- Email: [email protected]
Trends in Chemotherapy Utilization for Colorectal Cancer
Original Contribution
Trends in Chemotherapy Utilization for Colorectal Cancer Daniel Renouf, Hagen Kennecke, Sharlene Gill Abstract Background: Since 1990, significant advances have occurred in the adjuvant and metastatic treatment of colorectal cancer (CRC). Not all patients may be eligible for chemotherapy (CT), and the proportions and characteristics of patients who receive treatment are not well defined. In this study, treatment patterns of patients referred to the British Columbia Cancer Agency (BCCA) with early-stage colon cancer and metastatic CRC between 1990 and 2004 are described. Patients and Methods: This study included patients with stage II or III colon cancer or stage IV CRC at presentation referred to the BCCA during a 1-year period for 3 time cohorts: 1990, 2000, and 2004. Patients were considered treated with CT if they received ≥ 1 cycle of any CT for indication of the initial referral diagnosis. Results: A total of 1421 patients were included: stage II/III, n = 915; stage IV, n = 506. Chemotherapy utilization increased significantly from 1990 to 2004 for adjuvant CT (1990: 29%; 2000: 45%; 2004: 52%; P < .001) and for palliative CT (1990: 35%; 2000: 51%; 2004: 63%; P < .001). The proportion of patients with stage II disease treated with adjuvant CT dramatically increased (1990: 4%; 2000: 26%; 2004: 30%; P < .001). The use of palliative CT was significantly associated with male sex (P = .025). Among older patients, only 25% received adjuvant CT, and 31% received palliative CT. Conclusion: In this population-based study, adjuvant and palliative CT utilization increased significantly between 1990 and 2004. The majority of patients aged > 70 years did not receive CT, and women appeared less likely to receive palliative CT. Such disparities in CT utilization require further investigation. Clinical Colorectal Cancer, Vol. 7, No. 6, 386-389, 2008; DOI: 10.3816/CCC.2008.n.051 Keywords: Adjuvant therapy, Palliation, Metastatic disease
Introduction Colorectal cancer (CRC) is the second leading cause of cancer-related death in North America and Europe. Since 1990, there have been numerous advances in the treatment of CRC in both the adjuvant and metastatic setting, with commensurate improvements in survival. In 1990, the National Institute of Health guidelines recommended adjuvant 5-fluorouracil–based chemotherapy for stage III colon cancer.1 Although the data supporting the benefit of adjuvant chemotherapy for patients with stage II disease is limited,2,3,4 it can be considered for selected patients with resected higher-risk node-negative disease.3 Since 2000, advances in chemotherapy for metastatic CRC (mCRC) have led to more effective and more tolerable treatment options. In addition, recent reports have confirmed that the magnitude of benefit achieved from advances in adjuvant therapy and metastatic disease are similar for older and younger patients with CRC.5,6 British Columbia Cancer Agency, Vancouver, Canada Submitted: Mar 17, 2008; Revised: Jul 3, 2008; Accepted: Jul 24, 2008 Address for correspondence: Daniel Renouf, MD, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC, Canada, V5Z 4E6 Fax: 604-877-0585; e-mail: [email protected]
Previous studies have examined how prescription patterns for CRC and utilization patterns in various subgroups (based on age and sex) have changed over time. Faiver-Finn et al examined the use of adjuvant and palliative chemotherapy over a 10-year period (1989-1998) in a French population.7 Overall, 4093 patients were included in the analysis, which demonstrated that chemotherapy utilization had increased in the adjuvant setting (for both stage II and stage III colon cancer) and in the metastatic setting. Chemotherapy was noted to be underprescribed in the elderly (age > 75 years). In 2005, Jessup et al reported changes in prescription patterns of adjuvant chemotherapy for stage III colon cancer.8 They analyzed data from 85,934 patients from the United States treated between 1990 and 2002 and concluded that chemotherapy prescription had increased but was less frequently prescribed in women and the elderly. Other studies have also found that adjuvant chemotherapy for colon cancer is underprescribed in the elderly.9,10 This practice is contrary to emerging data demonstrating equivalent benefits of adjuvant and metastatic disease among the elderly.5,6,11,12 The notable findings of these aforementioned studies raise concerns regarding optimal utilization of chemotherapy; however, they are unable to control for referral biases and access to care. This
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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• Clinical Colorectal Cancer November 2008
Table 1 Patient Characteristics Total Year 2004, n Patients, N (%)
Characteristic
Year 1990, n
Year 2000, n
Median Age (Years)
65
69
68
–
Disease Stage IIA
78
121
133
332 (23)
Disease Stage IIB
10
28
37
75 (5)
Figure 1 Prescribing Trends for Adjuvant Chemotherapy in Colon Cancer (P < .001) 80 70
No Chemotherapy Chemotherapy
71
60
55
50
83
141
284
508 (36)
Disease Stage IV
118
196
192
506 (36)
Male Sex
144
272
342
758 (53)
30
Female Sex
145
214
304
663 (47)
20
Total
289
486
646
1421
10
Percent
Disease Stage III
45
29
1990
Table 2 Characteristics of Patients with Resected Stage II or III Colon Cancer by Adjuvant Chemotherapy Status Chemotherapy (n = 413)
P Value
80 (16)
155 (37)
127 (25)
159 (38)
Age > 70 Years
295 (59)
99 (24)
Male Sex
251 (50)
202 (49)
NS
80
Disease Stage IIA
273 (54)
59 (14)
–
70
Disease Stage IIB
43 (9)
32 (8)
–
100
96
No Chemotherapy Chemotherapy
90
< .001
question had not been examined within a referred population in a setting of universal care access. The purpose of this study is to evaluate temporal changes in chemotherapy utilization patterns among patients with early-stage colon cancer and mCRC using a Canadian provincial patient cohort.
Patients and Methods British Columbia (BC) is a province with a population of approximately 4 million people. The BC Cancer Agency (BCCA) is the provincial cancer referral agency and includes 4 regional cancer centers. The BCCA develops provincial guidelines for the systemic treatment of CRC. Chemotherapy is funded by the provincial government as a component of Canadian universal healthcare access. In BC, approximately 60% of patients with CRC are referred to the BCCA for treatment. The remaining 40% receive treatment at community oncology centers. The vast majority of patients treated at the BCCA are BC residents. This study included all patients with stage II or III colon cancer or stage IV CRC at presentation referred to the BCCA during a 1-year period for 3 time cohorts: January 1, 1990, through December 31, 1990; January 1, 2000, through December 31, 2000; and January 1, 2004, through December 31, 2004. Patients were identified from the British Columbia Colorectal Cancer Outcomes Unit (CRCOU) database. The CRCOU collects data prospectively, starting at the time of initial consultation and subsequently on follow-up visits. Data fields collected include the patient’s sex, age, histologic diagnosis, primary tumor site, stage at referral (both clini-
Percent
322 (78)
< .001
Abbreviation: NS = not significant
2004
Figure 2 Proportion of Patients with Stage II Colon Cancer Treated with Adjuvant Chemotherapy (P < .001)
Age 61-70 Years
186 (37)
2000 Year
Age < 60 Years
Disease Stage III
52
40
0
Characteristic, No Chemotherapy n (%) (n = 502)
48
74
70
60 50 40 30
26
30
20 10
4
0
1990
2000
2004
Year
cal and pathologic), date of the initial BCCA consultation, and the date of the first cycle of chemotherapy. Chemotherapy treatment data was cross referenced with the provincial pharmacy database. Patients were considered to have been treated with chemotherapy if they received ≥ 1 cycle of chemotherapy for their initial diagnosis at the time of referral within 6 months of the date of initial consultation. The primary endpoints were (1) proportion of patients with resected stage II and/or III colon cancer prescribed adjuvant-intent chemotherapy in each time cohort and (2) proportion of patients with stage IV CRC prescribed palliative-intent chemotherapy in each time cohort. Predefined secondary endpoints included (1) proportion of patients with stage II disease treated with adjuvant chemotherapy; (2) proportion of patients treated with chemotherapy in different age groups (< 60 years; 61-70 years; > 70 years), in both the adjuvant and palliative settings; and (3) proportion of male/female patients treated with chemotherapy in both the adjuvant and palliative settings. Comparison of proportions treated within each relevant subgroup across the 3 time cohorts was performed using standard frequency statistics including t test and χ2 analysis as applicable.
Clinical Colorectal Cancer November 2008 •
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Chemotherapy Utilization for CRC Table 3 Characteristics of Patients with Metastatic (Stage IV) Colorectal Cancer by Palliative Chemotherapy Status Chemotherapy (n = 261)
Age < 60 Years
51 (21)
130 (50)
Age 61-70 Years
82 (34)
81 (31)
Age > 70 Years
112 (46)
50 (19)
Male Sex
113 (54)
167 (64)
P Value
70
65
< .001
.025
49
50 40
63
No Chemotherapy Chemotherapy
60
Percent
Characteristic, No Chemotherapy n (%) (n = 245)
Figure 3 Prescribing Trends for Palliative Chemotherapy in Metastatic Colorectal Cancer (P < .001)
51 37
35
30 20
Table 4 Prescribing Trends for Adjuvant and Palliative Chemotherapy in Patients Aged > 70 Years
10
Year 1990
Year 2000
Year 2004
Patients aged > 70 years
8
28
28
Total cohort treated, all ages
29
45
52
Patients aged > 70 years
15
24
45
Total cohort treated, all ages
35
51
63
Chemotherapy Adjuvant Chemotherapy, %
1990
2000
2004
Year
Palliative Chemotherapy, %
Results A total of 1421 patients were included: stage II/III (n = 915), stage IV (n = 506; Table 1). Chemotherapy utilization increased significantly from 1990 to 2004 for adjuvant chemotherapy (1990: 49 [29%]; 2000: 129 [45%]; 2004: 235 [52%]; P < .001; Figure 1). The proportion of patients with stage II disease treated with adjuvant chemotherapy also significantly increased over the 3 time cohorts (1990: 3 [4%]; 2000: 38 [26%]; 2004: 50 [30%]; P < .001; Figure 2). Our data indicate that a greater number of patients with stage IIB (T4 N0, “high risk”) were referred for adjuvant chemotherapy over time (Table 1). The proportion of these patients treated also increased over time (n = 0; 0% [1990]; 13, 46% [2000]; 19, 51% [2004]). This might in part explain the increased use of adjuvant chemotherapy for stage II colon cancer. Adjuvant chemotherapy utilization was directly associated with later time cohort and younger age of presentation (Table 2). Use of palliative chemotherapy increased significantly from 1990 to 2004 (1990: 41 [35%]; 2000: 100 [51%]; 2004: 120 [63%]; P < .001; Figure 3). Palliative chemotherapy utilization was directly associated with later time cohort and younger age of presentation (Table 3). In addition, palliative chemotherapy use was significantly associated with male sex (P = .025; Table 3). This sex difference was not observed in the adjuvant setting. The use of chemotherapy in older patients (> 70 years) is presented in Table 4.
Discussion Since 1990, indications for adjuvant chemotherapy have expanded as have the treatment options for mCRC. In order for advances in therapy to translate into improvements in population-based outcomes, eligible patients need to receive the appropriate chemotherapy treatments. The aim of the current study was to describe the proportion of patients with early-stage colon cancer and mCRC
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who received chemotherapy and provide an analysis of treatment patterns based on stage, sex, and age. An examination of our primary endpoints revealed that both adjuvant and palliative chemotherapy utilization have increased significantly between 1990 and 2004. These results confirm the expectation of changes in practice patterns resulting from the increased indications for adjuvant chemotherapy and the increased effectiveness and tolerability of palliative chemotherapy. During the 1990s, the use of adjuvant chemotherapy for resected stage III colon cancer gained widespread acceptance. During this time period, parallel advances in palliative chemotherapy led to more effective and tolerable treatment options for metastatic disease. The advances in treatment efficacy likely contributed to increased prescription rates in patients with good performance status (PS). The advances in tolerability likely led to the expanded treatment of patients previously considered too frail for chemotherapy. It is interesting to note that, in addition to the increasing proportion of treated patients, the total number of referred patients also increased dramatically over this time period, despite the incidence of CRC remaining relatively stable. Although absolute increases in the catchment population size might be a factor, increasing awareness of the indications and advances in adjuvant and metastatic therapies among referring physicians and surgeons is believed to be a strong contributing factor. The growing use of adjuvant chemotherapy for stage II colon cancer over time warrants further examination. The use of adjuvant chemotherapy in this setting still remains controversial. A recent systematic review concluded that there is insufficient evidence to recommend the standard use of adjuvant therapy for stage II colon cancer.13 The American Society of Clinical Oncology (ASCO) published consensus guidelines in 2004 recommend its use in highrisk stage II patients (perforation, T4 lesions, poorly differentiated histology, inadequately sampled nodes)3 and in patients who want treatment (based upon the projected magnitude of benefit).14 The recently reported QUASAR trial did report a modest improvement in survival with adjuvant chemotherapy in patients with stage II colon or rectal cancer.4 It should be noted that the observed increase in chemotherapy use among patients with stage II disease was observed between 1990 and 2000, before the dissemination of the ASCO
Daniel Renouf et al guidelines. This magnitude of adjuvant chemotherapy prescription in patients with stage II disease is not unique to BC. In 2002, an analysis of US Surveillance, Epidemiology, and End Results data showed that between 1991 and 1996, 27% of patients with stage II colon cancer were being treated with adjuvant chemotherapy.15 The majority of referred elderly patients (age > 70 years) in our study cohort did not receive adjuvant or palliative chemotherapy. Elderly patients are more likely to have other comorbidities, and advanced age has been shown to be an independent risk factor for decreased survival in patients with cancer.16 Also, it might be that elderly patients are less willing to accept the side effects of chemotherapy and therefore might be offered treatment by the oncologist but decline it. Although these factors might be contributing to the underutilization of chemotherapy, it does not exclude the possibility of an age-related treatment bias. Patients who were referred for adjuvant chemotherapy for stage II or III colon cancer, for instance, have tolerated major surgery and therefore likely have an acceptable comorbidity profile and PS. There is evidence that the elderly can accrue similar proportional benefits from chemotherapy for CRC.5,6,11,12 Therefore, elderly patients should not be excluded from receiving chemotherapy on the basis of age alone. The results of this study also suggest that female patients might be less likely to receive palliative chemotherapy. Previous studies have demonstrated this finding in the adjuvant setting. A study examining a population in The Netherlands between 1990 and 2001 found that adjuvant chemotherapy was underprescribed in women.9 A similar study was performed in the United States from 1990-2002 that also found that adjuvant chemotherapy was less frequently prescribed in women.8 The explanation for the disparity in chemotherapy prescription in the adjuvant setting was unclear. One possible explanation for the disparity we found in the metastatic setting might be related to the concern of increased toxicity in women.17 It is possible that oncologists and patients are more willing to accept this toxicity in the adjuvant setting because of the potential curative nature of the chemotherapy. In the palliative setting, where oftentimes, especially in late-stage disease, the focus is on quality of life, the side effects might be less acceptable. There are acknowledged limitations of this study. It is an observational retrospective analysis, and relevant factors including comorbidities, PS, and patient choice could not be captured. That being said, these factors are expected to be relatively equally distributed across the 3 time cohorts and are unlikely to have a meaningful effect on the observed temporal trends in proportions of treated patients. The strength of this study is that it is a non-selected population-based analysis in a single-payer universal care system, thus largely mitigating concerns of inequities in care and access as a contributing factor to changes in chemotherapy utilization over time.
Conclusion To conclude, the numbers of patients with CRC being referred for both adjuvant and palliative chemotherapy rose significantly
from 1990-2004. Adjuvant and palliative chemotherapy utilization has increased since 1990. Despite the lack of definitive evidence, the use of adjuvant chemotherapy for stage II disease has increased significantly and reflects the tacit endorsement of use of adjuvant chemotherapy for stage II disease in real-world practice, particularly in high-risk stage II disease. Our findings suggest that the elderly are less likely to receive adjuvant and palliative chemotherapy, and women appear less likely to receive palliative chemotherapy. There have been numerous advances in adjuvant and palliative chemotherapy for CRC since 1990 that have undoubtedly contributed to the large increases in patients referred for treatment. Our results support previous findings, and because of the increasingly meaningful effectiveness of chemotherapy in the adjuvant setting, it is important to increase the investigation and awareness of potential biases for underutilization that might limit access to survival-prolonging therapies among female patients and the elderly.
References 1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444-50. 2. Gray RG, Barnwell RH, Hills R, et al. QUASAR: a randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol 2004; 22(14 suppl):246 (Abstract 3501). 3. Benson AB, III, Schrag D, Somerfield M, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22:3408-10. 4. Quasar collaborative group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet 2007; 370:2020-9. 5. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345:1091-7. 6. Sanoff HK, Bleiberg H, Goldberg RM. Managing older patients with colorectal cancer. J Clin Oncol 2007; 25:1891-7. 7. Faivre-Finn C, Bouvier AM, Mitry E, et al. Chemotherapy for colon cancer in a well-defined French population: is it under- or over-prescribed. Aliment Pharmacol Ther 2002; 16:353-9. 8. Jessup M, Stewart A, Greene FL, et al. Adjuvant chemotherapy for stage 3 colon cancer. Implications for race/ethnicity, age, and differentiation. JAMA 2005; 294:2703-11. 9. Lemmens VE, van Halteren AH, Janssen-Heijnen ML, et al. Adjuvant treatment for elderly patients with stage 3 colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity. Ann Oncol 2005; 16:767-72. 10. Ayanian JZ, Zaslavsky AM, Fuchs CS, et al. Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population based cohort. J Clin Oncol 2003; 21:1293-300. 11. Folprecht G, Cunningham D, Ross P, et al. Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials. Ann Oncol 2004; 15:1330-8. 12. Goldberg R, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24:4085-91. 13. Figueredo A, Charette ML, Maroun J, et al. Adjuvant therapy for stage II colon cancer: A systematic review from the cancer care Ontario program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol 2004; 22:3395-407. 14. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004; 22:1797-806. 15. Schrag D, Rifas-Shiman S, Saltz L, et al. Adjuvant chemotherapy use for medicare beneficiaries with stage II colon cancer. J Clin Oncol 2002; 20:3999-4005. 16. Wedding U, Rohrig B, Klippstein A, et al. Age, severe comorbidity and functional impairment independently contribute to poor survival in cancer patients. J Cancer Res Clin Oncol 2007; 133:945-50. 17. Sloan J, Goldberg R, Sargent DJ, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 2002; 20:1491-8.
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Trends in Chemotherapy Utilization for Colorectal Cancer Daniel Renouf, Hagen Kennecke, Sharlene Gill Abstract Background: Since 1990, significant advances have occurred in the adjuvant and metastatic treatment of colorectal cancer (CRC). Not all patients may be eligible for chemotherapy (CT), and the proportions and characteristics of patients who receive treatment are not well defined. In this study, treatment patterns of patients referred to the British Columbia Cancer Agency (BCCA) with early-stage colon cancer and metastatic CRC between 1990 and 2004 are described. Patients and Methods: This study included patients with stage II or III colon cancer or stage IV CRC at presentation referred to the BCCA during a 1-year period for 3 time cohorts: 1990, 2000, and 2004. Patients were considered treated with CT if they received ≥ 1 cycle of any CT for indication of the initial referral diagnosis. Results: A total of 1421 patients were included: stage II/III, n = 915; stage IV, n = 506. Chemotherapy utilization increased significantly from 1990 to 2004 for adjuvant CT (1990: 29%; 2000: 45%; 2004: 52%; P < .001) and for palliative CT (1990: 35%; 2000: 51%; 2004: 63%; P < .001). The proportion of patients with stage II disease treated with adjuvant CT dramatically increased (1990: 4%; 2000: 26%; 2004: 30%; P < .001). The use of palliative CT was significantly associated with male sex (P = .025). Among older patients, only 25% received adjuvant CT, and 31% received palliative CT. Conclusion: In this population-based study, adjuvant and palliative CT utilization increased significantly between 1990 and 2004. The majority of patients aged > 70 years did not receive CT, and women appeared less likely to receive palliative CT. Such disparities in CT utilization require further investigation. Clinical Colorectal Cancer, Vol. 7, No. 6, 386-389, 2008; DOI: 10.3816/CCC.2008.n.051 Keywords: Adjuvant therapy, Palliation, Metastatic disease
Introduction Colorectal cancer (CRC) is the second leading cause of cancer-related death in North America and Europe. Since 1990, there have been numerous advances in the treatment of CRC in both the adjuvant and metastatic setting, with commensurate improvements in survival. In 1990, the National Institute of Health guidelines recommended adjuvant 5-fluorouracil–based chemotherapy for stage III colon cancer.1 Although the data supporting the benefit of adjuvant chemotherapy for patients with stage II disease is limited,2,3,4 it can be considered for selected patients with resected higher-risk node-negative disease.3 Since 2000, advances in chemotherapy for metastatic CRC (mCRC) have led to more effective and more tolerable treatment options. In addition, recent reports have confirmed that the magnitude of benefit achieved from advances in adjuvant therapy and metastatic disease are similar for older and younger patients with CRC.5,6 British Columbia Cancer Agency, Vancouver, Canada Submitted: Mar 17, 2008; Revised: Jul 3, 2008; Accepted: Jul 24, 2008 Address for correspondence: Daniel Renouf, MD, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC, Canada, V5Z 4E6 Fax: 604-877-0585; e-mail: [email protected]
Previous studies have examined how prescription patterns for CRC and utilization patterns in various subgroups (based on age and sex) have changed over time. Faiver-Finn et al examined the use of adjuvant and palliative chemotherapy over a 10-year period (1989-1998) in a French population.7 Overall, 4093 patients were included in the analysis, which demonstrated that chemotherapy utilization had increased in the adjuvant setting (for both stage II and stage III colon cancer) and in the metastatic setting. Chemotherapy was noted to be underprescribed in the elderly (age > 75 years). In 2005, Jessup et al reported changes in prescription patterns of adjuvant chemotherapy for stage III colon cancer.8 They analyzed data from 85,934 patients from the United States treated between 1990 and 2002 and concluded that chemotherapy prescription had increased but was less frequently prescribed in women and the elderly. Other studies have also found that adjuvant chemotherapy for colon cancer is underprescribed in the elderly.9,10 This practice is contrary to emerging data demonstrating equivalent benefits of adjuvant and metastatic disease among the elderly.5,6,11,12 The notable findings of these aforementioned studies raise concerns regarding optimal utilization of chemotherapy; however, they are unable to control for referral biases and access to care. This
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Table 1 Patient Characteristics Total Year 2004, n Patients, N (%)
Characteristic
Year 1990, n
Year 2000, n
Median Age (Years)
65
69
68
–
Disease Stage IIA
78
121
133
332 (23)
Disease Stage IIB
10
28
37
75 (5)
Figure 1 Prescribing Trends for Adjuvant Chemotherapy in Colon Cancer (P < .001) 80 70
No Chemotherapy Chemotherapy
71
60
55
50
83
141
284
508 (36)
Disease Stage IV
118
196
192
506 (36)
Male Sex
144
272
342
758 (53)
30
Female Sex
145
214
304
663 (47)
20
Total
289
486
646
1421
10
Percent
Disease Stage III
45
29
1990
Table 2 Characteristics of Patients with Resected Stage II or III Colon Cancer by Adjuvant Chemotherapy Status Chemotherapy (n = 413)
P Value
80 (16)
155 (37)
127 (25)
159 (38)
Age > 70 Years
295 (59)
99 (24)
Male Sex
251 (50)
202 (49)
NS
80
Disease Stage IIA
273 (54)
59 (14)
–
70
Disease Stage IIB
43 (9)
32 (8)
–
100
96
No Chemotherapy Chemotherapy
90
< .001
question had not been examined within a referred population in a setting of universal care access. The purpose of this study is to evaluate temporal changes in chemotherapy utilization patterns among patients with early-stage colon cancer and mCRC using a Canadian provincial patient cohort.
Patients and Methods British Columbia (BC) is a province with a population of approximately 4 million people. The BC Cancer Agency (BCCA) is the provincial cancer referral agency and includes 4 regional cancer centers. The BCCA develops provincial guidelines for the systemic treatment of CRC. Chemotherapy is funded by the provincial government as a component of Canadian universal healthcare access. In BC, approximately 60% of patients with CRC are referred to the BCCA for treatment. The remaining 40% receive treatment at community oncology centers. The vast majority of patients treated at the BCCA are BC residents. This study included all patients with stage II or III colon cancer or stage IV CRC at presentation referred to the BCCA during a 1-year period for 3 time cohorts: January 1, 1990, through December 31, 1990; January 1, 2000, through December 31, 2000; and January 1, 2004, through December 31, 2004. Patients were identified from the British Columbia Colorectal Cancer Outcomes Unit (CRCOU) database. The CRCOU collects data prospectively, starting at the time of initial consultation and subsequently on follow-up visits. Data fields collected include the patient’s sex, age, histologic diagnosis, primary tumor site, stage at referral (both clini-
Percent
322 (78)
< .001
Abbreviation: NS = not significant
2004
Figure 2 Proportion of Patients with Stage II Colon Cancer Treated with Adjuvant Chemotherapy (P < .001)
Age 61-70 Years
186 (37)
2000 Year
Age < 60 Years
Disease Stage III
52
40
0
Characteristic, No Chemotherapy n (%) (n = 502)
48
74
70
60 50 40 30
26
30
20 10
4
0
1990
2000
2004
Year
cal and pathologic), date of the initial BCCA consultation, and the date of the first cycle of chemotherapy. Chemotherapy treatment data was cross referenced with the provincial pharmacy database. Patients were considered to have been treated with chemotherapy if they received ≥ 1 cycle of chemotherapy for their initial diagnosis at the time of referral within 6 months of the date of initial consultation. The primary endpoints were (1) proportion of patients with resected stage II and/or III colon cancer prescribed adjuvant-intent chemotherapy in each time cohort and (2) proportion of patients with stage IV CRC prescribed palliative-intent chemotherapy in each time cohort. Predefined secondary endpoints included (1) proportion of patients with stage II disease treated with adjuvant chemotherapy; (2) proportion of patients treated with chemotherapy in different age groups (< 60 years; 61-70 years; > 70 years), in both the adjuvant and palliative settings; and (3) proportion of male/female patients treated with chemotherapy in both the adjuvant and palliative settings. Comparison of proportions treated within each relevant subgroup across the 3 time cohorts was performed using standard frequency statistics including t test and χ2 analysis as applicable.
Clinical Colorectal Cancer November 2008 •
387
Chemotherapy Utilization for CRC Table 3 Characteristics of Patients with Metastatic (Stage IV) Colorectal Cancer by Palliative Chemotherapy Status Chemotherapy (n = 261)
Age < 60 Years
51 (21)
130 (50)
Age 61-70 Years
82 (34)
81 (31)
Age > 70 Years
112 (46)
50 (19)
Male Sex
113 (54)
167 (64)
P Value
70
65
< .001
.025
49
50 40
63
No Chemotherapy Chemotherapy
60
Percent
Characteristic, No Chemotherapy n (%) (n = 245)
Figure 3 Prescribing Trends for Palliative Chemotherapy in Metastatic Colorectal Cancer (P < .001)
51 37
35
30 20
Table 4 Prescribing Trends for Adjuvant and Palliative Chemotherapy in Patients Aged > 70 Years
10
Year 1990
Year 2000
Year 2004
Patients aged > 70 years
8
28
28
Total cohort treated, all ages
29
45
52
Patients aged > 70 years
15
24
45
Total cohort treated, all ages
35
51
63
Chemotherapy Adjuvant Chemotherapy, %
1990
2000
2004
Year
Palliative Chemotherapy, %
Results A total of 1421 patients were included: stage II/III (n = 915), stage IV (n = 506; Table 1). Chemotherapy utilization increased significantly from 1990 to 2004 for adjuvant chemotherapy (1990: 49 [29%]; 2000: 129 [45%]; 2004: 235 [52%]; P < .001; Figure 1). The proportion of patients with stage II disease treated with adjuvant chemotherapy also significantly increased over the 3 time cohorts (1990: 3 [4%]; 2000: 38 [26%]; 2004: 50 [30%]; P < .001; Figure 2). Our data indicate that a greater number of patients with stage IIB (T4 N0, “high risk”) were referred for adjuvant chemotherapy over time (Table 1). The proportion of these patients treated also increased over time (n = 0; 0% [1990]; 13, 46% [2000]; 19, 51% [2004]). This might in part explain the increased use of adjuvant chemotherapy for stage II colon cancer. Adjuvant chemotherapy utilization was directly associated with later time cohort and younger age of presentation (Table 2). Use of palliative chemotherapy increased significantly from 1990 to 2004 (1990: 41 [35%]; 2000: 100 [51%]; 2004: 120 [63%]; P < .001; Figure 3). Palliative chemotherapy utilization was directly associated with later time cohort and younger age of presentation (Table 3). In addition, palliative chemotherapy use was significantly associated with male sex (P = .025; Table 3). This sex difference was not observed in the adjuvant setting. The use of chemotherapy in older patients (> 70 years) is presented in Table 4.
Discussion Since 1990, indications for adjuvant chemotherapy have expanded as have the treatment options for mCRC. In order for advances in therapy to translate into improvements in population-based outcomes, eligible patients need to receive the appropriate chemotherapy treatments. The aim of the current study was to describe the proportion of patients with early-stage colon cancer and mCRC
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• Clinical Colorectal Cancer November 2008
who received chemotherapy and provide an analysis of treatment patterns based on stage, sex, and age. An examination of our primary endpoints revealed that both adjuvant and palliative chemotherapy utilization have increased significantly between 1990 and 2004. These results confirm the expectation of changes in practice patterns resulting from the increased indications for adjuvant chemotherapy and the increased effectiveness and tolerability of palliative chemotherapy. During the 1990s, the use of adjuvant chemotherapy for resected stage III colon cancer gained widespread acceptance. During this time period, parallel advances in palliative chemotherapy led to more effective and tolerable treatment options for metastatic disease. The advances in treatment efficacy likely contributed to increased prescription rates in patients with good performance status (PS). The advances in tolerability likely led to the expanded treatment of patients previously considered too frail for chemotherapy. It is interesting to note that, in addition to the increasing proportion of treated patients, the total number of referred patients also increased dramatically over this time period, despite the incidence of CRC remaining relatively stable. Although absolute increases in the catchment population size might be a factor, increasing awareness of the indications and advances in adjuvant and metastatic therapies among referring physicians and surgeons is believed to be a strong contributing factor. The growing use of adjuvant chemotherapy for stage II colon cancer over time warrants further examination. The use of adjuvant chemotherapy in this setting still remains controversial. A recent systematic review concluded that there is insufficient evidence to recommend the standard use of adjuvant therapy for stage II colon cancer.13 The American Society of Clinical Oncology (ASCO) published consensus guidelines in 2004 recommend its use in highrisk stage II patients (perforation, T4 lesions, poorly differentiated histology, inadequately sampled nodes)3 and in patients who want treatment (based upon the projected magnitude of benefit).14 The recently reported QUASAR trial did report a modest improvement in survival with adjuvant chemotherapy in patients with stage II colon or rectal cancer.4 It should be noted that the observed increase in chemotherapy use among patients with stage II disease was observed between 1990 and 2000, before the dissemination of the ASCO
Daniel Renouf et al guidelines. This magnitude of adjuvant chemotherapy prescription in patients with stage II disease is not unique to BC. In 2002, an analysis of US Surveillance, Epidemiology, and End Results data showed that between 1991 and 1996, 27% of patients with stage II colon cancer were being treated with adjuvant chemotherapy.15 The majority of referred elderly patients (age > 70 years) in our study cohort did not receive adjuvant or palliative chemotherapy. Elderly patients are more likely to have other comorbidities, and advanced age has been shown to be an independent risk factor for decreased survival in patients with cancer.16 Also, it might be that elderly patients are less willing to accept the side effects of chemotherapy and therefore might be offered treatment by the oncologist but decline it. Although these factors might be contributing to the underutilization of chemotherapy, it does not exclude the possibility of an age-related treatment bias. Patients who were referred for adjuvant chemotherapy for stage II or III colon cancer, for instance, have tolerated major surgery and therefore likely have an acceptable comorbidity profile and PS. There is evidence that the elderly can accrue similar proportional benefits from chemotherapy for CRC.5,6,11,12 Therefore, elderly patients should not be excluded from receiving chemotherapy on the basis of age alone. The results of this study also suggest that female patients might be less likely to receive palliative chemotherapy. Previous studies have demonstrated this finding in the adjuvant setting. A study examining a population in The Netherlands between 1990 and 2001 found that adjuvant chemotherapy was underprescribed in women.9 A similar study was performed in the United States from 1990-2002 that also found that adjuvant chemotherapy was less frequently prescribed in women.8 The explanation for the disparity in chemotherapy prescription in the adjuvant setting was unclear. One possible explanation for the disparity we found in the metastatic setting might be related to the concern of increased toxicity in women.17 It is possible that oncologists and patients are more willing to accept this toxicity in the adjuvant setting because of the potential curative nature of the chemotherapy. In the palliative setting, where oftentimes, especially in late-stage disease, the focus is on quality of life, the side effects might be less acceptable. There are acknowledged limitations of this study. It is an observational retrospective analysis, and relevant factors including comorbidities, PS, and patient choice could not be captured. That being said, these factors are expected to be relatively equally distributed across the 3 time cohorts and are unlikely to have a meaningful effect on the observed temporal trends in proportions of treated patients. The strength of this study is that it is a non-selected population-based analysis in a single-payer universal care system, thus largely mitigating concerns of inequities in care and access as a contributing factor to changes in chemotherapy utilization over time.
Conclusion To conclude, the numbers of patients with CRC being referred for both adjuvant and palliative chemotherapy rose significantly
from 1990-2004. Adjuvant and palliative chemotherapy utilization has increased since 1990. Despite the lack of definitive evidence, the use of adjuvant chemotherapy for stage II disease has increased significantly and reflects the tacit endorsement of use of adjuvant chemotherapy for stage II disease in real-world practice, particularly in high-risk stage II disease. Our findings suggest that the elderly are less likely to receive adjuvant and palliative chemotherapy, and women appear less likely to receive palliative chemotherapy. There have been numerous advances in adjuvant and palliative chemotherapy for CRC since 1990 that have undoubtedly contributed to the large increases in patients referred for treatment. Our results support previous findings, and because of the increasingly meaningful effectiveness of chemotherapy in the adjuvant setting, it is important to increase the investigation and awareness of potential biases for underutilization that might limit access to survival-prolonging therapies among female patients and the elderly.
References 1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444-50. 2. Gray RG, Barnwell RH, Hills R, et al. QUASAR: a randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol 2004; 22(14 suppl):246 (Abstract 3501). 3. Benson AB, III, Schrag D, Somerfield M, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22:3408-10. 4. Quasar collaborative group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet 2007; 370:2020-9. 5. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345:1091-7. 6. Sanoff HK, Bleiberg H, Goldberg RM. Managing older patients with colorectal cancer. J Clin Oncol 2007; 25:1891-7. 7. Faivre-Finn C, Bouvier AM, Mitry E, et al. Chemotherapy for colon cancer in a well-defined French population: is it under- or over-prescribed. Aliment Pharmacol Ther 2002; 16:353-9. 8. Jessup M, Stewart A, Greene FL, et al. Adjuvant chemotherapy for stage 3 colon cancer. Implications for race/ethnicity, age, and differentiation. JAMA 2005; 294:2703-11. 9. Lemmens VE, van Halteren AH, Janssen-Heijnen ML, et al. Adjuvant treatment for elderly patients with stage 3 colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity. Ann Oncol 2005; 16:767-72. 10. Ayanian JZ, Zaslavsky AM, Fuchs CS, et al. Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population based cohort. J Clin Oncol 2003; 21:1293-300. 11. Folprecht G, Cunningham D, Ross P, et al. Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials. Ann Oncol 2004; 15:1330-8. 12. Goldberg R, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24:4085-91. 13. Figueredo A, Charette ML, Maroun J, et al. Adjuvant therapy for stage II colon cancer: A systematic review from the cancer care Ontario program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol 2004; 22:3395-407. 14. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004; 22:1797-806. 15. Schrag D, Rifas-Shiman S, Saltz L, et al. Adjuvant chemotherapy use for medicare beneficiaries with stage II colon cancer. J Clin Oncol 2002; 20:3999-4005. 16. Wedding U, Rohrig B, Klippstein A, et al. Age, severe comorbidity and functional impairment independently contribute to poor survival in cancer patients. J Cancer Res Clin Oncol 2007; 133:945-50. 17. Sloan J, Goldberg R, Sargent DJ, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 2002; 20:1491-8.
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