The New Role(s) of Surgery After Neoadjuvant Systemic Therapy for Cancer

March 01, 2024

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Yale Cancer Center Grand Rounds | March 1, 2024

Presented by: Dr. Charles Balch

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00:00Folks, welcome to Yale Cancer Center,
00:03Grand Rounds. I'm Kevin Billingsley,
00:06and I have the pleasure of welcoming
00:09our visiting speaker today.
00:11Doctor Charles Balch is,
00:13no exaggeration,
00:14a giant of multidisciplinary
00:16cancer care and surgical oncology.
00:19We're thrilled to have him here today.
00:22Doctor Balch is a professor of Surgical
00:25Oncology in the past chair of the
00:27Department of Surgical Oncology at
00:29the UTMD Anderson Cancer Center.
00:31He has had an extensive and
00:34distinguished career as both a clinical
00:36and academic surgical oncologist,
00:38and he's one of the leading authorities
00:41in both Melanoma and Breast Cancer Care.
00:44Over the course of his career,
00:46Doctor Balsh has made significant
00:49contributions to laboratory research
00:51in tumor tumor immunology and
00:54human T lymphocyte differentiation.
00:57He started his medical career
00:59in Med school at Columbia,
01:01where he and then he went on to
01:03surgical training at both Duke
01:05and the University of Alabama,
01:08followed by additional laboratory
01:10experience with an immunology
01:12fellowship at the Scripps Clinic,
01:14which clearly laid the groundwork
01:17for his Seminole contributions
01:20in tumor immunology and Melanoma.
01:23He's the founding Editor in Chief
01:25of the Analysis Surgical Oncology
01:27and Editor in Chief for the
01:30Patient Resource Cancer Guides,
01:32which are distributed to over
01:341,000,000 patients every year.
01:38Doctor Balch has had an extensive
01:41history of prominent leadership roles
01:43in multiple centers across the country.
01:46He served as the Executive
01:48Vice President and CEO of ASCO.
01:51He's also served as the President and CEO
01:54of the City of Hope National Medical Center,
01:57as well as the Chair of
01:59Surgery at MD Anderson.
02:03Over the course of his career,
02:04he's accumulated over 700 publications
02:07across a variety of areas in
02:10research and clinical practice.
02:13And one of the things that in
02:15my conversations with him,
02:16he and I have truly connected
02:18on are the is the importance of
02:21leadership and community building
02:24around multidisciplinary cancer
02:26care and care coordination.
02:28So one of the things that I think I
02:30have taken away from my conversations
02:32with him that I'm sure he will be
02:35sharing today is the importance and
02:37our ability as oncologists to serve
02:41our patients and our communities
02:43and a variety of ways.
02:44And he's really shown how all of us
02:47can do this over the course of our careers,
02:50both through our direct clinical care,
02:53through education,
02:54through mentorship,
02:56through research,
02:57both clinical translational
02:59and basic science,
03:01through leadership and patient advocacy.
03:03So today,
03:04he will be speaking on the role of surgery
03:08after neoadjuvant systemic therapy.
03:10And it is a real pleasure to have you here,
03:12Doctor Balch.
03:13Thank you.
03:20Well, thank you, Kevin,
03:21Bill and Sleep for a wonderful
03:23introduction and I'm honored to
03:24be here with all of you today.
03:26So there are many themes we could
03:29talk about because we are now in
03:32a revolution of oncology care.
03:34Profound changes are occurring
03:37now and I thought what would be
03:40important today is a theme to talk
03:43about how the field of surgery
03:45and surgical oncology is going to
03:47have to change and adopt to the
03:51new advances in molecular profile
03:54diagnosis in systemic therapies,
03:57in immunotherapy and the changes
04:00we are going to have to adopt to.
04:04So for some of you might say that's not
04:06what I'm doing in my practice today,
04:08but I can almost guarantee you
04:10within the next 5 to 10 years,
04:12everybody in this room who is a
04:14surgeon is going to be impacted by
04:17the things that we're showing today.
04:19And so as I go over some of these themes,
04:21I'd like you to think about the
04:24strategies that work in one tumor area,
04:26but understand that these are common
04:28to our understanding about the
04:31management of other cancers as well.
04:33That's particularly true in
04:36the immunotherapy field.
04:38So I've I've presented examples that
04:42I think are larger strategies that
04:44apply to our cancer care delivery
04:47system that is now being almost
04:51exclusively multidisciplinary.
04:52There are very few circumstances now
04:55where one modality in solid tumors
04:58will treat the patient anymore.
05:00So let me go over this.
05:01This is flying above the trees.
05:03Think about the strategies,
05:05not the details on the slides.
05:06And there are many things I can't cover
05:09in the time allowed that we we can
05:12take for questions later on if necessary.
05:20So we're should I use this?
05:41Yeah, you can advance with the
05:42the keyboard if you want. OK. All
05:46right. Well, let me start out with just
05:48the key messages of what I'm going
05:50to present as examples over time,
05:53so that you can focus on the strategies.
05:56The first thing because of the theme
05:59of this talk is that surgery will
06:02not be the first treatment for most
06:05cancers except for stage 1 cancers.
06:08That's a revolutionary change.
06:10Where is heretofore the patients
06:12usually went to the surgeon first who
06:15then kind of coordinated the care.
06:17But now because of these advances
06:21in systemic therapy,
06:23that surgery will not be the first and we
06:27need to be part of a multidisciplinary
06:30team and we must emphasize that be
06:34involved in multidisciplinary treatment
06:36plans because each of us bring to the
06:39decision making a different perspective
06:42based upon our training and so forth.
06:45And it's the collective wisdom of the
06:47different oncology specialists that
06:49is really what's best for the patient.
06:52So all of us treating cancer in a
06:56specific disease need to be together
06:58and collectively decide on the
07:00best treatment plan for a patient,
07:02what's the right combination and sequence
07:05that involves all of our modalities.
07:08And that as I'll show you that
07:11the standard of care,
07:12what we called neoadjuvant surgery,
07:15think our medical colleagues are beginning
07:17to talk about neoadjuvant surgery,
07:19that the primary treatment is systemic now,
07:21but it doesn't make a difference in the term.
07:24But what we call neoadjuvant therapy is
07:27now becoming the standard of care for many,
07:30if not most cancers.
07:32And this is an area based upon clinical
07:35trials that is showing value in
07:37almost every cancer where it's tested.
07:39There's sure there's a few that are resisted,
07:43but if you think about the future
07:45and the advances we're making,
07:46this will be a common element of our
07:51treatment that the first treatment
07:53will not be surgery,
07:54it will be a systemic treatment.
07:57And I'll go over with you about the
07:59value of that to the patient in
08:01their management.
08:02The other part of this is that
08:05immunotherapy now is the established
08:084th modality of cancer.
08:10But I want to emphasize as I get
08:12to the slide,
08:13this is a totally different treatment
08:16and the standard chemotherapy,
08:18targeted therapy,
08:19endocrine therapy that directly
08:21treats the cancer immunotherapy,
08:23these checkpoint inhibitors do not
08:26treat cancer and that has to be the
08:29first part of the logic because we
08:31can't use the rules of chemotherapy
08:33when we applied to immunotherapy.
08:36It's a different process and we're
08:38treating a dysfunctional immune system
08:41that is common to most cancers.
08:45So the other emphasis on this
08:47because there's some emphasis, well,
08:49maybe we don't need surgery anymore,
08:51but I would argue that surgery is
08:53going to be incredibly important for staging,
08:56as I'll show you as a reliable means
08:59of staging the tumor response and
09:02giving to the pathologists not only
09:05whether there's a complete response,
09:07but the residual tumor burden is now
09:10an important prognostic factor that is
09:13going to dictate our subsequent treatment.
09:16And then because of these advances
09:18in systemic therapy that surgeons
09:20will no longer be performing the
09:22radical operations that we did in
09:24the past because that was all that
09:26was available for many cancers.
09:29And so we'll be doing de escalation
09:32much more conservative tissue sparing,
09:34organs sparing operations and even if,
09:37as I'll show you in three different
09:40cancers in our future watch and
09:42wait that we will not do surgery,
09:44we'll follow the patients.
09:46And then there's going to be a whole
09:48new lexicon that will need to do much
09:51more research on salvage surgery.
09:53Which patients can we select
09:54not to do surgery?
09:56How often do we follow them,
09:58What operation do we do when they relapse?
10:01And can we do this without
10:03compromising their survival by not
10:05doing an operation at the outset.
10:08And I'll show you three different examples.
10:10And then for those of you who are in training
10:13that in all of us who are in practice,
10:16the field is moving fast in
10:18both the continuing education
10:20through organizations like ASCO.
10:22And in our training we need to have
10:26surgeons who are trained in oncology.
10:29And as Kevin Billingsley
10:30and I've talked about,
10:31I really present myself because the
10:33way I think is I'm an oncologist who
10:37operates because oncology deals with
10:39the chronic condition of cancer,
10:42whereas surgery deals with the episode of
10:45the operation of the perioperative period.
10:48But once the patient's wounds have healed,
10:51they're still an obligation for
10:53us as surgical oncologist to
10:55continue being involved in the long
10:57term management of the patient.
10:59So that's the summary of what
11:02I'm going to talk about.
11:03I do want to just take a moment to say
11:06I predicted this 30 years ago in my
11:09presidential address in at the SSO,
11:12and I wanted to point out what I said,
11:15'cause this was about surgical
11:17oncology in the 21st century.
11:19And I said that in the 21st century,
11:22only a minority of patients with cancer
11:24will have surgery alone as a single modality.
11:28And it's more likely that chemotherapy
11:30and even radiation therapy will be the
11:33initial treatment for many patients,
11:35while surgical treatment for some
11:37types of cancer will be relegated
11:40to a secondary or tertiary level.
11:42That was 30 years ago.
11:44And that prediction now is really
11:47valid for most types of solid tumors.
11:51So why is that?
11:52Because we're now in a new pathology
11:55with molecular diagnostics in this slide,
11:58which is just a cartoon,
12:00showed the old way with these
12:03general diagnosis of solid tumors,
12:06we gave our therapy and hope that
12:0810% of the patients might respond
12:11and we declared that as a victory.
12:13But now with genomic analysis,
12:16we select patients based upon their
12:19specific mutational events and other factors.
12:22And now as you'll see,
12:24instead of getting 10% response rates,
12:26we're talking about 50 to 70%
12:29pathological complete responses based
12:31upon the selection of the patients and
12:34these new agents that are so much more
12:37effective. So as I mentioned,
12:40one of the things that is revolutionary
12:43is the advent of various immunotherapies
12:46because we now have discovered which
12:49is different than all of our strategies
12:52beforehand where we assumed the immune system
12:55was deficient and we gave various forms
12:57of immune stimulants which didn't work.
13:01So now we are discovered that in most human
13:04cancers that have survived in our patients,
13:08they've done that by releasing low doses
13:11of their tumor antigen and inducing
13:13tolerance so that no matter how much
13:16you try to stimulate the immune system,
13:19it can't respond because it's
13:21in a tolerant state.
13:23This is no different than if you
13:24were allergic to grass and you go
13:26to the allergist, what do they do?
13:28They inject low doses of grass so that
13:31regardless of your exposure to grass,
13:33your immune system does not recognize
13:36it as not self and does not react to it.
13:40And so I think we've learned now
13:42that for many human tumors and we're
13:45still sorting through this,
13:46but it is revolutionary as a discovery
13:50that the main reason that tumors have
13:53survived in patients we see clinically
13:56is because they have blindfolded the
13:58immune system into a tolerant state.
14:01So if we can unblindfold the immune system,
14:04we then have a personalized treatment
14:08that reacts against the specific array of
14:11tumor antigens in each individual patients.
14:15So if tolerance is broken now,
14:17then the immune system can
14:19reject the foreign invaders.
14:21And of course,
14:22there's a price for that when we're
14:24doing something profound by breaking
14:26tolerance that the spillover is
14:29breaking tolerance to self antigens.
14:31And so if you look at the array of
14:33complications we have with immunotherapy,
14:35you can explain them all as a
14:39form of autoimmunity.
14:41And that the good news is that we
14:43could treat autoimmune diseases
14:45with Prednisone and taper.
14:47Those over time reverse the toxicity.
14:51And interestingly,
14:51in contrast to chemotherapy,
14:53you can go back to the same immunotherapy
14:56in these patients and surprisingly
14:58they don't enter into toxicity the
15:00way they did the first time around.
15:02So there's a lot we have to learn about this.
15:04And when I wanted to point out if course
15:08as you know that Jim Allison and to
15:11Soko Hanjo received the Nobel Prize for this.
15:14But I think another person who profoundly
15:17influenced the field that I wanted
15:19to give a shout out is here at Yale.
15:21And that's my friend who I worked with,
15:23Li Ping Chen,
15:24when he was at Hopkins and we were
15:28working on Melanoma immunotherapy.
15:30And I wanted to give credit to Leipeng,
15:32which I think is under appreciated
15:34by the rest of the world.
15:36He was the first to specifically state
15:40that a monoclonal antibody against
15:42B7H1 would break tolerance in a mouse
15:46model and therefore be a effective
15:49therapeutic strategy for cancers.
15:51And Leipeng worked with a group of us.
15:55This is Li Ping and Suzanne Tipalian,
15:58who I helped recruit to the
16:00surgery department at Hopkins,
16:01and her husband, Drew Pardo,
16:03who is the chair of immunology.
16:05So this is an example of translational
16:08research in the collaboration
16:10with clinical scientists.
16:12So Li Ping's research directly
16:15stimulated Drew and Suzanne to
16:18take out a seed culture they had
16:21frozen to do a phase one study.
16:24They grew up this monoclonal antibody.
16:28Mike Carducci at Hopkins,
16:29the phase one director gave it
16:31to a young person as an assistant
16:34professor named Julie Bramer,
16:35who is a pulmonary oncologist.
16:38And our recommendations was that you
16:40use renal cell and Melanoma to test
16:43this new drug because everybody knows
16:45that's the only diseases that work
16:47with immunotherapy based upon the past work.
16:52But Julie came in one day at our Friday
16:54meeting said you won't believe this,
16:55but my lung cancer patients are
16:58responding to this new drug.
17:00So BMS swooped in,
17:02bought the biotech company that
17:04had done the seed culture and
17:06that became the volume up.
17:08But it's a great example of collaboration
17:11between clinical and laboratory
17:13scientists that led directly to a
17:16major advance in cancer treatment.
17:18And I use this.
17:19This is an unusual example,
17:21but it shows the power of the immune system.
17:24This is a grapefruit sized Melanoma
17:27that was treated with a single dose
17:30of nivolumab and epilumab with a
17:33complete destruction of that tumor.
17:36That's APCR after one treatment.
17:39And I use that only as an example to
17:40show you the power of the immune system
17:42when you take the blindfolds off,
17:44when you break tolerance.
17:46And that's unusual to have this,
17:48but as I'll show you,
17:50it's not uncommon either.
17:51So now there are 9 powerful
17:54checkpoint inhibitors with different
17:56mechanisms of action.
17:58And as we know with drugs that
18:00when we combined drugs with
18:03different mechanisms action,
18:04we can get an additive effect.
18:07So now we're showing that the
18:10combinations of anti CTLA 4 which
18:12works in the central lymphoid section
18:15and either anti PD one or PDL one
18:18which works in the periphery that they
18:22combination is better than either alone.
18:25And this slide just shows you briefly
18:27in a cartoon that they're now with
18:30different trade names but the same
18:32types of drugs working in this
18:35signaling pathway between PDL ONE and
18:37PD ONE and a separate mechanism of
18:39the first drug which was Ibilimed,
18:42which works in the central lymphoid tissue
18:45with a different mechanism of action.
18:48And now even after only 11 years
18:51when the 1st paper was presented,
18:54I'll show you a slide in a minute.
18:56You can see where the FDA has approved as
18:59an indication the use of immunotherapy,
19:02the same drug,
19:04the same drug course.
19:05We're not treating cancer.
19:07We're treating a common deficit in
19:10most cancers that come alongside our
19:13traditional treatments to treat the
19:15patients with a variety of cancers.
19:18And every month there's new indications
19:20that are approved based upon what
19:23is now over 1000 clinical trials
19:25going over various drug doses and
19:28indications for immunotherapy.
19:29So that those powerful drugs
19:31that were started out with
19:33advanced disease have now moved
19:36into the neoadjuvant space.
19:38And I want to show you the reason why
19:41that is valuable in neoadjuvant therapy.
19:43So from this wonderful paper from
19:46my colleagues at MD Anderson
19:49that the advantages are one that
19:52downstages tumors and increases
19:54the ease of surgical resection,
19:56including importantly the conversion
19:59of inoperable or borderline
20:02operable tumors into operable ones.
20:05Importantly, as I'll show you,
20:07the pathological response is a surrogate
20:10endpoint for long term benefit.
20:13So we can find out if drugs work
20:15within six weeks instead of giving
20:17them after surgery and following the
20:19patient for five years and then going
20:21back and seeing how many survived.
20:23So doing this up front gives us a
20:27better indication early on based
20:29upon the pathological response.
20:32And what what you'll see is the
20:34residual tumor burden is important
20:36now in a cancer management.
20:39It allows us to test novel combination
20:43strategies and investigational drugs
20:45because we can take out the tumor
20:48after the exposure to these drugs and
20:50determine the new molecular profile
20:52of the cells that are refractory.
20:55And I'll show you a classic clinical
20:57trial that she demonstrates that.
20:59And then the other reason is the
21:02improved responses are better than
21:04in patients with advanced burned
21:07out metastatic disease where their
21:09previous chemotherapy itself is
21:12immunosuppressive and their volume
21:14of cancer itself provides an antigen
21:17excess which is immunosuppressive itself.
21:19So if we're doing this up front,
21:21when there's a smaller tumor burden,
21:23you get a better immune response and
21:26then we have some molecular markers,
21:28the CPS score and and other markers,
21:32but we really need better and more
21:35precise markers to help select our patients.
21:38So these are just a partial example
21:42of successful neoadjuvant trials that
21:44have led to approved indication by the FDA.
21:48And my point is this is a range of cancers,
21:51this is a common abnormality to
21:54human cancers.
21:55And as we're learning how to use
21:57these checkpoint inhibitors and
21:59various combinations and sequences,
22:02they're adding to the advances
22:05of of our cancer management not
22:08as a substitute necessarily,
22:10but alongside is what I call the
22:134th modality of cancer treatment.
22:15So here's another hypothesis that has
22:18been proposed that I'll show you the
22:21results that led to a clinical trial.
22:24And as you could see in the upper cartoon
22:27that if the surgeon takes out the bulk
22:30of the tumor and leaves microscopic
22:32tumor left behind and gives immunotherapy,
22:35there's not many cancer cells
22:37to stimulate the immune system.
22:40But on the other hand,
22:41if you give the immunotherapy up front,
22:43when there is a larger and more
22:46representative tumor burden
22:47and tumor antigen exposure,
22:49you will get a more robust and
22:53consistent immune response.
22:55And this is demonstrated amazingly
22:58in this randomized clinical trial
23:02which proves this hypothesis.
23:04In fact, I'm astonished at the results.
23:07So this randomized trial gave
23:11everybody with metastatic Melanoma
23:1318 courses of a single drug.
23:16Drug in this case was pembro Elizabeth.
23:20And they were randomized
23:23to receive 18 courses,
23:25but half the group got three
23:27courses up front and everybody
23:29else got 18 courses afterwards.
23:31So that was the only difference
23:33with this monotherapy.
23:34We don't use monotherapy anymore like this,
23:37but look at the difference between
23:39those patients who had three courses
23:42of single agent immunotherapy
23:44up front and those who didn't,
23:46which demonstrates what I just
23:48showed you in that hypothesis is
23:51the value in survival rates by
23:53giving checkpoint inhibitors before
23:55they're to the bulk of their tumor is
23:59removed and this gives the rationale
24:02for neoadjuvant immunotherapy.
24:03Another example that I want to show
24:07you from my colleague Merrick Ross.
24:10This is a Melanoma patient who presented
24:13with borderline operable bulky nodal
24:15metastasis in the groin and the pelvis.
24:18And this patient would have ordinarily
24:20had a radical dissection of the groin
24:24and the pelvis after immunotherapy
24:27with combination immunotherapy,
24:30you can see that there is a down staging
24:33and the tumor size has decreased,
24:36so facilitating an operation.
24:38But it wouldn't surprise you that
24:41when all the tumor was removed
24:44there was nothing left.
24:46The masses that we're seeing were
24:49inflammation and scar tissue in
24:51a classic rejection response,
24:52the same as what you'd see with a
24:56transplanted organ or a viral infection.
24:58That the mass that we're seeing
25:00on X-ray was not tumor anymore,
25:03it was scar and inflammatory tissue.
25:07So the key point here is we can't
25:10gauge responses by X-ray verification.
25:13The surgeon needs to take it out,
25:15give it to the pathologist to determine
25:18the degree of response and to do a
25:21new molecular profile to look at the
25:23molecular profile of the refractory cells.
25:27So this was the first immunotherapy
25:30trial presented in the world 2010.
25:33So this is a very new field.
25:36This was using the maximum tolerated
25:38dose of a single agent EPI LUMA Med
25:41and of course the problem with this
25:43although this became a standard of
25:45treatment until we found out that
25:47at that MTD that 50% of patients
25:51had grade three grade 4 toxicity and
25:54some patients died because of that.
25:56It was also shown that as a single
25:59agents it's inferior to an anti
26:01PD1 checkpoint inhibitor.
26:03So in large part this drug was not
26:06used anymore because of the toxicity.
26:09However,
26:10the the teaching point here is you
26:13can't treat immunotherapy agents like
26:16drugs and in fact a dose now of 1 to
26:193 milligrams which is not very toxic
26:22when added to another checkpoint
26:25inhibitor has an added benefit.
26:28So we have to get away from testing
26:30these some of these agents by their
26:32maximum tolerated doses when actually
26:34lower doses work just as well if
26:36not better and a more tolerable.
26:38So we'll go over the details of this
26:41randomized study that looked at
26:44different dose schedules and doses of
26:47combining hippilumamid at 3kg and 1
26:49milligrams with combinations of nivo.
26:52And this Arm B,
26:54just to accelerate the talk,
26:57turned out to be the most
27:00efficacious in the least
27:01toxic. But here's the teaching point I
27:03wanted to make in this randomized study.
27:06This is the radiological response to patients
27:09being treated in this randomized study
27:11with metastatic Melanoma, mainly stage 3.
27:14And you can see there's a complete
27:17response radiologically in 10% of patients,
27:20a partial response in 50%.
27:22However, when the patients had surgery
27:24and the pathologist could examine it,
27:27you see the difference,
27:2957% of those patients had APCR
27:32and 7% had a near PCR.
27:35So compare the difference between
27:36the radiologic response and
27:38what the pathologist found.
27:41You cannot look at these masses on
27:43X-rays and know what's inside them
27:46because these tumors in many cases are
27:49replaced by inflammation and scar tissue.
27:52So the surgeon has to take them out and
27:55give the specimen to the pathologist.
27:57And as I'll show you in tumor after tumor,
28:00the determination of PCR near PCR versus
28:04more residual tumor burden is now an
28:08important part of our cancer management.
28:11But in my early days, giving interleukin
28:13interferons tumor cell vaccines,
28:16if we had a 5% PCR rate,
28:19that was a victory.
28:21If we had a 15% partial response,
28:23that was a victory.
28:25And as I told one person earlier,
28:27we tortured people with alpha
28:30interferon over many dose schedules
28:32in years because that's all we had
28:35and we improved survival rates by 2%.
28:37So now in this new era of Melanoma
28:40management with the advent of
28:42immunotherapy because we still
28:43don't have good chemotherapy,
28:45we have some targeted therapy.
28:47Look at the pathological responses
28:49now that range in this study between
28:5265 and 80% and pathological complete
28:57response in dose schedule BPCR in
29:0257% of patients Never in the history
29:05of treating cancer have we seen
29:08these kind of dramatic responses.
29:10So this also shows you just in one other
29:13cartoon the value of combining two
29:15different checkpoint inhibitors which
29:17have different mechanisms of action.
29:19And if you look on the two pies charts,
29:23you can see that with an anti PD one
29:26you get a 20% PCR but if you add low
29:31doses of ipilumab you double that to 43%.
29:35So again showing as we use with
29:38combination chemotherapy with
29:39different mechanisms of action,
29:41the new standard is using these
29:44combined checkpoint inhibitors.
29:46But the important point is the lower
29:49doses and shorter schedules work just
29:51as well as high doses given over a
29:54long time because what we're doing
29:56is like turning on and off switch,
29:59we're breaking tolerance.
30:00And I predict that we will not be
30:03giving a year of immunotherapy
30:05before we'll have to do the clinical
30:07studies to show that it's equally
30:09good of giving shorter courses.
30:14So this is one of my first key
30:17points about the impact on surgery.
30:19So this is a study Prada study going on
30:23now which is a randomized study but for
30:26which we have some of the early results.
30:29These are patients who present
30:31with stage 3B and 3C disease.
30:33They have clinically and radiologically
30:36detected nodal metastasis and index node has
30:40a marker placed in the largest lymph node.
30:44Then the patients gets only two cycles
30:46of combination of immunotherapy,
30:49only two cycles and then that index
30:52node that's all that is removed.
30:55And you can see the strategy those patients
30:58who had APCR or near PCR less than 10%
31:01viable cells had no therapeutic lymph
31:04node dissection and no adjuvant therapy.
31:07Where's those that had
31:09APCR did get a therapeutic,
31:12no dissection and follow up and
31:14those that did not get a response
31:17had both a therapeutic lymph node
31:20dissection and adjuvant immunotherapy.
31:22But the point is that's already been
31:25reported is that in the patients entered
31:28into this trial that 60% of them never
31:31needed a therapeutic lymph node dissection,
31:34which was their standard treatment before
31:37because they achieved APCR or near PCR.
31:40And I'll show you more examples of
31:43this and other diseases as well.
31:45So let me move on to breast
31:48cancer and neoadjuvant therapy.
31:50So there's another principle here that if we
31:54don't get a pathological complete response,
31:56you could predict that the residual
31:58tumors are going to be refractory
32:01to the drugs that you gave up front.
32:03So why continue them afterwards when
32:06these refractory tumors probably have
32:09a different molecular profile in the
32:12strategy here which is a classic in
32:14that I think applies to other tumors
32:16as well was this Catherine study
32:18which took her two positive patients
32:20who got neoadjuvant treatment.
32:23They all had residual invasive
32:26disease after getting their standard,
32:29her two therapy either single or dual
32:32therapy targeted therapy and then we're
32:35randomized to switch their treatment
32:37if they had residual disease into a
32:40different drug TDM one or continued
32:42the same drug that they were on before.
32:45And this study of course showed that
32:48by switching therapies intuitively
32:50this makes sense.
32:51You get an improved survival rate in
32:54those patients who we stopped after
32:56six weeks and switched to another
32:58therapy to treat the refractory
33:01tumors and that in turn increased
33:03survival rate in these patients.
33:06And this is going on in all the
33:08other subtypes of breast cancer.
33:10And my point here is you look
33:12at the residual tumor burden,
33:14which shown in the different colors
33:17the differences in survival rates over
33:218 years based upon the subtypes of
33:24breast cancer and how those patients
33:26who have APCR or new PCR do very
33:30well over 8 years.
33:31But in contrast,
33:32those patients who have more residual
33:35tumor burden obviously are going to
33:37need a different therapy and have a
33:39worse prognosis if we continue to give
33:41the same treatment and don't switch.
33:44And so now there are a number
33:46of clinical trials,
33:47I'm just showing one examples.
33:49It was showing that post neoadjuvant
33:51treatment options a different treatment
33:53than what was given up front but
33:56directed by the residual tumor burden
33:59cause can improve survival rates
34:01with a range of switching therapies.
34:03So the teaching point here is now we
34:07have enough agents we can go to second
34:10line therapy early based upon the
34:13residual tumor burden after the surgeon
34:15takes the area out where the tumor
34:17was and gives it to the pathologist.
34:20So here's another important strategy is
34:24if we're combining chemotherapy with
34:27immunotherapy that the chemotherapy that
34:29works directly on the tumor is going to
34:32break down the tumor into apoptosis.
34:35It will release tumor antigen
34:37and in so doing becomes a boost,
34:39an immunological boost or an internal
34:41vaccine if you will for the immune
34:44system where tolerance is broken.
34:46So it wouldn't surprise you if you
34:48use these combinations you will
34:50get better responses.
34:51And in these non randomized studies
34:54in the right you can see the PCR
34:58rates was 60% or more PCR by using
35:03a combination of neoadjuvant therapy
35:06and in a series of trials,
35:08I'll just go over them quickly,
35:10the KEYNOTE 522 and the impassioned
35:13O31 using different checkpoint
35:15inhibitors combined with the same
35:18classic chemotherapy up front for 12
35:21weeks and then randomizing the patients
35:24between checkpoint inhibitors or placebo.
35:28You can see in both of these trials
35:30that the PCR rate was higher in both
35:33trials by adding immunotherapy to
35:36chemotherapy is neoadjuvant therapy.
35:38So now for and this is only for right now
35:41been used in triple negative breast cancer.
35:44Although the recent studies to show
35:46that the addition of immunotherapy
35:48in selected patients with ER positive
35:51tumors also are have an additive effect.
35:54But now with these advances in this shift
35:58that neoadjuvant therapy is preferred
36:01in almost all breast cancer patients
36:03except for maybe stage 1A and 1B.
36:06And that is a profound change in how we
36:09treat breast cancer And that APCR is
36:12associated with markedly improved outcomes.
36:15And it gives us a an insight within
36:186 to 8 weeks how well our patients
36:21are going to do in contrast to our
36:24classic studies doing surgery 1st
36:26and then giving adjuvant therapy
36:28and then trying to measure 5 year
36:30survival rates 8 to 10 years later.
36:33So this is a very important advance.
36:35It allows us to keep moving on with
36:38new strategies and cancer management.
36:41The highest pathological response rates,
36:43around 63%,
36:44is used with the combination of
36:47pembrolizumab and a classic chemotherapy
36:51Carbotaxol followed by ACEC and the
36:55Pembro not only improves the PCR rates,
36:58but also results in smaller residual cancers
37:02across the entire spectrum of disease,
37:04and that means it facilitates
37:07more conservative operations.
37:09It switches patients who needed a
37:12mastectomy for for medical reasons into
37:15having the options of having lumpectomies
37:18because their tumors are smaller.
37:20So we also have learned that patients
37:22with residual disease have a poor
37:25prognosis and need additional
37:26or different treatment
37:28and allows us based upon the response
37:31to individualize their therapy.
37:33So this is our future,
37:34not only in breast cancer
37:36but in other tumors as well.
37:38So this is another part of our advance which
37:40I'll show you in other diseases as well.
37:43I showed you in Melanoma how we're
37:45now eliminating the therapeutic no
37:47dissections in those patients who have APCR.
37:50This is from my colleague Henry Cure
37:53at MD Anderson who's presenting this
37:55information for the first time next
37:57month in Miami and he kindly loaned
37:59me the slides to show to you today.
38:02So they have a prospective trial of
38:04eliminating breast surgery in selected
38:07patients who are exceptional responders
38:10for neoadjuvant systemic therapy.
38:12And the reason that they do this
38:15after their neoadjuvant therapy and
38:18they these are generally used with
38:21chemotherapy that they use a vacuum
38:24assisted core biopsy to in the area
38:27where the tumor is guided by ultrasound.
38:30And if there's no residual disease
38:33they have no further breast surgery
38:35but if they have residual disease
38:37they get standard treatment.
38:39So Henry is presenting for the first
38:41time they're multi institutional study,
38:4350 patients who had no breast
38:46surgery whose average size at the
38:48beginning was 2.3 centimeters and
38:51after a brief exposure to systemic
38:54chemotherapy was less than a centimeter.
38:57They had to do 15 vacuum assisted
39:01biopsies in these patients.
39:04But here are the results so far,
39:0862% had APCR among the triple
39:11negative breast cancer patients
39:13who had a checkpoint inhibitors
39:16plus chemotherapy was 71 percent,
39:1955% in the her two positive.
39:22And what he's going to present so
39:24far after 4.1 years of treatment
39:26with no surgical treatment,
39:28not a single patient has relapsed
39:30so far in the breast.
39:32And I could go over and show you
39:34other studies where we're now looking
39:36at eliminating radiation therapy
39:38in these patients who have APCR.
39:40It's changing how we treat patients
39:43based upon their responses to
39:46neoadjuvant treatment and they're
39:48now doing a study not yet reported
39:50in patients getting systemic therapy
39:52standard lumpectomy and being
39:54randomized to getting no radiation
39:56therapy to the breast if they had
39:59APCR including in their lymph nodes.
40:02So let me as another example
40:04go over lung cancer.
40:05This is another example where the
40:09molecular profile profoundly effects
40:11our targeted treatment even in subsets
40:13of patients now of three to 7%.
40:16And in these small subsets we not
40:18only have first line therapy,
40:20second line therapy,
40:21even third line therapy for these small
40:25subsets defined by molecular markers.
40:28And as we do more of this,
40:29this is going to be the standard
40:31of care for all cancers as our
40:34molecular profile allows us to
40:35select patients who are responsive
40:37to certain systemic therapy,
40:39but not for others.
40:41But I wanted to show you in terms
40:44of the immunotherapy,
40:45how these first studies of using
40:47neoadjuvant therapy had a major
40:50pathological response in 45% of patients.
40:52But the reason I wanted to show
40:55these slides is this is an example
40:57published in the New England Journal of
40:59Medicine of the pre treatment imaging.
41:01And after four weeks
41:03there was residual tumor.
41:04This was judged as a partial response,
41:07but when the surgeon took out that mass,
41:09there was no viable tumor left.
41:12And this is again illustrating
41:14and yet another disease,
41:15the importance of the surgeon
41:17doing the staging and giving
41:19the tumor to the pathologist.
41:21Here's another example from the same article,
41:23fairly large tumor that didn't move at all.
41:26This was judged as a non response,
41:28but nevertheless the surgeons took
41:30it out and that mass that you're
41:33seeing on X-ray was replaced
41:35completely by scar and inflammation,
41:37it was APCR.
41:39So now they're randomized studies
41:41of neoadjuvant therapy.
41:42I'll just go over this quickly in
41:44the interest of time using either
41:46nivolumab plus chemotherapy,
41:48platinum doublets or pembrolizumib
41:50with essentially the same results
41:52in randomized studies.
41:54And you could see in this one study
41:57Checkpoint 8.6 that adding the PD1
42:02nivolumab plus chemotherapy was
42:04better than chemotherapy alone.
42:06And in this study now moving from
42:09stage 3 to stage two lung cancer also
42:14demonstrated it with pembrolizumab
42:16that you get an additive effect
42:19with the hazard ratio of .58 in a
42:22highly significant difference in
42:24event free survival and later on
42:26with follow up in overall survival.
42:29So these two studies are just two
42:32examples demonstrating the additive
42:35value of checkpoint inhibitors
42:37plus standard chemotherapy.
42:39And the teaching point here is
42:41if you look at the responders in
42:43the outcome in the green lines,
42:46most of these patients will survive
42:48for a long time without relapsing.
42:51In fact,
42:51at MD Anderson and her Melanoma group,
42:53my colleagues tell me that it is
42:56less than 5% of patients who have
42:59APCR after neoadjuvant therapy have
43:02failed so far in their experience
43:04that now goes past five years.
43:06So let me show the last example
43:10on colorectal surgery,
43:11which is also another area where
43:14neoadjuvant therapy here using
43:16chemotherapy and radiation therapy.
43:19And I don't have time to go over
43:21the details other than to show you
43:23in randomized trials which I'll
43:25just briefly show the the results.
43:27Different combinations and sequences
43:29of chemotherapy and radiation therapy
43:33up front has caused a pathological
43:36or near pathological complete
43:38response in almost 50% of patients.
43:43So again just to show you the value
43:46of clinical trials in advancing
43:48our standards of care,
43:50these are two randomized studies
43:53showing different combinations and
43:55sequences of radiation therapy,
43:57both short term and long term therapy
44:00and then whether the chemotherapy was
44:03given sequentially or simultaneously.
44:06But the bottom line is the patients
44:08who got longer exposures to standard
44:10chemotherapy as neoadjuvant therapy did,
44:13those did better than those who
44:15got shorter courses and this was
44:18shown in the repeater study.
44:19The this is a failure rate.
44:22Those patients who got longer courses
44:25of chemotherapy did better than
44:27those who had standard treatment.
44:29And in this protege study now
44:32with seven years follow up that
44:34the patients who got radiation
44:36therapy first followed by
44:38long term course of more intensive
44:41chemotherapy with Fulfurinex did
44:43better than those who had the
44:45standard short term chemotherapy
44:47simultaneous with radiation therapy.
44:49And now overall survival at 7 years
44:53event free survival shows a benefit of
44:56this which became the standard treatment
44:59and in the experience at MD Anderson,
45:01this is from our Chair of Colorectal
45:04department, George Chang.
45:06You could see those patients again
45:09that achieved APCR did better
45:11with long term follow up.
45:13These were 18% of the patients but no
45:17local recurrences in a very low risk
45:19of distant metastasis based upon the
45:22responses to the neoadjuvant therapy,
45:26again showing this in yet
45:28another disease as a strategy.
45:31And then finally this Oprah study
45:33which again randomized patients
45:36with different combinations of
45:38of neoadjuvant chemotherapy,
45:40long term radiation therapy and
45:44chemotherapy and then we're randomized
45:47to receive either watch and wait
45:50if clinically and by X-ray they
45:52had a clinical complete response.
45:55They went into a watch and wait
45:58program and the results of this
46:00we're pretty striking.
46:01You can see that the patients who had
46:03the more intensive neoadjuvant therapy
46:05did better with long long course
46:09radiation therapy followed by FOLFOX.
46:12And the important point is that
46:15the that I wanted to show here
46:18is the three-year failure of the
46:22event free survival in patients who
46:25had no surgery was 53%.
46:27And if regrowth of the tumor
46:30then all of these patients were
46:33salvage with a TME operation.
46:36But in those who had shorter courses
46:40of chemotherapy did not do as well.
46:43But overall,
46:44as in this slide,
46:45nearly half the patients who
46:48received neoadjuvant therapy,
46:49especially with the longer courses
46:52of chemotherapy and longer
46:54courses of radiation therapy.
46:56You can see that half of the
46:59patients avoided surgery even
47:01after six years of follow up.
47:03And those who recurred and had
47:06salvage surgery had essentially
47:07the same survival rates based upon
47:09the time of diagnosis as those
47:12patients who had surgery up front.
47:16So I wanted to finish with what I
47:19think is an example of our future when
47:22we have the biomarkers that can give
47:26us an exact prediction of response
47:30rates with checkpoint inhibitors.
47:32So in standard pathology report
47:35usually shows the immunochemistry
47:37results with either microsatellite
47:40instability high or mixed
47:46mixed
47:50responses in mismatch repair deficiency.
47:55Sorry. And the point here is this is
47:58for the first time that the FDA approved
48:01a drug with checkpoint inhibitors
48:04based solely on the molecular profile.
48:07So regardless of which tumor type it is,
48:11colorectal, gastric, pediatric breasts,
48:13sarcomas which are very infrequent.
48:17The most common is in colorectal cancer
48:19which is 10 to 15% of patients have
48:22these biomarkers which is a surrogate
48:25for a poorly differentiated tumor.
48:28So think about it,
48:29the immune response is looking
48:31for foreigners, not self.
48:33The more foreign the object is in our body,
48:36the more robust the immune system is.
48:39So it shouldn't surprise you that
48:41the more poorly differentiated tumor,
48:43higher tumor mutation burden or have
48:46these biomarkers are going to be the
48:49most responsive to immunotherapy.
48:51But this is dramatic.
48:52When the first studies were done,
48:54you can see there was a pathological
48:56response,
48:57major response in every patients
48:59who were treated with a checkpoint
49:02inhibitor and look at these results.
49:04A single dose of ipilumab and only
49:08two doses of nivolumab led to 100%
49:11pathological response in these
49:14patients who were MMR deficient and
49:17even in 27% of those who did not
49:20have that mutation with this short
49:23term dual agent and his larger series
49:26have been presented like this.
49:28At ASCO you could see that 95% of
49:32patients have expressing this biomarker
49:34in this case in colon cancer had a
49:38major pathological response at 67% had
49:41APCR with short term dual immunotherapy
49:45based upon this tumor marker.
49:49And here's the other point is larger
49:51series have been reported again
49:53using one dose of IPI and at a low
49:56dose only 1 milligram per kilogram.
49:59Remember we started out at 10 milligrams,
50:01which was too toxic in that in 99% of
50:07patients they had a pathological response.
50:10So this is pretty dramatic.
50:11Now for the surgeons.
50:13This was published in the New England
50:15Journal of Medicine only on 12
50:18patients who expressed this biomarker
50:21and who got a checkpoint inhibitor
50:25and based upon that response had
50:28no radiation therapy and no surgery
50:31and had been followed up now for
50:33more than four to five years.
50:35And these aren't small tumors.
50:36You could see in this example published
50:38in the New England Journal Medicine,
50:39these were large tumors that over
50:43time with this checkpoint inhibitor
50:46disappeared and in these patients
50:47with the follow up with no radiation,
50:50no surgery,
50:51there were no recurrences based
50:53upon this tumor marker.
50:54So this also applies in the lower
50:57frequency of patients with GI tumors.
51:00Gastrointestinal and esophageal cancers,
51:02which you could see in these studies used
51:06in a combination of pembrolizumab and Folfox,
51:09achieved 23 of 26 patients were
51:13free of disease.
51:15And the overall survival in these patients
51:18who presented with advanced disease,
51:21treated with preoperative disease
51:25and that 65% of those patients
51:27based upon the tumor marker,
51:29it's a small percentage of patients had
51:33APCR with gastric and esophageal cancers.
51:36And now they're going on in this
51:39series of trials,
51:40the first one in Cohort 1,
51:42they found APCR in 60% of
51:45patients with this MMR deficiency.
51:48The the major response was 80%.
51:52And now the next phase of this
51:55trial is those patients who have a
51:58complete or near complete response
52:00radiologically and endoscopically
52:02get no surgery and follow up for GI,
52:05for gastric and gastroesophageal malignancy.
52:08So I've shown you in Melanoma,
52:10in lung cancer and breast cancer
52:12and now in colorectal cancer based
52:15upon tumor markers and usually based
52:17upon combinations of checkpoint
52:19inhibitors plus chemotherapy that
52:21we're now moving in selected patients
52:23to not doing surgery and watch and
52:26wait and then follow up with the
52:29patients and in those that fail,
52:31which is still the minority of
52:33patients to do salvage surgery.
52:36So these are my summary slides.
52:37There are changes now,
52:39but these strategies I've told you
52:42are increasingly going to be applied
52:44for all solid tumors that will
52:47impact all of us in oncology fields.
52:50That new adjuvant therapies selected
52:52by tumor molecular profiles is now
52:55and will increasingly become the
52:57standard of care for most cancers,
53:00for all but the earliest stage 1 cancers.
53:03And that surgery is vitally important for
53:06staging and local regional Disease Control.
53:10I've showed you data that there
53:11may be a place for watch and wait,
53:14but that's in a selected group of
53:16patients and then everybody else.
53:18There's still an important role for
53:21surgery in staging these patients.
53:23And interestingly now as we're doing
53:26less surgery for early disease,
53:28we're going to be doing more
53:30surgery for stage 4 and borderline
53:32resectable Stage 3 disease because
53:34we can downstage the patients.
53:37And those of us treating even Stage
53:394 disease need to know whether
53:41the masses we're seeing on X-ray
53:44is inflammation or viable tumor,
53:46take it out and do a molecular profile
53:49on those tumor cells that are not responding.
53:52So we need to better refine the
53:54role of watch and wait.
53:55This is a new thing.
53:56I'm not proposing it except in clinical
54:00trials and the intensity of follow
54:02up in the appropriate type of salvage
54:04surgery on relapse is going to be
54:06a new area for which we are going
54:08to need a lot of prospective data.
54:10And I think as I've shown you,
54:13we're changing the standards of
54:15care based upon these prospective
54:17clinical trials that are neoadjuvant
54:20trials that involve surgery as
54:22part of the clinical trial.
54:24So surgeons must engage their
54:26patients in the clinical trials where
54:29appropriate and design surgical
54:31trials to document the results
54:34of DE escalation strategies,
54:36new sequences of treatment and
54:38the results of salvage therapy.
54:41And I think for those of of us training
54:44residents and fellows that surgical
54:47training must include more exposure
54:49to contemporary cancer management.
54:52And that the pool of American Board of
54:55Surgery certified surgical oncologist
54:57must increase to meet the demands
55:00in the public to have surgeons who
55:02are also trained in oncology to be
55:05part of the multidisciplinary team.
55:07And as many of you know at least
55:10in the tertiary hospitals that in
55:12order to keep up with the rapidly
55:15moving field based upon one or two
55:19diseases are increasingly going to
55:22have to focus their treatment to one
55:25or two organ sites in order to stay
55:27current with the rapid advances.
55:30So here are my key messages for the
55:32surgeons 1 to be prepared and informed
55:35to make major changes in the surgical
55:38management of your cancer practice,
55:40including deferring surgery until
55:42after a trial of neoadjuvant therapy.
55:45Because of the benefit I've shown
55:47you now in multiple tumor types,
55:49to consider surgical excision for
55:52borderline or inoperable tumors that
55:55are downstage with systemic therapy and
55:58consider more conservative surgical
56:00procedures with the downstaging.
56:03And then we as surgeons have to adopt
56:06A mindset of being an oncologist
56:08who operates cancer management is
56:11dealing with now a chronic disease.
56:13Surgery is kind of a vertical specialty
56:16that focuses on the operation
56:18and the perioperative period.
56:20But our job is not done once
56:22the wounds have healed.
56:23There is another phase for which
56:25we need to be involved in giving
56:28systemic therapy up front and how
56:30we do what we do afterwards.
56:32And we also need to be at the arena
56:36when treatment plans are made to
56:39bring the surgeons perspective
56:41to multidisciplinary treatment
56:42And without being critical,
56:44I know that your medical oncology
56:46training and radiation oncology training
56:48does not include surgery as part
56:51of your training and in fact you're
56:54biased because you see our failures.
56:57I'll give you one example.
56:58My daughter who's APA in GI medical
57:01oncology at MD Anderson sees a few of
57:05these salvage surgery patients that
57:06say our patients come in with these
57:09huge inoperable, miserable tumors.
57:10I don't see why we're doing salvage surgery.
57:14So I immediately called my son Glenn,
57:16who's doing all the colorectal
57:18surgery and said,
57:19you know that happens but only
57:21in 5% of our patients.
57:22But my daughter thinks that we should be
57:25doing this because she sees the failures,
57:28the ones that do well don't go to
57:30those medical oncology clinics.
57:32So I think it's bringing the surgeon's
57:36perspective to those that are different
57:38in medical and radiation oncology.
57:41And it's the collective wisdom we
57:42all bring that is better for patient
57:45care decision making.
57:49And then this last thing I
57:51don't have a solution for,
57:52but I want to give you an example.
57:54My son Glenn, who's head of the
57:57division of colorectal surgery at Emory
57:59had a conversation with his chair.
58:03So John Sweeney said Glenn,
58:05I noticed your Rvus are down,
58:06what's going on and Glenn responded.
58:09Well, half of my rectal cancer
58:11patients are getting a clinical
58:13complete response and going into
58:15watch and weight status and now I'm
58:17flooded with these patients doing
58:19flexible sigmoidoscopy exams every
58:21three months and there is little RVU
58:24values for this new group of patients.
58:26And so my point is in this new
58:28era of oncology management,
58:30how are we going to gain gauge the
58:33clinical performance that here to
58:35for is based upon volume of care.
58:37When oncology advances in all
58:39of our fields are driving us to
58:42perform less intensive therapy,
58:44surgeons are doing more
58:46conservative operation,
58:46less frequent lymphadenectomies,
58:48more watch and wait.
58:50Radiation oncologists are going from six
58:52weeks standard courses to three weeks
58:55to weekly to no radiation oncology.
58:58So they'll be less income if you're
59:00doing shorter courses of radiation.
59:02And of course we're a medical
59:04oncology colleagues.
59:05I think we're going to be giving
59:07shorter courses of adjuvant therapy
59:09especially immunotherapy instead of
59:11one to two years of expensive drugs.
59:15And then what are we going to do
59:17with these patients who are in watch
59:18and wait and are well patients
59:20that just need to be follow up
59:22the the oncology specialist can't
59:23see the new patients in those
59:25interactive treatment if they're
59:27seeing well patients for follow up.
59:30So we have to delegate that follow
59:31up to mid level providers or even
59:34non oncology trained physicians
59:35who will follow these patients
59:37and send them back in those few
59:39that relapse and that's a change
59:41in how we manage our patients.
59:43It's a different team effect
59:46but with the like Glenn said if
59:48half of his patients are getting
59:50a clinical complete response,
59:52he can't follow all of those
59:53patients for a lifetime,
59:54somebody else has to do that and
59:57then send back those that relapse.
59:59So that's the end of my talk.
01:00:02I hope that this has been helpful
01:00:04in telling you about our.
01:00:06Present and future strategies and
01:00:08how that will impact on the surgical
01:00:10management of our cancer patients and
01:00:13the value of clinical trials in make
01:00:16in changing our standards of care.
01:00:18So thank you all for the opportunity of
01:00:20coming and I hope this was helpful to you.
01:00:28Thank you for a talk that
01:00:31was uplifting, exciting
01:00:33and also provocative.
01:00:35I know that I was getting late.
01:00:37There may be some time
01:00:38for one question from
01:00:39the audience for Hoocha.
01:00:41So thank you, Charles, for presenting,
01:00:43really just giving us food for
01:00:45thought and talking about where
01:00:47cancer care is and perhaps where it's.
01:00:49I want to come back to your last point,
01:00:52which is interdisciplinary collaborations.
01:00:54And for the trainees in the room,
01:00:56I thought it'd be helpful to share a lens of,
01:00:59you know I was in Hopkins during that period
01:01:02and many of those first offers were felons.
01:01:05Patrick Ford, the lung trial you showed and
01:01:08was a fellow sitting in a conference and
01:01:10we were talking about this with surgeons,
01:01:13medical oncologists and radiation
01:01:16oncologists and the colorectal trials.
01:01:18My very good friend Louise Diaz and I
01:01:21remember sitting with Louise running our
01:01:23colon tumor board and an observation
01:01:25that was made on a small trial that on
01:01:29our phase one trial one of the patients
01:01:31was mismatched repair efficient,
01:01:33it was one patient and it was an observation
01:01:37made and wrote Suzanne Topallion,
01:01:39he's a surgeon as you mentioned.
01:01:40He wrote that in the clinical Cancer
01:01:43Research it was an advance smaller
01:01:45than this that led to this entire
01:01:47field of opening up in multiple tumor
01:01:50types from that very small observation.
01:01:53So my question to you is that how do
01:01:57we encourage that as we're becoming
01:01:59bigger that event happenstance that's
01:02:01how research is done,
01:02:02that's how great clinical initiatives happen.
01:02:06How do we foster that as leaders
01:02:08we're sitting in this room that that's
01:02:10a luxury that we barely have.
01:02:11So I wondered what's your thoughts about,
01:02:14I think the answer is we're if we're
01:02:16looking for advances in care see
01:02:18opportunities and we can base a clinical
01:02:21trial prospectively on a hypothesis
01:02:24or even retrospective data that leads
01:02:26to the design of the trial that we
01:02:29need to be thinking about.
01:02:31We have to practice evidence based care.
01:02:35And if we don't have this in this
01:02:37rapidly developing field,
01:02:38we're going to go back to empirical
01:02:41medicine based upon marketing of drug
01:02:43companies and and instrument companies.
01:02:45So I think you know to add to what
01:02:48Nita has said that it's so important
01:02:50for us to insist on our patients
01:02:53wherever possible being in clinical
01:02:55trials where they're eligible so that
01:02:58we can advance the field based upon
01:03:01evidence and not based upon marketing
01:03:04strategies but it.
01:03:05But we all need to have an open mind
01:03:08is you know and I'm enthusiastic
01:03:10about the results,
01:03:11but if you looked at the slides,
01:03:12there are a lot of patients who failed
01:03:14with our current treatment.
01:03:15So there's still a lot to do and I
01:03:19think that's going to be based upon
01:03:21the team working together,
01:03:23each bringing different perspectives.
01:03:24I love the story with Lei Ping Chen
01:03:28who said this works in the mouse,
01:03:30maybe it works in the patient and
01:03:32he brought that hypothesis to what
01:03:35became a major immunotherapy advance.
01:03:39So the collaboration and between
01:03:42the clinical teams and between the
01:03:44research teams and the clinical
01:03:46teams is I think the
01:03:47what's important and championing the
01:03:51collective wisdom that we all bring
01:03:53with our different perspectives in
01:03:55bringing that together in our decision.
01:04:00Thank you very much.
01:04:01I think Doctor Balch will be
01:04:04here for a little bit longer.
01:04:06I don't want to take more
01:04:08practice to this point.
01:04:09If you people can come down and
01:04:11I know you'll be spending some
01:04:13time with the surgical residents,
01:04:15it's been wonderful.
01:04:15Thank you all for the honor
01:04:17of coming here today.
01:04:23No. And I get this. He get this luggage.