases of cervical cancer and 311,000 deaths from the disease occurred in 2018 worldwide. This was the fourth most common cancer in women suggesting it remains a major public health problem on a global scale [
In general, a prompt diagnosis followed by immediate treatment is advocated for treating cancers. Radiobiological modeling, illustrates that delays in the initiation of radiotherapy treatment have an adverse effect on tumor control, especially in fast-growing tumors [
Most studies of cervical cancer investigating the role of waiting time define late initiation of treatment as being more than 1–2 months from the pathological diagnosis [
The present study was undertaken in order to further explore this issue by assessing the effect of waiting time from diagnosis to treatment initiation on the outcome of patients with cervical cancer who were treated with CCRT within 2 months of the pathological diagnosis.
Among the 460 patients who had radiation-based treatment for newly diagnosed cervical cancer between 2001 and 2017, patients who had radiation alone (n=51), a waiting time of more than 60 days (n=8), and/or were diagnosed with other malignancies (n=12) during the study period were excluded, leaving 389 patients with cervical cancer for the final analysis (
Data, including patients’ demographics, cell type, FIGO stage (ver. 8), and the regimen of chemotherapy during CCRT, were collected retrospectively. For locally advanced cervical cancer (IB2 and IIA2 or above), definitive CCRT was recommended unless the patients had medical co-morbidities that were not eligible for receiving cytotoxic agents. For early cervical cancer patients who are not well enough to receive radical surgery, definitive CCRT (which was more preferred), or radiotherapy alone was recommended by the attending physician. For chemotherapy during CCRT, cisplatin-based combination chemotherapy or weekly cisplatin was used based on the attending physicians’ preference. However, recently weekly cisplatin has been used primarily, and details of the chemotherapy in each regimen was described previously [
Radiotherapy consisted of external beam radiotherapy to the whole pelvis with a standard fractionation (1.8 Gy/fraction, 5 fractions/wk) to a total dose of 45 to 50.4 Gy, depending on the tumor size. For gross pelvic lymph node nodal metastasis, a sequential boost was added. All patients received intracavitary brachytherapy, consisting of high-dose-rate brachytherapy to a total dose of 24 Gy, delivered in 6 fractions (3 times/wk).
Overall survival (OS) was defined as the date of death or last follow-up. Median with a range was used for non-normal distributions after a normality check with the Shapiro-Wilk test. Frequency distributions among categorical variables were compared using a chi-square test or Fisher exact test. Survival curves were calculated using the Kaplan-Meier method with a log-rank test. The Cox proportional hazards model was used for multivariate analysis. A p < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software ver. 25.0 (IBM Corp., Armonk, NY).
Basic patients’ characteristics are presented in
Shorter interval was significantly associated with better OSs as shown in
Further analyses were performed to investigate the association between intervals and progression-free survival and recurrence patterns (pelvic vs. systemic recurrence) according to intervals. Better recurrence-free survival showed in group 1 when compared with group 2 which is in line with that of OS as shown in
In this study, we evaluated the association between waiting time, from the initial pathological diagnosis to initiation of definitive CCRT, and survival of patients with cervical cancer. As shown in
There have been several studies that have investigated the waiting time in cervical cancer. Of note, most of the studies showed a longer median waiting time in their study cohorts than this study, from 30 to 114 days showing wide variation among the studies [
In patients with early cervical cancer treated with surgery, the role of waiting time on survival showed mixed results. For example, 441 patients with FIGO IA2 to IB1 cervical cancer were reviewed to evaluate the impact of surgical waiting time on survival [
Age is one of the independent factors involved in a longer waiting time in cervical cancer. For example, although a cohort study reported the effectiveness of a screening program in reducing cervical cancer mortality, the positive effects of the screening program were not observed in older women because of treatment delays [
There are other parameters in relation to a delayed waiting time. Besides the need for a medical point of view [
Delayed treatment can be categorized into four components—patient delay, healthcare provider delay, referral delay, and system delay [
Apart from the retrospective study design, there are other limitations in this study. First, there was heterogeneity in the regimens of chemotherapy during CCRT. A meta-analysis showed that radiotherapy plus platinum-based doublet therapy improved the survival compared to radiotherapy plus platinum single-agent therapy in patients with locally advanced cervical cancer [
In conclusion, our study shows the importance of minimizing time delays from diagnosis to treatment, especially for cervical cancer patients who are candidates for primary CCRT. Stakeholders in the medical health system should make an effort to expedite delivering treatments, within the limited medical resources, for patients with cervical cancer.
Supplementary materials are available at Cancer Research and Treatment website (
This study was approved by the Institutional Review Board (IRB No. 2020-04-126) of our institution, and waived the requirement for obtaining informed consent.
Conceived and designed the analysis: Noh KW, Kim B, Lee YY.
Collected the data: Noh KW, Kim B, Lee YY.
Contributed data or analysis tools: Noh KW, Kim B, Lee YY.
Performed the analysis: Noh KW, Kim B, Lee YY.
Wrote the paper: Noh KW, Kim B, Lee YY.
Supervision: Choi CH, Kim TJ, Cho WK, Park W.
Project administration: Lee JW, Kim BG, Bae DS.
Validation: Cho WK.
Conflict of interest relevant to this article was not reported.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2019R1F1A1063567).
This research was supported by Research and Business Development Program through the Korea Institute for Advancement of Technology (KIAT) funded by the Ministry of Trade, Industry and Energy (MOTIE) (P0014051).
We would like to thank Editage (
Number of patients based on waiting time from pathological diagnosis confirmed on pathologic report to the first day of concurrent chemoradiation.
Kaplan-Meier survival curves for overall survival. Patients were divided into four groups per week of intervals (A) or two groups based on median waiting time (B).
Patients’ baseline characteristics
All (n=389) | Group 1 (≤ 14 days) (n=215) | Group 2 (> 14 days) (n=174) | p-value | |
---|---|---|---|---|
14 (0–60) | 9 (0–14) | 22 (15–60) | < 0.001 | |
55 (25–85) | 53 (28–83) | 57 (25–85) | < 0.001 | |
0.066 | ||||
I | 31 (8.0) | 13 (6.0) | 18 (10.3) | |
II | 205 (52.7) | 106 (49.3) | 99 (56.9) | |
III | 83 (21.3) | 50 (23.3) | 33 (19.0) | |
IV | 70 (18.0) | 46 (21.4) | 24 (13.8) | |
0.152 | ||||
SCC | 337 (86.6) | 184 (85.6) | 153 (87.9) | |
AD/ADS | 47 (12.1) | 30 (14.0) | 17 (9.8) | |
Others | 5 (1.3) | 1 (0.5) | 4 (2.3) | |
0.015 | ||||
Single agent | 224 (57.6) | 112 (52.1) | 112 (64.0) | |
Combination | 165 (42.4) | 103 (47.9) | 62 (35.6) | |
0.525 | ||||
Yes | 40 (10.3) | 24 (11.2) | 16 (9.2) | |
No | 349 (89.7) | 191 (88.8) | 158 (90.8) |
AD, adenocarcinoma; ADS, adenosquamous cell carcinoma; CCRT, concurrent chemoradiation; FIGO, International Federation of Gynecology and Obstetrics; Others, small cell, clear cell, poorly differentiated carcinoma; SCC, squamous cell carcinoma.
Chemotherapy during CCRT,
Early discontinuation of chemotherapy during CCRT (e.g. 1 or 2 cycles for combination chemotherapy or 1, 2, or 3 for single agent).
Univariate and multivariate analyses for overall survival
Univariable analysis | Multivariable analysis | |||||
---|---|---|---|---|---|---|
|
| |||||
HR | 95% CI | p-value | HR | 95% CI | p-value | |
1.019 | 1.003–1.036 | 0.020 | 1.023 | 1.006–1.040 | 0.007 | |
| ||||||
1.015 | 0.999–1.030 | 0.059 | 1.016 | 1.000–1.032 | 0.054 | |
| ||||||
0.001 | 0.001 | |||||
| ||||||
I | 1 | 1 | ||||
| ||||||
II | 1.102 | 0.528–2.304 | 0.796 | 1.146 | 0.543–2.417 | 0.721 |
| ||||||
III | 2.015 | 0.941–4.316 | 0.071 | 2.211 | 1.028–4.759 | 0.042 |
| ||||||
IV | 2.255 | 1.040–4.890 | 0.039 | 2.410 | 1.108–5.241 | 0.026 |
| ||||||
< 0.001 | < 0.001 | |||||
| ||||||
SCC | 1 | 1 | ||||
| ||||||
AD/ADS | 2.337 | 1.540–3.548 | < 0.001 | 2.148 | 1.410–3.273 | < 0.001 |
| ||||||
Others | 4.550 | 1.440–14.372 | 0.010 | 5.855 | 1.802–19.031 | 0.003 |
| ||||||
| ||||||
Single agent | 1 | 1 | ||||
| ||||||
Combination | 1.279 | 0.917–1.784 | 0.147 | 1.256 | 0.876–1.800 | 0.215 |
| ||||||
| ||||||
Yes | 1 | 1 | ||||
| ||||||
No | 0.427 | 0.274–0.666 | < 0.001 | 0.426 | 0.270–0.671 | < 0.001 |
AD, adenocarcinoma; ADS, adenosquamous cell carcinoma; CCRT, concurrent chemoradiation; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; Others, small cell, clear cell, poorly differentiated carcinoma; SCC, squamous cell carcinoma.
Chemotherapy during CCRT,
Early discontinuation of chemotherapy during CCRT (e.g., 1 or 2 cycles for combination chemotherapy or 1, 2, or 3 for single agent).
Literature review of studies investigating waiting time in cervical cancer
Author | Year | No. | FIGO stage | Treatment | Definition of interval | Intervals (days) (No. of patients) | Effect on Survival |
---|---|---|---|---|---|---|---|
Perri et al. [ |
1999–2010 | 321 | I–IV | Surgery |
Bx to IT | ≤ 30 (134) |
No effect on 3-year survival |
Choan et al. [ |
1991–2001 | 195 | IB–IV | RT |
Bx to IT |
24 |
Adverse effect on DSS and OS |
Ferreira da Silva et al. [ |
2012–2014 | 865 | IA1–IVA | Surgery |
Bx to IT |
11 |
No survival outcome |
Nascimento et al. [ |
1995–2010 | 342 | I–IV | RT |
Bx to IT |
41 |
No survival outcome |
Umezu et al. [ |
1999–2010 | 117 | IA–IIA | Surgery | IV to IT | 48 |
No effect on DFS and OS |
Nanthamongkolkul and Hanprasertpong [ |
1996–2012 | 441 | IA2–IB1 | Surgery | CS to IT | ≤ 8 ws (284) |
Adverse effect on OS |
Chen et al. [ |
2004–2010 | 9,693 | I–IV | Surgery |
Bx to IT | ≤ 90 (9,431) |
Adverse effect on OS |
Benard et al. [ |
1996–2002 |
543 |
NA | NA | IV to Dx/Dx to IT | 33 |
No survival outcome |
AT, additional therapy; Bx, biopsy; CCRT, concurrent chemoradiation; CS, clinical staging; DFS, disease free survival; DSS, disease specific survival; Dx, diagnosis; EUA, examination under anesthesia; FIGO, International Federation of Gynecology and Obstetrics; IT, initial therapy; IV, initial visit; NA, not available; OS, overall survival; RO, radiation oncology consultation; RT, radiotherapy; TE, therapy end time.
Median value.