The Unconventional Lecture Series

In September I gave an eight-hour lecture series to the Roswell Park Cancer Institute fellows. It was unconventional as I didn't teach them what I thought they could get from journal articles, NCCN guidelines, etc. I focused on conveying a thought process to them. Indeed, as I reflected on my instruction when I was a fellow and what I've learned over the years, I realized that nobody really teaches you how to think. For so many, it comes naturally, but I felt it was worth detailing for them. Fortunately, the feedback I received was tremendous, as I was told I should make this into a Youtube lecture series for other fellows. The lectures series included:

Tuesday, September 7, 8-9 AM:  

1.     The forest is as important as the trees.

As the world continues to subspecialize we are losing sight of the forest as we focus on the trees. Many of the greatest clinical decisions and advances we make in the future will be at the interface of various tumors and disciplines. Extreme sub-specialization, as we are seeing now, may prove detrimental in numerous ways. Knowing developments in other tumors and fields may enable you to see connections to your tumor of interest before others do.

Examples of crosstalk were provided, including:

·        Recent approval of the AML drug, ivosidenib, for the treatment of IDH1 mutated cholangiocarcinoma.

·        Community physicians and academicians who treated melanoma in 2011 were initially far more familiar with immunotherapy than their counterparts when it was approved in almost all other tumor types. 

·        The use of BRAF V600E inhibitors in melanoma, colorectal cancer, thyroid cancer, hairy cell leukemia, etc.

·        The use of yttrium-90 for liver-predominant metastases in colorectal cancer, carcinoid, etc. 

2.     Play chess, not checkers 

Hematology/oncology patients, and all medical patients for that matter, require a short- and long-term therapeutic approach. It's imperative, in a world that will increasingly rely on precision medicine and clinical trials, that physicians develop a long-term treatment approach at first contact with their patients. The sequencing of conventional therapies in the context of clinical trials and molecular studies is critically important. In addition, treating a patient's underlying problem, as opposed to bandaging their wounds, is essential. 

Examples provided were:

·        Metastatic colon cancer was used as an example. We discussed the first five lines of therapy one would consider when initially meeting a patient with metastatic colorectal cancer with WT H/N/KRAS and WT BRAF, and no indicators for immunotherapy. We talked about how one would incorporate clinical trials into the treatment sequence and that failure to recognize a potential clinical trial could result in a patient being ineligible for it because conventional therapy was given that precluded them from being on it. 

·        We gave real-world examples of patients being discharged from hospitals with no consideration of their underlying problem, only to find them readmitted almost instantaneously.

3.     COMET acronym

In terminal patients, a systematic thought process is required at every treatment point. One should apply the COMET acronym, which I newly developed, frequently in this regard:

C=Conventional therapies: Evaluate all conventional (FDA approved) options available.

O=Operational: Although it may not be readily apparent, some patients with stage 4 disease may benefit from surgery.

M=Molecular studies: One must utilize precision medicine in the treatment of hematology/oncology patients. Ordering of such tests should be reflexive in the appropriate scenarios (e.g. theoretically terminal patients).

E=Everything else: Here we are talking specifically about locoregional options, including radiation, SBRT, TACE, yttrium 90, HIPEC, etc.

T=Trials: it's imperative physicians consider clinical trials for their patients at every step along their journey.

Examples provided were:

·        The use of yttrium-90, surgery, clinical trials, molecular studies, and conventional therapy in patients with stage 4 colorectal cancer.

·        A real-world case of a patient with stage 4 cholangiocarcinoma with a solitary anterior abdominal wall lesion was presented.

4.     The academician-community physician gap.

There is value to being either an academic or a community physician. 85% of hematology and medical oncology is practiced in the community. Moreover, the gap between the academician and the community physician has closed considerably. Access to trial data, NCCN guidelines, etc., has enabled community physicians to stay current. Moreover, numerous community practices now have robust clinical trial programs that rival many academic institutions.  Some community practices have their own phase 1, CART, and allogeneic bone marrow transplant programs. Many community physicians, like their academic counterparts, subspecialize. They submit and conduct investigator-initiated trials as pharmaceutical companies are increasingly aware of the talent outside academic institutions. However, there is still obviously a substantial role for the academician. As the academician, you are trying to widen the gap between what you provide and what a community physician can offer, and as a community physician, you are trying to close it. Academicians need to ask themselves where they can provide unique value in the ever-changing and increasingly accessible world of hematology/medical oncology clinical trials. They need to be innovative, at the cutting edge, participate in translational medicine, etc. Ideally, they will be engaged with discussions with basic science researchers, and take advantage of unique relationships unavailable to community physicians. 

Examples provided were:

·        US Oncology's robust clinical trial, CART and BMT program

·        Sarah Cannon's clinical trial expertise.

Tuesday, September 14, 8-9 AM:

1.     Calculated memorization is essential to staying afloat in the rapidly changing world of hematology/oncology. 

Memorize in the context of drug mechanism and molecular pathways. This seems intuitive, but many people don't do it. They give medications without knowing how they act. Knowing mechanism and molecular pathways ameliorate one's ability to extrapolate from one medical discipline to another and provides a solid foundation to assimilate new drug approvals.  It also facilitates the development of optimal treatment sequences for patients. 

Examples given were:

·        The MAP kinase pathway was outlined in great detail. It was illustrated in the context of colorectal cancer, melanoma, etc.

·        The RTK pathways were outlined, with particular focus on phospholipase-C, PI3-kinase, and MAP-kinase pathways. Reference to EGFR, HER2, HER3, VEGFR, PDGFR, NTRK, RET, MET, etc., was made.

·        Metastatic renal cell cancer was used as an example. Drugs available include VEGF/VEGFR inhibitors, immunotherapy, mTOR inhibitors, and others. We talked about knowing the available drugs in this framework. Based on this one can predict the future and understand new approvals (axitinib/Keytruda, opdivo/cabozantanib, axitinib/avelumab, Lenvatinib/Keytruda)

-VEGF/VEGFR inhibitors: avastin, sorafenib, sunitinib, lenvatinib, pazopanib, cabozantinib, tivozanib, axitinib,

-mTOR inhibitors: everolimus, temsirolimus

-PD1/PDL1 inhibitors: pembrolizumab, nivolumab, avelumab, atezolizumab

-CTLA4 inhibitors: ipilimumab

-Others: high-dose IL2, IFN

2.     Understanding the biology of disease 

No two cancer patients are created equal, even if they have the same stage tumor and histology. There is much we don't know about cancer, and the heterogeneity of cancer must be considered when treating patients. Getting a feel for the biology of a patient's specific tumor is essential to optimize their longevity. Developing a fundamental appreciation of the tumor's growth rate, response to treatment, heterogeneity, molecular profile, etc., should be of paramount importance to the treating physician.

Examples given included:

·        Occasional stage 4 non-small lung cancer patients with extremely slow-growing tumors

·        Patients with metastatic disease who have mixed responses to therapy

·        Continuum of stage 4 pancreatic cancer, and the benefit of treatment breaks for patients if the tumor allows for it.

Saturday, September 18, 10AM-2 PM:

1.     Precision medicine in the treatment of hematology/oncology patients 

Molecular characterization of tumors is now foundational in treating cancer patients. However, the art of precision medicine isn't in knowing which drugs can be used to target various mutations. This information is provided by all companies in the precision medicine space. Indeed, the true art of precision medicine is in incorporating molecular data with clinical trials and conventional therapies. Patient-specific treatment maps involving sequential treatments based on the aforementioned information differentiates true precision medicine experts from their colleagues.  

Examples included:

·        Eight real-world cases were presented in a molecular tumor board fashion. 

·        Emphasis was placed on how a fundamental understanding of conventional therapies was essential in developing treatment paradigms based on molecular studies. This was used to demonstrate how precision medicine experts must have a broad understanding of hematology/medical oncology conventional therapies. They must be able to see the forest, and not just the trees.

2.     Introduction to the molecular tumor board

Hematology/medical oncology fellows have little exposure to molecular tumor boards in their training. Molecular tumor boards are becoming ubiquitous, and early introduction to them is useful.

3.     Breast cancer and lung cancer real-world examples

Incorporation of the thought process provided is directly applicable to all tumor types. Lung cancer and breast cancer were used to illustrate this.

Examples included:

·        Stage 4 breast cancer was discussed in depth as all available agents were discussed based on mechanism and how would sequence them for a patient. HR+, HER2+, and triple-negative patients were discussed separately. For example, for HER2+ disease we discussed the use of THP/TCHP followed by HP, then TDM-1, then Enhertu or tucatinib/Herceptin/xeloda if brain lesions, then Enhertu or tucatinib/Herceptin/xeloda if not used, margetuximab + chemotherapy, lapatinib/xeloda, neratinib, lapatinib/Herceptin, etc. We discussed new trials looking at Enhertu+tucatinib and TDM-1+tucatinib.

·        Stage 4 NSCLC was discussed in depth. All RET, MET, NTRK, BRAF V600E, HER2, EGFR, ALK, KRAS G12C inhibitors, and conventional therapies were outlined in the treatment sequence framework. Resistance mechanisms, on-target (e.g. EGFR C797S) and off-target, were presented.

4.     How to negotiate your contrast

Having an understanding of your aspiration point, reservation point, and best alternative to a negotiated agreement (BATNA) is essential. Developing a weighted scoring system approach to what's important to you helps you negotiate complex contracts. 

·        Reference was made to rubrics provided to me in the negotiations class I took in my MBA coursework.

5.     Influence/formal authority

There is a difference between influence and formal authority. Assessing those around you in the context of an influence/formal authority rubric helps you navigate and understand the politics and culture of your organization.

·        Reference was made to coursework I took in my MBA Leading In the Middle class.

6.     EPO model of leadership

You will all be leaders of some sort. You may lead a very large group or a team comprised of you, your nurse, and your medical assistant. Understanding the EPO model (effort, performance, outcome) will help you motivate the individuals you're working with.  

·        Reference was made to coursework I took in my MBA Leadership core class.

Monday, September 20, 8-9AM:

1.     Importance of creativity and intuition in medical practice.

As the medical world has rightfully become more evidence-based, we are witnessing the death of intuition and creativity in medicine, particularly in hematology/medical oncology. We forget that NCCN guidelines are "guidelines", not dogma. We discuss phase 1 trial and phase 2 data as though it was definitive. Yet, only 13% of positive phase-1 trials, and 45% of positive phase-2 trials, manifest with FDA-approved drugs as many drugs fail in phase 3. In addition, many patients present in a way that no trial can possibly account for. Accordingly, there remains a marked role for measured creativity and intuition in the treatment of hematology/medical oncology patients, in the appropriate settings.

Examples included:

·        A stage 4 colon cancer case was presented to illustrate this

·        Stage 4 tumors with solitary metastases were discussed in this rubric.

2.     Think inside-out.

NCCN guidelines is an excellent benchmark for treatment decision, but it's not the end all be all. Use the COMET rubric to think inside out. Begin with conventional therapies outlined in NCCN, and determine if an outside-the-box approach is warranted. If you deviate from NCCN guidelines you should have an excellent rationale for doing so. However, it may be appropriate to extrapolate from one tumor to another if data to the contrary is lacking, insurance allows it, and the risk/benefit ratio is clearly reasonable.  Many clinical trial ideas can be derived from this. 

3.     The inches matter

In medicine, the details are monumentally important. Overlooking a single lab, radiographic finding, etc., can be the difference between life and death.

Examples included:

·        Early institution of antibiotics in neutropenic fever patients.

·        Missing a markedly elevated lactic acid in a patient with abdominal pain and no liver disease.

·        Decreasing a patient's BP too quickly if they come in with marked hypertension.

·        Increasing the sodium too quickly in a patient with hyponatremia.

·        Giving Rituxan to a patient with active HBV because you failed to draw the lab.

4.     Sometimes the target isn't as small as you think.

Often times we perseverate on minutia in medicine. We feel we have to hit the "medical target" perfectly; that there is only one right way to treat a patient. As you improve fundamentally you will recognize that is generally not the case. Often times the question has more than one right answer, and the therapeutic target isn't as small as you think. Knowing when this is the case requires mastery of your respective field. Assimilating this with the notion that the inches do matter in many situations in medicine absolutely separates the best physicians from their colleagues.  

Examples included:

·        Timing of initiation of therapy for CLL. A patient with a 9 cm LN was discussed, as starting treatment for such a patient even though they don't technically have bulky disease (10 cms) is perfectly reasonable.

·        Treatment in prostate cancer. We discussed how there are no set rules for much of what we do in the metastatic prostate cancer space pertaining to ADT initiation, whether to use zytiga, xtandi, or erleada, etc. 

Monday, September 27, 8-9 AM:

1.     The fundamentals are critical.

Kind of knowing is very different than knowing. In medicine, a little knowledge can be dangerous. Accordingly, focusing on fundamentals is essential and foundational.  

·        A deep dive into immune thrombocytopenia was done to discuss the intricacies of therapy, therapeutic expectations, etc.

2.     Ask the right questions 

Knowing the right questions to ask is extremely complicated, and often comes with mastery of a subject. Intuition, fundamental knowledge, etc., will help you to ask questions that may be life-saving for your patients. If the tumor acts in a way that is counterintuitive, do the tests required to know why. As you see patients, challenge paradigms. Always ask "why you are seeing what you are seeing?" in academia and in the community. The best advances often come from the best "why?" based questions. 

·        A case of a patient with DLBCL who had a mixed response to RCHOP after cycle 3 was discussed in detail. 

3.     See the future.

Try and always see where the discipline is going. See five years from now. When you're talking to pharmaceutical MSLs ask them about their broad pipelines and future directions, not just in the tumor your treat. When you read NCCN guidelines try and consider where the field is going. Often times it's extremely obvious. Whether it's trials involving the combination of conventional therapies or moving a drug from the metastatic setting to the adjuvant space to the neoadjuvant setting, much of what is being done in hematology/oncology is predictable. Recognizing this is important. Differentiating between trials that offer your patients novel mechanisms of attack from trials that are "copycat" in nature is important. When you develop trials try not to take the "throw everything against the wall and see if it sticks" approach by simply combining approved chemotherapy A with approved immunotherapy B. These trials are important, but they generally don't move the needle for your patient. Demand more and ask companies to do the hard trials that move the field forward. 

Examples provided were:

·        We discussed several trials we were recently offered that have been rendered largely obsolete before they even started due to changes in standard of care.

·        We discussed myeloma and how sequencing of therapy remains a profound question. Trials to date have avoided answering the difficult questions regarding which regimens are best head-to-head, largely due to the defensive posture pharmaceutical companies take.

·        The acalabrutinib vs ibrutinib head-to-head trial was provided as an example of an excellent trial where a company did the right thing for the field, as opposed to take the least risky approach (e.g. comparing to chlorambucil+Obinutuzumab). 

·        Reference was made to dual checkpoint inhibitor trials, including anti-TIGIT, anti-TIM3, anti-GITR, etc., and how we will see an explosion of combination therapies as pharmaceutical companies position themselves in various tumors.

4.     Survival

It's true there is too much to know in hematology/medical oncology. Stratify knowledge in terms of clinical relevance. Knowing NCCN guidelines and new FDA approvals is first priority. Start there and all will be well. Remember that the majority of phase 1 and phase 2 trials will not culminate in FDA approvals. Be measured in how you interpret these trials and how you incorporate them in your practice.

Examples given were:

·        Failure of rovalpituzumab in small cell lung cancer

·        Initial approval of mylotarg in AML, followed by its withdrawal and reintroduction into the market

·        Initial PARP inhibitor trials in metastatic breast cancer

·        Fellows were provided with this website, which I use frequently:

https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications

5.     Play football.

Practicing hematology/medical oncology is similar to playing football. As a quarterback, you have different passing routes (treatment options) with varying degrees of difficulty (risk) and yardage (benefit). The better you are at surveying the treatment field, the better your patients will do. Knowing when to throw a "hail mary" is just as important as knowing when not to.

6.     Is the juice worth the squeeze?

Patients are constantly faced with knowing whether the juice (the effort their exerting) is worth the squeeze (potential benefit of therapy). One of our most important jobs is educating them enough to be able to adequately determine this. Empathy plays a paramount role as patients will often perceive the juice and squeeze differently than you and other patients, even if they have similar tumor types and stages.

7.     You're the navigator.

I tell all my patients I'm the navigator and they're the captain. It's their boat; they decide where we go. My job is to give them treatment options and help them along whatever path they choose.  Educating your patients about their disease is imperative in this framework, and a special emphasis should be placed on this.

8.     The best of the heart and the best of the mind.

The best physicians I've met in my life had the best hearts and the best minds and knew how to infuse their hearts in the patient-doctor relationship. Although exceedingly difficult at times, try to make your heart and mind a central facet of your relationship with your patients.