Ann Surg Oncol DOI 10.1245/s10434-013-3438-z
ORIGINAL ARTICLE – COLORECTAL CANCER
Toxicity of Oxaliplatin Plus Fluorouracil/Leucovorin Adjuvant Chemotherapy in Elderly Patients with Stage III Colon Cancer: A Population-Based Study Samia Hamza, MD, Anne-Marie Bouvier, MD, PhD, Fabien Rollot, PhD, Coˆme Lepage, MD, PhD, Jean Faivre, MD, PhD, and Laurent Bedenne, MD, PhD Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital, University of Burgundy, Dijon, France
ABSTRACT Background. Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice. Methods. Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan–Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model. Results. There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68–2.41; p = 0.439). Conclusions. Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This
Ó Society of Surgical Oncology 2014 First Received: 22 June 2013 A.-M. Bouvier, MD, PhD e-mail: [email protected]
treatment should be considered regardless of patients’ age alone, but consideration should be given to the capacity of patients to tolerate adverse events.
Colon cancer is worrisome because of its frequency and severity. In France in 2008, it accounted for approximately two-thirds of colorectal cancers, corresponding to more than 26,000 new cases per year. Sixty percent of these cancers are diagnosed in people 70 years and over.1 The French population is ageing, and as a result of increased life expectancy, a growing number of older subjects will be exposed to the risk of developing cancer. Surgery is the benchmark treatment, and chemotherapy is effective for stage III colon cancer. Successive randomized controlled trials have shown first a significant advantage of 5-fluorouracil (5-FU)–based monochemotherapy compared with surgery alone and then the significant benefits of polychemotherapy using oxaliplatin associated with fluorouracil and leucovorin (FOLFOX 4) compared with 5-FU.2–4 However, these treatments have side effects that are dependent on the regimen (number and type of drugs, dose, and method of administration) and on patient characteristics (age, nutritional status, and comorbidity). In therapeutic trials, 5-FU adjuvant monochemotherapy had the same benefit and the same toxicity for patients aged 70 and over as for younger ones.5 The interest of oxaliplatin associated with 5-FU in terms of benefit and risk for patients aged 70 and over has recently been questioned in studies showing that toxicities were significantly higher with no benefit in terms of disease-free or overall survival.6,7 However, these findings remain controversial among patients aged 70 or 75 and over.8–10 Moreover, current knowledge is based on clinical trial results (or metaanalyses) that include by definition selected patients. This selection bias affects any conclusions that can be drawn. Population-based studies are
S. Hamza et al.
the only way to assess how chemotherapy regimens are administered and tolerated. The aim of the present study was to assess, within a well-defined French cohort, the use and the toxicity of leucovorin adjuvant chemotherapy as administered in current practice in patients aged 70 years and older with stage III colon cancer. METHODS Population A population-based registry records all the digestive tract cancers occurring in a well-defined geographic area (Saone-et-Loire; 553,968 inhabitants according to the 2011 census) in Burgundy, France. Information is regularly obtained from pathologists in public and private practice, public hospitals (university hospitals, including the cancer center, and general hospitals), private physicians (gastroenterologists, surgeons, oncologists, radiotherapists, and general practitioners), hospital administrative databases, the National Health System database, and death certificates. No case was registered through death certificates alone, but these were used to identify missing cases. Because of the multiplicity of clinical and administrative sources, we assumed that nearly all newly diagnosed cases had been recorded. The quality and comprehensiveness of registration is certified every 4 years by an audit of the National Committee on Population-Based Registries. Cancers were classified according to the International Classification of Diseases, 10th revision.11 Cancer extension at the time of diagnosis was classified according to the TNM classification, 1997 revision.12 All patients diagnosed with stage III colon adenocarcinoma between 2004 and 2009 and recorded in the registry were included in the analysis. During the study period, 1365 colon adenocarcinomas were registered, and 328 were classified as stage III. We excluded nine patients who were simultaneously affected by another cancer and 14 postoperative deaths. Among the 305 patients included, 210 (68.8 %) received adjuvant chemotherapy. The chemotherapy used was FOLFOX in 159 patients (75.7 %), fluorouracil/leucovorin alone in 39 patients (18.6 %), capecitabine (Xeloda) alone in nine patients, and fluorouracil/irinotecan, raltitrexed (Tomudex) alone, and oxaliplatin alone in one patient each. Information about possible adverse effects was not found for three patients. The analysis of chemotherapy-related toxicity was limited to the group receiving FOLFOX. Studied Variables The data routinely collected included sex, age at diagnosis, date of diagnosis, comorbidities, place of treatment,
diagnostic strategies, detailed treatment (including adjuvant, neoadjuvant, and palliative chemotherapy and radiotherapy), stage at diagnosis, and vital status of the patients. Additional data necessary to reach the aim of this study were obtained from a specific survey of patients’ medical files. Information was obtained from all clinicians (general practitioners and specialists) involved in the management and the follow-up of these patients. When given, adjuvant chemotherapy was defined as chemotherapy administered after resection with curative intent (R0 resection) for stage III tumors. The reason for the absence of adjuvant chemotherapy was recorded. In practice, 12 cycles of FOLFOX were recommended. Comorbidities at the time of diagnosis were listed by using the Charlson index.13 Individuals were classified into groups based on Charlson comorbidity scores of 0, 1, or C2. Precise data for all administered chemotherapy drugs and corresponding potential related toxicity were recorded according to the World Health Organization classification. The different types of toxicity were gathered in four groups of toxicity: hematologic (neutropenia, thrombopenia, and anemia), neurologic (paresthesias), digestive (anorexia, diarrhea, nausea, vomiting, and constipation), and general (fatigue, weight loss, cardiac complications, and allergic reaction to oxaliplatin) toxicity. Severe toxicity was defined as grade 3 or 4 toxicity. Statistical Analysis Univariate analyses were performed. The association between categorical or quantitative data was analyzed by using Chi square or Student’s test for heterogeneity. The level of statistical significance was set at p = 0.05 in twosided tests. The statistical analysis was conducted in patients less than 70 years and in older patients. Cumulative hematologic, neurologic, digestive, and general toxicity incidence rates were calculated by using the Kaplan–Meier method and were expressed with standard errors. The curves were compared by using the log-rank test. Patients who died were censored at the time of death, and patients who had toxicity were censored at the time of outcome for severe toxicity (grade 3 or 4). Differences in the hazard rate of global, hematologic, neurologic, digestive, general, and severe toxicity (grade 3 or 4) between patients under 70 years and older patients ([70 years) were analyzed by using Cox regression models, adjusting for sex and Charlson index. Two-sided p values less than 0.05 were considered statistically significant. Relative survival rates, defined as the ratio of the observed survival rate in the cancer patients under study to the expected survival rate in a population with similar sex and age distribution, were calculated. Relative survival reflects the excess mortality in the cancer patient group relative to background mortality.
Toxicity of Oxaliplatin in Older Patients TABLE 1 Distribution of patients according to age group and the presence of treatment Variable
Total
[70 years
B70 years Chemotherapy
No chemotherapy
n
%
n
109
95.6
p-Value
Chemotherapy
No chemotherapy
%
n
%
n
%
5
4.4
101
52.9
90
47.1
50 28
58.8 50.0
35 28
41.2 50.0
22
44.9
27
55.1
p-Value
Charlson scorea
a
0 1
71 23
98.6 95.8
1 1
1.4 4.2
C2
13
81.3
3
18.7
0.010
0.267
Unknown for 3 cases
FIG. 1 Kaplan–Meier failure estimates of cumulative rates of global and severe toxicity (3 or 4) toxicity in FOLFOX patients according to age
a
b
Global toxicity (whatever the grade)
Cumulative rate 1.0
P = 0.3555
Cumulative rate 1.0
0.8
0.8
0.6
0.6
0.4
70 years > 70 years
0.2
Severe toxicity (grade 3 or 4) P = 0.576
70 years > 70 years
0.4
0.2 0
2
4 6 8 10 Chemotherapy cycles
Statistical analyses were performed by using STATA (version 11.0; Stata Corporation, College Station, TX). RESULTS Among the 305 stage III patients affected by colon cancer, 210 received adjuvant chemotherapy (68.8 %), and among them 156 had FOLFOX (74.3 %). Reasons for not performing chemotherapy reported by practitioners were heavy comorbidities (37.9 %), old age (29.5 %), patients’ refusal (21.0 %), and postoperative complications (6.3 %). This information was not available for five patients. Patients older than 70 years were less likely to receive chemotherapy (52.9 %) than younger patients (95.6 %; p \ 0.001). Older patients were also less likely than younger patients to complete the recommended twelve cycles of chemotherapy (62 of 100 vs. 87 of 107; p = 0.002). Information concerning the number of cycles administered was unknown for three patients. When we considered only patients who had FOLFOX, there was no significant difference between younger (83.2 % had 12
12
0
2
4 6 8 10 Chemotherapy cycles
12
cycles) and older (72.1 % had 12 cycles; p = 0.100) individuals. Overall, patients aged more than 70 years received 26.7 % less oxaliplatin than did younger patients. Patients who had adjuvant chemotherapy had fewer comorbidities than did nontreated patients (p = 0.002). In the younger age group, the proportion of patients receiving chemotherapy decreased with Charlson score, whereas, in the older age group, there was no difference in comorbidity score between the chemotherapy group and the nontreated group (p = 0.267; Table 1). Figure 1 shows the cumulative rate of all adverse events (whatever the grade) and of severe events C3 according to chemotherapy cycles and age group for patients treated with FOLFOX. There was no difference between cumulative adverse event curves (p = 0.355 for all adverse events; p = 0.576 for severe adverse events). Different adverse events of chemotherapy according to the length of the FOLFOX adjuvant treatment in the two studied age groups are listed in Table 2. The cumulative incidence rate of hematologic toxicity after 12 chemotherapy cycles was 45.9 % in patients less than 70 years
S. Hamza et al. TABLE 2 Cumulative incidence rates for the different adverse events by duration of chemotherapy and age group for patients treated with FOLFOX [70 years
B70 years
p-Value
Variable
Cycle 4
Cycle 8
Cycle 12
Cycle 4
Cycle 8
Cycle 12
Global toxicity
74.2
82.4
86.2
71.4
89.6
93.7
0.355
Hematologic toxicity
16.5
37.2
45.9
22.3
40.5
43.4
0.920
Neurologic toxicity Digestive toxicity
54.6 36.1
72.0 45.6
78.0 52.4
45.9 41.1
58.4 54.0
72.3 61.2
0.271 0.378
General toxicity
25.7
38.8
47.9
32.9
57.0
64.2
0.095
12.4
25.1
31.4
11.8
23.6
39.0
0.576
Severe toxicity
and 43.4 % in older patients (p = 0.920). The corresponding cumulative incidence rates were respectively 78.0 and 72.3 % for neurologic toxicity (p = 0.271), 52.4 and 61.2 % for digestive toxicity (p = 0.378), and 47.9 and 64.2 % for general toxicity (p = 0.095). Among cases of general toxicity, there were four allergic reactions to oxaliplatin and five cardiac complications. For all grade C3 toxicities, the cumulative rate was 31.4 % for those under 70 years and 39.0 % in older patients (p = 0.576). Neurologic toxicity appeared earlier than other toxicities. From the eighth cycle onward, toxicity rates became steady. The description of side effects according to their severity and age group is given in Table 3. Severe grade 3 toxicity was reported in 27.3 % of the patients and grade 4 in 7.7 %. There was no statistically significant difference in the severity of side effects between patients under 70 and older patients (grade 3 or 4, 29.9 vs. 42.8 %; p = 0.354). Overall, severe adverse events consisted of hematologic toxicity (25.4 %), neurological toxicity (9.1 %), digestive toxicity (11.1 %), and general toxicity (27.5 %). Table 4 presents the Cox regression model for the risk of developing adverse events according to the two studied age groups, unadjusted or adjusted for sex and comorbidity. Patients receiving FOLFOX in both age groups were equally as likely to be affected by hematologic, neurologic, digestive, or general adverse events. The Cox model also confirmed the absence of difference when considering global toxicity and severe toxicity. Chemotherapy was not associated with an increased risk of severe side events C3 in patients over 70 compared with younger patients (hazard ratio, 1.28; 95 % CI 0.68–2.41; p = 0.439). The 3-year relative survival rate did not differ in patients receiving FOLFOX. It was 90.0 % in patients under 70 and 84.3 % in those 70 and over (p = 0.806). DISCUSSION The strength of the study lies in the fact that it was population based. Because of the involvement of the entire medical profession and the multiplicity of information
TABLE 3 Description of side effects according to their severity and age group in patients receiving FOLFOX Toxicity
B70 years
[70 years
(n = 87)
(n = 56) n
p-Value
n
%
%
No toxicity
13
14.9
Grade 1
11
12.7
4
7.1
Grade 2
37
42.5
24
42.9
Grade 3
20
23.0
19
33.9
Grade 4
6
6.9
5
9.0
4
7.1
0.354
Missing data 13 cases
sources, it can be assumed that all newly diagnosed cases were recorded. Information on adverse events was almost complete and collected by a specially trained staff. The findings are particularly important as they truly reflect how patients are treated in everyday practice in a country where chemotherapy in public and private practice is provided free of charge to patients. However, one limit of the study was its relatively small size. We cannot exclude the possibility that some differences may become significant with a larger number of patients. However, none of the reported differences was borderline significant. Several population-based studies have highlighted the undertreatment of elderly patients.14–16 There are several possible reasons for this inequality: reluctance of doctors, patients’ refusal, comorbidities, more frequent or more serious adverse reactions, and uncertainty about the gains in clinical effectiveness brought by new drugs in these patients. Moreover, the age at which a patient is considered elderly varies widely and is based on chronologic rather than physiologic age.17 Only half of the elderly patients with no associated comorbidity received adjuvant chemotherapy with FOLFOX, compared with 97 % in younger patients. This major discrepancy suggests that a larger proportion of elderly patients should receive adjuvant chemotherapy. It seems that comorbidity is not the only
Toxicity of Oxaliplatin in Older Patients TABLE 4 Risk of developing adverse events in the two studied age groups (Cox model) Variable
Unadjusted
Adjusted
HR
HR
(95 % CI)
(95 % CI)
Global toxicity B 70 years
1
[ 70 years 1.16 Hematologic toxicity B 70 years
1
[ 70 years
1.03
1 (0.81–1.65)
1.21
(0.83–1.77)
1 (0.60–1.77)
0.95
(0.52–1.73)
Neurologic toxicity B 70 years
1
[ 70 years
0.81
1 (0.53–1.22)
0.82
(0.53–1.26)
Digestive toxicity B 70 years
1
[ 70 years
1.22
1 (0.76–1.95)
1.21
(0.73–2.01)
General toxicity B 70 years
1
[ 70 years
1.47
1 (0.92–2.36)
1.33
(0.80–2.22)
Severe toxicity B 70 years
1
[ 70 years
1.27
1 (0.70–2.30)
1.28
(0.68–2.41)
CI confidence interval Adjusted for sex and Charlson comorbidity index
explanation for undertreatment. In a previous study, we provided evidence that adjuvant chemotherapy for colon cancer did not have a negative effect on the quality of life of elderly patients. This should encourage clinicians to treat these patients.18 The risk of toxicity is not sufficient to justify withholding chemotherapy of elderly patients with stage III colon cancer. However, we cannot exclude that the selection of patients could, at least partly, explain the similar toxicity in the elderly and younger patients. An American study suggested that the primary determinant of an elderly patient’s decision to accept or decline chemotherapy was their physician’s advice.19 This finding suggests that physician’s awareness of chemotherapy for the elderly must be improved. Treatment decisions should be taken in the context of a multidisciplinary meeting. If necessary, a comprehensive geriatric assessment should assist practitioners in the selection of patients with stage III colon cancer who appear unlikely to benefit from adjuvant chemotherapy. Although using 5-FU monotherapy in elderly patients gives the same benefit/risk ratio as for their younger counterparts, with no significant increase in toxic effects, there are some worries concerning the addition of oxaliplatin to the 5-FU regimens in this population.5 As regards oxaliplatin, the NSABP C-08 trial showed a significantly higher rate of grade 4 and 5 toxicity,
according to the National Cancer Institute Common Terminology Criteria for Adverse Events, among patients older than 69 years treated with oxaliplatin.6 A pooled analysis conducted in 2006 showed that FOLFOX 4 maintained its efficacy and safety in selected patients older than 70 years, except for hematologic toxicity, which was significantly more severe in elderly patients.8 An American randomized trial confirmed the benefit of the addition of oxaliplatin to fluorouracil on disease-free survival only in patients younger than age 70.20 Patients aged 70 years or older receiving FOLFOX were more likely to experience grade 3 or 4 toxicity than were those receiving 5-FU monotherapy. A large US study using data from two population-based cohorts (the SEER database and the New York State Cancer Registry) linked with Medicare also indicated that in patients older than 75 years, adverse events were more frequent in patients treated with 5-FU and oxaliplatin than in those treated with 5-FU alone.9 Study of this database also suggested that in a real-world setting, patients 75 years and older receiving FOLFOX had a survival benefit of the same order of magnitude as that reported in clinical trials (MOSAIC and NSABP-C-07). The present study provides complementary data to the US study by showing that there was no significant difference between very elderly and younger patients for overall toxicity and severe toxicity. Furthermore, survival rates did not differ between age groups. In the absence of randomization, the comparison of survival rates must be interpreted with caution. However, there was a trend toward a higher frequency of digestive and general toxicity, and neurologic toxicity can be severely incapacitating in the elderly. In conclusion, we demonstrated at a population level that tolerance to the FOLFOX regimen among elderly stage III colon cancer patients did not differ significantly from that in younger patients. However, there was a trend toward more frequent digestive and general toxicity in patients 70 years and above, and the treatment discontinuation rate was higher in older patients. The decision to recommend FOLFOX should be considered without regard to patients’ age alone, but consideration should be given to the patient’s overall state of health and potential for tolerating adverse events. Elderly patients need more attention regarding their functional, social, and mental status. Taking into account the data reported in this study, we suggest a more aggressive attitude in the elderly than actually proposed based on patient-by-patient decisions taken in multidisciplinary meetings after a thorough geriatric assessment whenever necessary. Given the increasing number of older patients with colon cancer and the continuing increase in life expectancy, identifying safe and effective therapies for elderly patients is imperative.
S. Hamza et al. ACKNOWLEDGMENT This work was supported by a Grant from the Ligue Re´gionale Contre le Cancer (2010). The authors thank all the gastroenterologists for their involvement: Drs. Abdelmajid, Andre´, Bellecoste, Bruneton, Derreveaux, El Khaddari, Fabre, Grozel, Guillaume, Lacourt, Levenq, Naouri, Petigny, Ramond, Saggio, Soupison, and Van Nieuwenhuyse. They also thank all the private and public physicians, specialists, and pathologists for their collaboration. DISCLAIMER None of the authors has any conflicts of interest to declare regarding this study.
REFERENCES 1. Colonna M, Bossard N, Remontet L, Grosclaude P. Changes in the risk of death from cancer up to five years after diagnosis in elderly patients: a study of five common cancers. Int J Cancer. 2010;127:924–931. 2. Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol. 1989;7:1447–1456. 3. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990; 322:352–358. 4. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350: 2343–2351. 5. Sargent DJ, Goldberg RM, Jacobson SD, Macdonald JS, Labianca R, Haller DG, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345:1091–1097. 6. Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Colangelo LH, Lopa SH, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009;27:3385–3390. 7. McCleary NJ, Meyerhardt JA, Green E, Yothers G, de Gramont A, Van Cutsem E, et al. Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database (abstract). J Clin Oncol. 2009;27:170 s.
8. Goldberg RM, Tabah-Fisch I, Bleiberg H, de Gramont A, Tournigand C, Andre T, 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: 4085–4091. 9. Sanoff HK, Carpenter WR, Sturmer T, Goldberg RM, Martin CF, Fine JP, et al. Effect of adjuvant chemotherapy on survival of patients with stage III colon cancer diagnosed after age 75 years. J Clin Oncol. 2012;30:2624–2634. 10. Muss HB, Bynum DL. Adjuvant chemotherapy in older patients with stage III colon cancer: an underused lifesaving treatment. J Clin Oncol. 2012;30:2576–2578. 11. World Health Organization. International classification of disease for oncology. 3rd ed. Geneva: World Health Organization; 2000. 12. Sobin L, Wittekin Ch, eds. TNM classification of malignant tumours. 6th ed. New York: Wiley; 2002. 13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40: 373–383. 14. Bouvier AM, Launoy G, Lepage C, Faivre J. Trends in the management and survival of digestive tract cancers among patients aged over 80 years. Aliment Pharmacol Ther. 2005;22: 233–241. 15. Ayanian JZ, Zaslavsky AM, Fuchs CS, Guadagnoli E, Creech CM, Cress RD, et al. Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population-based cohort. J Clin Oncol. 2003;21:1293–1300. 16. Sundararajan V, Grann VR, Jacobson JS, Ahsan H, Neugut AI. Variations in the use of adjuvant chemotherapy for node-positive colon cancer in the elderly: a population-based study. Cancer J. 2001;7:213–218. 17. Kohne CH, Grothey A, Bokemeyer C, Bontke N, Aapro M. Chemotherapy in elderly patients with colorectal cancer. Ann Oncol. 2001;12:435–442. 18. Bouvier AM, Jooste V, Bonnetain F, Cottet V, Bizollon MH, Bernard MP, et al. Adjuvant treatments do not alter the quality of life in elderly patients with colorectal cancer: a population-based study. Cancer. 2008;113:879–886. 19. Newcomb PA, Carbone PP. Cancer treatment and age: patient perspectives. J Natl Cancer Inst. 1993;85:1580–1584. 20. Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29:3768–3774.
ORIGINAL ARTICLE – COLORECTAL CANCER
Toxicity of Oxaliplatin Plus Fluorouracil/Leucovorin Adjuvant Chemotherapy in Elderly Patients with Stage III Colon Cancer: A Population-Based Study Samia Hamza, MD, Anne-Marie Bouvier, MD, PhD, Fabien Rollot, PhD, Coˆme Lepage, MD, PhD, Jean Faivre, MD, PhD, and Laurent Bedenne, MD, PhD Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital, University of Burgundy, Dijon, France
ABSTRACT Background. Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice. Methods. Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan–Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model. Results. There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68–2.41; p = 0.439). Conclusions. Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This
Ó Society of Surgical Oncology 2014 First Received: 22 June 2013 A.-M. Bouvier, MD, PhD e-mail: [email protected]
treatment should be considered regardless of patients’ age alone, but consideration should be given to the capacity of patients to tolerate adverse events.
Colon cancer is worrisome because of its frequency and severity. In France in 2008, it accounted for approximately two-thirds of colorectal cancers, corresponding to more than 26,000 new cases per year. Sixty percent of these cancers are diagnosed in people 70 years and over.1 The French population is ageing, and as a result of increased life expectancy, a growing number of older subjects will be exposed to the risk of developing cancer. Surgery is the benchmark treatment, and chemotherapy is effective for stage III colon cancer. Successive randomized controlled trials have shown first a significant advantage of 5-fluorouracil (5-FU)–based monochemotherapy compared with surgery alone and then the significant benefits of polychemotherapy using oxaliplatin associated with fluorouracil and leucovorin (FOLFOX 4) compared with 5-FU.2–4 However, these treatments have side effects that are dependent on the regimen (number and type of drugs, dose, and method of administration) and on patient characteristics (age, nutritional status, and comorbidity). In therapeutic trials, 5-FU adjuvant monochemotherapy had the same benefit and the same toxicity for patients aged 70 and over as for younger ones.5 The interest of oxaliplatin associated with 5-FU in terms of benefit and risk for patients aged 70 and over has recently been questioned in studies showing that toxicities were significantly higher with no benefit in terms of disease-free or overall survival.6,7 However, these findings remain controversial among patients aged 70 or 75 and over.8–10 Moreover, current knowledge is based on clinical trial results (or metaanalyses) that include by definition selected patients. This selection bias affects any conclusions that can be drawn. Population-based studies are
S. Hamza et al.
the only way to assess how chemotherapy regimens are administered and tolerated. The aim of the present study was to assess, within a well-defined French cohort, the use and the toxicity of leucovorin adjuvant chemotherapy as administered in current practice in patients aged 70 years and older with stage III colon cancer. METHODS Population A population-based registry records all the digestive tract cancers occurring in a well-defined geographic area (Saone-et-Loire; 553,968 inhabitants according to the 2011 census) in Burgundy, France. Information is regularly obtained from pathologists in public and private practice, public hospitals (university hospitals, including the cancer center, and general hospitals), private physicians (gastroenterologists, surgeons, oncologists, radiotherapists, and general practitioners), hospital administrative databases, the National Health System database, and death certificates. No case was registered through death certificates alone, but these were used to identify missing cases. Because of the multiplicity of clinical and administrative sources, we assumed that nearly all newly diagnosed cases had been recorded. The quality and comprehensiveness of registration is certified every 4 years by an audit of the National Committee on Population-Based Registries. Cancers were classified according to the International Classification of Diseases, 10th revision.11 Cancer extension at the time of diagnosis was classified according to the TNM classification, 1997 revision.12 All patients diagnosed with stage III colon adenocarcinoma between 2004 and 2009 and recorded in the registry were included in the analysis. During the study period, 1365 colon adenocarcinomas were registered, and 328 were classified as stage III. We excluded nine patients who were simultaneously affected by another cancer and 14 postoperative deaths. Among the 305 patients included, 210 (68.8 %) received adjuvant chemotherapy. The chemotherapy used was FOLFOX in 159 patients (75.7 %), fluorouracil/leucovorin alone in 39 patients (18.6 %), capecitabine (Xeloda) alone in nine patients, and fluorouracil/irinotecan, raltitrexed (Tomudex) alone, and oxaliplatin alone in one patient each. Information about possible adverse effects was not found for three patients. The analysis of chemotherapy-related toxicity was limited to the group receiving FOLFOX. Studied Variables The data routinely collected included sex, age at diagnosis, date of diagnosis, comorbidities, place of treatment,
diagnostic strategies, detailed treatment (including adjuvant, neoadjuvant, and palliative chemotherapy and radiotherapy), stage at diagnosis, and vital status of the patients. Additional data necessary to reach the aim of this study were obtained from a specific survey of patients’ medical files. Information was obtained from all clinicians (general practitioners and specialists) involved in the management and the follow-up of these patients. When given, adjuvant chemotherapy was defined as chemotherapy administered after resection with curative intent (R0 resection) for stage III tumors. The reason for the absence of adjuvant chemotherapy was recorded. In practice, 12 cycles of FOLFOX were recommended. Comorbidities at the time of diagnosis were listed by using the Charlson index.13 Individuals were classified into groups based on Charlson comorbidity scores of 0, 1, or C2. Precise data for all administered chemotherapy drugs and corresponding potential related toxicity were recorded according to the World Health Organization classification. The different types of toxicity were gathered in four groups of toxicity: hematologic (neutropenia, thrombopenia, and anemia), neurologic (paresthesias), digestive (anorexia, diarrhea, nausea, vomiting, and constipation), and general (fatigue, weight loss, cardiac complications, and allergic reaction to oxaliplatin) toxicity. Severe toxicity was defined as grade 3 or 4 toxicity. Statistical Analysis Univariate analyses were performed. The association between categorical or quantitative data was analyzed by using Chi square or Student’s test for heterogeneity. The level of statistical significance was set at p = 0.05 in twosided tests. The statistical analysis was conducted in patients less than 70 years and in older patients. Cumulative hematologic, neurologic, digestive, and general toxicity incidence rates were calculated by using the Kaplan–Meier method and were expressed with standard errors. The curves were compared by using the log-rank test. Patients who died were censored at the time of death, and patients who had toxicity were censored at the time of outcome for severe toxicity (grade 3 or 4). Differences in the hazard rate of global, hematologic, neurologic, digestive, general, and severe toxicity (grade 3 or 4) between patients under 70 years and older patients ([70 years) were analyzed by using Cox regression models, adjusting for sex and Charlson index. Two-sided p values less than 0.05 were considered statistically significant. Relative survival rates, defined as the ratio of the observed survival rate in the cancer patients under study to the expected survival rate in a population with similar sex and age distribution, were calculated. Relative survival reflects the excess mortality in the cancer patient group relative to background mortality.
Toxicity of Oxaliplatin in Older Patients TABLE 1 Distribution of patients according to age group and the presence of treatment Variable
Total
[70 years
B70 years Chemotherapy
No chemotherapy
n
%
n
109
95.6
p-Value
Chemotherapy
No chemotherapy
%
n
%
n
%
5
4.4
101
52.9
90
47.1
50 28
58.8 50.0
35 28
41.2 50.0
22
44.9
27
55.1
p-Value
Charlson scorea
a
0 1
71 23
98.6 95.8
1 1
1.4 4.2
C2
13
81.3
3
18.7
0.010
0.267
Unknown for 3 cases
FIG. 1 Kaplan–Meier failure estimates of cumulative rates of global and severe toxicity (3 or 4) toxicity in FOLFOX patients according to age
a
b
Global toxicity (whatever the grade)
Cumulative rate 1.0
P = 0.3555
Cumulative rate 1.0
0.8
0.8
0.6
0.6
0.4
70 years > 70 years
0.2
Severe toxicity (grade 3 or 4) P = 0.576
70 years > 70 years
0.4
0.2 0
2
4 6 8 10 Chemotherapy cycles
Statistical analyses were performed by using STATA (version 11.0; Stata Corporation, College Station, TX). RESULTS Among the 305 stage III patients affected by colon cancer, 210 received adjuvant chemotherapy (68.8 %), and among them 156 had FOLFOX (74.3 %). Reasons for not performing chemotherapy reported by practitioners were heavy comorbidities (37.9 %), old age (29.5 %), patients’ refusal (21.0 %), and postoperative complications (6.3 %). This information was not available for five patients. Patients older than 70 years were less likely to receive chemotherapy (52.9 %) than younger patients (95.6 %; p \ 0.001). Older patients were also less likely than younger patients to complete the recommended twelve cycles of chemotherapy (62 of 100 vs. 87 of 107; p = 0.002). Information concerning the number of cycles administered was unknown for three patients. When we considered only patients who had FOLFOX, there was no significant difference between younger (83.2 % had 12
12
0
2
4 6 8 10 Chemotherapy cycles
12
cycles) and older (72.1 % had 12 cycles; p = 0.100) individuals. Overall, patients aged more than 70 years received 26.7 % less oxaliplatin than did younger patients. Patients who had adjuvant chemotherapy had fewer comorbidities than did nontreated patients (p = 0.002). In the younger age group, the proportion of patients receiving chemotherapy decreased with Charlson score, whereas, in the older age group, there was no difference in comorbidity score between the chemotherapy group and the nontreated group (p = 0.267; Table 1). Figure 1 shows the cumulative rate of all adverse events (whatever the grade) and of severe events C3 according to chemotherapy cycles and age group for patients treated with FOLFOX. There was no difference between cumulative adverse event curves (p = 0.355 for all adverse events; p = 0.576 for severe adverse events). Different adverse events of chemotherapy according to the length of the FOLFOX adjuvant treatment in the two studied age groups are listed in Table 2. The cumulative incidence rate of hematologic toxicity after 12 chemotherapy cycles was 45.9 % in patients less than 70 years
S. Hamza et al. TABLE 2 Cumulative incidence rates for the different adverse events by duration of chemotherapy and age group for patients treated with FOLFOX [70 years
B70 years
p-Value
Variable
Cycle 4
Cycle 8
Cycle 12
Cycle 4
Cycle 8
Cycle 12
Global toxicity
74.2
82.4
86.2
71.4
89.6
93.7
0.355
Hematologic toxicity
16.5
37.2
45.9
22.3
40.5
43.4
0.920
Neurologic toxicity Digestive toxicity
54.6 36.1
72.0 45.6
78.0 52.4
45.9 41.1
58.4 54.0
72.3 61.2
0.271 0.378
General toxicity
25.7
38.8
47.9
32.9
57.0
64.2
0.095
12.4
25.1
31.4
11.8
23.6
39.0
0.576
Severe toxicity
and 43.4 % in older patients (p = 0.920). The corresponding cumulative incidence rates were respectively 78.0 and 72.3 % for neurologic toxicity (p = 0.271), 52.4 and 61.2 % for digestive toxicity (p = 0.378), and 47.9 and 64.2 % for general toxicity (p = 0.095). Among cases of general toxicity, there were four allergic reactions to oxaliplatin and five cardiac complications. For all grade C3 toxicities, the cumulative rate was 31.4 % for those under 70 years and 39.0 % in older patients (p = 0.576). Neurologic toxicity appeared earlier than other toxicities. From the eighth cycle onward, toxicity rates became steady. The description of side effects according to their severity and age group is given in Table 3. Severe grade 3 toxicity was reported in 27.3 % of the patients and grade 4 in 7.7 %. There was no statistically significant difference in the severity of side effects between patients under 70 and older patients (grade 3 or 4, 29.9 vs. 42.8 %; p = 0.354). Overall, severe adverse events consisted of hematologic toxicity (25.4 %), neurological toxicity (9.1 %), digestive toxicity (11.1 %), and general toxicity (27.5 %). Table 4 presents the Cox regression model for the risk of developing adverse events according to the two studied age groups, unadjusted or adjusted for sex and comorbidity. Patients receiving FOLFOX in both age groups were equally as likely to be affected by hematologic, neurologic, digestive, or general adverse events. The Cox model also confirmed the absence of difference when considering global toxicity and severe toxicity. Chemotherapy was not associated with an increased risk of severe side events C3 in patients over 70 compared with younger patients (hazard ratio, 1.28; 95 % CI 0.68–2.41; p = 0.439). The 3-year relative survival rate did not differ in patients receiving FOLFOX. It was 90.0 % in patients under 70 and 84.3 % in those 70 and over (p = 0.806). DISCUSSION The strength of the study lies in the fact that it was population based. Because of the involvement of the entire medical profession and the multiplicity of information
TABLE 3 Description of side effects according to their severity and age group in patients receiving FOLFOX Toxicity
B70 years
[70 years
(n = 87)
(n = 56) n
p-Value
n
%
%
No toxicity
13
14.9
Grade 1
11
12.7
4
7.1
Grade 2
37
42.5
24
42.9
Grade 3
20
23.0
19
33.9
Grade 4
6
6.9
5
9.0
4
7.1
0.354
Missing data 13 cases
sources, it can be assumed that all newly diagnosed cases were recorded. Information on adverse events was almost complete and collected by a specially trained staff. The findings are particularly important as they truly reflect how patients are treated in everyday practice in a country where chemotherapy in public and private practice is provided free of charge to patients. However, one limit of the study was its relatively small size. We cannot exclude the possibility that some differences may become significant with a larger number of patients. However, none of the reported differences was borderline significant. Several population-based studies have highlighted the undertreatment of elderly patients.14–16 There are several possible reasons for this inequality: reluctance of doctors, patients’ refusal, comorbidities, more frequent or more serious adverse reactions, and uncertainty about the gains in clinical effectiveness brought by new drugs in these patients. Moreover, the age at which a patient is considered elderly varies widely and is based on chronologic rather than physiologic age.17 Only half of the elderly patients with no associated comorbidity received adjuvant chemotherapy with FOLFOX, compared with 97 % in younger patients. This major discrepancy suggests that a larger proportion of elderly patients should receive adjuvant chemotherapy. It seems that comorbidity is not the only
Toxicity of Oxaliplatin in Older Patients TABLE 4 Risk of developing adverse events in the two studied age groups (Cox model) Variable
Unadjusted
Adjusted
HR
HR
(95 % CI)
(95 % CI)
Global toxicity B 70 years
1
[ 70 years 1.16 Hematologic toxicity B 70 years
1
[ 70 years
1.03
1 (0.81–1.65)
1.21
(0.83–1.77)
1 (0.60–1.77)
0.95
(0.52–1.73)
Neurologic toxicity B 70 years
1
[ 70 years
0.81
1 (0.53–1.22)
0.82
(0.53–1.26)
Digestive toxicity B 70 years
1
[ 70 years
1.22
1 (0.76–1.95)
1.21
(0.73–2.01)
General toxicity B 70 years
1
[ 70 years
1.47
1 (0.92–2.36)
1.33
(0.80–2.22)
Severe toxicity B 70 years
1
[ 70 years
1.27
1 (0.70–2.30)
1.28
(0.68–2.41)
CI confidence interval Adjusted for sex and Charlson comorbidity index
explanation for undertreatment. In a previous study, we provided evidence that adjuvant chemotherapy for colon cancer did not have a negative effect on the quality of life of elderly patients. This should encourage clinicians to treat these patients.18 The risk of toxicity is not sufficient to justify withholding chemotherapy of elderly patients with stage III colon cancer. However, we cannot exclude that the selection of patients could, at least partly, explain the similar toxicity in the elderly and younger patients. An American study suggested that the primary determinant of an elderly patient’s decision to accept or decline chemotherapy was their physician’s advice.19 This finding suggests that physician’s awareness of chemotherapy for the elderly must be improved. Treatment decisions should be taken in the context of a multidisciplinary meeting. If necessary, a comprehensive geriatric assessment should assist practitioners in the selection of patients with stage III colon cancer who appear unlikely to benefit from adjuvant chemotherapy. Although using 5-FU monotherapy in elderly patients gives the same benefit/risk ratio as for their younger counterparts, with no significant increase in toxic effects, there are some worries concerning the addition of oxaliplatin to the 5-FU regimens in this population.5 As regards oxaliplatin, the NSABP C-08 trial showed a significantly higher rate of grade 4 and 5 toxicity,
according to the National Cancer Institute Common Terminology Criteria for Adverse Events, among patients older than 69 years treated with oxaliplatin.6 A pooled analysis conducted in 2006 showed that FOLFOX 4 maintained its efficacy and safety in selected patients older than 70 years, except for hematologic toxicity, which was significantly more severe in elderly patients.8 An American randomized trial confirmed the benefit of the addition of oxaliplatin to fluorouracil on disease-free survival only in patients younger than age 70.20 Patients aged 70 years or older receiving FOLFOX were more likely to experience grade 3 or 4 toxicity than were those receiving 5-FU monotherapy. A large US study using data from two population-based cohorts (the SEER database and the New York State Cancer Registry) linked with Medicare also indicated that in patients older than 75 years, adverse events were more frequent in patients treated with 5-FU and oxaliplatin than in those treated with 5-FU alone.9 Study of this database also suggested that in a real-world setting, patients 75 years and older receiving FOLFOX had a survival benefit of the same order of magnitude as that reported in clinical trials (MOSAIC and NSABP-C-07). The present study provides complementary data to the US study by showing that there was no significant difference between very elderly and younger patients for overall toxicity and severe toxicity. Furthermore, survival rates did not differ between age groups. In the absence of randomization, the comparison of survival rates must be interpreted with caution. However, there was a trend toward a higher frequency of digestive and general toxicity, and neurologic toxicity can be severely incapacitating in the elderly. In conclusion, we demonstrated at a population level that tolerance to the FOLFOX regimen among elderly stage III colon cancer patients did not differ significantly from that in younger patients. However, there was a trend toward more frequent digestive and general toxicity in patients 70 years and above, and the treatment discontinuation rate was higher in older patients. The decision to recommend FOLFOX should be considered without regard to patients’ age alone, but consideration should be given to the patient’s overall state of health and potential for tolerating adverse events. Elderly patients need more attention regarding their functional, social, and mental status. Taking into account the data reported in this study, we suggest a more aggressive attitude in the elderly than actually proposed based on patient-by-patient decisions taken in multidisciplinary meetings after a thorough geriatric assessment whenever necessary. Given the increasing number of older patients with colon cancer and the continuing increase in life expectancy, identifying safe and effective therapies for elderly patients is imperative.
S. Hamza et al. ACKNOWLEDGMENT This work was supported by a Grant from the Ligue Re´gionale Contre le Cancer (2010). The authors thank all the gastroenterologists for their involvement: Drs. Abdelmajid, Andre´, Bellecoste, Bruneton, Derreveaux, El Khaddari, Fabre, Grozel, Guillaume, Lacourt, Levenq, Naouri, Petigny, Ramond, Saggio, Soupison, and Van Nieuwenhuyse. They also thank all the private and public physicians, specialists, and pathologists for their collaboration. DISCLAIMER None of the authors has any conflicts of interest to declare regarding this study.
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