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

March 01, 2024

Yale Cancer Center Grand Rounds | March 1, 2024

Presented by: Dr. Charles Balch

ID
11406

Transcript

  • 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.