Practice Update

New standard of care for low risk

stage 3 colorectal cancer?

Interview with Axel Grothey

Dr Farzanna Haffizulla speaks with Dr Grothey, Professor of

Oncology at the Mayo School of Medicine in Minnesota, on

results of the pooled analysis of six Phase 3 trials investigating

3 vs 6 months of adjuvant oxaliplatin-based therapy for patients

with stage 3 colon cancer.

Dr Haffizulla:

The perspective pooled anal-

ysis of six phase 3 trials investigating the

duration of adjuvant oxaliplatin-based ther-

apy, 3 versus 6 months for patients with

stage 3 colon cancer, appears to define a

new standard of care for patients with low-

risk stage 3 colon cancer. Can you describe

this particular trial further and any implica-

tions for clinical practice?

Dr Grothey:

First of all, the reason why we

ran this trial was to decrease toxicity for

patients with oxaliplatin-based adjuvant

therapy. It’s frustrating for clinicians and

for patients to go through 6 months of

treatment and be stuck with persistent

neuropathy, which can be life changing;

it affects patients for the rest of their life

because that’s really the main side effect

of oxaliplatin-based therapy – cumulative

neuropathy. So, the longer we treat, the

more neuropathy we see in severity and

persistence.

Now, the question of can you shorten the

duration of treatment without sacrificing

the efficacy, that’s a question that needs

to be addressed in a non-inferiority study

design. Meaning you need large num-

bers of patients; we actually calculated

we needed 10,500 patients. Not a single

country can pull that off in terms of run-

ning a clinical trial to get 10,500 patients

randomized to 3 or 6 months of therapy.

We needed an international collaboration.

Fortunately, this clinical question “can we

get away with shorter duration of ther-

apy?” was a worldwide question because

everyone struggles with these toxicities

that are inflicted in the worldwide standard

of 6 months of therapy. Dan Sargent, who

is a statistician at Mayo Clinic and myself,

went to groups around the world and said

“would you like to start a study? Would

you like to join in this endeavor?” And

six Phase 3 trials were started. Eventually

we had a pooled analysis, a pre-planned

pooled individual patient data analysis of

12,834 patients, which is by far the largest

endeavor ever conducted.

It’s important to realize this could only be

pulled off with public funding, philanthropy,

because which company would investigate

shorter duration of their therapy? That is

something where we needed an interna-

tional academic effort. And we presented

the data here at ASCO.

Dr Haffizulla:

That’s an excellent example of

global work, coming together.

Dr Grothey:

Global work and also identify-

ing a need, and then really making things

happen. It’s a very nice and collaborative

interaction.

Dr Haffizulla:

Given the results of that particu-

lar study, is there any low-risk colon cancer

patient who you would treat with more than

3 months of FOLFOX?

Dr Grothey:

Let me recap some of the results

because, first of all, we did show that neu-

rotoxicity and toxicities in general were

lower, and that’s not unexpected. You give

less chemotherapy, you have less toxic-

ity. That’s the benefit that patients have.

How much would they have to sacrifice

in terms of anti-tumor efficacy? When you

look at 3-year disease-free survival, which

is one of the hallmarks of efficacy assess-

ment for all patients combined, the sacrifice

was 0.9% in disease-free survival.

Unfortunately, for the study purpose, it

did not meet our non-inferiority criteria,

which were very strict, probably too strict;

it crossed the kind of pre-planned analysis

threshold. We had 12,800 patients to work

with, and then we were able to dive into

these subgroups that you just mentioned

because just from a rational perspective,

do patients with a lower risk of tumor recur-

rence, early stage disease, really need the

same amount of treatment as higher risk

tumors? The answer is no. About 60% of

patients have what we identified as low-

risk – T1, 2, 3, N1, so not more than 3 lymph

nodes involved. Those patients would

make up about 60% of the whole cohort,

they really do not need more than 3 months

of therapy.

For the higher-risk group of patients – T4

and/or N2s, so more lymph node involved

and with larger and more penetrating tum-

ors – some patients will still get away with

3 months of therapy. But we can discuss

with patients, is it worthwhile for a statis-

tical risk reduction of let’s say 1.5% in 3

years to push for more chemotherapy,

when patients might have already experi-

enced neurotoxicity, nausea, vomiting, etc?

So, I think what we are able to do now is

really individualize treatments, which ties

into all this precision medicine, but not with

a biomarker, but with more data available

to really engage patients in the discussion.

How much is it worth it for you? You know,

this might depend...might be different for

older patients, younger patients, different

socio-economic status, etc. There are a lot

of factors that we can now take into account,

but I think the message, the one message

that we agreed upon, which was very clear,

lower-risk tumors 60% should not receive

more than 3 months of treatment.

Dr Haffizulla:

I like that you mentioned about

the multiple variables with each patient,

and knowing that you’re personalizing care

and treatment options.

Dr Grothey:

Absolutely. We finally have a way

to really base our interaction on data. If the

patient asks me, “If I stop now, how much

does it mean for my cancer to come back

CONFERENCE COVERAGE

PRACTICEUPDATE ONCOLOGY