Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How Would an Expert Manage His Own Chronic Myelogenous Leukemia?

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Jerald P. Radich, MD, MA, MS
Professor, Translational Science & Therapeutics Division, Kurt Enslein Endowed Chair, Fred Hutchinson Cancer Center

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks expert oncologist Jerald P. Radich MD, MA, MS, how he would handle his own hypothetical case of chronic myelogenous leukemia (CML). Dr. Radich is the Kurt Enslein Endowed Chair in the Translational Science & Therapeutics Division of the Fred Hutchinson Cancer Center in Seattle, Washington.

Curious Dr. George: Please consider this hypothetical scenario: you are an active clinical and research oncologist in general good health, but lately you have lacked energy, have been feeling more tired than usual, have some dizziness on exertion, recent easy bruisability, have lost some weight without dieting, and are experiencing sweating at night. You decide to visit your primary care physician for a checkup. On physical examination, she notes that you are a little pale, finds arm bruises, and discovers an enlarged liver and spleen. She orders several lab tests. Your hematocrit is 38, hemoglobin 12, WBCs 120 000 with mostly mature granulocytes, a few blasts, and a normal lymphocyte count. Platelets are normal. A provisional diagnosis of chronic myelogenous leukemia is made. When you learn of this hypothetical situation, how do you proceed?

Jerald P. Radich MA, MS, MD: How ironic that I have been diagnosed with CML. On the other hand, if one is going to get the disease that they have devoted decades of studying, I guess I chose wisely.

How so, you might ask (after all, you are curious)? Because in CML, we now have an embarrassment of riches, with five approved tyrosine kinase inhibitors (TKIs) for newly diagnosed, chronic phase CML cases (which I am taking editorial license to place myself in that category, rather than advanced-phase disease, thank you very much). Taking these medications daily places you on the same natural life expectancy curve as the non-CML population. It is truly a mind-blowing example of the “bench-to-beside” paradigm so often utilized in grant writing, but so rarely attained in real life.

The current list of TKIs for newly diagnosed, chronic phase CML includes the original, imatinib, and the “second generation” TKIs, bosutinib, dasatinib, and nilotinib. Ponatinib is approved by the U.S. Food and Drug Administration (FDA) for resistant chronic phase and advanced phase disease. All these inhibitors work to block the ATP-binding domain in the tyrosine kinase of the chimeric BCR-ABL protein. Recently, a new allosteric inhibitor known as asciminib was approved for newly diagnosed CML (should we dub this a third-generation compound?). It acts outside the ATP domain by causing a structural change in the protein that abrogates kinase activity.

These TKI drugs share various degrees of common toxicity (low counts, lipase increase, potential cardiovascular events) and all have drug-specific toxicities (e.g., pleural effusions in dasatinib, diarrhea with bosutinib). In general, the second-generation TKIs are more potent, leading to faster reductions of disease, and less evolution to advanced phase disease compared to imatinib. But at the end of the day, large phase-three studies have shown that all these drugs yield near identical survival.

How then would one choose? Here are the factors I would consider, in my own order of prioritization:

  1. What are my goals of therapy? What do I want? First, to control the disease and put me on a normal lifespan trajectory. This requires a treatment strategy that allows for maximum compliance (the easier to take drug, the better), minimal toxicity (both preventing off-target injury and minimizing time off the TKI) and the prevention of progression to blast crisis (as noted above, the second-generation-and-beyond TKIs seem a little better than imatinib for blocking progression). If I was considerably younger, and especially if I wanted to have kids, then there would be the consideration of getting to a deeper molecular response faster, since there is ample data that roughly 25% of CML cases can successfully discontinue the drug after several years of a deep molecular response and stay in a treatment-free remission. Evidence suggests that patients taking the stronger, second-generation TKIs may have an advantage in getting a deeper molecular response, faster.
  2. What’s my risk of progression? The major therapeutic mission is to block progression, since once that happens, the only real path to cure is through allogeneic transplantation, and that’s not easy for a guy my age. There are various risk scores that map well to risk of progression (Sokal, Eutos, Hasford). I didn’t get my blast count, but I am worried about the large spleen, weight loss, and night sweats—all suggest a disease on the pathway towards progression. Thus, I would be hedging my bets and leaning towards the second-generation TKIs, including asciminib.
  3. Comorbidities and toxicity. TKIs are truly remarkable, since they are exceedingly effective, yet have relatively little toxicity compared to standard chemotherapeutic agents. A pervasive complication across all these drugs—except imatinib—is the shadow of cardiovascular events, including venous and arterial thrombosis. Hypertension is also a common problem. If I had some cardiovascular risks, I’d be leaning towards options that seem be on the lower side of the risk spectrum, such as imatinib, lower dose dasatinib, or asciminib.
  4. Financial toxicity. These drugs are very expensive. If I had to pay for these out of pocket, they run more than $100,000 per year, and since I’d likely have to take them the rest of my life, the overall cost would be insane. Fortunately, I have good insurance. But if not, I could go generic. For example, Mark Cuban’s drug store lists prices for generic imatinib at less than 1% of branded imatinib! A generic of dasatinib has been launched, and some new formulations of dasatinib designed for better bioavailability have been approved, though it is unclear where they are going to weigh in on cost.

No matter what drug I start with, I would be diligent about receiving routine peripheral blood testing for BCR-ABL to monitor response. If I didn’t meet the milestones (as set out in standard guidelines from the National Comprehensive Cancer Network), there are plenty of options for switching to another TKI. In general, if I need to switch because of side effects, options are open to move across generations (i.e., from a second-generation to the first-generation imatinib). However, if I need to change TKI for resistance, changes should be made within a generation (from dasatinib to nilotinib), or escalating to the next generation (dasatinib to ponatinib or asciminib).

Dr. Radich can be reached at jradich@fredhutch.org.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Treat Her Own Metastatic Melanoma: an Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Pauline Funchain, MD
Associate Professor of Medicine (Oncology), Stanford University School of Medicine

Cancer patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Stanford University School of Medicine oncologist Pauline Funchain, MD, how she would handle her own diagnosis of advanced melanoma. (Note: This piece originally appeared in 2021; now, Dr. Funchain provides her updated expert perspective.)

Curious Dr. George: What would you do if you personally were discovered on a routine exam to have abnormal liver function tests that led to scans and the finding of several liver masses? Remembering back some 15 years, you had surgery to remove a 7-mm-diameter, 2-mm-thick melanoma from the skin of your lower leg, treated by wide excision with clear margins. No spread detected at that time. No tumor testing then, aside from light microscopy. How would you proceed?

Pauline Funchain, MD:

Starting line: First, I would take a deep breath. I would remind myself that stage IV melanoma of the skin has become a disease state that can have durable remissions well over 10 years, and that such remissions are not rare. I would be heartened knowing that results approaching cure are possible for some stage IV melanomas.

Next, I would contact my nearest academic medical center. I would carefully research teams known to have good bedside manners, clear communication, and melanoma expertise. The field of melanoma is rapidly changing for the better, and I would want a team that is not only well aware of these developments, but that also would be able to clearly explain the multiple therapy options available to me in the context of a briskly moving field. Lastly, I would prefer a medical center where medical subspecialists were readily available and accustomed to timely multidisciplinary communication, as immune-related adverse events (irAEs) are commonly elicited during the course of systemic therapy for melanoma.

Workup: At this center, I would first undergo a biopsy of a liver mass. I would ensure BRAF mutation screening was performed by immunohistochemistry (IHC), the most rapid of the available BRAF testing modalities. If enough tissue was available, I would send for next generation sequencing (NGS) of the tumor specimen, to prepare for possible second- or third-line therapies. If I had a family history of cancer, personal history of multiple cancers, or was relatively young, I would see a genetic counselor to discuss germline genetic testing. For initial staging I would get either a CT chest/abdomen/pelvis or PET CT. Getting an MRI brain is absolutely essential, as brain metastases are common, often asymptomatic, and would influence first-line therapy choices.

First-line therapy: With staging complete, I would inquire about first-line immunotherapy-based trials. While the best outcomes for stage IV disease, particularly involving liver and/or brain, have been seen with combination ipilimumab/nivolumab, I would welcome the opportunity to try something new in a rapidly evolving melanoma treatment landscape. I would be reassured knowing that all gold standard therapies would still be available to me should a first-line clinical trial fail. If I was not eligible or did not like available clinical trials, I would proceed to first-line treatment with ipilimumab/nivolumab. If I had a personal history of autoimmune disease, I would request a consultation with the appropriate medical subspecialty prior to starting immunotherapy. Other medical conditions might influence me to prefer an alternative immunotherapy combination such as relatlimab/nivolumab, or single-agent immunotherapy, and it is these situations that highlight the importance of having a medical team who is able to have a careful discussion with me to understand my individual needs.

While on therapy I would undergo systemic imaging every three months to assess response to therapy. If my original staging did not demonstrate brain metastases, I would undergo MRI brain every 6 months in the stage IV setting. If my tumor had a BRAF mutation and I had fast-growing disease, was rapidly losing weight, had a very large burden of disease, or some combination of these factors, I may prefer to invoke the rapid response typically seen with targeted BRAF/MEK therapy. On targeted therapy, I would consider imaging every 2 months, given a higher likelihood of developing therapeutic resistance with the combination of factors that led me to start targeted therapy. I would follow my status closely with serial LDH levels, which correlate well with BRAF-mutant disease burden.

Closing thoughts: In the landmark trial of first-line combination immunotherapy for stage IV melanoma, median melanoma-specific survival had not yet been reached after 10 years of follow-up. In plain English, more than half of those who underwent combination immunotherapy had survived stage IV melanoma at the 10-year mark. Because not everyone experiences prolonged survival, I would be realistic about having a stage IV cancer diagnosis that might be fatal, yet remain optimistic given the pace of new drug development that immunotherapy and targeted therapy have precipitated in the last decade.

Requests for Dr. Funchain’s email address can be sent to Curious Dr. George at gdlundberg@gmail.com.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

A Better Way to Keep an Eye on Glioblastoma Tumors

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Michael Schmainda, MBA
President and CEO, Imaging Biometrics, LLC

For people with glioblastoma brain tumors, it can be vital yet challenging to determine the precise size, location, and extent of the tumor. A company called Imaging Biometrics, LLC, has developed novel imaging strategies to address this issue. Here, our Curious Dr. George asks its president and CEO Michael Schmainda about these innovations.

Curious Dr. George: Determining the extent of an intracranial neoplasm can be as important as securing the diagnosis. This also applies to postoperative follow-up: Was the tumor fully or only partly extirpated? Is the tumor recurring or is the evolving positive imaging only locating organizing hematoma or scar tissue?

Michael, how is your company striving to help solve these vital clinical puzzles?

Michael Schmainda: You’ve highlighted a critical challenge in neuro-oncology: distinguishing between tumor progression and treatment effects like pseudo-progression or post-treatment radiation effect (PTRE) using imaging techniques. This distinction is vital for accurate diagnosis, treatment planning, and monitoring.

Contrast enhanced magnetic resonance imaging (CE-MRI) is the standard imaging method but has limitations in differentiating between tumor and PTRE. In fact, PTRE often mimics tumor on CE-MRI, further conflating the issue. This often necessitates invasive biopsies for confirmation, which can be problematic, especially in heterogeneous tumors like glioblastoma. Targeting a biopsy site that is not consistent with aggressive tumor can lead to suboptimal treatment plans.

Response assessment techniques for brain tumors, such as response assessment in neuro-oncology (RANO), rely on CE-MRI to measure tumor size, which can be misleading if PTRE is present, potentially resulting in overly aggressive treatments with severe side effects.

At Imaging Biometrics (IB), we have developed and validated an automated processing platform that overcomes these limitations. This advanced imaging platform uses two quantitative technologies. The first, called a Delta T1 map, helps delineate true regions of contrast enhancement. Delta T1 maps incorporate an exclusive image-intensity calibration step, removing variability and artifacts to objectively highlight the true contrast-enhancing region.

Within the enhancing region identified by the Delta T1 map, additional information is obtained using our IB Neuro product. This uses dynamic susceptibility contrast (DSC) MR perfusion to measure several parameters including relative cerebral blood volume (rCBV). As tumors form and grow, they need increased oxygen and nutrients, which are supplied via the blood. Before a tumor can be detected on standard imaging, IB Neuro can accurately measure this increase in rCBV. IB Neuro also incorporates a calibration step that standardizes the rCBV output (sRCBV) independent of how it was collected. This enables a direct comparison of sRCBV measurements across time, MR scanners and field strengths, and patients. Furthermore, the sRCBV values have been independently validated by multiple academic centers using spatially matched tissue samples to establish cutoff thresholds that differentiate tumor from PTRE.

Combining IB Delta T1 and IB Neuro enable the creation of fractional tumor burden (FTB) maps, providing a quantitative assessment of tumor progression and treatment response across time. The maps are also imported into surgical navigation systems to target biopsies, plan surgical resection and radiation and, more recently, to help plan laser interstitial thermal therapy (LITT).

Several recent and ongoing studies have demonstrated the clinical benefit of using FTB for treatment surveillance for both primary and metastatic brain tumors and for biopsy guidance such that the most aggressive part of the tumor is sampled. They also have been shown to result in the greatest inter-reader agreement and confidence for glioblastoma response assessment over other techniques to which they were compared.

I encourage interested readers to learn more by watching Imaging Biometrics’ video on getting more out of your MRI exam, as well as our webinars on Delta T1 and the clinical applications of perfusion MRI in neuro-oncology.

Michael Schmainda can be reached at mike@imagingbiometrics.com.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Treat His Own Glioblastoma: An Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Al Musella, DPM President, Musella Foundation For Brain Tumor Research & Information, Inc.

When facing a new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Al Musella, DPM, how he would handle his own case of glioblastoma, a type of brain tumor. Dr. Musella is President of the Musella Foundation For Brain Tumor Research & Information, Inc., a partner of Cancer Commons (Note: This is an updated version of a piece that originally appeared in October 2020; now, Dr. Musella provides new information on his preferred treatments for glioblastoma.)

Curious Dr. George: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with glioblastoma?

Al Musella, DPM: If I were diagnosed with glioblastoma, the first thing I would do is seek help by joining the patient navigation program that my foundation operates in partnership with Cancer Commons and Head For The Cure. After registration, our team of experts evaluates each case and gives a personalized list of suggestions to look into. Below are some options that I would consider for my own hypothetical case.

Surgery: My first treatment would be surgery. It would be important to me to choose an experienced surgeon who has a better chance of removing more of the tumor with less damage. The American Brain Tumor Association has a list of experienced teams that I would consider.

I would also consider using the drug Gleolan (also known as 5-ALA) to increase the chances of a complete resection during surgery. A clinical trial is currently exploring Gleolan as part of photodynamic therapy at the time of surgery (see more below), and while it is too early to tell how much this might help, it does show promise, and I may consider enrolling.

Lastly, when considering surgical options, I would look into Gamma Tiles, which the U.S. Food and Drug Administration (FDA) has approved for both newly diagnosed and recurrent glioblastoma. These are radioactive implants placed near the tumor at the time of surgery, where they deliver a high dose of radiation precisely where it is needed and at the optimal time—immediately after tumor removal, before regrowth begins. This procedure might add, on average, about 8 months of progression-free survival, buying time for other treatments to work. However, Gamma Tiles may disqualify a patient from participating in certain clinical trials, so I would want to consider that possibility when deciding whether to use them myself.

Tumor sample for personalized vaccines and advanced testing: After surgery, I would consider sending part of the removed tumor to make a vaccine custom-designed to fight my glioblastoma, such as DCVax. This vaccine is not yet approved in the U.S. but is available in the U.K. under a special access program—although it can be expensive. I would send the rest of the tumor for advanced testing to further clarify which treatments might work best for me.

Scans: Standard MRIs may sometimes be unclear, as they can’t always differentiate between various tissue types (tumor, necrosis, swelling, normal brain tissue, or scar tissue). This can lead to misinterpretations, such as pseudo-progression, where the tumor appears to be growing when it is not, potentially leading to unnecessary changes in treatment.

Newer techniques can provide clearer results. Among the more easily available options, my current favorite is fractional tumor burden mapping. This type of scan is better than MRI (but not perfect) at discerning how much of the abnormality is an active, live tumor. I would insist on such an option for all of my scans, as comparing them over time would be the best way to tell how  treatment is going.

Radiation: There are many types of radiation, and the choice of which approach is best should be left to each patient’s medical team. Typically, the drug temozolomide is used alongside radiation to enhance its effects. Using the aforementioned Gamma Tiles at the time of surgery might allow a patient to delay standard radiation until after other treatments, or possibly replace standard radiation altogether.

FDA-approved treatments: These are the standard and FDA-approved treatments I would consider to treat my glioblastoma:

  • Temozolomide is a standard, FDA-approved treatment. A biomarker called MGMT can predict how well a patient might respond to temozolomide. If tumor testing returns the result “MGMT unmethylated,” there’s a lower chance of temozolomide being effective— not a zero chance, but lower than if MGMT is “methylated.” Temozolomide treatment typically lasts for 6 to 12 months after radiation treatment ends. In my case, I would probably choose to use temozolomide if my MGMT was methylated but might avoid it otherwise.
  • Gleostine is a drug also known as CCNU or lomustine. There is some evidence that adding Gleostine to temozolomide has better results than temozolomide alone—especially if MGMT is methylated. However, it also increases the chances of side effects. The combination may be best for younger, stronger patients, and I would consider it for myself, unless I was adding other drugs and did not want to risk needing to stop all drugs because of side effects.
  • Optune is an FDA-approved device applied to the skull using adhesive arrays that delivers tumor-treating fields. Optune has the best-reported outcomes of any FDA-approved treatments for glioblastomas. Suggested usage is at least 75% of the time, but using it over 90% of the time significantly improves outcomes. Adding a checkpoint inhibitor drug may increase the effectiveness of Optune.

Some doctors do not recommend Optune, as it can be a hassle to use or make some patients ineligible for certain clinical trials. However, as always, each patient should make their own decision based on information about their choices and their personal values. I would definitely try Optune, most likely alongside a checkpoint inhibitor. I would also be careful not to stop treatment too early. The first scan after starting Optune may show worsening (pseudo-progression), but advanced scans can clarify the situation.

  • Avastin: This is a type of drug known as a VEGF inhibitor. By itself, it has not been shown to significantly improve overall survival, but it does work well to reduce swelling, like a “super steroid.” It could be a helpful addition because some of the aforementioned treatments can cause potentially life-threatening swelling, which Avastin may be able to reverse or prevent. In addition, steroids are detrimental to the action of all immunotherapies and to Optune, so Avastin might be useful to reduce or eliminate the use of steroids.

Experimental and off-label treatments: I would also consider treatments that have shown promise but have not yet been approved by the FDA. Our patient navigation program would be especially helpful for identifying these treatments. Among my favorites, below,  I would choose the ones that I could most easily access. I would follow up with advanced imaging and change my approach at the first sign of treatment failure.

  • Onc-201: If my tumor was in the midline structures of my brain, especially the thalamus or brainstem, I would consider testing it for an H3K27M mutation or low EGFR levels. This approach is also prudent for younger patients. If either abnormality was present, I would consider treatment with Onc-201. This drug is currently available through a clinical trial and potentially through expanded access.
  • Gleolan, or 5-ALA: The concept behind this drug—introduced above as an option to use during surgery—is elegant. When exposed to a special frequency of light, it causes tumor cells to glow, helping the surgeon identify any remaining tumor tissue. Then, when the surgeon applies a laser, the dye-absorbed cells are destroyed. This is the essence of photodynamic therapy.

It should be noted that photodynamic therapy with 5-ALA has some limitations, as the laser cannot penetrate deeply into the brain or pass through the skull, making the procedure invasive. It is currently experimental, but if the surgeon I chose to remove my tumor was willing, I would consider trying it. However, I wouldn’t have surgery purely to use this treatment.

I might also consider a non-invasive approach to targeting cells that absorb 5-ALA called sonodynamic therapy. In this method, focused ultrasound is directed at the tumor through the skull. When 5-ALA is excited by the ultrasound, tumor cells are selectively destroyed, while normal cells are spared. This technique can be repeated as needed, either to treat new areas of growth or prophylactically in regions where recurrence is anticipated. I would likely opt for sonodynamic therapy once a month for my first year after diagnosis, then as needed thereafter. While sonodynamic therapy for glioblastoma is not yet FDA-approved, it is currently in clinical trials. The components of this treatment are already approved, which might expedite its pathway to full approval.

  • Niraparib is a type of drug known as a PARP inhibitor. It is already FDA-approved for other types of cancers and should be accessible off label. Niraparib stops cancer calls from repairing DNA damage, which could make most other treatments work better. The best combination of niraparib with other treatments has not yet been determined, but I would consider it for myself, especially if my glioblastoma was MGMT unmethylated.
  • Gallium maltolate is an experimental oral drug that also has an elegant mechanism of action and early promise. It is available through clinical trials and via an expanded access program.
  • MDNA55 is a drug that targets a protein called IL4R, with impressive preliminary evidence for treating glioblastoma.
  • SurVaxM, CeGaT, Gliovac, the Jaime Leandro Foundation vaccine, Imvax, the PanAm VAX vaccine, CMV vaccine, and other vaccines: I like the concept of vaccines for cancer treatment and would choose to use at least one for myself. My top choice would be DCVaxor Gliovac because they would be custom-made for my tumor and therefore designed to attack all of the known targets in my tumor. If those were not available, I would choose one of the other vaccines. Evidence has not yet conclusively shown which is best, so I would select whichever was easiest to access. None are yet FDA-approved, so access would likely be challenging and expensive.
  • CAR T-cells and viral therapies: There is a lot of excitement about CAR T-cell therapies, which modify a patient’s own T cells to fight cancer. The CAR T-cell approach can cure certain types of cancer for some patients, but it has not yet been shown to cure glioblastoma. However, every generation of CAR T-cell therapy gets better, and we are getting closer to a version that could potentially be curative for glioblastoma.

Meanwhile, many viral therapies—which use viruses to destroy tumor cells—are currently in development, and they show some early promise. For instance, the viral therapy lerapolturev (previously known as PVSRIPO) has shown enough promise that a new clinical trial recently launched to continue testing it. Delytact is another viral therapy with impressive results; it is approved in Japan but not easily accessible for Americans.

  • Some antidepressant drugs are thought to help treat tumors and can also help treat the depression that often follows a brain tumor diagnosis.
  • Combining off-label drugs is another approach I would consider. Two specific protocols for this strategy appeal to me. The first is the Care Oncology Protocol, which combines several off-label drugs with temozolomide in an attempt to target a tumor from several different angles. CUSP9v3 is another protocol that has caught my eye. Both are worth considering, but it is not yet clear which combination is best, and it is possible that a subset of the drugs combined in CUSP9v3 might work just as well with less side effects and a lower cost.
  • Checkpoint inhibitors: Cancer cells are tricky. They often manage to avoid being attacked by the immune system by generating signals called checkpoints that block immune attack—as though the tumor cells have put up a “do not disturb” sign. Drugs known as checkpoint inhibitors—many of which are FDA-approved for other cancer types and can easily be used off label—essentially remove that “do not disturb” sign, allowing the immune system to attack the tumor.

Many clinical trials have shown that, on their own, checkpoint inhibitors are not very effective (except in a small trial showing that using them before surgery may help). The reason for this lack of effectiveness is that there are not enough immune cells near the tumor to fight it. I believe an effective solution would be to apply another strategy to trigger an immune response that would get the immune cells in place, then apply a checkpoint inhibitor to unleash their response. Such a strategy could be anything that causes tumor cells to die, such as a cancer vaccine, a viral therapy, or even Optune, which would trigger an immune response.

In all, I would consider one or more of the options outlined above, especially those that can be combined with each other. And for anyone dealing with their own glioblastoma case, I highly recommend signing up for our powerful patient navigation program.

Dr. Musella can be reached at musella@virtualtrials.com.

Disclosure: The following companies are or have been sponsors of the Musella Foundation: Novocure Ltd (Optune), GT Medical (Gamma Tiles), Chimerix (Onc-201), Genentech (Avastin).

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage His Own Advanced Bladder Cancer: An Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Genitourinary Oncologist and Researcher, Beth Israel Deaconess Medical Center; Instructor in Medicine, Harvard Medical School

When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Daniel E.C. Fein, MD, how he would handle his own case of advanced bladder cancer. Dr. Fein is a genitourinary oncologist at Beth Israel Deaconess Medical Center (BIDMC) in Boston, MA, as well as an Instructor in Medicine at Harvard Medical School. (Note: This piece originally appeared in May 2023; now, Dr. Fein provides his updated expert perspective, with new information on preferred treatments for people with bladder cancer.)

Curious Dr. George: Imagine a hypothetical scenario in which, as a non-smoking, very busy genitourinary medical oncologist, you were surprised to experience painless gross hematuria. Rapid subsequent microscopic urinalysis confirmed many red blood cells and some white blood cells. Urine cytology was suspicious for malignant cells, not otherwise specified. A complete blood count and blood chemistry panel were normal. At cystoscopy a sessile mass was found and biopsied, revealing a high-grade urothelial carcinoma. You then recognized a 10-pound loss of weight. The upper urinary tract was normal by imaging studies, but your pelvic lymph nodes were enlarged, and three suspicious lesions were found in your left lung. How would you proceed?

Daniel E.C. Fein, MD: Although I care for many patients with bladder cancer and have been intimately involved in the medical field for some time, I can only imagine how I might react to such shocking news. Why me? What did I do wrong? How should I tell my family? Do I need to take time off work? My mind would be spinning out of control.

I would try to take a deep breath and tell myself that it is likely that I have been diagnosed with an advanced bladder cancer. I would know that although this is likely incurable, there are new treatments available that can help me live longer and improve my quality of life. While establishing care with a cancer treatment team, I would reach out to my primary care doctor and therapist to disclose to them this new diagnosis and ask for the best way for me to manage my mental and physical health while beginning my journey.

Some background: Bladder cancer accounts for approximately 4% of new cancer cases in the US, with around 10% of those presenting with metastatic disease. Most cases are confined to the bladder and can be treated with resections and medicines instilled into the bladder. When cancer invades into the muscle of the bladder wall, patients can be potentially cured using a combination of treatments, such as chemotherapy followed by removal of the bladder, or chemotherapy with radiation. When bladder cancer has spread to distant sites outside of the area of the bladder (such as the lung) they are typically not curable but can be controlled with a combination of medications to help patients live in the range of years.

Before treatment: The approach to treating advanced bladder cancer is changing rapidly, with new approvals of medications and combinations coming out every year. Because of this, I would seek care at a nearby academic center that has experience treating bladder cancer using a multidisciplinary team of urologists, medical oncologists, and radiation oncologists.

I would undergo a biopsy of a lung lesion to confirm this is metastatic bladder cancer. I would direct this biopsy to be sent for molecular testing for gene mutations in FGFR2/3 and for expression of the marker HER2, which would tell me what kind of treatments I could receive in the future. I would also undergo germline genetic testing to see if I was born with a gene mutation that made me more likely to get this cancer and potentially others. I would also ask if I should have any additional imaging, such as an MRI head, as this may be helpful for some patients.

Choosing treatment: Because of how quickly this field is changing, I would ask my care team if there were any clinical trials in my region with new and promising treatment combinations available. As a member of the Innovation in Cancer Program at BIDMC, I have seen firsthand the outstanding care provided to cancer patients on clinical trials and would certainly participate in one if it was right for my cancer treatment and quality of life.

If I thought a clinical trial wasn’t right for me, I would ask if I could be a candidate for the newly FDA-approved combination of enfortumab vedotin and pembrolizumab (EV + P), a combination of a targeted chemotherapy and immunotherapy. Because of a recently published clinical trial, this combination is now considered the preferred first-line therapy for all patients with metastatic bladder cancer.

If I was unable receive EV + P because of other medical conditions (such as severe autoimmune disease, difficult to control diabetes, or severe peripheral neuropathy), I would ask if I could receive a platinum-based chemotherapy combination. Conventional platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine, or dose-dense MVAC) has been the standard-of-care treatment for advanced bladder cancer for many years and can still be an option for some patients if they are unable to receive or decline the EV + P combination. In recent years we would give at least four cycles of platinum-based chemotherapy, and if there is some control of the cancer, switch to a maintenance immunotherapy called avelumab. There is actually another combination of platinum-based chemotherapy with an immunotherapy called nivolumab that was also recently approved based on a clinical trial, but because of how effective enfortumab vedotin plus pembrolizumab seems to be, I generally recommend EV + P first.

What next?: I may have challenges with managing side effects of treatment, coping with my new diagnosis and limited life expectancy, or sharing my experiences with friends and family members. I would seek assistance from a palliative care team and a local cancer support group who can focus on these mental, emotional, and physical challenges to improve my quality of life.

A new diagnosis of cancer, at any stage, can be life changing. If you are going through this, please know that you are not alone and that there are people around the world with and without cancer who have dedicated their lives to making yours better.

Dr. Fein can be reached at dfein@bidmc.harvard.edu or on Twitter at @DFein_MD.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage His Wife’s Metastatic Breast Cancer: An Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Senior Medical Director, Breast Morpheus/Giredestrant, Genentech Product Development Oncology

For most people with breast cancer, a lump is the first sign that leads to diagnosis. But some cases are not detected until after spread has already occurred. Here, our Curious Dr. George asks Richard B. Schwab, MD, how he would approach such a case if his own wife were the patient. Dr. Schwab is Senior Medical Director at Genentech Product Development Oncology. (Note: This piece was first published in October 2021. We now present it with Dr. Schwab’s updated affiliation. His reply below remains up to date and relevant for people dealing with advanced breast cancer.)

Curious Dr. George: How would you, as a breast cancer expert, manage your wife’s cancer if it were to present as shortness of breath or back pain, with a breast mass only then detected?

Richard B. Schwab, MD: Doctors frequently take care of their family members for minor problems; cancer is not one of them. Even caring for patients, managing one’s own anxiety about the normal uncertainties of medicine is not easy. Managing of my wife’s cancer would not be possible, so I would have one of my excellent colleagues be her oncologist.

That said, I would be answering my wife’s questions about this frightening situation and trying to guide her. She gets her screening mammogram every year, so presenting with metastatic breast cancer would be very unusual. Only 5% of breast cancer is de novo metastatic, and many of these patients did not have recommended screening before diagnosis. However, screening mammograms are not perfect, so your hypothetical scenario is possible.

If she was short of breath, I think we would utilize the emergency department. Although cancer is usually a relatively slow process, there are rare times when patients can become very ill during the normal time required for diagnosis and treatment initiation. CT scans can be done quickly and could identify a pulmonary embolism, pleural effusion, or lymphangitic spread. Starting appropriate therapy quickly (anti-coagulation, thoracentesis, or chemotherapy respectively) could be critically important.

Making a pathologic diagnosis would be the next step, and would radically alter treatment (and life) plans. Breast cancer is not one disease. Oddly we would be hoping for an aggressive estrogen receptor-negative and HER2-positive cancer. These cancers are highly responsive to numerous treatments, and cures—even with metastatic disease—are becoming more and more common. A triple-negative cancer would be complicated. Some patients with triple-negative breast cancer, particularly limited to the lungs, do end up cured, but these cases are rare and overall this type of breast cancer has the fewest treatment options. Last but most common, particularly if her cancer had spread to the bones, would be estrogen receptor-positive disease. These cancers generally grow more slowly and on average patients survive longer with this type of disease. However, these cancers are never truly cured, although for older patients lifelong disease control can sometimes be obtained. For a patient as young as my wife new therapies would be needed to have any reasonable hope of lifelong disease control.

Which location to biopsy is a common challenge we would need to address. Biopsy of the breast is the easiest, but may not reflect the more dangerous disease that has spread to other organs. Lung biopsy has some additional risk, it is anxiety provoking, and sample quantity (or even successful sampling) can be challenging. Biopsy of the bone, while very safe, can give unreliable results due to the need to decalcify the sample prior to testing. The details of the patient’s case and the expertise of the doctor performing the biopsy matter. Having expert trusted colleagues in radiology and pulmonology would be a significant advantage for my wife.

I mentioned the idea of truly curing my wife. I define true cure as a lack of cancer progression for at least 5 years after stopping therapy. I have cared for many patients with metastatic disease that has been cured, and that knowledge would help my family get through what is fortunately only a hypothetical situation.

Dr. Schwab can be reached at schwab.richard@gene.com.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage Her Own Advanced Colorectal Cancer: An Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Christina Wu, MD
Professor of Medicine, Mayo Clinic, Phoenix

When facing a new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks oncologist Christina Wu, MD, how she would handle her own diagnosis of metastatic colorectal cancer. Dr. Wu is a Professor of Medicine at the Mayo Clinic in Phoenix, Arizona. (Note: This piece originally appeared in 2020; now, Dr. Wu provides her updated expert perspective on molecular testing, targeted therapies, surgery, and clinical trials.)

Curious Dr. George: As an experienced academic and practicing clinical oncologist at the Mayo Clinic, you have particular interest, training, and experience in colorectal cancer. What would you do if you personally were discovered to have an asymptomatic, unsuspected, non-obstructing adenocarcinoma of the ascending colon that had already metastasized to your liver?

Christina Wu, MD: Colorectal cancer is one of the most common cancers in the U.S., and there has been a noticeable rise in early-onset colorectal cancer. Every patient with metastatic colon cancer to the liver is uniquely assessed because there are systemic and liver-directed treatment options. If I were diagnosed with colon cancer and liver metastasis, I would want a multi-pronged approach to include the following:

Next-generation sequencing (NGS): First of all, I would want both blood and tumor NGS testing. Blood NGS results can be back within a week, and tumor NGS is more expansive and complete. The tumor biomarkers I would want to know first are mismatch repair (MMR) protein or microsatellite instability (MSI) status. If deficient MMR or MSI-high, I could benefit from immunotherapy (pembrolizumab or nivolumab with or without ipilumumab) and be spared chemotherapy. Other tumor markers include KRAS/NRAS/BRAF mutation (mt), HER2 amplification, and NTRK and RET gene fusion.

I would be eligible for anti-EGFR antibody (panitumumab or cetuximab) in combination with doublet chemotherapy (FOLFOX or FOLFIRI) if my tumors were KRAS/NRAS/BRAF wild-type (wt) and HER2-negative with a left-sided primary cancer. HER2-targeted therapy such as tucatinib and trastuzumab could be a chemotherapy-free option if the tumor was KRAS/NRAS/BRAF wt and HER2 positive. Trastuzumab-deruxtecan could also be offered if I was HER2 positive. A BRAF V600E mt would be targeted with encorafenib and an anti-EGFR antibody. A KRAS G12C mt would be targeted with sotorasib/adagrasib and cetuximab/panitumumab. If I had the rare NTRK fusion mutation, I could be treated with entrectinib, larotrectinib, or repotrectinib. RET gene fusion could be targeted with selpercatinib.

Multi-disciplinary tumor board: I would want high-quality imaging and experts from medical oncology, surgical oncology, colorectal surgery, radiation oncology, gastroenterology, radiology, and interventional radiology reviewing my case in a tumor board. It would be meaningful to know upfront whether the liver metastasis was surgically resectable, because I may opt to receive systemic chemotherapy followed by surgical resection. If I required conversion therapy or reduction in my tumor burden, I would consider triplet chemotherapy (FOLFOXIRI) or systemic targeted therapy to get more of a response so that I could get to surgery. However, if I had clearly unresectable disease, I would choose systemic targeted therapy or doublet chemotherapy, such as FOLFOX or FOLFIRI and bevacizumab, to improve my quality of life.

With unresectable disease, I could also consider radiation, Y90 treatment, or ablation to the liver tumors, if I had good control or surgical resection of the extrahepatic disease. In addition, liver transplant may be a future consideration if I had well-controlled, unresectable liver metastasis, with no evidence of extrahepatic metastasis. Although not present at a tumor board, the palliative care team would be a crucial component of my care.

Genetic counseling: Some hereditary syndromes lead to colon cancer development, including Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis. I would choose to pursue germline testing to screen for such conditions.

Clinical trials: There are studies looking at targeting KRAS mutations, bringing targeted therapy to the first-line setting, and providing immunotherapy combinations. I would definitely want to expand my therapy options by enrolling in clinical studies.

Final thoughts: Systemic and liver-directed treatment options are evolving, and thus a multi-disciplinary approach would be essential from the moment of my diagnosis.

Dr. Wu can be reached at wu.christina@mayo.edu.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Treat His Own Advanced Lung Cancer: An Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Howard (Jack) West, MD, FASCO
Vice President, Clinical Development, Summit Therapeutics

A new cancer diagnosis is overwhelming. Patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks lung cancer expert Howard (Jack) West, MD, FASCO, how he would handle his own diagnosis of advanced lung cancer. Dr. West is a Princeton- and Harvard-educated oncologist with additional training and experience in Boston and Seattle focusing on lung cancer. He is now Vice President of Clinical Development at Summit Therapeutics. (Note: This piece was first published in March 2021. We now present it anew with Dr. West’s updated affiliation. His reply below remains up to date and relevant for people dealing with advanced lung cancer.)

Curious Dr. George: What would you do if you personally were discovered on a routine chest X-ray to have a unilateral pleural effusion which was found by cytopathology to contain mixed squamous and adenocarcinoma cells? How would you proceed?

Jack West, MD, FASCO: Though I’m a never-smoker, we know that is no guarantee of immunity from lung cancer, the cancer type I’ve focused on for the past two decades. Perhaps I develop a persistent cough and worsening shortness of breath over a few months. I get a chest X-ray that shows a large right pleural effusion, and a same-day chest CT confirms this and bilateral lung nodules, perhaps along with several enlarged right hilar and mediastinal lymph nodes. The effusion is drained, and the pathologist gives my doctor and me the immediate feedback that this is a carcinoma, and we quickly learn that the immunohistochemistry profile is consistent with an adenocarcinoma. Where do we go from here?

My next step is to order broad next-generation sequencing, which may entail a new biopsy, either CT-guided or an endobronchial ultrasound and biopsy of whatever is accessible. We need sufficient tissue to send off for broad molecular testing that includes a look for all of the growing collection of lung cancer “driver mutations.” These include long-established markers like a mutation in the epidermal growth factor receptor (EGFR) gene or a rearrangement in the anaplastic lymphoma kinase (ALK) gene, but now also a rearrangement in ROS1, mutation of BRAF V600E, a MET exon 14 skipping mutation, RET fusion, or fusion in the TRK gene. These genetic alterations are found in approximately 0.5% to 10% each in patients with non-small cell lung cancer (NSCLC) and far more commonly in patients with a non-squamous NSCLC tumor. They all have FDA-approved oral targeted therapies with efficacy that generally exceeds what we could expect with our best standard non-targeted approaches involving immunotherapy with or without chemotherapy. Most of these targeted therapies also better tolerated and can work for a prolonged period that may reach the range of years.

This mutation testing typically takes at least 2 to 4 weeks, but the importance of identifying one of these mutations, when present, makes it critical to seek this information at the time of initial diagnosis. Moreover, in addition to the array of markers we currently have targeted therapies for, we expect an FDA approval for an inhibitor of KRAS G12C-mutated NSCLC, seen in about 12% to 13% of advanced NSCLC, in the coming months; all in all, comprehensive molecular testing guides us to an optimal targeted therapy for at least 20% of patients, and that proportion will continue to increase as new targets with effective therapies become available.

In the hypothetical scenario of my own diagnosis, as this testing is being done we’re also testing for tumor PD-L1 expression, which identifies tumors most likely to respond well to immune checkpoint inhibitors, potentially sparing patients first line chemotherapy if they don’t receive a targeted therapy. And I’d seek to complete imaging with a PET/CT and brain MRI, in order to identify whether the cancer has spread to other sites beyond those already identified.

Once these tests are completed, I’d prioritize a targeted therapy if my tumor harbors a driver mutation. If not, I’d generally favor pembrolizumab monotherapy if my cancer is among the approximately 28% to 30% that demonstrates high tumor PD-L1 expression (greater than 50%). Otherwise, if my cancer has neither a driver mutation nor high tumor PD-L1 expression, I’d generally favor a platinum-based chemotherapy doublet with pembrolizumab—an option I would also favor in a patient with a tumor that doesn’t harbor a driver mutation and with high tumor PD-L1 if that patient had many cancer-related symptoms or otherwise showed a pattern of rapid progression in the early weeks of the workup. Though I’d be happy to sequence the immunotherapy with subsequent chemotherapy in patients in whom I’m confident they will still have the performance status to tolerate platinum doublet chemotherapy after progressing on chemotherapy, I’d favor “front-loading” with chemo-immunotherapy together in patients in whom I’m concerned I may only have “one shot on goal.”

Dr. West can be reached at JackWestMD@gmail.com or on Twitter at @JackWestMD.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage His Own Advanced Prostate Cancer: An Update

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Marc B. Garnick, MD
Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center

When facing a new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Marc B. Garnick, MD, how he would handle his own advanced prostate cancer. Dr. Garnick is the Gorman Brothers Professor of Medicine at Harvard Medical School (HMS) and Beth Israel Deaconess Medical Center in Boston, MA. He is also Editor in Chief of the HMS Annual Report on Prostate Diseases. (Note: This piece was first published in June 2022 and has now been updated with additional information about neuroendocrine elements, mismatch repair deficiency, and cardiovascular considerations.)

Curious Dr. George: In 2021, you shared with our readers how you, as an expert, would proceed with handling your own severe back pain and spine lesions.

Let’s revisit that hypothetical scenario with some new developments: Further rapid lab studies demonstrated normal peripheral blood counts and no abnormal serum proteins. The back pain stabilized. Digital rectal exam discovered an enlarged, diffusely firm prostate gland with scattered hard foci. Ten transrectal prostate biopsy cores all contained adenocarcinoma with varying degrees of dedifferentiation, Gleason score of 8, repeat PSA was 25.

How should the pathologist handle the remaining tissues? What procedures should a reference laboratory perform? How would genomic, metabolomic, or proteomics inform next steps? And would imaging be helpful?

Marc B. Garnick, MD: With these new developments, the differential diagnosis has now been narrowed. The likelihood of the bone lesions being related to a plasmacytoma or multiple myeloma, though not completely excluded, are less likely. The lead diagnosis now has been established to be a Gleason score 8 prostate adenocarcinoma, which I presume is a Gleason 4+4. Please recognize that based upon the International Expert Consensus on Prostate Cancer nomenclature, this is now best described as Grade Group 4 (GG 4). Grade Group 1 (GG 1) contains Gleason patterns 3+3; GG 2 contains Gleason patterns 3+4; GG 3 contains Gleason patterns 4+3; GG 4 contains Gleason patterns 4+4; and GG 5 contains Gleason patterns 4+5 or 5+5. If this patient did not have suspected metastases to the bones (and even in the setting of metastatic prostate cancer), the pathology biopsy note should mention the presence of any intraductal component, perineural invasion, or lymphovascular invasion, all of which commonly accompany high-grade Gleason cancers. Neuroendocrine elements, although uncommon, can also accompany high-grade Gleason scores. If present, such transformation following treatment to neuroendocrine/small cell-like pathologies represents an ominous development, which is often accompanied by visceral involvement and the need for systemic chemotherapy.

Recent recommendations now suggest that genomic profiling of the patient both for germline and somatic mutations be assessed. The importance of BRCA (either germline or somatic) mutation has increased in significance, especially since there are emerging associations of prostate cancer being found in families of women with BRCA mutations. The finding of a BRCA2 mutation is associated with a more aggressive biology and could help inform treatments at some later day with the PARP class of therapeutics of platinum-containing agents, given the increased sensitivity of BRCA + cancers to respond to these therapies. Likewise, the presence of microsatellite instability (MSI high, or MSI-H) or mismatch repair deficient (dMMR) mutations may prompt treatment with an immunotherapy agent such as pembrolizumab.

The above consideration of more precise pathologic assessment is more important in a patient who has a GG 4 or 5, in whom there is no obvious evidence of metastatic disease. In such cases, one is trying to assess a probability of the patient having subclinical metastatic disease or being likely to develop metastatic disease. For the patient with already-established evidence of abnormal foci (in this case, the bone lesions), we in the past would have assessed with an Axumin scan; now, the availability of either Ga or F linked prostate-specific membrane antigen (PSMA) scanning would be indicated, both for diagnostic purposes as well as assessing down-the-line utility of PSMA-specific therapeutic ligands, such as Lutetium 177.

An assessment of cardiovascular history is increasingly important in helping determine a treatment program that helps minimize any therapy-induced increase in morbidity. Traditional androgen-deprivation therapy (ADT) has long been associated with cardiovascular issues, and now, with the standard addition of second-generation androgen receptor signaling inhibitors to ADT, the cardiovascular risk can double and even quadruple. Patient evaluation by experts in cardiology, internal medicine, or the emerging field of cardio-oncology is becoming increasingly important.

Curious Dr. George: What additional testing and what therapy would you deem to be most appropriate at this point?

Marc B. Garnick, MD: Please recall that this patient (hypothetically me) presented with back pain and multiple bony lytic lesions. Regardless of the etiology of these lesions, identification of any impending spinal cord compression must be assessed. While spinal cord compression is an unusual manifestation of de novo metastatic prostate cancer, it is clinically more common in the setting of treated prostate cancer that has progressed to become castration resistant. I would reassess the anatomic locations of the bone lesions, and then obtain a spinal MRI directed diagnostic evaluation, along with a good neurological examination to inform preemptive radiation or surgical considerations if either impending or actual compression is found.

For treatment of newly diagnosed presumably castration-sensitive metastatic prostate cancer, we now have multiple advances that have been established in this disease setting. First-line ADT (generally with an LHRH agonist or GnRH antagonist) is now supplanted with second-generation agents, such as abiraterone (+ prednisone) or enzalutamide, or other androgen-receptor signaling inhibitor agents, such as apalutamide. ADT + chemotherapy with docetaxel is also appropriate. Given the bone pain and potential neurological issues here, I would select a GnRH antagonist (either degarelix or relugolix) as the preferred therapy.

Dr. Garnick can be reached at mgarnick@bidmc.harvard.edu.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Personalized Power of the “N-of-1” Approach

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Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Glenn Sabin
Director of Strategy & Business Development, Cancer Commons and Author of n of 1

Randomized, controlled clinical trials with a large N—number of participants—are the recognized “gold standard” of evidence-based medicine. Even so, the results of large-N trials can only reveal population averages, and are not predictive of any individual’s response to a given treatment. On the other hand, one can consider every patient with cancer as the sole participant in their own clinical trial with an Nof1, even if the trial is not officially registered, reported, or supported like a traditional trial.

Here, our Curious Dr. George discusses the value of the “n-of-1” approach with Glenn Sabin, director of strategy and business development at Cancer Commons. Sabin is a 33-year cancer thriver and author of n of 1: One Man’s Harvard-Documented Remission of Incurable Cancer Using Only Natural Methods.

Curious Dr. George: Among the many people whose cancer progresses beyond guideline-based standards of curative care, how might one become an n-of-1 trial participant, if they so choose? What actions should be taken by the physicians who bear responsibility for such individuals who desire to further collective knowledge—and their own welfare—by voluntary participation in use of investigational drugs or drug combinations, or off-label use of drugs approved for other contexts by the US Food and Drug administration (FDA)?

In my view, the n-of-1 approach is clinical care and should be paid for by reputable insurance companies. And, the patient can provide fully informed consent, even with the proviso that the process and outcome be shared for educational purposes. Could this approach become a nimble form of adaptive clinical trial? What are its pros and cons?

Glenn Sabin: From my perspective, randomized, controlled trials (RCTs) will continue to be important for population-based investigational cancer drug development—especially when effectively translated to clinical practice.  Standard-of-care treatment that follows guidelines from the National Comprehensive Cancer Network (NCCN) remains effective for many patients who host early-stage and more indolent disease.

However, for those living with advanced and rare cancers—and for whom standard care has not enabled deep and durable remissions after multiple lines of treatment—it is critical to consider a more personalized approach to testing and treatment.

After all, there is only one host (the unique person living with cancer) and one tissue/tumor type (no two malignancies are exactly alike). This is why we are each an Nof1—an experiment of one. This is the distinction between population-based investigations (RCTs) and truly personalized cancer care (Nof1): averages versus individualization.

I see a future close on the horizon where each patient goes through a deep set of diagnostic testing beyond today’s molecular testing (which itself is not used nearly often enough). The resulting data, consisting of multiple datasets, are then precisely interpreted to inform—with the assistance of artificial intelligence—the patient’s best option for their next treatment. Then, the chosen therapeutics are secured, typically in combinations and often as off-label, and administered to the patient.

Alas, in today’s reality, this type of n-of-1 care—even among the most affluent, educated and connected patients—is largely inaccessible. Access is key.

Novel Testing
Testing beyond certain FDA-approved molecular (sequencing of DNA/RNA) and other diagnostics is not currently covered by Medicare or commercial insurance. Those interested in functional testing—the testing of their own tumor tissue across scores of drugs and combinations—need to pay out of pocket, and some of these novel assays can get quite expensive.

Interpretation of Testing Results
These novel tests produce lots of data. Now what? The problem is that very few oncologists can interpret beyond the “targetable” biomarkers and mutations shown in molecular sequencing reports, which typically cover a small set of genes. Add to the mix novel multi-omics assays (looking at proteins, metabolism, the microbiome, and more) and functional testing, and oncologists are not trained to review in a way that supports the treatment decision-making process. Third-party professional services are needed.

N-of-1 Physicians
Oncologists are trained to deliver standard-of-care cancer treatment as defined by NCCN guidelines. Across the US, some oncologists within community practices will consider prescribing outside of these guidelines when patients have relapsed multiple times. Other oncologists, especially within academia, will only depart from NCCN guidelines under an institutional review board (IRB) and investigative new-drug (IND) study setting, even if such a study is created for only one patient (N of 1). In general, oncologists need internal institutional support to prescribe off label, both from their tumor board colleagues and from colleagues who ensure they feel comfortable about potential toxicity when using drugs with limited or no studies capturing potential for severe adverse events.

Drug Access
Today, approximately 30% of all FDA-approved anticancer therapeutics are prescribed off label. Physicians always have the option to prescribe in this way. One major issue is getting off-label drugs covered by Medicare or commercial payors. Otherwise, providers must advocate for their patients (without reimbursement for their efforts) to apply to various programs such as Expanded Access and Compassionate Use. And there is no financial incentive to do so because drugs secured through these channels cannot be marked up.

Data Collection and Registry Studies
The most effective and efficient way to capture n-of-1 managed and treated patient data is within an IRB-compliant registry connected to a learning health system. This approach collects real-world evidence and allows us to learn from each patient in near-real time. The gold-standard comprehensive learning health system does not yet exist, but I understand that progress is moving apace.

Making N-of-1 Cancer Care a Reality
At Cancer Commons, we are actively pursuing solutions to making comprehensive, end-to-end, n-of-1 patient navigation and treatment a reality. Every day we are working on eliminating the obstacles to access, in service of improving the human condition for those hosting advanced disease, and their families and loved ones.

Progress is inexorable.

Mr. Sabin can be reached at glenn.sabin@cancercommons.org.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.