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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.
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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.
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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?
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
13:42
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.