Clinical Investigation
Adjuvant Chemoradiation Therapy for Cervical Cancer and Effect of Timing and Duration on Treatment Outcome

https://doi.org/10.1016/j.ijrobp.2017.03.045Get rights and content

Purpose

Worse treatment outcomes can be expected with prolongation of the overall treatment time (OTT) during definitive chemoradiation therapy (CRT) for cervical cancer. In the adjuvant setting, data on the relative importance of the OTT and the importance of RT and chemotherapy synchronization are scarce. Using the National Cancer Database, we evaluated the effect of these treatment variables on overall survival in the adjuvant CRT setting.

Methods and Materials

The present analysis included nonmetastatic cervical cancer patients undergoing hysterectomy followed by adjuvant CRT. The proportional hazard model was used to estimate the effect of prognostic factors (age, comorbidity, race, tumor size, tumor grade, tumor histologic type, number of high-risk pathologic factors) and time-related variables (surgery to RT start interval [SR], OTT [RT start to end dates], package time [from diagnosis date to CRT end date] and optimum CRT synchronization [whether chemotherapy and RT start dates coincided]) on survival.

Results

Of 3051 patients, 60% finished RT within 7 weeks and 85% received optimum CRT. Among other factors, univariate analysis identified longer OTT (hazards ratio [HR] 1.33; P<.001), longer SR (HR 1.17; P=.05), and nonoptimum CRT timing (HR 1.21; P=.04) as poor prognosticators. Of these factors, SR (HR 1.20; P=.04) and OTT (HR 1.21; P=.002) retained significance on multivariate analysis. An OTT >7 weeks remained a significant factor even after propensity score matching (P=.04).

Conclusions

The results of our analysis suggest that prolongation of the adjuvant CRT duration >7 weeks is associated with poor survival and SR of <8 weeks should be attempted whenever clinically feasible.

Introduction

Cervical cancer is the fourth most common cancer in women worldwide (1), annually affecting 12,200 patients in the United States (2) and >500,000 patients worldwide (3). Adjuvant chemoradiation therapy (ACRT) is typically delivered after radical hysterectomy for early-stage (stage IB-IIA) cervical cancer in the presence of certain pathologic risk factors (4). High-risk factors such as positive lymph nodes, positive surgical margins, and/or parametrial invasion increase the recurrence risk by ≤40% (5). In the presence of these factors, ACRT improves both progression-free survival and overall survival (OS) compared with adjuvant RT alone (80% vs 63%, P=.003; and 81% vs 71%, P=.007, respectively) (6).

Various studies have established that prolongation of the overall treatment time (OTT) is an independent negative prognostic factor in the definitive treatment of cervical cancer 7, 8, 9, 10, 11, 12. The effect of OTT prolongation >8 weeks is even more pronounced for bulkier and higher stage disease 8, 10, 12. Among the potential factors, the rapid repopulation of cancer cells, which gains momentum at the end of the treatment, especially with an increased treatment duration, could possibly render the typical RT dose incapable of controlling the growing mass of rapidly dividing cancer cells 13, 14. However, certain studies have suggested that concurrent administration of CRT might hinder cancer cell repopulation and, potentially, remedy the detrimental effect of OTT prolongation 15, 16. A current Radiation Therapy Oncology Group (RTOG) protocol (RTOG study 1174) recognized a treatment duration extension >67 days as an unacceptable deviation. However, similar formalism is lacking in the current RTOG study 724 adjuvant protocol, in which the external beam phase of the treatment can be as long as 38 days, with the optional brachytherapy boost resulting in a 56- to 63-day treatment duration. The effect of the OTT, with or without chemotherapy, has not been well established in the postoperative management of cervical cancer, although it has been extensively described in the adjuvant management of other disease sites, for which OTT shortening is highly recommended 17, 18.

Moreover, the radiosensitization properties of concurrent chemotherapy and its synergistic tumoricidal effect might be closely related to the timing of its administration in relation to RT. The importance of synchronizing chemotherapy initiation with the start of RT has been poorly characterized in the published data. However, studies of other malignancies have shown that concurrent therapy is superior to sequential therapy 19, 20.

We hypothesized that any increase in time—whether from diagnosis to surgery (DS), surgery to ACRT (SR), or ACRT duration (OTT)—would be associated with a negative effect on the treatment outcome. Moreover, we tested the deleterious effect of nonsynchronous administration of chemotherapy and RT on the outcome of ACRT for cervical cancer. The National Cancer Database (NCDB) was used to validate this hypothesis in the community setting.

Section snippets

Study design

In 2016, our institutional review board granted the present study an exemption to query the NCDB database, which abstracts hospital registry data from >1500 accredited facilities that collect nearly 70% of newly diagnosed cancer cases nationwide under American College of Surgeons and American Cancer Society sponsorship (21). Of the 76,155 patients diagnosed with nonmetastatic, pathologically confirmed, single primary cervical cancer, those with data entered from 2004 through 2013 were included

Baseline characteristics

Of the 76,155 nonmetastatic cervical carcinoma patients, 9058 underwent surgical resection, followed by ACRT. After excluding potential outliers because the treatment could not be initiated within 3 months or the ACRT duration was excessively short (<4 weeks) or prolonged (>10 weeks), the study cohort included only 3051 patient with ≥1 documented pathologic high-risk factors to justify the ACRT approach.

In the present cohort, the median age was 46 years (interquartile range [IQR] 38-56, range

Discussion

For women receiving adjuvant concurrent CRT for high-risk cervical cancer, we hypothesized that, among other treatment-related variables, the prolongation of OTT might result in inferior survival. The results of the present analysis have confirmed our hypothesis. To the best of our knowledge, the present study is the first to examine the effect of DS, SR, OTT, chemotherapy/RT timing superposition, and total package time on survival in the postoperative CRT setting.

The detrimental effect of OTT

Conclusions

Adjuvant CRT for high-risk cervical carcinoma represents the epitome of multidisciplinary care and mandates the coordination of chemotherapy by gynecologists and RT by radiation oncologists, both delivered in concert and in a timely fashion after hysterectomy. Preventing undue delays to the start adjuvant therapy after radical hysterectomy, avoiding treatment breaks, keeping the OTT as short as possible, and ensuring the start of chemotherapy on the same day as RT are all crucial elements for

Acknowledgments

The National Cancer Database is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society and neither organization verified or is responsible for the analytic or statistical method used or the conclusions drawn from these data by us.

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