I'm Greg Kalemkerian, medical oncologist and

professor of medicine at the University of Michigan.

And this lecture is going to cover the adjuvant therapy for

non-small cell lung cancer.

The objective of the lecture is to review the role of adjuvant chemotherapy after

surgical resection of early stage non-small cell lung cancer.

About 25% of patients with non-small cell lung cancer

present with surgically resectable disease.

Stage-specific survival for

these patients with early-stage cancer is suboptimal with surgery alone.

Many of these patients relapse after resection and

these relapses tend to be due to hematogenous spread.

So our pre-lecture question is that, a 62 year old man

undergoes right upper lobectomy for biopsy proven adenocarcinoma.

Pathology reveals a 6 cm mass with clean margins but

three hilar lymph nodes contain cancer.

Mediastinal lymph nodes are negative.

PET scan prior to surgery showed no evidence of distant metastases.

What is the most appropriate step in further management?

A, surveillance with annual chest x-rays.

B, radiotherapy to the mediastinum.

C, adjuvant chemotherapy.

Or d, selenium for the prevention of second primary lung cancer.

We will come back to the answer of this question at the end of the lecture.

Non-small cell lung cancer is a disease that tends to present with

very advanced stage in either stage three or four as we can see from this slide,

with 75% or more patients presenting with high stage disease.

However, about 25, 30% of people will present with early stage disease,

defined as stage one or two lung cancer, for

which surgery is the primary treatment modality, done with curative intent.

Unfortunately, from looking at the right side of this slide,

we see that the five year survival with stage one or two lung cancers is not

quite as good as we would hope it would be, and nowhere near as good as it is in

other common cancers such as breast, prostate, or colon cancer.

So that begs the question of what can we do to try and

improve the outcome of these patients?

And what's been evaluated are a number of studies

that have look at giving adjuvant chemotherapy with these patients.

So the term adjuvant refers to any treatment that is given

without the presence of disease.

So clearly those patients who were going to recur do have some

micrometastatic disease floating around in their body.

But in general, we aren't able to identify it, and

that's why they underwent a potentially curative surgery.

In order to try and

mop up those stray cancer cells, we can try giving chemotherapy.

And this slide lays down six of the most recent

adjuvant chemotherapy trials that have been done.

We can see that the stage of patients

enrolled in these trials varies greatly between the studies.

Most of them did include some stage one through 3A of patients.

The chemo regiments also are quite varied that were used.

However, all of them are based on cisplatin containing regiments.

Except for one study, the CALGB study near the bottom,

that incorporated a carboplatinum based chemotherapy regimen.

Some of the studies allowed radiation to be given, primarily for

people with stage three disease while others excluded

the ability to give radiation post-operatively.

And have note radiation has not been demonstrated to improve survival.

And though there are some potential evidence of improvement and

survival in stage three patients.

Most importantly the median age or people enrolled on to this trial

was relatively young with the median age are about 60 years.

Some studies excluded patients over the age of 75 and

we know that the median age at which people get lung cancer is around 70 or 71.

So this is a relatively young population of patients and

that's important when we look at trying to apply the results of these studies

to our patients we see in the clinic,

because of how well they apply to the elderly population still in question.

So these are the results of those studies.

The studies are listed in the same order here.

We see that some were quite large, with over a thousand patients included.

And the results are such that the studies written in gray with the gray shading,

our studies that were positive from the IALT study with the four

4% improvement in five years survival.

The JBR10 study with a 15% improvement in five years survival.

And the Anita study with an 8% improvement in five years survival.

All of which were statistically significant.

So let's take a closer look at one of these studies,

let's look at the JBR10 study that was done in Canada and

the US and in which the University of Michigan did participate.

So this study enrolled 482 patients, all of them had either stage 1B or

II non-small cell lung cancer that were completely receptive.

Patients were randomized very simply to either Cisplatin

+Vinorelbine chemotherapy given for four cycles.

Or to observation with no further treatment.

Radiation was not allowed on this study.

The initial results of JBR10 were that there was a significant improvement in

progression three survival or relapse free survival seen int he middle of this slide.

And over on the right we see an improvement in overall survival with

the 15% jump in five years survival that was statistically significant.

This study was updated several years later with longer follow up and

we see that the median survival in the update over on

the right is still maintained at a significant level

now within 11% improvement in five year overall survival.

So this is a durable improvement in the cure of lung cancer.

Another aspect of the updated analysis was that

the investigators looked at stage specific survival.

We see for Stage II lung cancer in the left column,

there is this 15% improvement in survival.

But for all patients with stage 1B cancer

there are actually was not a statistically significant improvement in survival.

However, when we then sub-classify the stage 1B patients into low-risk,

less than 4 centimeter tumors or high-risk patients for

relapsed with tumors greater than or equal the 4 centimeters.

That those with the bigger tumors, the higher risk of recurrence

do appear to have an improvement in survival though this did not

reach statistical significance given a fairly small subset analysis.

Putting together a number of the modern trials that looked at adjuvant therapy.

The Lace Meta analysis evaluated five of the trials

since 1995 that incorporated four and a half thousand patients.

Five of these trials were noted

in the initial slides that I presented on the modern studies.

All of them were cisplatin-based treatments versus no chemotherapy.

And again, we see that there was a relatively young median age.

Importantly less than 10% of people on all of these trials combined

were over the aged of 70.

So again, becoming hard to necessarily apply this data to an elderly population.

Overall looking at the LACE Meta-analysis there was a 5.5%

benefit in overall survival with adjuvant chemotherapy.

However we see looking at this stage specific outcomes that for stage 1A

patients there actually was a detriment though not statistically significant.

Stage 1B patients trended towards benefit, but again non-significantly.

And most of the benefit was seen in patients with stage II or III disease.

So in general, when I discuss this situation with patients,

I use a 10% improvement in outcome to describe

the potential benefits of chemotherapy in patients with stage II and III disease.

Which is somewhat of an average of the IALT study and the JBR10 study and

the ANITA trial, the three positive studies in non-small cell lung cancer.

10% is also a number that is easy for patients to understand and

get their heads around.

So in summarizing the use of adjuvant chemotherapy in non-small cell lung

cancer, we see on this slide the studies going up and down on the left side,

and the stage is going across at the top of the slide with red boxes meaning

that there is no evidence of benefiting that study at that stage.

Green boxes showing that yes, there's a benefit for adjuvant therapy.

And the yellow box is signifying the stage 1B studies in

which there may be a benefit for patients with the higher risk of larger tumors.

So overall no big benefit for patients with stage 1A or

1B tumors except perhaps those larger more higher risk tumors in 1B.

But for stage twos and threes, the overall preponderance of the evidence is favoring

chemotherapy, particularly when we look at both the laced meta-analysis and

other meta-analyses that have been done of these trials in conglomerate.

So summarizing adjuvant therapy, adjuvant chemotherapy is used for

completely resected stage II and III non-small

cell lung cancer it can be considered for high risk stage 1B patients.

Patients have to have recovered from surgery well and

an uncomplicated fashion by about eight

weeks after surgery which is when you want to start the chemotherapy by.

They have to have good performance status so they can tolerate treatment.

And it's preferable that chemotherapy be applied to younger individuals.

Generally people less than 75 years of age, since two of the three positive

studies actually excluded people over this age due to concerns of toxicity.

The chemotherapy applied can be a platinum-based to drug therapy for

four cycles.

We are yet to have any comparative studies of chemotherapy in the adjuvant setting,

so we do not necessarily know which treatment is optimal.

So as an important aside,

we know that we are now in the molecular age of cancer treatments.

And we do have some likely targeted therapies for

people with non-small cell lung cancer.

The most common targeted therapy we use is against the EGFR mutations for

which we have EGFR inhibitors.

One of these inhibitor is called Erlotinib and

can be use in the advance stage patients in order to improve response rates and

improve progression for survival.

This was a study, the radiant study that looked at incorporating EGFR

inhibition with Erlotinib earlier into the treatment course as an adjuvant treatment

in people who had resected stage 1B through IIIA non small cell lung cancer.

Importantly, these patients were not selected based on having an EGFR mutation.

This was a trial done in all covers.

So it's a randomized study where people, some people got adjuvant chemotherapy,

some did not.

But then they were randomized to either receive erlotinib or

to receive placebo for two years.

So overall in the radiant trial, there was no overall survival benefit for

the use of allotment in adjuvant therapy in non small cell lung cancer.

As we see on this slide looking at overall survival

with curves that generally overlap throughout their course.

Unfortunately, when we do a subset analysis and look only at the patients who

have EGFR sensitizing mutations, we also see no benefit in overall survival.

This is seen in figure five on the right of this slide, where

again the curves overlap throughout their course with placebo or Erlotinib use.

However, when we look at the left side of this slide at figure four at disease free

survival or relapse free survival, we do see an improvement in survival,

in the patients who had erlotinib though the curves do join at a later point.

What this suggests is that the erlotinib is merely the laying recurrence and

not absolutely preventing recurrence in these patients.

Such that for patients on placebo who do recur they can placed on

a erlotinib progression and gain the same type of benefit that the other patients

gained by being on erlotinib early on thus having similar overall survival.

So returning to our question with a 62 year old man

who underwent a right upper lobectomy for an adenocarcinoma.

That revealed a 6 cm mass with clear margins,

but three hilar lymph nodes that contained cancer.

Mediastinal lymph nodes were negative, and

PET scan showed no metastases prior to surgery.

What is the most appropriate further management of this patient?

So this fellow has stage two non small cell lung cancer,

specifically stage two B non-small cell lung cancer.

And we see that the most appropriate therapy would be adjuvant chemotherapy

to give him approximately a 10% improvement in his chance for

overall five-year survival.

So what have we learned?

We've learned that adjuvant chemotherapy improves survival in patients with stages

II and III and maybe larger stage 1B non-small cell lung cancers

that have been surgically resected.

That the overall five years survival improvement is between 5 and 15%.

That people getting adjuvant therapy should be younger, overly less

than 75 years of age, fir and have uncomplicated recoveries from surgeries so

that they can tolerate therapy.

And that the chemotherapy should consist of a platinum-based two-drug regimen given

for four cycles.

I want to thank you for taking the time to watch this lecture.

Adjuvant Therapy for Non-Small Cell Lung Cancer

Thoracic Oncology

Meet the Instructors