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Dr West

Dr West


Dr. West attended Princeton University before heading to the University of Cambridge on a Fulbright Scholarship. He then returned to the US to attend Harvard Medical School, where he was honored as a Howard Hughes Medical Institute Research Fellow. He did his internship and residency training at Brigham & Women’s Hospital in Boston before moving to Seattle for his specialty training at the Fred Hutchinson Cancer Research Center/University of Washington, where he served on faculty after completing his fellowship in medical oncology. Since that time, he has fused his commitment to patient care at Swedish Cancer Institute in Seattle, focusing on thoracic and genitourinary oncology with a commitment to clinical research as well as entrepreneurial ventures. While overseeing a cancer clinic that draws patients from all over the world, he offers a wide array of clinical trials and leads several, including serving as Principal Investigator of several phase II national trials with the Southwest Oncology Group. He has emerged as a very rare oncologist based in a private practice setting yet remains a nationally to internationally recognized expert, thought leader, speaker and writer. Dr. West has also pioneered many new ventures that exercise his interests in social media, new educational platforms, and even marketing. He founded Go West Health Care Consulting in 2004, which has flourished into a very successful company that enabled him to pursue roles in developing of a wide range of oncology products, lead dozens of pharmaceutical advisory boards, speak and write for professional and patient oriented audiences, help in developing educational and marketing materials, serve as a medical director for a CME company, and even work as the dedicated oncology consultant to a large marketing agency. He is widely recognized as an oncologist who understands the complex market forces from scientific background to commercial development strategies to current and future practical market forces within the oncology space – the only oncologist who has delivered a TEDx presentation and attends not only ASCO but TEDMED, South by SouthWest interactive, and the American Telemedicine Association’s annual conference. Finally, recognizing that patients and caregivers are a remarkably underutilized resource and critical voice in medical decision-making, Dr. West developed OncTalk.com in 2006 as a mechanism to provide very timely, specialized free information about cancer directly to a global patient community. This effort transitioned to become the nonprofit Global Resource for Advancing Cancer Education (GRACE) (www.cancerGRACE.org) in 2007, which has continued to grow rapidly, now integrating participation from many expert physicians and other health care specialists and reaching tens of thousands of people in over 130 countries each month. His efforts have provided expert content in a wide range of formats, including blog posts, audio and video podcasts, and an interactive discussion forum that have led to his being recognized as an international leader in the growing role of the educated patient as a means of shaping medical care and ultimately improving patient outcomes. “You are truly a Godsend -- I am thankful for the support and compassion you offer people throughout the world. I appreciate it more than words can convey.” —GRACE Member Linda P.
Dr West

What Are the Potential Side Effects? (An Immunotherapy Primer for Patients, Pt. 4)

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While immunotherapies are sometimes considered to be nontoxic or minimally toxic alternatives to standard treatments such as chemotherapy, it is more appropriate to recognize that they can be exceptionally well tolerated but can also be associated with a distinct constellation of potential immune-mediated side effects that range from trivial to serious and potentially life-threatening (Figure 3). Serious side effects are seen in less than 10% of patients, and typically emerge an average of 6 to 12 weeks after the start of treatment; however, they may also start within days of the first dose, many months into treatment, or sometimes even after discontinuation of therapy. The risk of side effects increases with higher doses, and overall seems to increase with cumulative exposure. Moreover, as immunotherapies are being tested in combination, side effects tend to be additive.

Figure 3: Range of Potential Immune-Related Adverse Events Associated With Checkpoint Blockade Therapies

Figure 3: Range of Potential Immune-Related Adverse Events Associated with Checkpoint Blockade Therapies

The more common adverse effects are related to GI inflammation, which can be as minor as slight irritation or as severe as colitis (inflammation of the colon), potentially even leading to perforation of the bowel. Symptoms can include bloating, cramps, diarrhea, bloody stools, abdominal pain, and nausea. A medical evaluation includes reporting on the frequency and volume of diarrhea, potentially a stool sample to check for infection, imaging that may include an abdominal ultrasound and/or CT scan, and possibly direct visualization with a colonoscopy. Treatment often includes hydration when needed, anti-spasmodic medication such as dicyclomine (Bentyl), anti-diarrheal medications, and potentially steroids or the medication infliximab (Remicade).

Thyroiditis, or inflammation of the thyroid, is another common side effect, and it may lead to excessively high activity (hyperthyroidism) or low activity (hypothyroidism). Because the thyroid gland regulates metabolism, growth, and temperature control, typical symptoms of hyperthyroidism include weight loss, a fast heart rate, irritability, diarrhea, and feeling warm most of the time, while the symptoms of hypothyroidism often include weight gain, fatigue, dry skin, constipation, and feeling cold. It is common for hyperthyroidism to later transition to a normal or hypothyroid state. Blood tests can determine the function of the thyroid. Hyperthyroidism is generally treated with “beta blockers,” blood pressure medications that slow the heart rate, combined with symptomatic management of patient’s symptoms. Hypothyroidism is readily treated with thyroid hormone replacement (evothyroxine/Synthroid).

Other endocrine glands are also subject to auto-immune inflammation in this setting. Inflammation of the pituitary gland, also known as hypophysitis, can lead to vision changes, confusion, headaches, and other neurologic issues. Similarly, the adrenal glands may become inflamed, leading to nonspecific symptoms such as fatigue, nausea, and low blood pressure or blood sugar. Both of these complications are treated with steroid therapy to reduce inflammation, as well as replacement of deficient hormones.

The lungs are also subject to inflammation, or pneumonitis, in about 1% to 3% of patients. The common symptoms of pneumonitis include shortness of breath, cough, and wheezing and are often associated with low oxygen-saturation levels in the blood. Changes in the appearance of the lungs are visible on a CT scan, but diagnosis is definitively made with a biopsy, commonly done at bronchoscopy. Along with supplemental oxygen, possibly antibiotics, other supportive measures, or steroids are the cornerstone of treatment.

Rash is another very common side effect of immunotherapies, often appearing as a red, bumpy, and potentially itchy rash on the trunk, hands, and feet, although it may also be more diffuse. At its most extreme, the rash may cause severe blistering that may be very serious and require hospitalization, although, fortunately, a rash this severe is very rare. Mouth sores/ulcers may also be seen. Management is based on the severity of the rash and may require as little as topical steroids and medications for itching to IV steroids.

Other organs, including the liver, kidneys, and brain/nervous system, may also develop immune-mediated inflammation. Accordingly, clinical trials and increasingly common use of these immunotherapies in routine practice will always require vigilant follow-up with the cancer care team, including regular physical examinations and blood work, as well as close communication about new symptoms between scheduled visits. Most side effects are able to be treated effectively and are reversible if detected and addressed readily.

Summary

Immuno-oncology has evolved dramatically over the past few years from an approach with limited applicability, often accompanied by skepticism about its broad utility, to a strategy with clear evidence of efficacy that is poised to transform our management of many cancer types, potentially from early-stage to metastatic disease. Trials with multiple agents are ongoing, leading to expected new approvals in the next few years. Nevertheless, our enthusiasm about the benefits of these treatments must be tempered by a recognition that the dramatic and prolonged responses seen in some patients with melanoma, lung cancer, renal cell carcinoma, bladder cancer, and several other cancer types are not demonstrated by the vast majority, but rather by a limited subset. We also do not yet have a reliable biomarker or clinical profile to identify prospectively which patients are likely to be the major beneficiaries. While immunotherapies are typically quite well tolerated, they have the potential for a complex array of side effects that may be severe, develop late in the treatment, and be challenging to manage.

Taken together, evidence suggests that we are on the cusp of incorporating immunotherapies as an integral component of treatment for many more cancer patients in the coming years, but we await the results of ongoing clinical research to better understand which patients will benefit and where and how to best assimilate them into care plans or substitute them for existing treatment strategies.

This educational summary is intended for patients with cancer, their caregivers, and other interested non-clinicians, and is part of a broader educational platform focused on immuno-oncology, available at www.peerviewpress.com/e158

The Immunotherapy Primer for Patients is a collaboration between GRACE and PVI, PeerView Institute for Medical Education


Dr West

Which Cancers, and Which Patients? (An Immunotherapy Primer for Patients, Pt. 3)

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It has been recognized for decades that some cancer types are more subject to immune-based treatments than others. Melanoma and renal cell carcinoma have historically been identified as among those most immunologically mediated, with spontaneous tumor shrinkage or even complete regression, presumably related to the patient’s immune system, documented in a minority of cases. Lymphomas are also identified as being mediated significantly by the immune system, such that patients with immunosuppression, including those with human immunodeficiency virus (HIV) or those receiving long-term, powerful immunosuppressive agents to combat organ rejection, are known to have high risks of some forms of lymphoma. Conversely, infusion of donor T lymphocytes or strengthening the patient’s immune system through a non-myeloablative stem cell transplant can lead to good responses in some patients with leukemia or non-Hodgkin’s lymphoma. Overall, it remains poorly understood why some cancers are more responsive to immunotherapy and the patient’s own immune system than others. Some recent work suggests that cancers with a greater “mutational load,” the number of genetic mutations in a particular type of cancer, is associated with a greater tendency to respond to immunotherapy, as a wide range of mutations provides a broad array of potential targets for the immune system.

Despite these general observations and trends, one of the more exciting aspects of immuno-oncology research in recent years has been the breadth of cancer types in which activity of immunotherapies has been seen. Cancers such as bladder cancer and lung cancer, as well as others that have not historically been recognized as “immune-sensitive” cancers, have also demonstrated favorable results using many of these approaches that were previously largely presumed to primarily be most amenable to treating patients with melanoma, kidney cancer, and lymphomas.

Nevertheless, clinical trials with immunotherapies ranging from cytokines such as IL-2 to CTLA-4 inhibitors such as ipilimumab or PD-1 inhibitors such as nivolumab or pembrolizumab share the common theme that the benefits associated with these agents can be both profound and prolonged but are not experienced by the majority of patients. As we consider the various cancer treatment options for patients, it would be remarkably helpful to be able to identify, before starting treatment, whether a particular patient is especially likely or unlikely to benefit from immunotherapy—ideally, we would hope to find one or more biomarkers on the cancer that is associated with a strong response to immunotherapy. The most promising of these for immune checkpoint therapies such as PD-1 and PD-L1 inhibitors has been expression of the protein PD-L1 on the patient’s tumor cells. Many trials with PD-1 or PD-L1 inhibitors have demonstrated a higher response rate to these immunotherapies in patients with PD-L1 expression, particular in those with levels above a certain threshold. But with a multitude of testing methods available, there is no remote consensus of how best to test for PD-L1 expression or what constitutes a “positive” result. Most importantly, there is no cutoff point that reliably separates one group of patients with a very high probability of tumor shrinkage from a group with little chance of benefit; even if the response rate of “PD-L1 positive” patients is higher, the difference is of such a limited magnitude that PD-L1 positivity is not reliably associated with a response rate greater than 50%, while patients with low or no PD-L1 expression may still respond well, even if less likely. Consequently, PD-L1 has not emerged as a robust, reliable biomarker for predicting which patients should or should not receive PD-1 or PD-L1 inhibitors, even though it remains the leading candidate at this time.

This educational summary is intended for patients with cancer, their caregivers, and other interested non-clinicians, and is part of a broader educational platform focused on immuno-oncology, available at www.peerviewpress.com/e158

The Immunotherapy Primer for Patients is a collaboration between GRACE and PVI, PeerView Institute for Medical Education


Dr West

How Is Immunotherapy Administered? (An Immunotherapy Primer for Patients, Pt. 2)

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Although the different types of immunotherapy, including vaccines, cytokines, and checkpoint blockade therapies, have many distinct features, they are all administered either into the skin or as intravenous (IV) infusion, despite the convenience and appeal of oral therapies to many people with cancer. Immunotherapies are not administered orally because the gastrointestinal (GI) tract would break down the immunologically active large proteins into small, inactive peptide components. In general, vaccines are administered every few weeks for a period of time through skin injections. Cytokines are administered into the skin or, in some situations, via IV. Immune checkpoint blockade therapies are administered via IV, typically every 2 to 3 weeks. Most IV antibodies can lead to acute immune reactions if given quickly, so they are commonly administered over 45 to 120 minutes at a time.

Because the purpose of these immunotherapies is to stimulate the immune system, it is generally recommended that immunosuppressive therapies such as steroids are not given while a patient is receiving an immunotherapy. While conventional cancer chemotherapy is also potentially immunosuppressive, it is still a matter of debate and controversy whether it is helpful or detrimental to administer agents such as checkpoint blockade therapies concurrent with standard chemotherapy. Clinical trials are seeking to answer this question.

Another issue that remains undefined is the optimal duration of immunotherapy. In some cases, the toxicity profile has limited the duration of these treatments, such as with ipilimumab, where treatment beyond four cycles is not typically feasible. Thus, treatment with this agent is intended to be capped at four treatments administered every 3 weeks. In contrast, many PD-1 and PD-L1 inhibitors are administered on an ongoing basis every 2 or 3 weeks, in the absence of significant progression or prohibitive toxicity. There may, however, be cumulative side effects, not to mention the inconvenience and expense of treatment given continuously for potentially well over a year. Although trials with some cytokines, CTLA-4 inhibitors such as ipilimumab, and also some PD-1 or PD-L1 inhibitors have ended treatment after a fixed duration or when patients have expressed concerns related to side effects, these agents have demonstrated very sustained responses/nonprogression that can be ascribed to the “memory” of the immune system. It remains to be determined whether patients who achieve good responses to some well-tolerated therapies such as PD-1 or PD-L1 inhibitors need to continue receiving these agents indefinitely, even if they can, to achieve the best results possible. It has been exciting to see responses that potentially last years, leading to questions of whether these responses may be indefinite and tantamount to cures for some patients. With benefits that may last for years, it will become important to clarify the required duration of treatment, so that patients are not obliged to receive ongoing, indefinite treatment that may not be truly necessary and may be associated with a greater risk of cumulative side effects, which are discussed here.

Importantly, patients receiving immunotherapies can demonstrate a distinct pattern of response compared with cancer treatments we have used for many years, such as standard chemotherapy and some molecular-targeted therapies. For decades, we have come to expect to see the most dramatic responses to our cancer treatments very early in the course of treatment, with diminished efficacy over time. Immunotherapies often demonstrate a different pattern of stable disease or even the appearance of enlargement of existing areas of disease, followed by delayed tumor shrinkage that may continue over many subsequent scans. This is sometimes visualized in the form of a “spider plot,” in which the tumor burden of a given patient is plotted over time as a line moving from a horizontal level up or down, going from left to right as treatment continues (Figure 2). The unusual pattern of initial enlargement of measurable areas of disease or sometimes even the appearance of new lesions after the start of immunotherapy followed by delayed response is known as pseudoprogression. When biopsied, these lesions actually demonstrate infiltration by lymphocytes, the cells of the immune system that mediate an anticancer immune response, which can precede the shrinkage or eradication of the cancer in that area. Presumably, each apparent new lesion that subsequently resolves represents an area that was a small cancer focus below the level of visibility on scans prior to immunotherapy, which then became newly visible after getting infiltrated with lymphocytes following the initiation of immunotherapy, only to shrink or resolve later.

Responses to immunotherapies may follow a delayed timeline and be preceded by a period of tumor enlargement and/or new lesions appearing. In this “spider plot”, lines from left to right track the change in the overall disease burden of patients on nivolumab, and the rise or fall in the line represents a relative increase or decrease, respectively, in the overall size of measurable “target” lesions on imaging for each patient.  These lines demonstrate the variability of the patterns seen, as well as the potential for prolonged response that may be of delayed onset. 1.	From: Topalian SL et al. J Clin Oncol. 2013;31(suppl: abstract 3002).

Figure 2: Responses to immunotherapies may follow a delayed timeline and be preceded by a period of tumor enlargement and/or new lesions appearing. In this “spider plot”, lines from left to right track the change in the overall disease burden of patients on nivolumab, and the rise or fall in the line represents a relative increase or decrease, respectively, in the overall size of measurable “target” lesions on imaging for each patient. These lines demonstrate the variability of the patterns seen, as well as the potential for prolonged response that may be of delayed onset.
1. From: Topalian SL et al. J Clin Oncol. 2013;31(suppl: abstract 3002).

While delayed responses and pseudoprogression are important possibilities to consider, to avoid discontinuing a potentially effective therapy too early, it is important to recognize that pseudoprogression occurs only in a minority of cases (perhaps 10%). Many experts recommend that, in the face of what appears to be progression on early scans, it is important to evaluate other factors that can help distinguish pseudoprogression from true progression, such as whether a patient is experiencing increasing pain, losing weight, or generally feeling well. In the absence of other signals of deterioration, it is very appropriate for patients to continue on immunotherapy and monitor their clinical response through scans over time. On the other hand, it is also important not to delay an appropriate change in treatment if a patient is experiencing escalating cancer-related symptoms along with ambiguous scan findings, in which case the patient is far more likely to be experiencing true progression rather than pseudoprogression.

This educational summary is intended for patients with cancer, their caregivers, and other interested non-clinicians, and is part of a broader educational platform focused on immuno-oncology, available at www.peerviewpress.com/e158

The Immunotherapy Primer for Patients is a collaboration between GRACE and PVI, PeerView Institute for Medical Education


Dr West

What Is Immunotherapy, and Why Pursue It? (An Immunotherapy Primer for Patients, Pt. 1)

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Immunotherapy has rapidly emerged as one of the most transformative influences on cancer care since the detection of a specific target with matched molecular therapies for many cancers. Antibodies against target receptors on cancer cells, such as rituximab (Rituxan) and trastuzumab (Herceptin), or against components of the cancer growth process, such as bevacizumab (Avastin), have been integral tools in treatment regimens for at least a decade. The mechanisms of action of these therapies involve passive processes that contribute the immune function directly to the host, who is essentially a bystander in the process. In contrast, an array of novel immunotherapy agents help regulate the vigilance of a patient’s own immune system to better channel its power to actively fight a cancer. These include vaccines to help stimulate the immune system directly, as well as factors that remove the body’s natural inhibitors of the immune system.

The immune system requires a delicate balance of vigilance against threats, whether cancer or infection, and controls to ensure that it does not become excessively sensitive and attack the body’s own cells—a process that causes auto-immune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Similar to a home security system, the immune system needs to be a regulated balance in which real threats raise an alarm, but harmless incidents, such as the wind blowing or a dog jumping on the couch, do not set it off. That regulation is a complex process of many stimulatory and inhibitory factors, and one of the ways in which cancer cells can evade destruction is lulling the immune system into inhibition using some key “checkpoint inhibitors” that mislead the immune system into believing that the cancer cells are “self.” Conversely, several of the most important new advances in cancer immunotherapy, also known as immuno-oncology, work by removing these blocks on the immune system and helping to raise the level of vigilance against the threat posed by the cancer.

Interestingly, a role for the immune system in cancer has been identified for more than a century, when an 1893 report* of tumors reduced by repeat injections of a virus gave the initial proof of a principle that is still widely practiced today: the local administration of bacillus Calmette-Guerin (BCG) into the bladder of patients with superficial bladder cancer can stimulate the immune system to eradicate the cancer. While patients with some cancers, such as kidney cancer and melanoma, have been identified as potentially having spontaneous tumor shrinkage or even eradication presumably caused by a patient’s immune function, relatively nonspecific stimulants of the immune system, known as cytokines, such as interferon and interleukin-2, have been shown to improve survival modestly or, rarely, more significantly. Unfortunately, these approaches are associated with such severe side effects that they have had very limited overall utility. But we have now entered a new era in which agents that remove the braking mechanism for the immune system can provide broad activity without very challenging toxicity.

There are two main classes of immune checkpoint blockade therapies that have entered into limited use in the practice setting, along with very extensive use in clinical trials. The first approach inhibits cytotoxic T lymphocyte–associated protein-4 (CTLA-4), which is a protein expressed on the surface of “helper” T lymphocytes that suppress an immune response to cancer cells, essentially functioning as an “off switch” for the immune system. Ipilimumab (Yervoy) is an antibody to CTLA-4 that removes that braking effect and can therefore release the immune system to combat certain cancers. Ipilimumab is typically given for four treatments and has been demonstrated to significantly improve response and survival in patients with metastatic melanoma compared with other treatment options.

Figure 1: Mechanism of Action of Checkpoint Blockade Therapies: This image is from a patient education video on immunotherapies for lung cancer, developed by the Society for Immunotherapy of Cancer (SITC). To learn more about how the novel checkpoint blockade therapies work, click the image.

The second class of checkpoint blockade therapies targets programmed cell death-1 (PD-1), a receptor on host T cells, or programmed death ligand-1 (PD-L1), its partner protein on the surface of some cancer cells. Activation of these receptors also leads to an inhibitory effect on the host immune function. Conversely, antibodies that block PD-1, such as nivolumab (Opdivo) or pembrolizumab (Keytruda),both now FDA approved as treatments for metastatic melanoma skin cancer, or those that block PD-L1, such as MPDL3280A or MEDI4736, can remove that suppressive signal and thereby activate the immune system to better recognize and attack the cancer (Figure 1).

All of these mechanisms of immunotherapy have demonstrated clinical activity in a range of cancer types as single agents. In addition, clinical trials are also testing the value of some of these different strategies employed as combinations. One such combination, the CTLA-4 inhibitor ipilimumab combined with the PD-1 inhibitor nivolumab, has been shown in early clinical trials in metastatic melanoma to lead to very encouraging response rates and survival results that eclipse the efficacy of either of these approaches alone.** Combinations of immunotherapies with established treatments such as standard chemotherapy or molecularly targeted therapies are also being pursued across a spectrum of cancer types and settings.

REFERENCES
* Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci. 1893;105:487–511.
** Wolchok JD et al. Nivolumab plus ipilimumab in advanced melanoma. New Engl J Med. 2013;369:122-133.

This educational summary is intended for patients with cancer, their caregivers, and other interested non-clinicians, and is part of a broader educational platform focused on immuno-oncology, available at www.peerviewpress.com/e158

The Immunotherapy Primer for Patients is a collaboration between GRACE and PVI, PeerView Institute for Medical Education

 

 


Dr West

Hospice is HELP: Avoid it at Your Peril

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I’m on call for my oncology group this weekend, and I’ve had the situation come up twice in less than 24 hours that a patient is in dire need of home-based symptom management, with plans for hospice just getting initiated in a mad scramble on a Saturday or Sunday.  In both cases, the patient is sick enough and far enough from the hospital that just evacuating them with a 911 call isn’t an effective way to solve the problem.  And so what could otherwise be a legal urgent delivery of pain medications to a hospice patient is a difficult night of toil and unnecessary suffering because there isn’t a mechanism to get medications or support for someone who will be enrolling on hospice tomorrow, after weeks of the patient and/or family resisting an appropriate and well-meaning recommendation to enroll earlier.

It’s a terrible shame that, in the US at least, hospice care is usually initiated at a point when death is just a few days or even hours away.  Too often it’s a race for hospice nurses to get to the patient in time to provide needed comfort and support in the last moments of a person’s life, after the patient and their family and friends have already struggled through the rapid changes and symptoms of dying.  If it isn’t “too little, too late”, it’s close.   But hospice teams can provide critical value and support if referrals are made long enough for the patients and families to develop a good relationship with the folks from hospice.

This seems to stem from a tendency to want to deny, to wish away, any acknowledgement that a person’s disease is terminal (sometimes by doctors, sometimes by families, sometimes by the patient himself or herself), as if avoiding the subject and the needed action will keep it from happening.  But a person will continue to decline, death will unfortunately ensue, and the only consequence of postponing to the point of critical distress and unavoidable recognition of the reality is that everyone experiences far, far more suffering and chaos than they would have otherwise.

It’s understandable that people don’t want to embrace a sad reality when death is becoming close enough to anticipate and plan for. In truth, death is rarely a beautiful experience, but it can often go from being terribly challenging and unpleasant to minimally so when there are people nearby who are equipped and motivated to help, and who have the experience to guide people.  I think it’s a very sad, regrettable mistake to not avail themselves of that help until it’s an absolute crisis.  


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