Timing of Adjuvant Chemotherapy and Survival in Patients with Stage II/III Rectal Cancer ()
1. Introduction
The National Institute of Health (NIH) Consensus Conference in 1990 established surgical resection of adenocarcinoma of the rectum followed by chemo-radiotherapy as the recommended treatment for patients diagnosed with stage II or III disease [1]. This guideline was based on the results of several large randomized controlled trials [2-4] and became the standard of care for patients with stage II/III rectal cancer in the United States. More recent studies have shown that pre-operative (neoadjuvant) chemoradiotherapy significantly reduces local recurrence rates [5-9] and improves disease-free survival among stage II/III rectal cancer patients [9,10]. The majority of the patients in the clinical trials initiated adjuvant treatment within 6 weeks after surgery; this may not be easy to achieve in practice due to post-operative complications and/or healthcare system limitations. The optimum timing for adjuvant treatment initiation for surgically resected stage II/III rectal patients, therefore, remains unclear.
In Alberta, Canada, the recommendation for patients diagnosed with stage II/III rectal adenocarcinoma is neoadjuvant radiation with or without chemotherapy and/or adjuvant chemotherapy with or without radiation; the minimum recommended treatment is, therefore, surgery plus adjuvant chemotherapy. Adjuvant chemotherapy should be initiated within twelve weeks of surgery. These guidelines are consistent with current ones from the National Comprehensive Cancer Network [11] and European Society for Medical Oncology [12].
The goals of this study are to: 1) Describe treatment patterns of patients diagnosed with stage II/III rectal cancer between 2000 and 2005; 2) Estimate the proportion of patients receiving adjuvant chemotherapy within 12 weeks after surgery; 3) Identify patient/clinical characteristics associated with receipt of adjuvant chemotherapy within 12 weeks after surgery; and 4) Investigate the association between the timing of adjuvant chemotherapy and survival of patients diagnosed with stage II/III rectal cancer.
2. Methods
2.1. Study Population and Inclusion Criteria
The province of Alberta has approximately 3 million residents; about two-thirds live in Edmonton or Calgary, the two largest cities. The province provides universal, publicly-funded health care system for its residents. Standard cancer treatments are free to patients as are associated visits to cancer facilities, including consultations with oncologists. Physicians and hospitals are legally required to report every cancer case they diagnose to the Alberta Cancer Registry, a member of the North American Association of Comprehensive Cancer Registries. The Alberta Cancer Registry, established in 1942, is routinely recognized for the high quality and completeness of its data [13].
All residents of Alberta diagnosed in 2000 to 2005 with stage II or III rectal adenocarcinoma (International Classification of Diseases for Oncology (ICD-O) [14] code c19 and C20) were identified from the Alberta Cancer Registry. Patients were excluded if they did not receive surgery, died within 16 weeks of their surgery, were diagnosed with another primary cancer 6 months prior or subsequent to their rectal cancer diagnosis, did not have histologically confirmed adenocarcinoma, or were treated outside of Alberta. Cancer staging was based on the TNM (Tumor, Node, and Metastasis) system from the American Joint Committee on Cancer (AJCC version 6) [15]. Local invasive tumors (T3-4) that have not spread to regional lymph nodes (N0) or distant metastatic sites (M0) were defined as stage II. Invasive tumors of any size (T1-4) that have spread to at least one regional lymph node (N1-2) but not to distant metastatic sites (M0) were defined as stage III.
2.2. Data Sources
Data were linked from four different data sources: Alberta Cancer Registry, Ambulatory Care Classification System (ACCS), Discharge Abstract Database (DAD), and the 2001 Canadian census. The Alberta Cancer Registry is responsible for recording and maintaining data on all cancer cases and cancer deaths in Alberta. Patient demographics, tumor histology and stage, postal code of residence at diagnosis, initial treatment modalities and start dates, and date of death, if deceased, were obtained from the Alberta Cancer Registry. Mortality data are updated monthly using provincial vital statistics; cause of death is verified by the Alberta Cancer Registry using the International Classification of Disease (ICD-10) coding rules [16].
The ACCS and DAD databases contain diagnosis and procedure codes on all outpatient and inpatient hospital visits, respectively, in the province of Alberta. All hospital visits that occurred in the year prior to the patient’s cancer diagnosis were used to identify co-morbidities using an enhancement [17] to the Charlson Co-morbidity Index [18].
The 2001 Canadian census was used to obtain socioeconomic indicators at the neighborhood level (census dissemination areas) for each patient. Four variables were used as measures of the neighborhood socioeconomic status: 1) Median income; 2) Proportion of employment; 3) Proportion separated, divorced, or widowed; and 4) Proportion not graduated from high school.
2.3. Statistical Analysis
Descriptive statistics were calculated and Chi-square or Fisher’s Exact tests, as appropriate, were used to assess associations between patient/clinical characteristics and treatment regimen received. Treatment was categorized as: “Adjuvant treatment only” if post-operative chemotherapy with or without radiotherapy was received without any pre-operative treatment; “Neoadjuvant treatment only” if radiotherapy with or without chemotherapy was received prior to surgery, without any post-operative treatment; “Neo + adjuvant treatment” if both neoadjuvant and adjuvant treatment, as defined above, were received; and “Other treatment” if curative surgery or surgery followed by radiation therapy was received.
Time from the date of surgery to the date of first adjuvant chemotherapy session was calculated and patients were categorized into the following four groups for statistical analysis: received adjuvant chemotherapy within 8 weeks after surgery; 8 - 12 weeks after surgery; 12 - 16 weeks after surgery; or no adjuvant chemotherapy within 16 weeks of surgery. This latter group includes patients who received one of: 1) Adjuvant chemotherapy more than 16 weeks after surgery; 2) Neoadjuvant treatment (chemotherapy and/or radiotherapy) plus surgery; 3) Surgery plus adjuvant radiotherapy but no adjuvant chemotherapy; or 4) Only surgery. The outer limit of 16 weeks for adjuvant chemotherapy was determined based on expected clinical practice and previous studies [19]. These categories were used to evaluate the association between timing of adjuvant chemotherapy initiation and patient survival.
Kaplan-Meier curves were used to describe patient survival stratified by time from surgery to adjuvant chemotherapy. Cumulative incidence curves were used to describe the cumulative mortality due to rectal cancerspecific deaths, treating other causes of death as competing risk [20]. The Kaplan-Meier and cumulative incidence curves were started at 16 weeks after surgery. Deaths prior to this starting time were not included in the analysis as this is the earliest time point that allows all “time from surgery to adjuvant chemotherapy” groups to be defined.
Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) of overall and cancer-specific mortality by time from surgery to adjuvant chemotherapy (time dependent covariate), starting at 16 weeks after surgery. In order to closely adjust for age at diagnosis, a natural cubic spline of age at diagnosis was used with four knots [21]. Test for trends were performed for time to adjuvant chemotherapy and year of diagnosis; p-values were calculated adjusting for all variables in the model. Patients were followed to the first event of death or March 31, 2009.
All statistical analyses were conducted using SAS statistical software version 9.2 (SAS Institute, Cary, NC, USA) and R version 2.9 (R Foundation for Statistical Computing, Vienna, Austria).
3. Results
There were 1394 residents of Alberta diagnosed with stage II or III rectal cancer in the years 2000 to 2005. The following number of patients were excluded from the study based on the exclusion criteria described above: 40 patients did not have surgery; 50 patients were diagnosed with another cancer within six months prior or subsequent to their rectal cancer diagnosis; 14 patients did not have histological confirmation of their disease; 6 patients had a histology other than adenocarcinoma; 1 patient was treated outside of Alberta; and 40 patients died within 16 weeks after surgery. The remaining 1243 patients were included in the study.
Table 1 shows the baseline characteristics of the 1243 patients included in the study stratified by type of treatment received. Overall, 473 (38%) of the stage II/III rectal cancer patients had surgery only or surgery followed by radiotherapy without post-operative chemotherapy, 134 (11%) received neoadjuvant treatment only, 501 (40%) received adjuvant treatment only, and 135 (11%) patients received both neoadjuvant and adjuvant treatment. The “neoadjuvant + adjuvant” and “adjuvant only” groups (51%) include the patients who had treatment consistent with guidelines whereas the other two groups (49%) include the patients who did not receive treatment consistent with treatment guidelines.
Treatment differed by stage (p < 0.001); 61% of patients diagnosed with stage II rectal cancer received incomplete treatment, 431 (91%) received surgery only and the remaining 42 (9%) patients received radiotherapy prior to surgery without chemotherapy. Conversely, 11% of the patients with stage III rectal cancer received both neoadjuvant treatment and adjuvant chemotherapy and 53% received adjuvant treatment that includes chemotherapy only. Higher co-morbidity scores, older age, and living in lower socioeconomic neighborhoods were each associated with lower rates of both preand post-surgical treatment (Table 1).
Table 2 shows the demographic, clinical, and neighborhood-level socioeconomic characteristics of patients stratified by time from surgery to the receipt of adjuvant chemotherapy. Stage II rectal cancer patients, those aged 75 years and older, and those with two or more severe co-morbidities were least likely to receive adjuvant chemotherapy or receive it within 12 weeks of surgery. Lower rates of adjuvant chemotherapy were also seen among those who live in neighborhoods with a high percentage of divorced, separated or widowed, a low employment rate, low high school graduation rate, and/or a low median household income.
Figures 1 and 2 show the Kaplan-Meier and cumulative incidence curves for the overall survival and rectal cancer-specific mortality, respectively, by time from surgery to adjuvant chemotherapy. In Figure 2, the rectal cancer-specific mortality appears to be grouped into two groups: 1) Those who did not receive adjuvant chemotherapy or received it 12 weeks or more after surgery; and 2) Those who received it within 12 weeks. Those who received adjuvant chemotherapy within 12 weeks of their surgery had a considerably lower rectal cancerspecific mortality compared to those who did not receive it (Figure 2).
Table 3 presents the fit of the Cox proportional hazards models. The adjusted mortality HRs and corresponding 95% confidence intervals (overall and rectal cancerspecific) for patients with stage II/III rectal cancer were adjusted for all variables shown in the table. There was no difference in the overall or rectal cancer-specific mortality hazard for patients who received adjuvant chemotherapy 8 - 12 weeks after surgery relative to those who received it within 8 weeks. The rectal cancer-specific HR for patients who received adjuvant chemotherapy 12 - 16 weeks after surgery, compared to those who received it within 8 weeks after surgery, was 1.43 (95% confidence interval (CI) 0.81 - 2.53). This estimate was similar to the HR for those who received it 16 weeks after surgery or more or did not receive adjuvant chemotherapy, 1.58 (95% CI 1.09 - 2.30). The same group of patients also had a 1.68 times higher overall mortality hazard compared to those who received chemotherapy within 8 weeks after surgery (HR = 1.68, 95% CI 1.22 - 2.32).