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Impact of Adoption of Chemoradiotherapy on the Outcome of Cervical Cancer in Ontario: Results of a Population-Based Cohort Study

Robert Pearcey, Qun Miao, Weidong Kong, Jina Zhang-Salomons, William J. Mackillop

From the Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Ontario; and the Cross Cancer Institute, Edmonton, Alberta, Canada

Address reprint requests to W.J. Mackillop, MD, Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, 10 Stuart St, Level 2, Kingston, Ontario K7L 3N6 Canada; e-mail: william.mackillop{at}krcc.on.ca

	ABSTRACT

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Purpose: To describe the adoption of concurrent cisplatin-based chemoradiotherapy (C-CRT), and to evaluate its impact on the outcome of cervical cancer in Ontario.

Methods: We used a population-based cancer registry to identify the 4,069 patients with invasive carcinoma of the cervix diagnosed in Ontario between 1992 and 2001. We linked electronic records of treatment to the registry. We described time trends in the use of C-CRT, and we compared survival before and after widespread adoption of C-CRT.

Results: Over the study period, the proportion of patients treated with primary radical radiotherapy (RT) remained constant at approximately 42%. Between 1992 and 1998, less than 10% of RT cases received chemotherapy. Early in 1999, there was rapid adoption of C-CRT. Between 1999 and 2001, more than 60% of RT cases received C-CRT. There was a contemporaneous increase in overall 3-year survival from 71.1% in the 1995 to 1998 cohort to 75.9% in the 1999 to 2001 cohort (P = .03). There was no change in survival in patients treated with surgery alone. However, there was a significant increase in 3-year survival from 58.6% in the 1995 to 1998 cohort to 69.8% in the 1999 to 2001 cohort (P < .01) in the subpopulation of patients treated with primary RT ± chemotherapy.

Conclusion: The adoption of C-CRT was associated with a significant improvement in overall survival of cervical cancer at the population level. The magnitude of the benefit of C-CRT in the general population was consistent with the results of the relevant clinical trials.

	INTRODUCTION

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Surgery and radiotherapy (RT), either alone or in combination, have long been the standard treatments for cervical cancer, and the outcomes of treatment have changed little since the widespread introduction of megavoltage RT three decades ago.¹ There have been repeated efforts to increase the effectiveness of RT by adding concurrent chemotherapy.² Between 1989 and 2002, the results of eight trials of RT alone versus RT with concurrent cisplatin (C-CRT) were published, each involving different subgroups of patient stages, different regimens of cisplatin (with or without other drugs), and different RT regimens.^3-10 Five trials demonstrated significantly increased survival with C-CRT compared to that with RT alone.^5-9 Three trials had a negative result,^3,4,10 including one published in 2002 by the National Cancer Institute of Canada (NCIC; Toronto, Ontario).¹⁰ It remains unclear why the results of this trial differed from those of the five positive-result trials,^11,12 although it may simply have been underpowered, and this failed to achieve statistical significance. Two meta-analyses confirmed the benefit of C-CRT.^13,14

In 1999, the National Cancer Institute (NCI; Bethesda, MD) released a clinical announcement citing the results of the five positive trials, and recommending that [strong consideration should be given to adding chemotherapy to radiation therapy in the treatment of invasive cervical cancer.]¹⁵ The Program in Evidence-Based Care of Cancer Care Ontario (CCO) later also published a guideline recommending C-CRT for selected cases despite the negative results of the multicenter Canadian trial.¹⁶ Although there is now little argument about the efficacy of C-CRT in the clinical trials context, the generalizability of cancer clinical trial results to the population at large cannot be taken for granted.¹⁷ There is evidence from other contexts that guidelines alone do not necessarily change practice,^18,19 and there is no information available about the extent to which CRT for cervical cancer has been adopted. Adoption requires not only that doctors intend to provide the new treatment, but also that the treatment is widely available, that cases are correctly selected, and that the treatment is correctly prescribed and delivered.¹⁹ Furthermore, adoption is necessary, but not sufficient for generalizability, because the subpopulation of patients involved in randomized trials may not be representative of the population as a whole.^20,21 Therefore, we undertook this phase IV population-based cohort study to describe the adoption of C-CRT, and to examine its impact on the outcome of the cervical cancer in the general population.

	METHODS

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Study Design
We carried out a retrospective, population-based cohort study of the management and outcome of cervical cancer in the Canadian province of Ontario.

Sources of Data
The Ontario Cancer Registry (OCR) is a population-based registry that covers the province's entire population of approximately 11.6 million people.²² The OCR provided the following information: International Classification of Disease, version 9 (ICD-9) code; the International Classification of Disease for Oncology (ICD-O) histology code; date of diagnosis; date of birth; place of residence at diagnosis; vital status; date of death; and cause of death. Complete information about vital status was available only up to the end of 2002. The OCR does not compile information about extent of disease or treatment.

We linked additional electronic records of treatment to the OCR. The Canadian Institute of Health Information (CIHI) provided information about surgical procedures and hospital admissions. Over the study period, hospital participation in collection of separation records was consistent, and complete throughout Ontario.²³ The eight regional cancer centers and the Princess Margaret Hospital (PMH) in Toronto, which were the only providers of RT in Ontario, provided RT electronic records including type of treatment machine, total dose, number of fractions, dates of first and last treatment, body region irradiated, and treatment intent. This database is known to be 95% complete and 99% accurate with respect to these variables.²⁴ Detailed chemotherapy records were provided by eight provincial regional cancer centers. Most of these chemotherapy records were captured automatically at the point of prescription through the center's information system and were, therefore, of high quality. Unlike the RT system, much of the chemotherapy in Ontario is provided by medical oncologists who are not associated with a regional cancer center, but to our knowledge, when chemotherapy is administered concurrently with RT, it is always provided at a CCO regional cancer center or PMH. Indicators of the socioeconomic status of the community in which patients resided at time of diagnosis were linked to the OCR, as described previously.²⁵

Study Population
All cases of invasive cervical cancer diagnosed in Ontario between January 1, 1992, and December 31, 2001, were identified by the OCR. Microinvasive carcinoma was not included.²⁶ Patients with sarcoma, melanoma, neuroendocrine carcinoma, and small-cell carcinoma were excluded. A small number of patients diagnosed without microscopic confirmation on the basis of death certificate only were also excluded. The remainder were classified into four groups: squamous carcinoma, adenocarcinoma, poorly differentiated carcinoma, and poorly characterized carcinoma. Adenosquamous carcinoma was included here with adenocarcinoma.

Definition of Initial Management
Initial management was first classified as [surgery,] [combined surgery and RT] (time between surgery and RT 3 months irrespective of sequence), [curative RT,] and [no curative treatment.] Within the curative RT group, all patients who also received chemotherapy within 3 months of RT were assigned to the CRT group. If the courses of RT and chemotherapy overlapped, treatment was considered to be concurrent. Chemotherapy completed before the start of RT was classified as neoadjuvant. Chemotherapy started after completion of RT was classified as adjuvant.

Survival
Three-year overall survival was calculated for each of the three cohorts and dates from the time of diagnosis.

Statistical Analysis
Statistical analyses were done using SAS 8.2 (SAS Institute, Cary, NC) for Sun Solaris (Sun Microsystems, Santa Clara, CA) and S-Plus 7.0 (Insightful Corp, Seattle, WA) for Windows (Microsoft Corp, Redmond, WA). The Mantel-Haenszel ² test was used to compare the change of proportions of patients diagnosed with invasive cervical cancer by age, histology group, and socioeconomic status. Patients’ overall survival was estimated with Kaplan-Meier product-limit method and the survivals at different time periods were compared with log-rank tests.

Key Quality Indications for RT
We measured the important factors known to influence outcome in patients treated by curative RT to determine whether there were differences between the different cohorts in this regard. Factors analyzed included radiotherapy dose (both external beam and brachytherapy), proportion of patients treated by brachytherapy, overall treatment time, and delay in starting treatment.

	RESULTS

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Patients
Table 1 shows the characteristics of the 4,069 cases of cervical cancer diagnosed in Ontario between 1992 and 2001.

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. The uptake of chemoradiotherapy for cervical cancer in Ontario. The histogram illustrates the proportion of radiotherapy cases who also received chemotherapy in each calendar year between 1992 and 2001. Dates of key publications are indicated with arrows. NCI, National Cancer Institute; ChemoRT, concurrent chemoradiotherapy.

Key Quality Indicators for Curative RT
There was no significant change in the way that curative RT was delivered before and after 1999. Most patients (88%) received both external-beam RT and brachytherapy. All external beam RT was administered with high-energy photons, and the majority of patients received 46 to 50 Gy in 26 to 28 fractions. The mean dose was 45.752 Gy before 1999, and 46.095 Gy after 1999 (P = .74). Among those who received brachytherapy, 83.3% received one application at the low-dose rate (LDR) with a median dose of 35 Gy to point A; 7.8% received two applications at the LDR with a median dose of 40 Gy; and 8.4% received three applications at the high-dose rate (HDR) with a median dose of 24 Gy. There was no significant difference in the proportion of patients receiving brachytherapy before 1999 (88.4%) and after 1999 (89.3%; P = .70). The mean brachytherapy dose was 32.94 Gy before 1999, and 33.253 Gy after 1999 (P = .74). The mean overall duration of RT was 45.5 days before 1999 and 44.8 days after 1999 (P = .27). There was a small increase in median waiting time from diagnosis to start of RT from 43 days before 1999 to 49 days after 1999 (P .01).

There was also no significant difference in the curative RT prescription between the RT only and CRT groups between 1999 and 2001. The mean dose of external-beam RT administered was 45.604 Gy without chemotherapy, and 46.621 Gy with chemotherapy (P = .2). The mean brachytherapy dose was 32.687 Gy without chemotherapy, and 32.974 Gy with chemotherapy.

Outcomes
Survival. Figure 2 illustrates temporal trends in survival for the entire cervical cancer population of Ontario, and for each of the main treatment groups. Three-year overall survival for this population remained stable between 1992 and 1998, but increased significantly from 71.1% in the 1995 to 1998 cohort to 75.9% in the 1999 to 2001 cohort (P = .03). There was no significant change in survival in the surgery group (P = .69), but there was a significant increase in survival in the curative RT group from 58.6% in the 1995 to 1998 cohort to 69.8% in the 1999 to 2001 cohort (P < .01). There was also an increase in 3-year survival among those who received surgery plus RT from 83.6% in the 1995 to 1998 cohort to 94.4% in the 1999 to 2001 cohort, but this was not statistically significant (P = .20).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Survival of cancer of the cervix in Ontario before and after the widespread adoption of radiochemotherapy. The four panels illustrate the overall survival of three cohorts of incident cases in Ontario. (A) Patients treated with surgery; (B) those treated with radiotherapy (RT); and (C) those treated with combined RT and surgery. (D) Survival of all incident cases, regardless of treatment.

However, in the following 21 months (between 3 months and 2 years post-treatment), there was a significant reduction in the proportion of patients admitted from 42.7% in the 1997 to 1998 cohort to 34.1% in the 1999 to 2000 cohort (P = .03). There was also a marginally significant reduction in the mean total time spent in hospital from 12.8 days in the 1997 to 1998 cohort to 8.9 days in the 1999 to 2000 cohort (P = .06). We had initially intended to use admissions over this period as a surrogate measure to late toxicity, but analysis of admitting diagnoses showed that the majority of these admissions were for the management of recurrence or progression of the cancer rather than toxicity (data not shown).

	DISCUSSION

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We observed rapid adoption of C-CRT in the management of cervical cancer in Ontario shortly after the dissemination of the results of five important clinical trials and the NCI alert.^5-9,15 The increase from 10% to 60% in proportion of curative RT cases receiving chemotherapy was associated with a statistically significant 4.8% increase in 3-year survival in the overall population of cervical cancer patients in Ontario. Our results strongly suggest that the observed improvement in survival was a consequence of the adoption of CRT.

We recognize that it is notoriously difficult to attribute an observed change in outcome to a specific change in practice based on the results of a retrospective study that relies on historical controls.²⁶ The first major problem is that the comparability of the treatment groups may be compromised by treatment selection bias and/or referral bias.²⁶ Moreover, attempts to control for overt differences in case mix by multivariate analysis may be inadequate to deal with this problem, because there may also be invisible differences between the groups and the phenomenon of stage migration.²⁷ This study, however, differs fundamentally from typical retrospective reviews in that we did not focus on the outcomes in the treated subpopulation, but instead compared outcomes in the overall population before and after adoption of the new treatment. The case mix in this type of study can change only if there is a real change in the spectrum of cases at the population level.^28,29 Although we lacked the information necessary to confirm that the pre- and postadoption cohorts were comparable with respect to all known prognostic factors, it is highly improbable that case mix changed in the very short interval over which we observed both the change in practice and the change in outcome. We are unaware of any changes in screening or diagnostic practices in Ontario that might have altered the stage distribution at diagnosis over this period. Pap screening has been widely used in Ontario since the 1970s, and the incidence of invasive cervical cancer in the province continued to decrease steadily in the 1990s.³⁰ However, although increasing the use of screening reduces the incidence of invasive cervical cancer, it has not been shown to influence survival among patients with invasive cancer.^31,32 We have previously shown that patients with cervical cancer who reside in poorer communities in Ontario have a significantly poorer survival,²⁵ but we found no difference in socioeconomic status between the pre–and post–C-CRT-adoption cohorts.

The second major problem inherent to the use of historical controls is that any change in outcome that is observed may have been caused by a change in some aspect of patient care other than the intervention targeted for evaluation. We, therefore, looked for any changes in patient care other than in the use of chemotherapy that might have affected survival. We found that the improvement in outcome was confined to patients who received radiotherapy, and that the proportions of patients treated with RT and surgery did not change over the study period. We, therefore, explored the details of radiation treatment before and after 1999, with emphasis on those aspects of RT that are known to be associated with local control and survival.

The outcome of curative RT for cervical cancer may be improved by the inclusion of brachytherapy,³³ but we found no difference in the proportion of patients receiving brachytherapy before and after 1999. Higher total doses of RT may also improve outcomes, but there was no difference in the dose of external beam or brachytherapy between the pre–and post–CRT-adoption cohorts. The outcome for patients treated with protracted courses of RT is inferior to that of those treated without treatment breaks,³⁴ and it has been suggested that the greatest benefit from CRT may occur in the former group.³⁵ However, we found no difference in overall treatment time before and after 1999, and, indeed, the duration of RT was consistent with good medical practice throughout the study period. Low hemoglobin during RT may be associated with poorer survival,³⁶ but we are not aware of any change in transfusion policy or the use of erythropoietin before and after 1999, which might have translated into the observed improvement in outcome. Waiting lists for cancer treatment have been a recurrent problem in Ontario during the last two decades, and longer waiting times for RT for cervical cancer have been shown to be associated with poorer outcomes.³⁷ We considered the possibility that the improvement in survival might have resulted from shorter waiting times in the post–CRT-adoption cohort, but found that waiting times were actually somewhat longer after 1999.

We also explored the possibility that the improvement in survival associated with adoption of CRT might have been achieved at the expense of increased toxicity. We did not have access to direct measures of toxicity and, therefore, had to rely on hospital admissions as a surrogate for toxicity. The administration of chemotherapy was on an outpatient basis, and the majority of admissions during treatment and immediately after were for surgery, brachytherapy, or acute complications of treatment. After adoption of CRT, there was a trend toward patients spending slightly longer in hospital during treatment and in the following 3 months. We speculate that this might be due to increased acute toxicity. The increase in the time spent in hospital during treatment was offset by a significant decrease in the time spent in hospital in the subsequent 21 months. We found no evidence that the introduction of CRT increased late complication rates.

As in other studies that rely heavily on administrative data,³⁸ the questions we were able to address here were circumscribed by our limited access to information. We evaluated adoption of CRT in the eight regional cancer centers, but we lacked the chemotherapy data from one large cancer hospital, which would have enabled us to study adoption at the population level. Complete information about vital status in the OCR is out-of-date and we were, therefore, able to describe only survival at 3 years; further follow-up will be necessary to quantify the long-term benefits of C-CRT. We were unable to describe the appropriateness of case selection for C-CRT for lack of information about the extent of the disease, and comorbidity.

Despite its limitations, this study provides clear evidence to our knowledge of the effectiveness of C-CRT in routine practice and provides a model for further phase IV studies of the effectiveness of cancer treatment. This type of evaluation is increasingly being used in other contexts,³⁹ and may in future prove to be particularly useful in evaluating the societal benefits of cancer treatments that demonstrated only a modest degree of efficacy in phase III trials. The results of the present study will perhaps lay to rest concerns that C-CRT might really be less effective in the context of Canadian RT practice.²⁹ It is both interesting and commendable that the practice of Canadian doctors appears to have been guided by the overall positive results of the relevant clinical trials, rather than the negative result of the NCIC trial.

We conclude that the adoption of C-CRT for cervical cancer resulted in a significant improvement in overall survival at the population level. The magnitude of the observed effect was consistent with that which would be predicted on the basis of the results of the clinical trials that led to the change in clinical practice.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: William J. Mackillop

Collection and assembly of data: Weidong Kong, Jina Zhang-Salomons

Data analysis and interpretation: Robert Pearcey, Qun Miao, Weidong Kong, Jina Zhang-Salomons

Manuscript writing: Robert Pearcey, Qun Miao, William J. Mackillop

Final approval of manuscript: Robert Pearcey, William J. Mackillop

Other: Jina Zhang-Salomons

	NOTES

 
Supported by the Ontario Cancer Research Network (W.J.M.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted October 3, 2006; accepted March 19, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pearcey, R. Articles by Mackillop, W. J. Search for Related Content PubMed PubMed Citation Articles by Pearcey, R. Articles by Mackillop, W. J.