Effect of treatment delay on survival in patients with cervical cancer: a historical cohort study.

ORIGINAL STUDY

Effect of Treatment Delay on Survival in Patients With Cervical Cancer A Historical Cohort Study Tamar Perri, MD,*Þ Gal Issakov, MD,*Þ Gilad Ben-Baruch, MD,*Þ Shira Felder, MD,Þþ Mario E. Beiner, MD,*Þ Limor Helpman, MD,*Þ Liat Hogen, MD,*Þ Ariella Jakobson-Setton, MD,*Þ and Jacob Korach, MD*Þ

Objective: The objective of this study was to evaluate the effect of treatment delay on prognosis in patients with cervical cancer. Methods: The study group of this historic cohort study comprised 321 patients newly diagnosed with cervical cancer between 1999 and 2010. Time from diagnosis to treatment was analyzed both as a continuous variable and as a categorical variable in 3 groups that differed in waiting time between diagnosis and treatment initiation: 30 days or less (group 1, n = 134), 30 to 45 days (group 2, n = 86), and more than 45 days (group 3, n = 101). Associations between waiting time group, patients’ characteristics, and disease outcome were investigated using t tests, analyses of variance and Cox regression analyses, KaplanMeier survival analysis, and log-rank (Mantel-Cox) tests. Results: Time from diagnosis to treatment initiation, when analyzed as a continuous variable, was not a significant factor in survival. There were no between-group differences in age, smoking rate, marital status, gravidity, parity, tumor histology, or lymph node involvement. Early-stage disease and small tumor diameter were diagnosed most frequently in group 3. However, there was no significant between-group difference in 3-year survival rates (74.6%, 82.2%, and 80.8% in groups 1, 2, and 3, respectively; P = 0.38). On multivariate analysis, only stage, histology, and lymph node involvement were significant prognostic factors for survival. Before starting treatment, 28 patients underwent ovarian preservation procedures. Conclusions: Longer waiting time from diagnosis to treatment was not associated with worse survival. Our findings imply that if patients desire fertility or ovarian preservation procedures before starting treatment, it is acceptable to allow time for them. Key Words: Cervical cancer, Treatment, Delay, Prognosis Received May 4, 2014, and in revised form May 9, 2014. Accepted for publication May 9, 2014. (Int J Gynecol Cancer 2014;24: 1326Y1332)

*Department of Gynecologic Oncology, Sheba Medical Center, Tel Hashomer, and †Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, and ‡Division of Oncology, Sheba Medical Center, Tel Hashomer, Israel. Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000211

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Address correspondence and reprint requests to Tamar Perri, MD, Department of Gynecologic Oncology, Sheba Medical Center, 52621 Tel Hashomer, Israel. E-mail: [email protected]. Drs Perri and Issakov contributed equally to this work. This work was performed in partial fulfillment of the MD thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University, Israel. No financial support was given to this study. The authors declare no conflicts of interest.

International Journal of Gynecological Cancer

& Volume 24, Number 7, September 2014

Copyright © 2014 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.



of the cervix is the second most common cancer C arcinoma affecting women worldwide. Treatment is usually either 1

chemoradiation or radical hysterectomy/trachelectomy with lymph node dissection in early stages and chemoradiation in advanced stages. In many institutions, patients experience a delay between diagnosis and initiation of treatment. Waiting times for surgery or radiation can be long. In general, long waiting times are associated with poor access to services and poor quality of care.2,3 However, delays can also be due to requests for a second opinion or time-consuming pathologist

Treatment Delay in Cervical Cancer

reviews that might affect treatment.4 In addition, the high incidence of cervical cancer at early age has led to revised treatment strategies in young cancer patients, and many institutes consider different methods for preservation of fertility or ovarian function, including ovarian transposition and/or ovarian stimulation and oocyte retrieval prior to initiation of cancer treatment.5Y7 These procedures might lead to an intentional delay in treatment of the primary disease. The effect of treatment delay on the risk of recurrence and mortality is a matter of concern to both patients and physicians.8

TABLE 1. Demographic and clinical characteristics of the 321 patients by wait-time groups Waiting Time From Diagnosis to Treatment Variables Age, mean T SD, y Smoking, n (%) Marital status, n (%)

Gravidity, n (%)

Parity, n (%)

Stage, n (%)

Histology, n (%)

Tumor diameter, n (%)

Lymph nodes, n (%) Treatment, n (%)

Status, n (%) Recurrence, n (%)

No Yes Single Married Divorced Widowed 0 1Y3 4+ 0 1Y3 4+ Local early Bulky Local advanced Pelvic + distant Squamous cell carcinoma Adenocarcinoma Other G1 cm 1 to G2 cm 2 to G4 cm 94 cm Negative Positive Surgery Chemoradiotherapy Neoadjuvant Alive Deceased No Yes Persistent disease

Group 1: e30 d

Group 2: 30Y45 d

Group 3: 945 d

Total

45.7 T 11.6 68 (57.1) 51 (42.9) 9 (6.7) 96 (71.6) 21 (15.7) 8 (6.0) 12 (9.2) 73 (55.7) 46 (35.1) 14 (10.4) 103 (76.9) 17 (12.7) 53 (39.6) 45 (33.6) 14 (10.4) 22 (16.4) 107 (79.9)

47.5 T 13.7 55 (67.9) 26 (32.1) 5 (5.8) 65 (75.6) 10 (11.6) 6 (7.0) 7 (8.5) 40 (48.8) 35 (42.7) 9 (10.5) 63 (73.3) 14 (16.3) 38 (44.2) 26 (30.2) 10 (11.6) 12 (14.0) 68 (79.1)

46.8 T 13.9 60 (65.2) 32 (34.8) 13 (13.3) 61 (62.2) 18 (18.4) 6 (6.1) 7 (7.5) 55 (59.1) 31 (33.3) 13 (13.3) 68 (69.4) 17 (17.3) 57 (56.4) 16 (15 .8) 19 (18.8) 9 (8.9) 75 (74.3)

46.5 T 12.9 183 (62.7) 109 (37.3) 27 (8.5) 222 (69.8) 49 (15.4) 20 (6.3) 26 (8.5) 168 (54.9) 112 (36.6) 36 (11.3) 234 (73.6) 48 (15.1) 148 (46.1) 87 (27.1) 43 (13.4) 43 (13.4) 250 (77.9)

13 5 4 9 27 43 59 21 37 37 12 62 24 62 21 3

21 (20.8) 5 (5.0) 10 (10.3) 13 (13.4) 38 (39.2) 36 (37.1) 63 (65.6) 33 (34.4) 49 (48.5) 46 (45.5) 6 (5.9) 77 (76.2) 24 (23.8) 75 (74.3) 19 (18.8) 7 (6.9)

57 14 16 30 94 168 209 92 138 129 54 227 94 225 75 21

23 (17.2) 4 (3.0) 2 (1.6) 8 (6.3) 29 (22.7) 89 (69.5) 87 (69.6) 38 (30.4) 52 (38.8) 46 (34.3) 36 (26.9) 88 (65.7) 46 (34.3) 88 (65.7) 35 (26.1) 11 (8.2)

(15.1) (5.8) (4.8) (10.8) (32.5) (51.8) (73.8) (26.3) (43.0) (43.0) (14.0) (72.1) (27.9) (72.1) (24.4) (3.5)

* 2014 IGCS and ESGO


(17.8) (4.4) (5.2) (9.7) (30.5) (54.5) (69.4) (30.6) (43.0) (40.2) (16.8) (70.7) (29.3) (70.1) (23.4) (6.5)

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The question of whether a delay between the diagnosis of cancer and its treatment has a negative effect on the patient’s clinical outcome has been examined in several malignancies, with conflicting results.9Y23 We found only 2 studies assessing the effect of waiting time on survival in cervical cancer patients. Umezu et al8 reported that waiting time from diagnosis to surgical intervention was not associated with adverse overall survival in early-stage cervical cancer, whereas Choan et al24 reported that delay in radiotherapy had a consistently adverse effect on survival regardless of the duration of delay. 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 in patients with cervical cancer treated with surgery or radiation or both.

PATIENTS AND METHODS The study was approved by the ethics committee of our medical center. All consecutive patients (N = 354) with cervical cancer stage IA2 to IVB who were treated in our institute between 1999 and 2010 were identified from our prospectively created database. Included in the study were all patients with a date of diagnosis recorded on a cervical biopsy pathology report, as well as a documented date of treatment start. Excluded were patients who were diagnosed during pregnancy (n = 4) or during hysterectomy for reasons other than cervical cancer (n = 4), or who did not continue treatment (n = 2), or for whom information was incomplete (n = 23). The remaining 321 patients constituted the study group. The collected data consisted of demographics, cancer and treatment characteristics, and clinical outcomes. Stage and grade were established according to the International Federation of Gynecology and Obstetrics.25 Treatment at stages IA2, IB, and IIA was either radical hysterectomy/radical trachelectomy with bilateral lymph node dissection or alternatively concurrent chemoradiation with platinum based regimen for radiosensitization. The latter treatment combination was administered to patients at stages IB2, IIB, III, and IVA. Treatment of patients at stage IVB included chemotherapy with whole-pelvic radiation for symptomatic relief. Adjuvant radiation was prescribed for patients who had undergone radical hysterectomy/trachelectomy but were found postoperatively to have lymph node metastases, close or involved surgical margins, or parametrial involvement,26 or if they had at least 2 of the following risk factors: deep stromal invasion, lymphovascular space invasion, or tumor diameter greater than 4 cm.27 Radiotherapy consisted of external beam radiotherapy to the pelvis with standard fractionation (1.8 Gy/fraction, 5 fractions/wk) to a total dose of 45 to 50.4 Gy, depending on tumor size. For nodal or parametrial involvement, a sequential or an integrated boost was added. In addition, all patients received intracavitary brachytherapy, consisting of high-dose-rate brachytherapy to a total dose of 24 Gy, delivered in 3 fractions. Waiting times were calculated from the date of diagnostic biopsy to the date of surgery or first neoadjuvant chemotherapy or chemoradiation. Waiting time was analyzed both as a continuous variable and as a categorical variable after patients were categorized into 3 groups based on the number of days between diagnosis and treatment initiation: 30 days or less (group 1, n =

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134), 30 to 45 days (group 2, n = 84), and more than 45 days (group 3, n = 101). Stages were grouped as local early (stages IB1 and IIB1), bulky (stages IB2 and IIA2), locally advanced (stages IIB2YIIIA), and pelvic side-wall involvement or metastatic (IIIBYIVB). Histology was grouped as squamous cell carcinoma and adenosquamous carcinoma (group 1), adenocarcinoma (group 2), and others, including small cell, clear cell, transitional cell, and glassy cell carcinomas (group 3). The duration of progression-free survival and overall survival was defined as the interval from the day of diagnosis to the date of event (disease recurrence or death). Patients without event by the end of the study were censored at the last date on which the patient had any contact with the health care system, as recorded in the administrative database. IBM SPSS Statistics for Windows, version 21.0 (IBM, Armonk, NY) was used for statistical analyses, which included Kaplan-Meier survival analysis and log-rank (MantelCox) tests. Cox proportional hazards regression models were used to assess associations between different characteristics and survival. A multivariable Cox model was constructed by using a forward stepwise selection process with an entry criterion of any factor found to be significant on univariate analysis, and waiting time was then added to the model to evaluate its significance after adjustment for all other factors. P G 0.05 was considered statistically significant. The power of the study to detect an effect of longer waiting times on clinical outcome is reported in Results.

RESULTS Mean age at diagnosis for the whole group was 46.5 T 12.9 years. Demographic and clinical characteristics of the 321 patients by wait-time groups are presented in Table 1. A total of 86 patients (26%) waited 30 to 45 days from the date of diagnosis to treatment initiation, and 101 (31%), of whom 28 had ovarian transposition surgery before treatment was initiated, waited more than 45 days. The 3 wait-time groups did not differ in mean age, smoking rate, marital status, gravidity, parity,

FIGURE 1. Mean overall survival in each of 3 wait-time groups, adjusted for age, stage, lymph node status, and histological type. * 2014 IGCS and ESGO





TABLE 2. Multivariate analysis of survival in 3 wait-time groups (e30 days, 30Y45 days, 945 days) Factor Stage IB1 and IIA1 IB2 and IIA2 IIBYIIIA IIIBYIVB Histology Squamous cell carcinoma Adenocarcinoma Other Lymph node involvement Age Wait time e30 d 30Y45 d 945 d

Hazard Ratio

95% Confidence Interval

Reference 1.16 4.08 5.57

0.60Y2.26 2.11Y7.88 2.85Y10.87

Reference 1.79 2.32 2.82 1.01

1.01Y3.18 0.90Y5.96 1.74Y4.56 0.99Y1.03

Reference 0.80 0.6

tumor histology, or rate of lymph node involvement. However, there was a significantly larger percentage of patients with local early disease as well as with small tumor diameter in group 3 (945 days’ wait) than in the other 2 groups. Three-year survival rates did not differ significantly between the 3 groups (74.6%, 82.2%, and 80.8% in groups 1, 2, and 3, respectively; P = 0.38). Overall survival is presented in Figure 1. Multivariate analysis revealed that the only significant prognostic variables for overall survival were stage, histological type, and lymph node involvement (Table 2). Waiting time was not found to be significant. Some patients waited as long as 60 days or more between diagnosis and treatment initiation, but multivariate analysis of survival in these patients (n = 48)

P G0.001

0.04

G0.001 0.26 0.207

0.46Y1.40 0.33Y1.06 compared with that of patients in group 1 also showed no significant effect of the longer waiting time (Table 3). A separate analysis was performed to compare the effects of waiting time on survival of patients diagnosed with earlier stages and those diagnosed with advanced stages of disease. Here too, 3-year survival rates did not differ between wait-time groups 1, 2, and 3 in patients diagnosed at an early stage (84.9%, 88.5%, and 90.4%, respectively; P = 0.617) or at an advanced stage (50%, 66.7%, and 61.5%, respectively; P = 0.422). When analyzed by treatment modality, no differences in overall survival were detected between wait-time groups 1, 2, and 3 either in patients who underwent surgery (84.2%, 92.1%, and 91.9%, respectively; P = 0.33) or in those

TABLE 3. Multivariate analysis of survival in 2 wait-time groups (e60 days, 960 days) Factor Stage IB1 and IIA1 IB2 and IIA2 IIBYIIIA IIIBYIVB Histology Squamous cell carcinoma Adenocarcinoma Other Lymph node involvement Age Wait time e60 d 960 d

Hazard Ratio

95% Confidence Interval

Reference 1.27 3.80 6.05

0.65Y2.46 1.97Y7.31 3.11Y11.78

Reference 1.67 2.34 2.857 1.01

0.94Y2.97 0.92Y5.98 1.61Y4.10 0.99Y1.03

Reference 1.02

0.54Y1.92

P G0.001

0.06

G0.001 0.34 0.94



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treated with chemoradiation (58.7%, 71.4%, and 70.7%, respectively; P = 0.37).

Power of Study The study group comprised 321 patients. This sample size would have been sufficient to detect a hazard ratio of 2 in death associated with longer waiting times, with the use of a 2-sided test and a significance level of 0.05.

DISCUSSION We could not detect an effect of the waiting time from diagnostic biopsy to initiation of treatment on the survival of patients with cervical carcinoma, regardless of the stage of disease at diagnosis or the treatment protocol (surgery or chemoradiation). A delay in treatment might be attributable to many factors, including availability of pretreatment evaluation such as imaging (positron emission tomographyYcomputed tomography), limited treatment resources (availability of radiation facilities), surgical scheduling, the ability to obtain funding (although this is not the situation in our country because there is a national insurance coverage for everybody at any stage). It can also result from a second-opinion request by the patient or the doctor, such as a pathology review that might alter treatment.4 Recent years have seen the introduction of ovarian function preservation, necessitating ovarian transposition surgery prior to starting radiotherapy, and even fertility treatments with ovarian stimulation and oocyte retrieval, as part of the flowchart of treatment in young women with cervical cancer. These procedures inevitably cause intentional delays in treatment. In our cohort, 28 patients chose to delay treatment in order to undergo ovarian transposition. Another possible cause of treatment delay is the incentive to correctly determine lymph nodes involvement by laparoscopy, an advantageous procedure even in the era of positron emission tomography imaging,28 and/or to perform laparoscopic tumor staging on locally advanced cervical cancer.29 The safety of any delay is of primary concern to both patients and physicians. The principal finding of this study was that the wait does not worsen prognosis. Our finding is in agreement with that of authors who have investigated various nongynecologic tumors and tumor sites, including colorectal,9 pancreas,10 acute myeloid leukemia,11 prostate,13 glioblastoma,14 bladder,17 glottic laryngeal carcinoma,20 and esophageal carcinoma.23 Findings in breast cancer patients are conflicting: McLaughlin et al12 found that prolonged waiting time had no effect on survival among early-stage patients, but led to significantly worsened overall survival among late-stage patients. However, Brazda et al,3 in a study of 1337 patients, found no effect of waiting time on survival when controlling for stage, and this finding was confirmed in a meta-analysis of high-quality studies of breast cancer.16 Waiting-time effect in gynecologic tumors has been investigated in only a few studies. Kirwan et al22 reported that delays in the referral or diagnosis of patients with ovarian cancer had no effect on survival at 18 months. Menczer et al19 found that survival in patients with endometrial cancers was not affected by a delay of 4 months in treatment. Moreover, Crawford et al18 described a ‘‘waiting time paradox’’ in which patients with the shortest delay in diagnosis had the worst survival rates. This could be

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explained in part by the observation that those treated within a shorter time had presented with more advanced disease, suggesting that tumor aggressiveness influences delay and that waiting time is a confounding factor in such cases. Patients with worse prognoses might often be considered to be higher priority and therefore have reduced waiting times. In a recent study by Elit et al,21 endometrial cancer patients who had waited less than 2 weeks between diagnosis and treatment initiation turned out to have the worst 5-year survival rates. In those patients, the rates of acute presentation and emergent/ weekend surgery were higher, and disease at diagnosis had been more advanced and had been characterized by a higher rate of histology types considered to be biologically aggressive (such as uterine sarcoma) than in patients with longer waiting times. However, in contrast to the previous reports, when patients who had waited no longer than 2 weeks were excluded, those with waiting times of more than 12 weeks had significantly worse survival rates than those who had waited 2.1 to 12 weeks.21 In our cohort, patients who had waited more than 45 days had smaller and earlier-stage tumors; however, even when we controlled for stage and size, waiting time in our study did not significantly affect survival. To the best of our knowledge, only 2 studies have explored the effect of waiting time between diagnosis and treatment initiation on survival in cervical cancer patients. Umezu et al8 reported on 117 cervical cancer patients in stages IA to IIA who were treated surgically. In agreement with our findings, rates of recurrence-free and overall survival in that study were not affected by the waiting time to surgery. In a report on 195 cervical cancer patients who underwent radiotherapy, Choan et al24 found that prolonged waiting times had a negative impact on overall and disease-specific survival (but not on disease progression rates). Although the stage distribution in our cohort was similar to that in the latter study, our overall survival rate was higher (70% vs 50%). Our study also included larger groups of patients at all stages and with different treatment protocols (surgery, radiation, neoadjuvant chemotherapy), and according to our results, waiting time did not affect survival in any treatment group (surgery or chemoradiation) or at any stage (early or advanced). Differences might be applied to different treatment protocols at our center, including different fractionation of radiotherapy with fewer treatments, each of a higher dose given at our center. Also, only 25% of their patients received concomitant chemotherapy as opposed to all our radiation-treated patients. Lymph node metastasis and the International Federation of Gynecology and Obstetrics stage are well-known prognostic factors in any tumor. Earlier studies30,31 suggested that histology has no prognostic significance in cervical carcinomas: squamous cell carcinoma and adenocarcinoma have similar prognoses. About 18% of the tumors in our cohort were adenocarcinomas, and patients with this histological type had a poor prognosis compared with patients with squamous cell carcinoma. This finding is in agreement with later reports.32Y34 Our finding is also supported by a recent report by Wright et al,35 who examined the genomic differences between cervical squamous cell carcinoma and adenocarcinoma. Both of these tumor types were found to have distinct molecular profiles, suggesting that novel treatment strategies such as PI3K and * 2014 IGCS and ESGO




MEK inhibition should be tailored to different histological subtypes in order to improve clinical outcome.35 Our study suffers from certain limitations. There is a complex relationship of different prognostic factors and reasons for treatment delay, and given the sample size, the power of this study was adequate only to detect a survival difference hazard ratio of 2. As such, our results do not provide assurance that treatment delay does not have an impact on overall survival. We can only conclude that twice the risk per unit time was not detected. Nevertheless, it is the largest study to date in which waiting time is assessed as a prognostic factor in patients with cervical cancer. Another limitation derives from the fact that this study was conducted in a single center, meaning that our experience is not necessarily always applicable to other practices. However, presenting the experience of a single institute experience does have a certain advantage: it allows comparison between patients who receive uniform treatment protocols for each stage and lymph node status, within the same facilities and by the same surgeons. This makes it possible to achieve an accurate evaluation of wait-time groups within that institute. The major limitation of the study is its retrospective nature; however, for ethical reasons, it is obviously not possible to conduct a waiting-time trial prospectively. Despite these limitations, our results indicate that the impact of tumor-related factors (stage, histology, lymph node status) on survival seems to be more powerful than waiting time. Larger-scale studies are needed to confirm our results and provide physicians with some guidance in counseling patients and their families about the safety issues involved in delaying the initiation of treatment for the purpose of tailoring the treatment according to individual needs. These might include allowing time for better planning, obtaining a second opinion, and, in young patients, even undergoing procedures for retaining ovarian function or preserving fertility.

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Clinical outcomes and resource utilisation in Medicare patients with chronic liver disease: a historical cohort study.

Elderly patients with colorectal cancer: treatment modalities and survival in France. National data from the ThInDiT cohort study.

Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies.

Impact of postdiagnosis smoking on long-term survival of cancer patients: the Shanghai cohort study.

Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies.

Analysis of treatment modalities and prognosis on microinvasive cervical cancer: a 10-year cohort study in China.