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

When is the Best Time to Seek a Clinical Trial for Glioblastoma?

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

Eric T. Wong, MD
Cancer Commons Expert Physician Advisor, Associate Professor of Neurology at Harvard Medical School, and Co-Director of the Brain Tumor Center at Beth Israel Deaconess Medical Center

For some people with glioblastoma brain tumors, enrolling in a clinical trial enables access to cutting-edge treatment. Here, our Curious Dr. George talks clinical trials with Cancer Commons Expert Physician Advisor, Eric T. Wong, MD. Dr. Wong is also Associate Professor of Neurology at Harvard Medical School and Co-Director of the Brain Tumor Center at Beth Israel Deaconess Medical Center.

Curious Dr. George: Malignant brain tumors are often treated initially by surgery and follow-up radiation. However, many recur and progress. Glioblastoma patients have many treatment options from which to choose, including clinical trials. But when is the best time to look for a clinical trial? Prior to initial therapy, immediately after initial treatment, or upon recognized tumor progression? How should a patient and their physician seek the most appropriate clinical trials?

Dr. Wong: This is a very important question for adult patients with glioblastoma and for a clinical neuro-oncologist like me who cares for them. At the time of diagnosis, the tumor is unstable and it is often difficult to determine the extent of microscopic spread to the adjacent brain. This is because glioblastoma is an infiltrative disease. Although MRI scans allow us to visualize the tumor, there are still microscopic tumors that we cannot see on head MRI scans. I always have to watch out for microscopic tumors causing motor or language dysfunctions.

Radiation is the mainstay of glioblastoma treatment, and it takes 6 weeks to administer. The reason is that we can only give a small fraction of radiation daily because normal brain and nerve cells cannot handle large fractions of radiation. The total dose needed to control the tumor is also at the maximum of brain tolerance. It takes at least 4 to 5 weeks to accumulate enough radiation dosage to exert an effect on the glioblastoma to halt tumor growth. Therefore, it is often a misconception that once radiation is started, tumor growth is controlled. In fact, the tumor can still grow during the initial 4 to 5 weeks of radiation, and it is not until the last week of 1.5 weeks that the radiation exerts its full effect on halting tumor progression.

For these reasons, it is often difficult to find a trial that fits a newly diagnosed patient with glioblastoma without delaying radiation. This is a logistics problem—a patient needs to be at the right time and right place where a clinical trial is available for them, and radiation can still be initiated within 4 to 6 weeks after surgery. It is my opinion that if a clinical trial cannot be found in a timely fashion, the patient should take conventional treatment. The time to look for clinical trials is when the tumor is stabilized with radiation and temozolomide.

After radiation and temozolomide, the patient goes into the adjuvant phase of treatment with monthly adjuvant temozolomide and monitoring with periodic head MRI scans. It is during this period that the patient has more time to look for a clinical trial in the event of recurrence or disease progression.

If you are at this point and looking for a trial, ask a family member to help you navigate the clinicaltrials.gov website or contact Cancer Commons and work with our Scientists to find a promising trial. At this point, you will also have more time to think about traveling and lodging in a faraway city, while talking to your neuro-oncologist about options. You and your care team should look at the inclusion and exclusion criteria to see if you fit into a particular trial. If none fits, your treating neuro-oncologist can still develop a personalized treatment for you.

Dr. Wong can be reached at ewong@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

How Can Detection of Tumor DNA in the Blood Aid Advanced Cancer Treatment?

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

Paul Billings, MD, PhD
Chief Medical Officer at Natera

Alexey Aleshin, MD, MBA
VP Medical Affairs, Oncology, at Natera

 

As a tumor grows, it may shed fragments of its DNA into the patient’s bloodstream. After treatment, if part of the tumor remains or it begins to grow again, more of this circulating tumor DNA (ctDNA) may enter the blood. That raises the possibility that detecting ctDNA could help clinicians monitor molecular or minimal residual disease—cancer that remains after treatment and cannot be detected by traditional imaging methods.

Here, our Curious Dr. George talks ctDNA with two leaders at Natera, a company that develops ctDNA tests: Chief Medical Officer Paul Billings, MD, PhD, and VP Medical Affairs, Oncology, Alexey Aleshin, MD, MBA.

Curious Dr. George: When initially diagnosed, potentially lethal cancers found at advanced stages can pose quandaries for treatment and management. Many advanced technologies are now being applied to address these challenges. How might the detection of ctDNA be used to assess molecular residual disease and assist in cancer monitoring and management?

Drs. Billings and Aleshin: Treating advanced-stage cancer is challenging. While treatments are available, they have toxicities and can impact patients’ quality of life. Moreover, as tumors evolve over time, they may become treatment resistant. Determining treatment resistance early can have significant clinical implications.

With the advent of next-generation sequencing, it is now possible to sequence the tumor tissue and identify a set of mutations that are specific to the patient’s tumor. These mutations, which are linked to early tumor development and are not related to specific response to treatment, can be tracked later by analyzing free-floating fragments of tumor DNA—circulating tumor DNA (ctDNA)—in the patient’s blood, without the need for any additional biopsy.

Moreover, the short half-life of ctDNA provides a real-time snapshot of subtle changes in the tumor burden, and is far more effective than a radiological scan that relies on detecting a visible lesion. Such a personalized and tumor-informed approach has emerged as a sensitive, non-invasive, and cost-effective tool for identifying tumor molecules (molecular residual disease) down to a single molecule in a tube of blood.

Immunotherapy has fundamentally changed how cancer is managed. However, only a fraction of patients respond to immunotherapy, while all patients are at risk of developing side effects from this treatment. An example of how ctDNA could address this issue is a hypothetical patient who was treated with pembrolizumab (Keytruda) for her non-small cell lung cancer. Initial imaging showed a mixed result that was difficult to interpret. However, ctDNA showed a markedly elevated ctDNA level suggestive of progression. This allowed the oncologist to reconcile ambiguous findings on imaging and alter the patient’s clinical course by switching to an alternative therapy.

Our recently published study, in Nature Cancer, highlights the advantage of monitoring ctDNA dynamics in a cohort of patients with 25 different types of histologies. The study showed significantly better outcomes for patients who cleared their ctDNA posttreatment, indicating exceptional response. The study also illustrated molecular progression as early as 6 weeks in a percentage of patients who received, on average, two cycles (six weeks) of additional treatment, which could have been avoided. This shows a clear utility of ctDNA that could have enabled an earlier switch to alternative treatment with a higher degree of efficacy and a lower financial burden.

More recently, the U.S. Food and Drug Administration (FDA) approved pembrolizumab as a first-line treatment for patients with unresectable or metastatic mismatch repair deficient/microsatellite instability status (dMMR/MSI-H) colorectal cancer (CRC), which constitutes 15 percent of metastatic CRC (mCRC) patients. The remaining have a microsatellite-stable status. Both of these subtypes have shown poor expression of CEA, which is a commonly used protein biomarker. Many studies have alluded to its poor sensitivity, specificity, and unreliability in predicting treatment response or risk of relapse. We recently presented a few case examples at the Society for Immunotherapy of Cancer (SITC) conference that highlight a physician’s experience in treating patients with mCRC and the value of ctDNA over conventional methodologies.

In summary, there is strong scientific evidence showing that the incorporation of ctDNA analysis into routine clinical practice can help physicians make better-informed decisions for patients battling an aggressive disease.

Drs. Billings and Aleshin can be reached at pbillings@natera.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

Can Really Big Data Inform Precise Decisions for Individual Patients?

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

Matvey B. Palchuk, MD, MS, FAMIA
VP of Informatics at TriNetX, LLC

New technologies are transforming cancer research. By optimizing research protocols and leveraging data more efficiently and intelligently, these tools hold the promise to improve personalized cancer care. Here, our Curious Dr. George asks Matvey B. Palchuk, MD, MS, FAMIA, VP of Informatics at TriNetX, LLC, about the capabilities of his company’s platform.

Curious Dr. George: Translational medicine has evolved to include personalized medicine and precision oncology. We have learned that all individual cancers may be unique, but that they do share some common “…omic” elements that can inform treatment decisions.

TriNetX encompasses a global network of millions of patients with real-world evidence on their responsiveness to a range of interventions for a multitude of diseases. How might the data about interventions for advanced cancers in your global network inform the best treatment options for patients with these conditions?

Dr. Palchuk: TriNetX is the global research network dedicated to optimizing clinical trial operations and real-world evidence generation. We built a data and analytics platform that is powered by an impressive collective of 170 healthcare organizations across 28 countries. A researcher utilizing our platform has instantaneous access to clinical data of tens of millions of patients. The data represents billions of observations collected in electronic health record systems, ancillary systems, cancer registries, billing and financial systems, and many more.

Users of the TriNetX platform can define patient cohorts of interest and go on to learn about their size and how that size evolved over time and what we expect it to be in the future, examine the details of clinical characteristics of the patients, assess trial feasibility, and much more. They can ask sophisticated research questions ranging from comparing outcomes to treatment pathways, burden of illness to incidence and prevalence, and more. And the platform responds in seconds—an entire panoply of actionable insight is at their fingertips, literally at the speed of thought.

One of the top considerations in creating and maintaining our platform is the protection of patient privacy, and the privacy of our member organizations. We take a conservative stance when it comes to working with clinical data and are always very diligent with how the data is handled and used.

The users of the TriNetX platform mainly focus on clinical trial optimization and population research. The capabilities of the tools we are developing lead to working with cohorts of patients and generating evidence on entire populations. However, questions similar to yours naturally arise when contemplating large sources of clinical data. We certainly face these questions in regard to the TriNetX platform—can our data asset be used to inform decisions about treatment options? Certainly, we enable doing so at population-levels all the time. But what about individual patients? Let me describe two possible scenarios:

In the first scenario, a clinician and their patient need to select a treatment option. To take advantage of the existing historical data, the first challenge is to find other patients “like this one.” It is not a trivial problem—how to choose the important characteristics? Do we focus on demographics, comorbid conditions, socio-economic status, or any number of other possible characteristics? There is early work on this topic, but much still needs to be done. Another challenge is the relative paucity of information about outcomes of care, but we won’t tackle this subject here. Of course, it is crucial that my data covers a sufficient number of patients to ensure that the sample of patients “like this one” is large enough to provide the necessary information. This is where a network like TriNetX is really powerful.

In the second scenario, let’s consider a machine-learning model capable of making a prediction about a diagnosis based on historical patterns in the data before any recognizable symptoms arise. As you know, early diagnosis leads to a significant improvement in survival. TriNetX is collaborating with a team of scientists focusing on early prediction of pancreatic cancer using such a model. When high-risk patients are found, what is the mechanism for getting in touch with them? The data in our platform is de-identified—we do not know who those patients are—and only their healthcare provider has the capability to “break the glass” and navigate the intricacies of contacting those patients.

Although not directly intended for use in improving the care of a single patient, you can see how the research-oriented clinical data can lend itself to go beyond population medicine and make a difference in individual lives. We at TriNetX are working diligently to bring this promise closer to reality.

Dr. Palchuk can be reached at matvey.palchuk@trinetx.com. TriNetX is located at at 125 Cambridgepark Drive, Suite 500, Cambridge, MA 02140.

Related Links:

Can Preclinical Data Guide Clinical Cancer Therapy?

Capturing Patients’ Real-World Experiences to Improve Cancer Research and Care

How to Beat COVID-19 with Real-Time, Real-World Data

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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

Just Diagnosed with Advanced Lung Cancer: What Now?

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

Howard (Jack) West, MD
Associate Clinical Professor in Medical Oncology and Executive Director of Employer Services at City of Hope Comprehensive Cancer Center

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, 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 an Associate Clinical Professor in Medical Oncology and Executive Director of Employer Services at City of Hope Comprehensive Cancer Center in Duarte, California.

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?

Dr. West: 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.

Related Links:

Molecular Testing Guides Treatment for Claudius’s Lung Cancer

What’s New in Immunotherapy for Non-Small Cell Lung Cancer?

Comprehensive Molecular Testing Needed for Stage IV Lung Cancer

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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 Ovarian Cancer

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

Summer Dewdney, MD
Director of the Division of Gynecologic Oncology at Rush University Medical Center

Cancer patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks oncologist Summer Dewdney, MD, how she would handle her own diagnosis of advanced ovarian cancer. Dr. Dewdney is Director of the Division of Gynecologic Oncology at Rush University Medical Center in Chicago, Illinois.

Curious Dr. George: You are an expert clinical oncologist treating patients with gynecological malignancies. Imagine that you personally began to experience vague abdominal symptoms and were found to have ascites (excess fluid in the abdomen) with positive cytology for malignancy cells. How would you proceed to manage your own likely ovarian malignancy?

Summer Dewdney, MD: Ovarian cancer is the leading cause of death from a gynecologic malignancy in the United States. However, we have made great strides in the treatment of ovarian cancer in the past couples of years, and this has really become a cancer that can be treated chronically. Each patient’s treatment is individualized, and knowing specific information about genetics and molecular analysis is very important.

Initially, I would get a CT scan of the chest, abdomen, and pelvis to look for evidence of metastatic disease and tumor burden. The majority of the time this cancer is found at stage III or IV, and patients usually present with minimal symptoms despite advanced disease. I would have my tumor markers checked, including CA-125 and CEA, depending on which ones are elevated (mostly likely CA-125); these could be monitored moving forward through treatment and surveillance. Depending on the exact pathology and CT results we would then determine if I would undergo a debulking surgery versus neoadjuvant chemotherapy first. I would ensure my care was being managed at a tertiary care center by a gynecologic oncologist. Having an optimal tumor debulking done by a gynecologic oncologist would be very important as this would impact my overall prognosis. I would also see if there were any clinical trials available for me in an upfront setting and make sure I was at an institution that offered clinical trials. If I was not enrolled in a clinical trial, I would receive carboplatin and paclitaxel either before surgery or after surgery, which would likely be the backbone of any clinical trial too.

I would want information on my BRCA status, both germline and somatic as soon as possible to see if I would need maintenance therapy with a PARP inhibitor after treatment. In addition, my surgical pathology would also be tested for molecular analysis. If my germline testing was negative, my tumor would be tested for HRD (homologous recombination deficiency) and BRCA, and if either was positive this would also help inform the decision on PARP inhibitor maintenance. I know my risk of recurrence would be high if I was found to be at stage III or IV, and therefore would want some sort of maintenance therapy after initial surgery and treatment.

If a recurrence was ever found, it would be important for me to be in a clinical trial. If my recurrence didn’t occur for years after treatment and was isolated or only minimal disease, I would consider undergoing a secondary debulking surgery first, followed by systemic treatment (hopefully a clinical trial). My hope would be that the recurrence occurred more than 6 months from the end of treatment and define me as platinum-sensitive, as this prognosis is better.

Personally, quality of life and time with family would be very important, and I would have palliative care involved earlier than later. I would make sure if I did succumb to this disease after hopefully years of living with it, that my last days were not in a hospital and spent with my family.

In summary, ovarian cancer is a tough disease but can be treated for years. Some patients may even be “cured” and not experience a recurrence, but this is the exception rather than the rule. I want to emphasize that many patients are able to have this disease controlled for “years” and often patients experience times of remission.

I want to recognize all the work that scientists have done to move the mark and improve the treatment of ovarian cancer over many years. More importantly, I would like to thank all the patients and families that have participated in clinical trials to get us this information so we can continue to advance the treatment of ovarian cancer.

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

Related Links:

New Treatments for Ovarian Cancer in 2020

Behind the Scenes at Cancer Commons: Working with Patients

How an Expert Would Manage Her Own Advanced Colorectal Cancer

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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

Behind the Scenes at Cancer Commons: Working with Patients

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

Emma Shtivelman, PhD
Cancer Commons Chief Scientist

Cancer Commons helps advanced cancer patients identify and access their best-possible treatments. Here, our Curious Dr. George asks Chief Scientist Emma Shtivelman, PhD, for an inside look at how she helps the people who turn to us for guidance.

Curious Dr. George: As Chief Scientist at Cancer Commons for many years, you have helped thousands of patients with advanced cancer to better understand their options in difficult circumstances. What is the process you typically follow to provide useful information in a compassionate manner without instilling false hope?

Emma Shtivelman, PhD: The “simple” goal of Cancer Commons is to help cancer patients to find better treatments. Most of the patients who register with Cancer Commons have advanced or metastatic cancers, and the range of questions they ask is very wide. To name a few: requests to find clinical trials, advice for dealing with adverse effects of treatments, questions about drugs’ efficacy and side effects, suggestions for the “best” oncologist near them, and more.

To answer these questions, here is the process I follow:

  • Collect and review all relevant medical records after securing the patient’s consent to share them.
  • Decide whether the patient needs a new treatment (most often they do, because patients typically contact us when they experience progression) or a new oncologist.
  • If indicated, suggest seeking a second opinion at a nearby comprehensive cancer center.
  • Mutational profiling often opens new treatment options for cancer patients. Thanks to our collaboration with the company Tempus, we offer mutational testing to Cancer Common patients who have no other means to have this done—even though it should be an integral part of modern cancer care. The results, which we can access immediately and directly, often generate suggestions for new treatment options.
  • If the patient’s performance status does not warrant further active treatment, we may suggest considering palliative care only, or hospice, usually in support of the opinion of the treating oncologist. These are difficult emails and calls. Some patients (and often their caregivers) do not understand the gravity of their situation.
  • Search for clinical trials: I have always considered finding relevant clinical trials as the most important contribution Cancer Commons can make to patients’ treatment. I try to suggest trials with investigational drugs that have, preferably, preliminary evidence of clinical activity, or at least very strong evidence of relevant preclinical activity. The search for clinical trials can be both the most rewarding and most frustrating part of my work. If I see a highly relevant trial, I rejoice, but later I may hear from patients that they are unable to enroll for a variety of reasons. For instance, travel for trial treatment may be not feasible, the treating oncologist might prefer to start another line of chemotherapy (which may make patient ineligible for most trials in the future), or the particular cohort may no longer be enrolling at a trial site nearby.

My work with patients can pose significant challenges. Here are the major problems that can arise:

  • Patients often do not provide relevant information about their conditions and treatments, because they may not have a clear understanding of what information is most important, or because they do not have access to their medical records.
  • Patients sometimes seek only “alternative” treatments not supported by clinical evidence.
  • Because I communicate with patients and not with their doctors, the information I provide—in particular about relevant clinical trials—may not be conveyed to or discussed with the treating oncologist. Some patients are hesitant to do so because they are afraid to offend their doctors. Others may have difficulty understanding the information they receive and dismiss it.
  • The most daunting obstacles I face have to do with obscure and often inconsequential medical history that excludes patients from participating in clinical trials. For a given patient, I can easily screen out trials based on listed eligibility criteria (such as preexisting health conditions, organ dysfunction, brain metastases, HIV infection, number of previous lines of treatment, or previous malignancies). However, on occasion, we encounter what I consider to be unjustified pre-existing conditions that preclude enrollment. Two examples of this are a left bundled branch block in a patient without a history of heart disease and asymptomatic pulmonary mycobacterium avium complex diagnosed incidentally 15 years earlier. When trial exclusion happens because of rigid and hard-to-justify trial protocols, it is very frustrating for me and the patients I work with.

Despite the challenges of our work, I always hope, and sometimes know, that patients and their oncologists can arrive at new, more promising treatments based on Cancer Commons’ personalized research. This is what drives me to continue working with cancer patients.

Dr. Shtivelman can be reached at emma@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.

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

How an Expert Would Manage Her Own Advanced Colorectal Cancer

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

Christina Wu, MD Associate Professor of Hematology and Medical Oncology, Emory University

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 Cancer Commons Expert Physician Advisor Christina Wu, MD, how she would handle her own diagnosis of metastatic colorectal cancer. Dr. Wu is Associate Professor of Hematology/Oncology and Associate Division Director of Medical Oncology at Winship Cancer Institute of Emory University.

Curious Dr. George: As an experienced academic and practicing clinical oncologist at Emory University, 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?

Dr. Wu: Colorectal cancer is the third most common cancer in the U.S., and one of the leading causes of cancer deaths. However, every patient with metastatic colon cancer to the liver is treated individually because there are various 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: First of all, I would want to know if I could benefit from immunotherapy so that I could be spared the side effects of chemotherapy. I would test for mismatch repair protein status or microsatellite instability. I would want to know the tumor’s KRAS/NRAS/BRAF mutation status, because I would be a candidate for anti-EGFR therapy if my tumor was RAS wild-type and the primary cancer was left-sided. The presence of a BRAF mutation would direct me to targeted therapies, such as encorafenib and an anti-EGFR antibody or vemurafenib, irinotecan, and an anti-EGFR antibody. If the tumor was RAS wild-type with HER2 amplification, I would be interested in HER2-targeted therapies. In addition, if I had the rare NTRK fusion mutation, I would be a candidate for larotrectinib. There are also ongoing clinical trials testing drugs that target KRAS mutations, such as KRAS G12C.

Multi-disciplinary tumor board: I would want high-quality imaging and experts from medical oncology, surgical oncology, 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, I would consider triplet chemotherapy (FOLFOXIRI) to get more of a response so that I could get to surgery. However, if I had clearly unresectable disease, I would choose doublet chemotherapy such as FOLFOX or FOLFIRI with a biologic agent to improve my quality of life. With unresectable disease, I could also consider radiation, Y90 treatment, or ablation to the liver tumors, should I have good control or surgical resection of the extrahepatic disease.

Genetic counseling: There are hereditary syndromes that lead to colon cancer development, including Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis. All patients with a new diagnosis of colorectal cancer are recommended to have universal screening for Lynch syndrome, and identifying a hereditary syndrome may help family members with early detection.

Palliative care: This is such an important team that treats the symptoms patients have from their cancer as well their cancer treatment. They also provide great support to patients and their caregivers in navigating their way through their cancer diagnosis.

Clinical trials: I personally would want to be part of clinical trials that could help move new drugs forward for colorectal cancer patients, and thus I would consider this an essential team in my cancer care.

Final thoughts: As I reflect on all the teamwork and different moving pieces that have to come together for one cancer patient, I am certainly grateful for all the multi-disciplinary clinical staff and physicians who are caring for cancer patients.

Dr. Wu can be reached at Christina.wu@emoryhealthcare.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.

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

What Is a Cancer Commons Options Report?

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

Lola Rahib, PhD Lead Scientist in Pancreatic Cancer at Cancer Commons

As a Cancer Commons Scientist, Lola Rahib, PhD, helps cancer patients and caregivers navigate treatment. Some of these patients receive a Cancer Commons Options Report. Here, our Curious Dr. George asks Dr. Rahib to share what goes into each Options Report.

Curious Dr. George: Cancer Commons provides advanced cancer patients who seek information with additional options for them to consider, all free of charge. What does a typical Cancer Commons Options Report consist of and look like?

The first page of the report contains information about the patient, including patient goals, molecular alterations, and a short case summary. Patient goals may include treatment and quality of life goals, ability to travel for treatment, and any other life goals or preferences the patient or their caregiver shares with us. The molecular alterations section is extracted from the patient’s molecular profiling report(s). Molecular profiling is an important consideration, as it can guide treatment. The short case summary gives a brief overview of the patient’s diagnosis and treatment history.

The report also contains a comprehensive, personalized case summary detailing the patient’s cancer history. The personalized case summary is created by reviewing the patient’s medical records, and includes information about the patient’s diagnosis, pathology, treatment history, treatment response, genomic sequencing, and other testing as available. This detailed summary is found at the end of the report and may be helpful for patients to take with them to appointments, especially if they are visiting with a new physician.

A sample Cancer Commons Options Report; click to see full report.

The detailed summary is used to generate personalized therapeutic options, including investigational therapies, clinical trials, off-label combinations, and testing modalities such as next generation sequencing, liquid biopsies, and other diagnostics. These options are presented in a table format with therapy descriptions and scientific rationale. Molecular targets for specific treatment options are indicated when appropriate.

Feedback and consensus from a Virtual Tumor Board is also provided when applicable. Currently, Cancer Commons has a Virtual Tumor Board program for brain and pancreatic cancer patients. The Virtual Tumor Board program allows Cancer Commons to present a patient’s case to nationally recognized experts. The panel performs a comprehensive review of the patient’s diagnosis, treatment history, molecular profiling, genetics, and other relevant information. Based on this information they discuss and provide feedback on treatment options including clinical trials, and any further diagnostics and evaluations. This feedback is provided in a summary along with the detailed treatment options.

The final decision regarding tests and treatments is always up to the patient and their care team. We encourage patients to discuss these options with their treating oncologist.

We capture decisions and rationales, and patients’ progress is monitored over time. This supports learnings and insights from every patient. Our artificial intelligence platform uses the Virtual Tumor Board’s recommendations, treatment decisions, and clinical results to get smarter. Our goal is to continuously learn from every patient’s experience and use that knowledge in real-time to help the next patient.

Dr. Rahib can be reached at lola.rahib@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.

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

Hydrogen Peroxide Appears to Treat Pre-Cancerous Oral Lesion in “N-of-One” Experiment

Ronald Piana
Freelance science writer, specializing in oncology

Numerous patients come to Cancer Commons because they wonder if their best cancer treatment option may lie beyond standard care. For many patients, this will mean receiving treatment through a clinical trial. However, with the input and supervision of their medical care team, a select number of patients may arrange to try a non-standard treatment outside of a normal clinical trial. This approach is often called an “N-of-one” experiment, because it is like a clinical trial where the number of participants (N) is just one—the patient.

Here, our Curious Dr. George speaks with Ronald Piana about an N-of-one approach he took to treat his own oral leukoplakia, a condition that can develop into oral cancer. Ronald Piana is a freelance science writer specializing in oncology.

Curious Dr. George: In a recently published study, Neil Mundi, MD, of the University of Western Ontario and colleagues reported success in minimizing or even eradicating biopsy-proven non-melanoma cutaneous malignancies by the topical application of concentrated hydrogen peroxide. You had a similar recent experience with an oral premalignant lesion in an N-of-one clinical trial. What was your experience?

Ronald Piana: In 2018, during a routine dental examination my dentist discovered a small whitish patch on the left lateral border of my tongue. He ordered a biopsy, and the lesion was diagnosed as benign leukoplakia. The lesion recurred and progressed, and approximately 1 year after the initial diagnosis presented as a raised, red-white lesion about 3 cm in diameter that was causing discomfort. On follow-up, my dentist found the lesion “very concerning” and scheduled a consultation with an oral surgeon.

I’m a 25-year veteran science writer in the oncology sector, and I’d chanced to read Mundi’s study, in which he and his colleagues successfully treated non-melanoma skin cancers with topical 33% hydrogen peroxide (H2O2). I decided to do an N-of-1 experiment on my oral lesion. I brushed the lesion until blanching with a cotton swab soaked in a solution of 35% H2O2 twice a day for 2 days prior to my appointment. At the appointment, the oral surgeon viewed a digital image of the lesion obtained by my dentist and prepared for excision. Upon oral examination, however, he found no evidence of the 3 cm lesion. On 3-month follow-up, no visual indication of recurrence could be detected.

Curious Dr. George: What biological effects might explain the result?

Ronald Piana: Hydrogen peroxide is a well-established apoptosis-inducer with broad cytotoxic activity in a range of cell types. Other H2O2 cytotoxic pathways have been identified, such as lysosomal membrane permeabilization (LMP). In LMP, the lysosome (described as a “suicide bag”) is compromised by H2O2-driven oxidative stress, during which large amounts of H2O2 enter the lysosomal compartment, forming abundant hydroxyl radicals, or highly reactive iron-centered radicals, which leads to degradation of cellular structures and, ultimately, cell death. Yet another intriguing explanation considers the Warburg effect, wherein transformed cells, such as those in cutaneous malignancies, undergo a shift from oxidative to glycolytic metabolism, rendering cells more susceptible to H2O2-induced oxidative stress. H2O2 has other cytotoxic pathways, yet, in short, this potent agent kills cancer cells by inducing oxidative stress.

Curious Dr. George: What do you propose as next steps?

Ronald Piana: Mundi’s study is the first in the literature to evaluate high-concentrate H2O2 as a topical treatment for cervicofacial cutaneous malignancies. The results have broad health implications for the millions of Americans diagnosed each year with skin cancers, and further indicate that topical H2O2 treatment could be a valuable clinical option for a variety of healthcare professionals including surgeons, dermatologists, and primary care physicians. Therefore, I hold that prior investigative work coupled with findings from Mundi, et al., should be viewed as proof-of-concept in safety and efficacy leading to larger scale evaluation and recognition of topical H2O2 as a treatment option for select carcinomas and, equally important, opening the investigative door into other exciting clinical opportunities.

My concern is that further serious investigation of this cheap and readily available agent, for various reasons beyond the scope of this post, will be ignored or rebuffed by the research and medical communities. To that end, I encourage others in the healthcare community not to let this valuable clinical opportunity pass.

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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 to Learn About Cancer in a Classroom: Shaping Compassionate Doctors

Marin Langlieb
Clinical Research Coordinator at Massachusetts General Hospital

The patients and caregivers we serve here at Cancer Commons rely on their doctors to provide expert, compassionate care. Building the skills to give such care can begin early in a doctor’s education. Here, for a change of pace, our Curious Dr. George asks a future doctor about a unique experience that helped her learn how to connect with cancer patients. Marin Langlieb is a Clinical Research Coordinator at Massachusetts General Hospital in Boston, Massachusetts.

Curious Dr. George: As a recent college graduate in pre-med now working in Boston in research, and as a student interacting with cancer patients, how would you rate your educational experience in preparation for medical school and for a lifetime of work as a physician?

Marin Langlieb: The answer to this question lies in a seminar I took as an undergrad that exemplifies why teaching both the sciences and the humanities to pre-meds is so critical.

After losing my pediatrician to cancer during college, I knew that I wanted to understand more about the disease. From a scientific perspective, my pre-med classes prepared me very well. In biology, it seemed like every semester I had a lecture about p53, a protein that regulates the cell cycle to prevent unregulated cell division. Yet, although I knew all this information about cancer at the micro-scale, I still wanted to understand cancer in the context of real human experiences. In other words, what was it like to actually live with cancer?

At most universities this is a topic that is probably not taught in a classroom. But my junior year, I enrolled in a seminar course called “Community Based Cancer Research Presentations and Discussions” that was part of a broader partnership between cancer researchers at my university and the local cancer resource center. Each class we would have lectures from people with a wide variety of science and humanities backgrounds—such as communication professors, physicians, ethicists, and community participants who were cancer patients themselves—all on cancer-related topics.

The lectures were extremely interesting (for example, one was on the importance of patient advocacy from “Congress to the Bedside”), but the primary goal of this unique program was the connections it fostered. For the scientists, who were researching cancer with cells or mice, it helped connect them to those who would be most affected by their work. For the community participants, they told me they joined the class because they wanted to better understand and communicate the science behind their disease. For example, many of the people I talked to wanted to be able to read complex scientific literature and understand some of the treatments they were receiving. Even more so, they stated that understanding the mechanisms and pathways behind their disease helped give them a sense of reassurance—people actually understood some of what was happening inside their body.

I think my pre-med classes did prepare me for a future career in medicine, although opportunities that connect students and members of the community are critical. For example, this class taught me how to actually apply what I was learning in my science classes to scenarios I might experience as a physician. That is, speaking with the community members taught me that being a good physician goes beyond using science solely to treat patients, but also to help patients clearly understand their diagnosis, their treatment, and their disease. In addition, learning how to communicate science effectively has been crucial to my current work in clinical research, from conducting informed consents to helping write grants.

However, the most important thing the class did was introduce me to some of the kindest people I have ever met. Even now, they push me to study harder, think bigger, and realize just how much of an incredible privilege a career in medicine is.

Marin Langlieb can be reached at mlanglieb@mgh.harvard.edu.