| Tracks 1-12 |
| Track 1 |
Adjuvant Colon Cancer Endpoints
(ACCENT) Group |
| Track 2 |
Disease-free survival as a surrogate endpoint for overall survival |
| Track 3 |
Perspective on the treatment for Hodgkin’s disease during childhood |
| Track 4 |
FDA approval of adjuvant oxaliplatin based on subset analysis of the MOSAIC trial results |
| Track 5 |
Commentary on FDA approval of oxaliplatin for adjuvant therapy of Stage III CRC |
| Track 6 |
Evolution of the MOSAIC trial
results over time |
| Track 7 |
Time-dependent patterns of
failure and treatment benefit
with adjuvant therapy for
resectable colon cancer
in the ACCENT data set |
|
| Track 8 |
Survival following recurrence among patients with adjuvant colon cancer in the ACCENT data set |
| Track 9 |
Applicability of standard
statistical approaches to
disease-free survival endpoints
in clinical trials |
| Track 10 |
Potential use of a shorter
disease-free survival interval
as a surrogate for overall
survival |
| Track 11 |
Adequacy of lymph node
sampling in colon and rectal
cancer |
| Track 12 |
Perspective on accepting
treatment for potentially
small benefits |
|
|
Select Excerpts from the Interview
Tracks 1, 7
DR LOVE: How did the ACCENT group develop?
DR SARGENT: Dr Aimery de Gramont held a meeting at which I was invited
to speak about disease-free survival as a possible endpoint for adjuvant trials.
As a statistician, I said that I couldn’t discuss something without data.
So I evaluated the few trials we had conducted at Mayo, and the data showed
a slight trend suggesting disease-free survival may be correlated to overall
survival, but it wasn’t convincing.
We only had about four trials within the North Central and Mayo groups, so
that was promising but not definitive, so we set out to gather more data, more
trials and more trialists.
We continued to add clinical trial after clinical trial, and in 2003, we initiated
what we call ACCENT, the Adjuvant Colon Cancer Endpoints Group, which
includes 18 trials and 21,000 patients.
DR LOVE: Can you summarize the data you presented at ASCO 2007 from
the ACCENT database (Sargent 2007)?
DR SARGENT: Since we were using disease-free survival as a clinical trial
endpoint, we wanted to consider how that changed the way we designed
clinical trials and viewed results.
First, we examined how adjuvant therapy provides benefit. For overall
survival, it provides a consistent benefit over time — the first year, second
year, sixth year and eighth year.
Patients who received adjuvant therapy had a reduced risk of death over a
long period of time. We wondered if that was true for disease-free survival, as
disease recurs early. Patients die all the time, but they recur early.
Perhaps not surprisingly, we found that adjuvant therapy reduced the risk of
recurrence early in a substantial manner. In the first year, adjuvant therapy
reduced the risk by one half. In the second year, it reduced the risk of recurrence
by approximately 40 percent.
Then the reduction in risk of recurrence decreased over time so that by the
fourth year, no significant difference in recurrence rate existed between
treated and untreated patients.
That observation is not terribly surprising because adjuvant therapy is only
administered for six months or one year. For adjuvant therapy to have a lasting
effect and prevent recurrences in year three and year four is not necessarily a
reasonable expectation.
Next, we demonstrated that this profound benefit in preventing early recurrences
in the first two years translated into long-term overall survival benefits.
I believe that now we more fully understand the mechanism by which chemotherapy
can provide the long-term survival benefit, which is preventing the
bolus of early recurrences that will occur in untreated patients.
Track 5
DR LOVE: In 2003, the MOSAIC trial was presented in toto, but the
FDA approved the use of oxaliplatin based on a subset analysis. What was
the rationale for this?
DR SARGENT: From the FDA’s perspective, no trial has ever demonstrated
that chemotherapy is better than observation for patients with Stage II disease.
Although the QUASAR trial for patients with Stage II disease has been
presented in abstract form at ASCO (Gray 2004), it still has not been published.
Therefore, when the FDA was presented with a trial of FOLFOX versus
5-FU/leucovorin that showed a nonsignificant benefit in the subgroup of
patients with Stage II disease, the FDA also considered that no other data exist
showing that treatment benefits patients with Stage II disease. Based on this,
the FDA did not consider an interpolation justified.
That was the FDA’s perspective, but Dr Grothey and I wrote an editorial in
the Journal of Clinical Oncology criticizing that decision (Grothey 2005). Our
feelings were based on a fundamental paradigm with clinical trials, which is
that, in the absence of compelling data, the best result is the overall result.
The overall results should be based on all patients in the trial — that result
is consistent with the prospectively designed, planned analysis of the clinical
trial.
Based on that paradigm and the fact that in MOSAIC (André 2004) the
relative risks of relapse for patients with Stage III (HR = 0.76) and Stage II
disease (HR = 0.80) were similar and the formal test result for interaction was
highly nonsignificant — suggesting that the benefit of treatment was the same
for Stage III disease as it was for Stage II — we did not see any compelling
reason to go against the fundamental principle of clinical trials, which is to use
the data from the entire trial.
Select publications
