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VOLUME           27        NUMBER      6    FEBRUARY       20   2009



        JOURNAL OF CLINICAL ONCOLOGY                                                            O R I G I N A L             R E P O R T




                                              Evidence for Cure by Adjuvant Therapy in Colon Cancer:
                                              Observations Based on Individual Patient Data From 20,898
                                              Patients on 18 Randomized Trials
                                              Daniel Sargent, Alberto Sobrero, Axel Grothey, Michael J. O’Connell, Marc Buyse, Thierry Andre, Yan Zheng,
                                              Erin Green, Roberto Labianca, Chris O’Callaghan, Jean Francois Seitz, Guido Francini, Daniel Haller,
                                              Greg Yothers, Richard Goldberg, and Aimery de Gramont
From the Divisions of Biostatistics and
Medical Oncology, Mayo Clinic, Roch-                                                 A    B    S    T   R   A   C    T
ester, MN; Department of Biostatistics,
University of California, Los Angeles,        Purpose
Los Angeles, CA; National Surgical            Limited data are available on the time course of treatment failures (recurrence and/or death), the
Adjuvant Breast and Bowel Project             nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with
Operations Office and Biostatistical           resected stage II and III colon cancer.
Center, Pittsburgh; Abramson Cancer
Center at the University of Pennsylva-        Methods
nia, Philadelphia, PA; University of          The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual
North Carolina, Chapel Hill, NC; Medical      patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant
Oncology, Ospedale S. Martino,                therapy in patients with stage II or III colon cancer, was analyzed.
Genova; Ospedali Riuniti, Bergamo;
University of Siena, Siena, Italy; Interna-   Results
tional Drug Development Institute,            A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year
Louvain-la-Neuve, Belgium; Hopital            follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never
Pitie-Salpetiere, Paris; University of the    exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed
Mediterranean, Marseilles; Hopital Saint      to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8
Antoine, Paris, France; and National
                                              years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from
Cancer Institute of Canada Clinical
Trials Group, Queens University, King-
                                              adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and
ston, Ontario, Canada.                        control patients were not significantly different, and after 4 years, no trend toward benefit was
Submitted August 8, 2008; accepted
                                              demonstrated. This benefit was primarily driven by patients with stage III disease.
October 1, 2008; published online             Conclusion
ahead of print at www.jco.org on              Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence
January 5, 2009.
                                              rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into
Written on behalf of the Adjuvant Colon       long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After
Cancer Endpoints Group.                       5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are
Supported by National Cancer Institute        minimal; thus, long-term follow-up for recurrence is of little value.
Grants No. CA 25224, CA 12027, CA
69974, CA 37377, and CA 69651.                J Clin Oncol 27:872-877. © 2009 by American Society of Clinical Oncology
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this                                                                      apparently leads to long-term benefits in outcome,
                                                                INTRODUCTION
article.                                                                                                usually measured in terms of 3- and 5-year rates of
Corresponding author: Daniel Sargent,         Approximately 145,000 new patients with colorectal        OS or DFS.
PhD, Professor of Biostatistics and
                                              cancer are diagnosed annually in the United States.            Graphical presentations of survival or recur-
Oncology, Division of Biomedical Statis-
tics and Informatics, Mayo Clinic, 200        When diagnosed at a stage when curative surgical          rence data from clinical trials, typically presented
1st St SW, Rochester, MN 55905;               resection is possible, fluorouracil (FU)-based adju-       using Kaplan-Meier plots, convey information re-
e-mail: sargent.daniel@mayo.edu.
                                              vant chemotherapy for colon cancer has repeatedly         garding the absolute rate of recurrence, DFS, and OS
The Appendix is included in the               been shown to improve patient overall survival            at any given time point. However, these plots do not
full-text version of this article,
available online at www.jco.org.
                                              (OS). FU with leucovorin became standard of care          readily convey the risk of an event at a specific time
It is not included in the PDF version         for patients with stage III and selected stage II colon   point, and a separation in survival curves does not
(via Adobe® Reader®).                         cancer in the early 1990s1-4 and provided the basis       convey the interpretation of an early advantage
© 2009 by American Society of Clinical        for the addition of oxaliplatin, which has been dem-      that is maintained over time as opposed to a con-
Oncology
                                              onstrated to further improve disease-free survival        tinued difference in the relative risk of an event.
0732-183X/09/2706-872/$20.00
                                              (DFS) and OS in stage III patients.5,6 Although ad-       Therefore, the clinical demonstration of actual
DOI: 10.1200/JCO.2008.19.5362                 juvant chemotherapy is routinely administered for         cure of patients by adjuvant therapy is poorly
                                              only a limited duration of time (usually 6 months), it    understood, both in colorectal cancer and in

872    © 2009 by American Society of Clinical Oncology
                        Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission.
                                    Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
Curative Adjuvant Therapy in Colon Cancer



other solid tumors. More detailed information on the time course                  over time. This is in contrast to the usual estimated HR from a Cox propor-
of recurrence, such as both short- and long-term year-by-year                     tional hazards regression, which assumes that the HR between the two treat-
failure rates stratified by untreated and treated patients, may assist             ment arms has a single value that is constant over time. Hazard rates over time
                                                                                  were estimated by the method of Muller and Wang.8 HRs, with 95% pointwise
                                                                                                                       ¨
in patient counseling and in determining follow-up recommenda-
                                                                                  CIs, were estimated using the method of Gilbert et al.9 The end points of OS,
tions. Furthermore, such analyses also provide information on the                 DFS, and time to recurrence (TTR) were considered. OS is defined as time to
long-standing question of whether adjuvant therapy in colon can-                  death from any cause. DFS is defined as the time to recurrence or death,
cer completely eradicates tumor cells, thus allowing for higher cure              whichever occurs first. TTR is defined as the time to disease recurrence, where
rates, or whether treatment only delays tumor recurrence. On the                  deaths without recurrence were censored at the time of death. Recurrence was
basis of individual patient data from 20,898 patients randomly                    defined only by a reappearance of primary colon cancer; second primary colon
assigned on 18 trials of adjuvant therapy for colon cancer, we                    cancers or other noncolon cancers were not classified as recurrences. Because
                                                                                  the definitions of these terms (DFS and TTR) were not consistent across all
studied the time course of treatment failure and long-term recur-                 included trials, the definitions here may differ from those used in the original
rence rates.                                                                      trial. The analysis of the overall treatment benefit was performed with a
                                                                                  log-rank test comparing treatment with control, stratified by the original trial.
                                                                                         Analyses comparing FU-based treatment with control were limited to
                                 METHODS                                          the nine trials with a no-treatment control arm (n 4,922; National Surgical
                                                                                  Adjuvant Breast and Bowel Project [NSABP] C-01 and C-02, North Central
The data set assembled by the Adjuvant Colon Cancer Endpoints (ACCENT)            Cancer Treatment Group [NCCTG] 784852, Federation Francophone de
                                                                                                                                      ´ ´
Group was used for all analyses.7 As previously described, ACCENT identified       Cancerologie Digestive, Intergroup 0035, Interdisciplinary Group for Cancer
                                                                                         ´
and obtained individual patient data from 18 phase III adjuvant trials in colon   Care Evaluation, NCCTG 874651, Siena, and National Cancer Institute of
primary tumors conducted from 1978 to 1999. A total of 20,898 patients and        Canada trials in Table 1). Because of inconsistent long-term follow-up for the
43 distinct treatment arms (34 active treatment arms and nine surgery-only        hazard rate and HR analyses, all patients were censored at 8 years for analysis of
arms) are included in the ACCENT database. Table 1 and Appendix Table             treatment benefit. Long-term event rates were estimated using data from all
A1 (online only) list the details regarding the trials and patient character-     trials where the median follow-up time for living patients exceeded 9 years
istics, respectively.                                                             (eight trials, n 11,615; NCCTG 784852, Intergroup 0035, Intergroup 0089,
       This analysis focused on continuous time estimation of the hazard rate     and NSABP C-01, C-02, C-03, C-04, and C-05 trials in Table 1).
(risk of recurrence or death) by treatment over time, as well as the continuous
time estimation of the hazard ratio (HR) comparing FU-based treatment with
control. The continuous time estimation of these rates and ratios allows the                                         RESULTS
risk of an event (for hazard rates) and benefit of treatment (for HRs) to vary
                                                                                  Hazard Rates
                                                                                        Of the 20,898 patients, 35% experienced recurrence and 38%
                                                                                  died in the initial 8-year follow-up period. Sixty-six percent of patients
                            Table 1. Trials Included                              had stage III disease, and 33% had stage II disease. When the analyses
                     Accrual                                         No. of       were restricted to the 4,922 patients on trials in which they were
        Trial        Period               Treatment Arms            Patients      randomly assigned to adjuvant treatment versus surgery alone, 1,670
 NSABP C-01         1977-1983    Control v MOF                          724       patients (34%) experienced recurrence, and 1,910 patients (39%)
 NCCTG 784852       1978-1984    Control v FU/LEV                       247       died. Traditional Kaplan-Meier plots of OS by stage for patients ran-
 FFCD               1982-1990    Control v FU/LV                        239
                                                                                  domly assigned to treatment versus control are presented in Figure 1.
 NSABP C-02         1984-1988    Control v PVI FU                       896
 INT 0035           1984-1987    Control v FU/LEV                       926
                                                                                        To provide additional insight into the time-related nature of
 Siena              1985-1990    Control v FU/LV                        256       adjuvant therapy benefit, hazard rates over time for OS, DFS, and TTR
 NCIC               1987-1992    Control v FU/LV                        359       by treatment group are shown in Figure 2. For both treated and
 NSABP C-03         1987-1989    MOF v FU/LV                          1,042       untreated patients, the risk of death from any cause (Fig 2A) peaks at
 NCCTG 874651       1988-1989    Control v FU/LV                        408       approximately 2 years after surgery and gradually declines over the
 GIVIO              1989-1992    Control v FU/LV                        867
                                                                                  8-year estimation period. For the DFS and TTR end points (Figs 2B
 NCCTG 894651       1989-1991    FU/LV LEV for 6 or 12 months           915
 NSABP C-04         1989-1990    FU/LEV v FU/LV v FU/LV/LEV           2,083
                                                                                  and 2C), in untreated patients, the risk of an event clearly is highest in
 INT 0089           1990-1992    FU/LEV v FU/LV (HD or LD) v          3,561       the year after surgery, with a rapid reduction until approximately year
                                   FU/LV/LEV                                      4. The failure rate in treated patients is low initially and then increases
 NSABP C-05         1991-1994    FU/LV v FU/LV IFN                    2,136       in years 1 to 3, only to recede close to the rate in untreated patients by
 NCCTG 914653       1993-1998    FU/LV HD or standard LEV               878       year 4. The DFS curves (Fig 2B) remain slightly separated in years 4 to
 SWOG 9415          1994-1999    Bolus v infusional FU/LEV/LV           939
                                                                                  8 between treatment and control, whereas the TTR curves (Fig 2C) are
 QUASAR             1994-1997    FU/LV (HD or LD) LEV                 3,517
 GERCOR             1996-1999    Bolus v infusional FU/LV               905
                                                                                  virtually superimposable in that time period. For none of the end
 Total                                                               20,898       points does the failure rate for treated patients ever exceed that of the
                                                                                  untreated patients during the 8-year follow-up period.
 Abbreviations: NSABP, National Surgical Adjuvant Breast and Bowel Project;
MOF, semustine, vincristine, and fluorouracil; NCCTG, North Central Cancer               These patterns of treatment failure over time are substantially
Treatment Group; FU, fluorouracil; LEV, levamisole; FFCD, Fédération Fran-         different for stage II and stage III patients (Fig 3). In stage III patients,
cophone de Cancérologie Digestive; LV, leucovorin; PVI, protracted venous
infusion; INT, Intergroup; NCIC, National Cancer Institute of Canada; GIVIO,      the absolute risk of a DFS event is greater than for stage II patients in
Interdisciplinary Group for Cancer Care Evaluation; HD, high dose; LD, low        the first 4 years of follow-up, becoming similar after years 5 to 6 as the
dose; IFN, interferon alfa-2a; SWOG, Southwest Oncology Group; QUASAR,
Quick and Simple and Reliable Collaborative Group; GERCOR, French Multi-
                                                                                  DFS end point becomes dominated by death events. In addition, the
disciplinary Clinical Research Group.                                             relative benefit of treatment is considerably larger in stage III patients,
                                                                                  with a longer duration of benefit. In stage II patients, the modest early

www.jco.org                                                                                                      © 2009 by American Society of Clinical Oncology   873
                   Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission.
                               Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
Sargent et al




  A                                                                                                              A
                              100                                                                                              0.0006                                         Control Arms
                                                                                                                                                                              Experimental Arms
                               90
      Overall Survival (%)




                               80




                                                                                                                 Hazard Rate
                               70
                                                                                                                               0.0004
                               60
                               50
                                                     Surgery Alone
                               40                    8-year OS Rate (95% CI): 54.3% (52.2% to 56.4%)

                               30                    Surgey + FU-Based Chemotherapy                                            0.0002
                                                     8-year OS Rate (95% CI): 61.5% (59.5% to 63.6%)
                               20
                               10     P < .0001

                                0          1        2        3        4        5       6        7      8                           0          2                 4                6                8
                                                        Follow-Up Time (years)                                                                    Follow-Up Time (years)
  B                                                                                                              B
                              100                                                                                              0.0006                                         Control Arms
                               90                                                                                                                                             Experimental Arms
      Overall Survival (%)




                               80
                               70



                                                                                                                 Hazard Rate
                                                                                                                               0.0004
                               60
                               50
                                                     Surgey Alone
                               40                    8-year OS Rate (95% CI): 66.8% (63.7% to 70.0%)

                               30                    Surgey + FU-Based Chemotherapy                                            0.0002
                                                     8-year OS Rate (95% CI): 72.2% (69.3% to 75.2%)
                               20
                               10     P = .026

                                0          1        2        3        4        5       6        7      8
                                                                                                                                   0          2                 4                6                8
                                                        Follow-Up Time (years)                                                                    Follow-Up Time (years)
  C
                              100                                                                                C
                                                                                                                               0.0006
                               90                                                                                                                                             Control Arms
                                                                                                                                                                              Experimental Arms
      Overall Survival (%)




                               80
                               70
                                                                                                                 Hazard Rate




                               60                                                                                              0.0004
                               50
                               40                    Surgey Alone
                                                     8-year OS Rate (95% CI): 42.7% (39.9% to 45.7%)
                               30
                                                     Surgey + FU-Based Chemotherapy                                            0.0002
                               20                    8-year OS Rate (95% CI): 53.0% (50.2% to 55.9%)
                               10     P < .0001

                                0          1        2        3        4        5       6        7      8
                                                                                                                                   0          2                 4                6                8
                                                        Follow-Up Time (years)
                                                                                                                                                  Follow-Up Time (years)
  Fig 1. Kaplan-Meier plots of overall survival (OS) in treatment arm versus
control arm for (A) all patients, (B) stage II patients, and (C) stage III patients.                             Fig 2. Hazard rates by time from random assignment and treatment arm. Plots
FU, fluorouracil.                                                                                               of the hazard rate for (A) overall survival, (B) disease-free survival, and (C) time to
                                                                                                               recurrence by arm (treatment and control) over the 8-year follow-up period. The
                                                                                                               y axis plots the risk of recurrence on a daily scale; thus, for example, the value
                                                                                                               0.0002 represents an annualized 7.3% risk of an event (0.0002 365 0.073).
benefit in reducing DFS events is entirely absent after 2 to 3 years,
whereas in stage III patients, it remains for at least 4 years.                                                time. In contrast, in Figures 4B and 4C, there is a substantial benefit of
     HRs (with 95% pointwise CIs) comparing patients on the treat-                                             adjuvant therapy in reducing the risk of a DFS or recurrence event the
ment versus control arms of trials, plotted on the logarithmic scale, for                                      first 1 to 2 years after resection (estimated log-HR in the range of
the OS, DFS, and TTR end points are shown in Figure 4. Figure 4A                                                 0.50; HR 0.61) that diminishes over time and becomes nonsignif-
demonstrates that the addition of adjuvant therapy provides a consis-                                          icant (based on 95% pointwise CIs) after year 4, signifying that the
tent and durable beneficial effect on OS over the follow-up period,                                             DFS and recurrence rates are statistically similar between treatment
with an estimated log-HR of 0.30 (HR 0.74) that is consistent over                                             and control arms after 4 years.

874                          © 2009 by American Society of Clinical Oncology                                                                                           JOURNAL OF CLINICAL ONCOLOGY
                                           Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission.
                                                       Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
Curative Adjuvant Therapy in Colon Cancer




 A                                                                                  A                      1.0
                0.0010
                                                         Control Arms
                                                         Experimental Arms
                                                                                                           0.5




                                                                                        Log Hazard Ratio
  Hazard Rate




                                                                                                           0.0
                0.0006

                                                                                                           -0.5


                                                                                                           -1.0

                0.0002
                                                                                                           -1.5       95% pointwise CIs


                                                                                                           -2.0
                    0            2             4              6              8
                                                                                                                  0       2               4             6              8
                                     Follow-Up Time (years)
                                                                                                                                Time (years)
 B
                0.0010                                                              B                      1.0
                                                         Control Arms
                                                         Experimental Arms
                                                                                                           0.5




                                                                                        Log Hazard Ratio
                                                                                                           0.0
  Hazard Rate




                0.0006

                                                                                                           -0.5


                                                                                                           -1.0

                0.0002
                                                                                                           -1.5
                                                                                                                      95% pointwise CIs


                    0            2             4              6              8                             -2.0

                                     Follow-Up Time (years)                                                       0       2               4             6              8
                                                                                                                                Time (years)
   Fig 3. Disease-free survival hazard rates by time from random assignment and     C                      1.0
treatment arm in (A) stage II patients and (B) stage III patients.

                                                                                                           0.5
                                                                                        Log Hazard Ratio




Long-Term Recurrence Rates                                                                                 0.0
      Of the 20,898 patients, 11,615 were enrolled onto trials where the
median follow-up time exceeds 9 years. Figure 5 presents the recur-
                                                                                                           -0.5
rence rates, by 6-month intervals, to 15 years of follow-up. After 5
years, the recurrence rate by year never exceeds 1.5%, and after 8 years,
                                                                                                           -1.0
it never exceeds 0.5%.

                                                                                                           -1.5
                                     DISCUSSION
                                                                                                           -2.0       95% pointwise CIs

These results illustrate the following three important concepts for the                                           0       2               4             6              8
management of early colon cancer: adjuvant FU-based treatment
                                                                                                                                Time (years)
actually eradicates colon cancer cells, thereby curing patients; late
relapses can occur, but after 8 years, the notion of cure is appropriate;            Fig 4. Continuous time estimate of the log-hazard ratios for (A) overall survival,
and most relapses occur in the first 2 years after surgery. These con-             (B) disease-free survival, and (C) time to recurrence comparing treatment arm
cepts are relevant to our understanding of tumor biology, clinical                with control arm over the 8-year follow-up period, with 95% pointwise CIs.
                                                                                  Values less than 0 indicate a benefit from treatment. For example, a value of
practice, and future clinical trial design.                                         0.50 for the log-hazard ratio indicates a hazard ratio of 0.61 comparing
      A previous pooled analysis of FU-based adjuvant colon cancer                treatment with control at that time point (e– 0.50 0.61), that is, a 39% reduction
                                                                                  in the risk of an event.
trials demonstrated a highly statistically significant 11% absolute
improvement in 5-year freedom from recurrence as a result of FU-
based adjuvant therapy.10 In the current analysis, including additional

www.jco.org                                                                                                                © 2009 by American Society of Clinical Oncology   875
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                                     Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
Sargent et al


                                                                                                  over time, because few late recurrences are to be expected. However,
                    8                                                                             although irinotecan combined with FU and leucovorin produces a
                    7                                                                             benefit similar to oxaliplatin with FU and leucovorin in the advanced
                                                                                                  disease setting, this benefit has failed to translate into any significant
  Recurrene Rate



                    7
                    5                                                                             benefit when irinotecan is added to adjuvant FU and leucovorin.12,13
                    4                                                                             Therefore, the empirical data demonstrate that the paradigm that
                    3                                                                             efficacy in advanced disease leads to efficacy in the adjuvant setting is
                                                                                                  indeed agent dependent. Extending this concept to other tumors, the
                    2
                                                                                                  positive early experience with adjuvant trastuzumab in breast cancer14
                    1
                                                                                                  and adjuvant imatinib in GI stromal cell tumors15 provides hope that
                    0      1    2    3    4    5    6    7   8       9   10   11 12 13 14 15      this paradigm will hold for biologic agents as well. More specifically,
                                                                                                  this concept is relevant to the adjuvant therapy of colon cancer because
                                                        Year                                      clinical trials using oxaliplatin with FU and leucovorin plus either
  Fig 5. Risk of recurrence in each 6-month interval after random assignment                      bevacizumab or cetuximab have completed or are about to complete
among patients remaining recurrence free at the start of each interval, by time.                  accrual or are ongoing (NSABP C-08; AVANT; E5202; Quick and
                                                                                                  Simple and Reliable Collaborative Group-2: bevacizumab; NCCTG
                                                                                                  N0147; and PETACC-8: cetuximab).16 However, the unique mecha-
patients, overall adjuvant therapy resulted in a 7% improvement in                                nism of action of these biologic agents may require additional years of
8-year OS rate (5% in stage II patients and 10% in stage III patients).                           follow-up before conclusions regarding a relapse-delaying versus a
Because the current analysis included two trials without FU/leucov-                               curative effect of these complex treatments can be reliably ascertained.
orin or FU/levamisole chemotherapy arms, these survival improve-                                  It is possible that biologic agents such as angiogenesis inhibitors might
ments likely underestimate the true survival benefit of FU and                                     delay the occurrence of detectable metastatic disease without actually
leucovorin therapy. Importantly, in the current analysis, the hazard                              eradicating tumor cells, thereby leading to improvements in early DFS
rates of OS, DFS, and TTR in treated patients never exceed the corre-
                                                                                                  without affecting long-term OS.16 Regardless of the agent’s mecha-
sponding rates in untreated patients, at least in the 8-year follow-up
                                                                                                  nism of action, as survival after recurrence is extended by effective
period reported here. The lack of any crossing of the hazard rate curves
                                                                                                  therapy for metastatic disease, longer term follow-up is likely to be
indicates that adjuvant therapy is a curative intervention by intent. If
                                                                                                  required to establish a long-term survival benefit.17
therapy simply delayed, as opposed to prevented, recurrences, we
                                                                                                         Our results also provide valuable data to clinical practice regard-
would expect the TTR hazard rate for treated patients to eventually
                                                                                                  ing the long-term risk of recurrence in patients with colon cancer who
exceed the rate in the untreated patients. Instead, the hazard rates
                                                                                                  undergo curative resection. We have previously demonstrated that
separate between 6 months and 2 years from random assignment, a
                                                                                                  80% of colon cancer patients who experienced recurrence in the first 8
time perfectly compatible with the effect of chemotherapy. In addi-
                                                                                                  years after surgery do so in the first 3 years.7 These new results not only
tion, at least in the 8-year follow-up period, the fact that the OS hazard
                                                                                                  confirm this finding, but also demonstrate that the risk of recurrence
rate in the treated patients remains lower than in the untreated pa-
tients supports the lack of a meaningful detrimental long-term effect                             continues to be low for up to 15 years of follow-up. On the basis of this
of FU-based chemotherapy, as measured by OS.                                                      information, from a clinical trials perspective, there is little value in
      Itmaybeconsideredsurprisingthatsingle-agentFU-basedchem-                                    mandating follow-up for recurrence beyond 5 years in future adjuvant
otherapy, which produces only a modest benefit in the advanced                                     colon cancer trials. From a clinical perspective, once a patient has been
disease setting (consistent response rate of 15%, progression-free sur-                           recurrence free for 5 years from surgery, continued medical care can
vival time of 4 month, and median survival time of 11 to 12 months),                              focus on other issues beyond the patient’s prior colon cancer such as
ultimately leads to an approximate 10% cure rate in the pooled pop-                               long-term adverse effects of the adjuvant therapy or secondary can-
ulation of high-risk stage II and III patients included in these trials                           cers, which are issues that may be more clinically relevant and preva-
when used in the adjuvant setting. Biologic plausibility may tempt us                             lent in these patients.
to extend this paradigm to combinations of newer cytotoxic drugs                                         Finally, these analyses clearly demonstrate that in untreated pa-
(oxaliplatin and irinotecan) or to targeted agents such as bevacizumab                            tients, the risk of recurrence is dominated by the early postsurgical
or cetuximab, and beyond (biologics). However, great caution must                                 period, in particular the first 2 years. The clear major benefit of adju-
be exercised. The results to date in the adjuvant setting demonstrate                             vant therapy is to significantly and meaningfully reduce this risk of
that the paradigm of predicting activity in the adjuvant setting based                            early recurrence by approximately 40%. From years 2 to 4, the TTR
on studies in advanced disease works for combining oxaliplatin with                               and DFS rates remain slightly reduced in patients receiving adjuvant
FU and leucovorin. On the basis of the results of the Adjuvant                                    therapy; however, the magnitude of benefit is clearly less than in the
Treatment of Colon Cancer (MOSAIC) trial,5 the 20% improve-                                       early time period. Careful follow-up in the first 5 years for recurrence
ment in response rate and 3 months of additional PFS time afforded                                is critical because an increasing number of patients found to have early
by infusional FU, leucovorin, and oxaliplatin compared with FU and                                recurrence have the potential for cure by salvage surgery.18,19 The OS
leucovorin in the advanced setting translate into an approximately                                hazard rate and HR plots (Figs 2A and 3A) indicate that this short-
additional 7% gain in 3-year DFS in the adjuvant setting for stage III                            term reduction in risk of recurrence translates into long-term advan-
patients. Recently, this early DFS improvement has translated into a                              tages in OS. As previously discussed,20 this early effect of adjuvant
longer-term OS benefit after 6 years of follow-up.11 Our findings                                   chemotherapy could further reduce the required time to obtain rele-
suggest that this OS benefit will be maintained and may even grow                                  vant information from clinical trials in the adjuvant setting.

876                © 2009 by American Society of Clinical Oncology                                                                                JOURNAL OF CLINICAL ONCOLOGY
                                 Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission.
                                             Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
Curative Adjuvant Therapy in Colon Cancer



      Continued analyses of large datasets, such as ACCENT, provide                      Financial support: Daniel Sargent
valuable information that is useful to statisticians (eg, the adequacy of                Administrative support: Daniel Sargent, Axel Grothey, Erin Green
statistical models), clinical trialists (eg, event rates over time), and                 Provision of study materials or patients: Daniel Sargent, Michael J.
practicing oncologists (eg, surveillance patterns and prediction of cure                 O’Connell, Thierry Andre, Erin Green, Roberto Labianca, Chris
                                                                                         O’Callaghan, Jean Francois Seitz, Guido Francini, Daniel Haller,
rates). The ACCENT group will continue to seek to include data from
                                                                                         Aimery de Gramont
all large randomized adjuvant colon cancer clinical trials to update                     Collection and assembly of data: Daniel Sargent, Michael J. O’Connell,
these findings from single-agent FU adjuvant studies with data from                       Yan Zheng, Erin Green, Roberto Labianca, Chris O’Callaghan, Jean
current and next-generation treatment regimens.                                          Francois Seitz, Guido Francini, Greg Yothers, Aimery de Gramont
                                                                                         Data analysis and interpretation: Daniel Sargent, Alberto Sobrero,
                                                                                         Marc Buyse, Yan Zheng, Erin Green, Daniel Haller, Greg Yothers,
         AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
                         OF INTEREST                                                     Aimery de Gramont
                                                                                         Manuscript writing: Daniel Sargent, Alberto Sobrero, Axel Grothey,
The author(s) indicated no potential conflicts of interest.                               Michael J. O’Connell, Marc Buyse, Thierry Andre, Erin Green, Roberto
                                                                                         Labianca, Daniel Haller, Richard Goldberg, Aimery de Gramont
                                                                                         Final approval of manuscript: Daniel Sargent, Alberto Sobrero, Axel
                          AUTHOR CONTRIBUTIONS                                           Grothey, Michael J. O’Connell, Marc Buyse, Thierry Andre, Yan Zheng,
                                                                                         Erin Green, Roberto Labianca, Chris O’Callaghan, Jean Francois Seitz,
Conception and design: Daniel Sargent, Axel Grothey, Marc Buyse, Yan                     Guido Francini, Daniel Haller, Greg Yothers, Richard Goldberg,
Zheng, Daniel Haller, Aimery de Gramont                                                  Aimery de Gramont

                                                           primary end point for adjuvant colon cancer studies:          15. DeMatteo R, Owzar K, Maki R, et al: Adjuvant
                   REFERENCES                              Individual patient data from 20,898 patients on 18         imatinib mesylate increases recurrence free survival
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Levamisole and fluorouracil for adjuvant therapy of         under random censoring with varying kernels and            American Intergroup Phase III trial ACOSOG Z9001.
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358, 1990                                                       9. Gilbert PB, Wei LJ, Kosorok MR, et al: Simul-         16. Grothey A: Biological therapy and other novel
    2. Wolmark N, Rockette H, Mamounas EP, et al:          taneous inferences on the contrast of two hazard           therapies in early-stage disease: Are they appropri-
Clinical trial to assess the relative efficacy of fluorou-   functions with censored observations. Biometrics           ate? Clin Cancer Res 13:6909s-6912s, 2007
racil and leucovorin, fluorouracil and levamisole, and      58:773-780, 2002                                              17. de Gramont A: Association between 3-year
fluorouracil, leucovorin, and levamisole in patients            10. Sargent DJ, Goldberg RM, Jacobson SD, et al:       (yr) disease free survival (DFS) and overall survival
with Dukes’ B and C carcinoma of the colon: Results        A pooled analysis of adjuvant chemotherapy for             (OS) delayed with improved survival after recur-
from National Surgical Adjuvant Breast and Bowel           resected colon cancer in elderly patients. N Engl          rence (rec) in patients receiving cytotoxic adjuvant
Project C-04. J Clin Oncol 17:3553-3559, 1999                                                                         therapy for colon cancer: Findings from the 20,800
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benefit of leucovorin-modulated fluorouracil as post-                                                                   2008 (suppl; abstr 4007)
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                                                           dated efficacy results of the MOSAIC trial, including
Results from National Surgical Adjuvant Breast and                                                                    Surgery for recurrent colon cancer: Strategies for
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                                                               12. Saltz LB, Niedzwiecki D, Hollis D, et al: Irino-
    4. O’Connell MJ, Laurie JA, Kahn M, et al:                                                                        Group, the North Central Cancer Treatment Group,
Prospectively randomized trial of postoperative ad-        tecan fluorouracil plus leucovorin is not superior to
                                                                                                                      and the Southwest Oncology Group. Ann Intern
juvant chemotherapy in patients with high-risk colon       fluorouracil plus leucovorin alone as adjuvant treat-       Med 129:27-35, 1998
cancer. J Clin Oncol 16:295-300, 1998                      ment for stage III colon cancer: Results of CALGB             19. Chau I, Allen MJ, Cunningham D, et al: The
    5. Andre T, Boni C, Mounedji-Boudiaf L, et al:
              ´                                            89803. J Clin Oncol 25:3456-3461, 2007                     value of routine serum carcinoembryonic antigen
Oxaliplatin, 5-fluorouracil, and leucovorin as adjuvant         13. van Cutsem E, Labianca R, Hossfeld D, et al:       measurement and computed tomography in the
treatment for colon cancer. N Engl J Med 350:2343-         Randomized phase III trial comparing infused               surveillance of patients after adjuvant chemotherapy
2351, 2004                                                 irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus   for colorectal cancer. J Clin Oncol 22:1420-1429,
    6. Kuebler JP, Wieand HS, O’Connell MJ, et al:         5-FU/FA (F) in stage III colon cancer patients (pts)       2004
Oxaliplatin combined with weekly bolus fluorouracil         (PETACC 3). J Clin Oncol 23:3s, 2005 (suppl; abstr            20. Sargent DJ, Patiyil S, Yothers G, et al: End
and leucovorin as surgical adjuvant chemotherapy           LBA8)                                                      points for colon cancer adjuvant trials: Observations
for stage II and III colon cancer: Results from                14. Romond EH, Perez EA, Bryant J, et al: Tras-        and recommendations based on individual patient
NSABP C-07. J Clin Oncol 25:2198-2204, 2007                tuzumab plus adjuvant chemotherapy for operable            data from 20,898 patients enrolled onto 18 random-
    7. Sargent DJ, Wieand HS, Haller DG, et al:            HER2-positive breast cancer. N Engl J Med 353:             ized trials from the ACCENT Group. J Clin Oncol
Disease-free survival versus overall survival as a         1673-1684, 2005                                            25:4569-4574, 2007


                                                                                   ■ ■ ■




www.jco.org                                                                                                             © 2009 by American Society of Clinical Oncology   877
                     Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission.
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Evidence for Cure by Adjuvant Therapy in Colon Cancer: Observations Based on Individual Patient Data From 20,898 Patients on 18 Randomized Trials

  • 1. VOLUME 27 NUMBER 6 FEBRUARY 20 2009 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Evidence for Cure by Adjuvant Therapy in Colon Cancer: Observations Based on Individual Patient Data From 20,898 Patients on 18 Randomized Trials Daniel Sargent, Alberto Sobrero, Axel Grothey, Michael J. O’Connell, Marc Buyse, Thierry Andre, Yan Zheng, Erin Green, Roberto Labianca, Chris O’Callaghan, Jean Francois Seitz, Guido Francini, Daniel Haller, Greg Yothers, Richard Goldberg, and Aimery de Gramont From the Divisions of Biostatistics and Medical Oncology, Mayo Clinic, Roch- A B S T R A C T ester, MN; Department of Biostatistics, University of California, Los Angeles, Purpose Los Angeles, CA; National Surgical Limited data are available on the time course of treatment failures (recurrence and/or death), the Adjuvant Breast and Bowel Project nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with Operations Office and Biostatistical resected stage II and III colon cancer. Center, Pittsburgh; Abramson Cancer Center at the University of Pennsylva- Methods nia, Philadelphia, PA; University of The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual North Carolina, Chapel Hill, NC; Medical patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant Oncology, Ospedale S. Martino, therapy in patients with stage II or III colon cancer, was analyzed. Genova; Ospedali Riuniti, Bergamo; University of Siena, Siena, Italy; Interna- Results tional Drug Development Institute, A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year Louvain-la-Neuve, Belgium; Hopital follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never Pitie-Salpetiere, Paris; University of the exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed Mediterranean, Marseilles; Hopital Saint to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 Antoine, Paris, France; and National years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from Cancer Institute of Canada Clinical Trials Group, Queens University, King- adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and ston, Ontario, Canada. control patients were not significantly different, and after 4 years, no trend toward benefit was Submitted August 8, 2008; accepted demonstrated. This benefit was primarily driven by patients with stage III disease. October 1, 2008; published online Conclusion ahead of print at www.jco.org on Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence January 5, 2009. rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into Written on behalf of the Adjuvant Colon long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After Cancer Endpoints Group. 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are Supported by National Cancer Institute minimal; thus, long-term follow-up for recurrence is of little value. Grants No. CA 25224, CA 12027, CA 69974, CA 37377, and CA 69651. J Clin Oncol 27:872-877. © 2009 by American Society of Clinical Oncology Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this apparently leads to long-term benefits in outcome, INTRODUCTION article. usually measured in terms of 3- and 5-year rates of Corresponding author: Daniel Sargent, Approximately 145,000 new patients with colorectal OS or DFS. PhD, Professor of Biostatistics and cancer are diagnosed annually in the United States. Graphical presentations of survival or recur- Oncology, Division of Biomedical Statis- tics and Informatics, Mayo Clinic, 200 When diagnosed at a stage when curative surgical rence data from clinical trials, typically presented 1st St SW, Rochester, MN 55905; resection is possible, fluorouracil (FU)-based adju- using Kaplan-Meier plots, convey information re- e-mail: sargent.daniel@mayo.edu. vant chemotherapy for colon cancer has repeatedly garding the absolute rate of recurrence, DFS, and OS The Appendix is included in the been shown to improve patient overall survival at any given time point. However, these plots do not full-text version of this article, available online at www.jco.org. (OS). FU with leucovorin became standard of care readily convey the risk of an event at a specific time It is not included in the PDF version for patients with stage III and selected stage II colon point, and a separation in survival curves does not (via Adobe® Reader®). cancer in the early 1990s1-4 and provided the basis convey the interpretation of an early advantage © 2009 by American Society of Clinical for the addition of oxaliplatin, which has been dem- that is maintained over time as opposed to a con- Oncology onstrated to further improve disease-free survival tinued difference in the relative risk of an event. 0732-183X/09/2706-872/$20.00 (DFS) and OS in stage III patients.5,6 Although ad- Therefore, the clinical demonstration of actual DOI: 10.1200/JCO.2008.19.5362 juvant chemotherapy is routinely administered for cure of patients by adjuvant therapy is poorly only a limited duration of time (usually 6 months), it understood, both in colorectal cancer and in 872 © 2009 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission. Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
  • 2. Curative Adjuvant Therapy in Colon Cancer other solid tumors. More detailed information on the time course over time. This is in contrast to the usual estimated HR from a Cox propor- of recurrence, such as both short- and long-term year-by-year tional hazards regression, which assumes that the HR between the two treat- failure rates stratified by untreated and treated patients, may assist ment arms has a single value that is constant over time. Hazard rates over time were estimated by the method of Muller and Wang.8 HRs, with 95% pointwise ¨ in patient counseling and in determining follow-up recommenda- CIs, were estimated using the method of Gilbert et al.9 The end points of OS, tions. Furthermore, such analyses also provide information on the DFS, and time to recurrence (TTR) were considered. OS is defined as time to long-standing question of whether adjuvant therapy in colon can- death from any cause. DFS is defined as the time to recurrence or death, cer completely eradicates tumor cells, thus allowing for higher cure whichever occurs first. TTR is defined as the time to disease recurrence, where rates, or whether treatment only delays tumor recurrence. On the deaths without recurrence were censored at the time of death. Recurrence was basis of individual patient data from 20,898 patients randomly defined only by a reappearance of primary colon cancer; second primary colon assigned on 18 trials of adjuvant therapy for colon cancer, we cancers or other noncolon cancers were not classified as recurrences. Because the definitions of these terms (DFS and TTR) were not consistent across all studied the time course of treatment failure and long-term recur- included trials, the definitions here may differ from those used in the original rence rates. trial. The analysis of the overall treatment benefit was performed with a log-rank test comparing treatment with control, stratified by the original trial. Analyses comparing FU-based treatment with control were limited to METHODS the nine trials with a no-treatment control arm (n 4,922; National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01 and C-02, North Central The data set assembled by the Adjuvant Colon Cancer Endpoints (ACCENT) Cancer Treatment Group [NCCTG] 784852, Federation Francophone de ´ ´ Group was used for all analyses.7 As previously described, ACCENT identified Cancerologie Digestive, Intergroup 0035, Interdisciplinary Group for Cancer ´ and obtained individual patient data from 18 phase III adjuvant trials in colon Care Evaluation, NCCTG 874651, Siena, and National Cancer Institute of primary tumors conducted from 1978 to 1999. A total of 20,898 patients and Canada trials in Table 1). Because of inconsistent long-term follow-up for the 43 distinct treatment arms (34 active treatment arms and nine surgery-only hazard rate and HR analyses, all patients were censored at 8 years for analysis of arms) are included in the ACCENT database. Table 1 and Appendix Table treatment benefit. Long-term event rates were estimated using data from all A1 (online only) list the details regarding the trials and patient character- trials where the median follow-up time for living patients exceeded 9 years istics, respectively. (eight trials, n 11,615; NCCTG 784852, Intergroup 0035, Intergroup 0089, This analysis focused on continuous time estimation of the hazard rate and NSABP C-01, C-02, C-03, C-04, and C-05 trials in Table 1). (risk of recurrence or death) by treatment over time, as well as the continuous time estimation of the hazard ratio (HR) comparing FU-based treatment with control. The continuous time estimation of these rates and ratios allows the RESULTS risk of an event (for hazard rates) and benefit of treatment (for HRs) to vary Hazard Rates Of the 20,898 patients, 35% experienced recurrence and 38% died in the initial 8-year follow-up period. Sixty-six percent of patients Table 1. Trials Included had stage III disease, and 33% had stage II disease. When the analyses Accrual No. of were restricted to the 4,922 patients on trials in which they were Trial Period Treatment Arms Patients randomly assigned to adjuvant treatment versus surgery alone, 1,670 NSABP C-01 1977-1983 Control v MOF 724 patients (34%) experienced recurrence, and 1,910 patients (39%) NCCTG 784852 1978-1984 Control v FU/LEV 247 died. Traditional Kaplan-Meier plots of OS by stage for patients ran- FFCD 1982-1990 Control v FU/LV 239 domly assigned to treatment versus control are presented in Figure 1. NSABP C-02 1984-1988 Control v PVI FU 896 INT 0035 1984-1987 Control v FU/LEV 926 To provide additional insight into the time-related nature of Siena 1985-1990 Control v FU/LV 256 adjuvant therapy benefit, hazard rates over time for OS, DFS, and TTR NCIC 1987-1992 Control v FU/LV 359 by treatment group are shown in Figure 2. For both treated and NSABP C-03 1987-1989 MOF v FU/LV 1,042 untreated patients, the risk of death from any cause (Fig 2A) peaks at NCCTG 874651 1988-1989 Control v FU/LV 408 approximately 2 years after surgery and gradually declines over the GIVIO 1989-1992 Control v FU/LV 867 8-year estimation period. For the DFS and TTR end points (Figs 2B NCCTG 894651 1989-1991 FU/LV LEV for 6 or 12 months 915 NSABP C-04 1989-1990 FU/LEV v FU/LV v FU/LV/LEV 2,083 and 2C), in untreated patients, the risk of an event clearly is highest in INT 0089 1990-1992 FU/LEV v FU/LV (HD or LD) v 3,561 the year after surgery, with a rapid reduction until approximately year FU/LV/LEV 4. The failure rate in treated patients is low initially and then increases NSABP C-05 1991-1994 FU/LV v FU/LV IFN 2,136 in years 1 to 3, only to recede close to the rate in untreated patients by NCCTG 914653 1993-1998 FU/LV HD or standard LEV 878 year 4. The DFS curves (Fig 2B) remain slightly separated in years 4 to SWOG 9415 1994-1999 Bolus v infusional FU/LEV/LV 939 8 between treatment and control, whereas the TTR curves (Fig 2C) are QUASAR 1994-1997 FU/LV (HD or LD) LEV 3,517 GERCOR 1996-1999 Bolus v infusional FU/LV 905 virtually superimposable in that time period. For none of the end Total 20,898 points does the failure rate for treated patients ever exceed that of the untreated patients during the 8-year follow-up period. Abbreviations: NSABP, National Surgical Adjuvant Breast and Bowel Project; MOF, semustine, vincristine, and fluorouracil; NCCTG, North Central Cancer These patterns of treatment failure over time are substantially Treatment Group; FU, fluorouracil; LEV, levamisole; FFCD, Fédération Fran- different for stage II and stage III patients (Fig 3). In stage III patients, cophone de Cancérologie Digestive; LV, leucovorin; PVI, protracted venous infusion; INT, Intergroup; NCIC, National Cancer Institute of Canada; GIVIO, the absolute risk of a DFS event is greater than for stage II patients in Interdisciplinary Group for Cancer Care Evaluation; HD, high dose; LD, low the first 4 years of follow-up, becoming similar after years 5 to 6 as the dose; IFN, interferon alfa-2a; SWOG, Southwest Oncology Group; QUASAR, Quick and Simple and Reliable Collaborative Group; GERCOR, French Multi- DFS end point becomes dominated by death events. In addition, the disciplinary Clinical Research Group. relative benefit of treatment is considerably larger in stage III patients, with a longer duration of benefit. In stage II patients, the modest early www.jco.org © 2009 by American Society of Clinical Oncology 873 Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission. Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
  • 3. Sargent et al A A 100 0.0006 Control Arms Experimental Arms 90 Overall Survival (%) 80 Hazard Rate 70 0.0004 60 50 Surgery Alone 40 8-year OS Rate (95% CI): 54.3% (52.2% to 56.4%) 30 Surgey + FU-Based Chemotherapy 0.0002 8-year OS Rate (95% CI): 61.5% (59.5% to 63.6%) 20 10 P < .0001 0 1 2 3 4 5 6 7 8 0 2 4 6 8 Follow-Up Time (years) Follow-Up Time (years) B B 100 0.0006 Control Arms 90 Experimental Arms Overall Survival (%) 80 70 Hazard Rate 0.0004 60 50 Surgey Alone 40 8-year OS Rate (95% CI): 66.8% (63.7% to 70.0%) 30 Surgey + FU-Based Chemotherapy 0.0002 8-year OS Rate (95% CI): 72.2% (69.3% to 75.2%) 20 10 P = .026 0 1 2 3 4 5 6 7 8 0 2 4 6 8 Follow-Up Time (years) Follow-Up Time (years) C 100 C 0.0006 90 Control Arms Experimental Arms Overall Survival (%) 80 70 Hazard Rate 60 0.0004 50 40 Surgey Alone 8-year OS Rate (95% CI): 42.7% (39.9% to 45.7%) 30 Surgey + FU-Based Chemotherapy 0.0002 20 8-year OS Rate (95% CI): 53.0% (50.2% to 55.9%) 10 P < .0001 0 1 2 3 4 5 6 7 8 0 2 4 6 8 Follow-Up Time (years) Follow-Up Time (years) Fig 1. Kaplan-Meier plots of overall survival (OS) in treatment arm versus control arm for (A) all patients, (B) stage II patients, and (C) stage III patients. Fig 2. Hazard rates by time from random assignment and treatment arm. Plots FU, fluorouracil. of the hazard rate for (A) overall survival, (B) disease-free survival, and (C) time to recurrence by arm (treatment and control) over the 8-year follow-up period. The y axis plots the risk of recurrence on a daily scale; thus, for example, the value 0.0002 represents an annualized 7.3% risk of an event (0.0002 365 0.073). benefit in reducing DFS events is entirely absent after 2 to 3 years, whereas in stage III patients, it remains for at least 4 years. time. In contrast, in Figures 4B and 4C, there is a substantial benefit of HRs (with 95% pointwise CIs) comparing patients on the treat- adjuvant therapy in reducing the risk of a DFS or recurrence event the ment versus control arms of trials, plotted on the logarithmic scale, for first 1 to 2 years after resection (estimated log-HR in the range of the OS, DFS, and TTR end points are shown in Figure 4. Figure 4A 0.50; HR 0.61) that diminishes over time and becomes nonsignif- demonstrates that the addition of adjuvant therapy provides a consis- icant (based on 95% pointwise CIs) after year 4, signifying that the tent and durable beneficial effect on OS over the follow-up period, DFS and recurrence rates are statistically similar between treatment with an estimated log-HR of 0.30 (HR 0.74) that is consistent over and control arms after 4 years. 874 © 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission. Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
  • 4. Curative Adjuvant Therapy in Colon Cancer A A 1.0 0.0010 Control Arms Experimental Arms 0.5 Log Hazard Ratio Hazard Rate 0.0 0.0006 -0.5 -1.0 0.0002 -1.5 95% pointwise CIs -2.0 0 2 4 6 8 0 2 4 6 8 Follow-Up Time (years) Time (years) B 0.0010 B 1.0 Control Arms Experimental Arms 0.5 Log Hazard Ratio 0.0 Hazard Rate 0.0006 -0.5 -1.0 0.0002 -1.5 95% pointwise CIs 0 2 4 6 8 -2.0 Follow-Up Time (years) 0 2 4 6 8 Time (years) Fig 3. Disease-free survival hazard rates by time from random assignment and C 1.0 treatment arm in (A) stage II patients and (B) stage III patients. 0.5 Log Hazard Ratio Long-Term Recurrence Rates 0.0 Of the 20,898 patients, 11,615 were enrolled onto trials where the median follow-up time exceeds 9 years. Figure 5 presents the recur- -0.5 rence rates, by 6-month intervals, to 15 years of follow-up. After 5 years, the recurrence rate by year never exceeds 1.5%, and after 8 years, -1.0 it never exceeds 0.5%. -1.5 DISCUSSION -2.0 95% pointwise CIs These results illustrate the following three important concepts for the 0 2 4 6 8 management of early colon cancer: adjuvant FU-based treatment Time (years) actually eradicates colon cancer cells, thereby curing patients; late relapses can occur, but after 8 years, the notion of cure is appropriate; Fig 4. Continuous time estimate of the log-hazard ratios for (A) overall survival, and most relapses occur in the first 2 years after surgery. These con- (B) disease-free survival, and (C) time to recurrence comparing treatment arm cepts are relevant to our understanding of tumor biology, clinical with control arm over the 8-year follow-up period, with 95% pointwise CIs. Values less than 0 indicate a benefit from treatment. For example, a value of practice, and future clinical trial design. 0.50 for the log-hazard ratio indicates a hazard ratio of 0.61 comparing A previous pooled analysis of FU-based adjuvant colon cancer treatment with control at that time point (e– 0.50 0.61), that is, a 39% reduction in the risk of an event. trials demonstrated a highly statistically significant 11% absolute improvement in 5-year freedom from recurrence as a result of FU- based adjuvant therapy.10 In the current analysis, including additional www.jco.org © 2009 by American Society of Clinical Oncology 875 Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission. Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
  • 5. Sargent et al over time, because few late recurrences are to be expected. However, 8 although irinotecan combined with FU and leucovorin produces a 7 benefit similar to oxaliplatin with FU and leucovorin in the advanced disease setting, this benefit has failed to translate into any significant Recurrene Rate 7 5 benefit when irinotecan is added to adjuvant FU and leucovorin.12,13 4 Therefore, the empirical data demonstrate that the paradigm that 3 efficacy in advanced disease leads to efficacy in the adjuvant setting is indeed agent dependent. Extending this concept to other tumors, the 2 positive early experience with adjuvant trastuzumab in breast cancer14 1 and adjuvant imatinib in GI stromal cell tumors15 provides hope that 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 this paradigm will hold for biologic agents as well. More specifically, this concept is relevant to the adjuvant therapy of colon cancer because Year clinical trials using oxaliplatin with FU and leucovorin plus either Fig 5. Risk of recurrence in each 6-month interval after random assignment bevacizumab or cetuximab have completed or are about to complete among patients remaining recurrence free at the start of each interval, by time. accrual or are ongoing (NSABP C-08; AVANT; E5202; Quick and Simple and Reliable Collaborative Group-2: bevacizumab; NCCTG N0147; and PETACC-8: cetuximab).16 However, the unique mecha- patients, overall adjuvant therapy resulted in a 7% improvement in nism of action of these biologic agents may require additional years of 8-year OS rate (5% in stage II patients and 10% in stage III patients). follow-up before conclusions regarding a relapse-delaying versus a Because the current analysis included two trials without FU/leucov- curative effect of these complex treatments can be reliably ascertained. orin or FU/levamisole chemotherapy arms, these survival improve- It is possible that biologic agents such as angiogenesis inhibitors might ments likely underestimate the true survival benefit of FU and delay the occurrence of detectable metastatic disease without actually leucovorin therapy. Importantly, in the current analysis, the hazard eradicating tumor cells, thereby leading to improvements in early DFS rates of OS, DFS, and TTR in treated patients never exceed the corre- without affecting long-term OS.16 Regardless of the agent’s mecha- sponding rates in untreated patients, at least in the 8-year follow-up nism of action, as survival after recurrence is extended by effective period reported here. The lack of any crossing of the hazard rate curves therapy for metastatic disease, longer term follow-up is likely to be indicates that adjuvant therapy is a curative intervention by intent. If required to establish a long-term survival benefit.17 therapy simply delayed, as opposed to prevented, recurrences, we Our results also provide valuable data to clinical practice regard- would expect the TTR hazard rate for treated patients to eventually ing the long-term risk of recurrence in patients with colon cancer who exceed the rate in the untreated patients. Instead, the hazard rates undergo curative resection. We have previously demonstrated that separate between 6 months and 2 years from random assignment, a 80% of colon cancer patients who experienced recurrence in the first 8 time perfectly compatible with the effect of chemotherapy. In addi- years after surgery do so in the first 3 years.7 These new results not only tion, at least in the 8-year follow-up period, the fact that the OS hazard confirm this finding, but also demonstrate that the risk of recurrence rate in the treated patients remains lower than in the untreated pa- tients supports the lack of a meaningful detrimental long-term effect continues to be low for up to 15 years of follow-up. On the basis of this of FU-based chemotherapy, as measured by OS. information, from a clinical trials perspective, there is little value in Itmaybeconsideredsurprisingthatsingle-agentFU-basedchem- mandating follow-up for recurrence beyond 5 years in future adjuvant otherapy, which produces only a modest benefit in the advanced colon cancer trials. From a clinical perspective, once a patient has been disease setting (consistent response rate of 15%, progression-free sur- recurrence free for 5 years from surgery, continued medical care can vival time of 4 month, and median survival time of 11 to 12 months), focus on other issues beyond the patient’s prior colon cancer such as ultimately leads to an approximate 10% cure rate in the pooled pop- long-term adverse effects of the adjuvant therapy or secondary can- ulation of high-risk stage II and III patients included in these trials cers, which are issues that may be more clinically relevant and preva- when used in the adjuvant setting. Biologic plausibility may tempt us lent in these patients. to extend this paradigm to combinations of newer cytotoxic drugs Finally, these analyses clearly demonstrate that in untreated pa- (oxaliplatin and irinotecan) or to targeted agents such as bevacizumab tients, the risk of recurrence is dominated by the early postsurgical or cetuximab, and beyond (biologics). However, great caution must period, in particular the first 2 years. The clear major benefit of adju- be exercised. The results to date in the adjuvant setting demonstrate vant therapy is to significantly and meaningfully reduce this risk of that the paradigm of predicting activity in the adjuvant setting based early recurrence by approximately 40%. From years 2 to 4, the TTR on studies in advanced disease works for combining oxaliplatin with and DFS rates remain slightly reduced in patients receiving adjuvant FU and leucovorin. On the basis of the results of the Adjuvant therapy; however, the magnitude of benefit is clearly less than in the Treatment of Colon Cancer (MOSAIC) trial,5 the 20% improve- early time period. Careful follow-up in the first 5 years for recurrence ment in response rate and 3 months of additional PFS time afforded is critical because an increasing number of patients found to have early by infusional FU, leucovorin, and oxaliplatin compared with FU and recurrence have the potential for cure by salvage surgery.18,19 The OS leucovorin in the advanced setting translate into an approximately hazard rate and HR plots (Figs 2A and 3A) indicate that this short- additional 7% gain in 3-year DFS in the adjuvant setting for stage III term reduction in risk of recurrence translates into long-term advan- patients. Recently, this early DFS improvement has translated into a tages in OS. As previously discussed,20 this early effect of adjuvant longer-term OS benefit after 6 years of follow-up.11 Our findings chemotherapy could further reduce the required time to obtain rele- suggest that this OS benefit will be maintained and may even grow vant information from clinical trials in the adjuvant setting. 876 © 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission. Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.
  • 6. Curative Adjuvant Therapy in Colon Cancer Continued analyses of large datasets, such as ACCENT, provide Financial support: Daniel Sargent valuable information that is useful to statisticians (eg, the adequacy of Administrative support: Daniel Sargent, Axel Grothey, Erin Green statistical models), clinical trialists (eg, event rates over time), and Provision of study materials or patients: Daniel Sargent, Michael J. practicing oncologists (eg, surveillance patterns and prediction of cure O’Connell, Thierry Andre, Erin Green, Roberto Labianca, Chris O’Callaghan, Jean Francois Seitz, Guido Francini, Daniel Haller, rates). The ACCENT group will continue to seek to include data from Aimery de Gramont all large randomized adjuvant colon cancer clinical trials to update Collection and assembly of data: Daniel Sargent, Michael J. O’Connell, these findings from single-agent FU adjuvant studies with data from Yan Zheng, Erin Green, Roberto Labianca, Chris O’Callaghan, Jean current and next-generation treatment regimens. Francois Seitz, Guido Francini, Greg Yothers, Aimery de Gramont Data analysis and interpretation: Daniel Sargent, Alberto Sobrero, Marc Buyse, Yan Zheng, Erin Green, Daniel Haller, Greg Yothers, AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Aimery de Gramont Manuscript writing: Daniel Sargent, Alberto Sobrero, Axel Grothey, The author(s) indicated no potential conflicts of interest. Michael J. O’Connell, Marc Buyse, Thierry Andre, Erin Green, Roberto Labianca, Daniel Haller, Richard Goldberg, Aimery de Gramont Final approval of manuscript: Daniel Sargent, Alberto Sobrero, Axel AUTHOR CONTRIBUTIONS Grothey, Michael J. O’Connell, Marc Buyse, Thierry Andre, Yan Zheng, Erin Green, Roberto Labianca, Chris O’Callaghan, Jean Francois Seitz, Conception and design: Daniel Sargent, Axel Grothey, Marc Buyse, Yan Guido Francini, Daniel Haller, Greg Yothers, Richard Goldberg, Zheng, Daniel Haller, Aimery de Gramont Aimery de Gramont primary end point for adjuvant colon cancer studies: 15. DeMatteo R, Owzar K, Maki R, et al: Adjuvant REFERENCES Individual patient data from 20,898 patients on 18 imatinib mesylate increases recurrence free survival randomized trials. J Clin Oncol 23:8664-8670, 2005 (RFS) in patients with completely resected localized 1. Moertel CG, Fleming TR, Macdonald JS, et al: 8. Muller HG, Wang JL: Hazard rates estimation ¨ primary gastrointestinal stromal tumor (GIST): North Levamisole and fluorouracil for adjuvant therapy of under random censoring with varying kernels and American Intergroup Phase III trial ACOSOG Z9001. resected colon carcinoma. N Engl J Med 322:352- bandwidths. Biometrics 50:61-76, 1994 J Clin Oncol 25:564s, 2007 (suppl; abstr 10079) 358, 1990 9. Gilbert PB, Wei LJ, Kosorok MR, et al: Simul- 16. Grothey A: Biological therapy and other novel 2. Wolmark N, Rockette H, Mamounas EP, et al: taneous inferences on the contrast of two hazard therapies in early-stage disease: Are they appropri- Clinical trial to assess the relative efficacy of fluorou- functions with censored observations. Biometrics ate? Clin Cancer Res 13:6909s-6912s, 2007 racil and leucovorin, fluorouracil and levamisole, and 58:773-780, 2002 17. de Gramont A: Association between 3-year fluorouracil, leucovorin, and levamisole in patients 10. Sargent DJ, Goldberg RM, Jacobson SD, et al: (yr) disease free survival (DFS) and overall survival with Dukes’ B and C carcinoma of the colon: Results A pooled analysis of adjuvant chemotherapy for (OS) delayed with improved survival after recur- from National Surgical Adjuvant Breast and Bowel resected colon cancer in elderly patients. N Engl rence (rec) in patients receiving cytotoxic adjuvant Project C-04. J Clin Oncol 17:3553-3559, 1999 therapy for colon cancer: Findings from the 20,800 J Med 345:1091-1097, 2001 3. Wolmark N, Rockette H, Fisher B, et al: The patient (pt) ACCENT dataset. J Clin Oncol 26:179s, 11. De Gramont A, Boni C, Navarro M, et al: benefit of leucovorin-modulated fluorouracil as post- 2008 (suppl; abstr 4007) Oxaliplatin/5FU/LV in adjuvant colon cancer: Up- operative adjuvant therapy for primary colon cancer: 18. Goldberg RM, Fleming TR, Tangen CM, et al: dated efficacy results of the MOSAIC trial, including Results from National Surgical Adjuvant Breast and Surgery for recurrent colon cancer: Strategies for survival, with a median follow-up of six years. J Clin Bowel Project protocol C-03. J Clin Oncol 11:1879- identifying resectable recurrence and success rates Oncol 25:165s, 2007 (suppl; abstr 4007) 1887, 1993 after resection—Eastern Cooperative Oncology 12. Saltz LB, Niedzwiecki D, Hollis D, et al: Irino- 4. O’Connell MJ, Laurie JA, Kahn M, et al: Group, the North Central Cancer Treatment Group, Prospectively randomized trial of postoperative ad- tecan fluorouracil plus leucovorin is not superior to and the Southwest Oncology Group. Ann Intern juvant chemotherapy in patients with high-risk colon fluorouracil plus leucovorin alone as adjuvant treat- Med 129:27-35, 1998 cancer. J Clin Oncol 16:295-300, 1998 ment for stage III colon cancer: Results of CALGB 19. Chau I, Allen MJ, Cunningham D, et al: The 5. Andre T, Boni C, Mounedji-Boudiaf L, et al: ´ 89803. J Clin Oncol 25:3456-3461, 2007 value of routine serum carcinoembryonic antigen Oxaliplatin, 5-fluorouracil, and leucovorin as adjuvant 13. van Cutsem E, Labianca R, Hossfeld D, et al: measurement and computed tomography in the treatment for colon cancer. N Engl J Med 350:2343- Randomized phase III trial comparing infused surveillance of patients after adjuvant chemotherapy 2351, 2004 irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus for colorectal cancer. J Clin Oncol 22:1420-1429, 6. Kuebler JP, Wieand HS, O’Connell MJ, et al: 5-FU/FA (F) in stage III colon cancer patients (pts) 2004 Oxaliplatin combined with weekly bolus fluorouracil (PETACC 3). J Clin Oncol 23:3s, 2005 (suppl; abstr 20. Sargent DJ, Patiyil S, Yothers G, et al: End and leucovorin as surgical adjuvant chemotherapy LBA8) points for colon cancer adjuvant trials: Observations for stage II and III colon cancer: Results from 14. Romond EH, Perez EA, Bryant J, et al: Tras- and recommendations based on individual patient NSABP C-07. J Clin Oncol 25:2198-2204, 2007 tuzumab plus adjuvant chemotherapy for operable data from 20,898 patients enrolled onto 18 random- 7. Sargent DJ, Wieand HS, Haller DG, et al: HER2-positive breast cancer. N Engl J Med 353: ized trials from the ACCENT Group. J Clin Oncol Disease-free survival versus overall survival as a 1673-1684, 2005 25:4569-4574, 2007 ■ ■ ■ www.jco.org © 2009 by American Society of Clinical Oncology 877 Downloaded from jco.ascopubs.org on May 1, 2010 . For personal use only. No other uses without permission. Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved.