Sledge, George W. Jr., MD
GEORGE W. SLEDGE JR., MD
Every year the ASCO meeting seems to revolve around a few themes, or sometimes memes, that define where we are at and where we are going as a profession. This year's meeting was no different. Outgoing President Sandra Swain, in her presidential address, presented the meeting's dominant theme: ASCO as ISCO. A for American, I for International, a reflection of the global nature, not just of our professional society, but also of our scientific collaborations and our collective public health task.
ASCO, to its credit, is doubling the resources it devotes to international activities. Given the large number of ASCO members hailing from outside the U.S., and the even larger percentage of international attendees at the meeting, this is certainly appropriate. But the larger reason is the growing cancer burden around the world, a burden that we should take on, if only by providing educational and scientific support.
The plenary session both reinforced “ASCO as ISCO” and provided important nuance. In the United States, cervical cancer belongs to the land of rare cancers: it is not a major public health challenge, given the ubiquity of screening and early intervention. In contrast, it is a major public health issue in large portions of the globe, where inadequate health care systems doom large numbers of women to untimely and miserable deaths.
For this reason if no other it was a delight to see a plenary session lecture emanating from India, where a randomized clinical trial demonstrated that visual inspection of the cervix with acetic acid, performed by a non-physician health care worker, was an effective and inexpensive means of screening. The authors estimated that this approach could save 73,000 lives per year on a worldwide basis.
I loved everything about this study. This approach has a potentially greater public health impact than anything I have seen presented at the annual meeting for years. The intervention is low-tech, cheap, and widely available. The trial was funded by our National Cancer Institute: if ever federal government spending for clinical trials needed justification (and, alas, it does, even within the NCI), this trial should provide validation for decades to come.
But the plenary session was not finished with cervical cancer. A separate randomized Phase III trial (also NCI-funded) examined the role of the antiangiogenic agent bevacizumab in advanced cervical cancer, and demonstrated a 3.7 month overall survival advantage. It was, as both the presenter and the discussant pointed out, the first ray of hope for metastatic cervical cancer in many a year.
There was just one false note in this presentation, or so it seemed to me. The presenter, in his conclusion, opined on the need to find a way of making this treatment approach available on a worldwide basis. This remark was clearly well intentioned, attempting to address the disparity between high-income health care systems and the many low- or middle-income countries where modern cancer care is unavailable. ASCO as ISCO, right?
And yet, as I have said, it came across as wrong-footed. If vinegar can save 73,000 lives per year at trivial cost, why on earth would an impoverished health care system consider paying for a pricy biologic, requiring highly trained health care professionals, and curing no one?
I know I wasn't the only one to be struck by the apparent disconnect between these two plenary lectures, and by the stark contrast between the price: life-years saved of the two interventions. Several of my colleagues mentioned it to me as well. The cervical cancer theme became an ASCO meme, or a collection of related memes: the need for early as opposed to late interventions, the value of population-based public health measures as opposed to individual treatments, and the need for us to take a serious look at which therapeutic interventions provide the most bang for the buck.
Add to the vinegar story (a low-tech solution) the success of HPV vaccines in preventing cervical cancer, and the story expands a step further. Prevention, added to early detection, should be our goal for cervical cancer.
Should it be the goal for every cancer? That is the basis for a large number of arguments, as the screening mammography quagmire suggests. Early detection isn't always cost-effective, doesn't always save more lives than advanced treatment, and doesn't always have solid scientific underpinnings. Prevention techniques require huge trials with long follow-up, and even if the intervention is successful (tamoxifen in breast cancer) it may not be used.
But for cervical cancer there is no question: early detection and prevention work. They save lives, and do so at an acceptable price. Late therapeutic interventions (chemotherapy, and now antiangiogenic therapy) cost more, require higher levels of technology and health care personnel, and don't cure anyone.
Again, I don't mean this to sound like an attack on the bevacizumab trial. This trial was a success. It is a randomized controlled trial with a statistically significant improvement in overall survival, in a disease where nothing positive has happened for a very long time. Most patients would happily take an agent that extended their life by several months, particularly an agent that is not particularly toxic.
And certainly it is a false dichotomy to say that we should save lives through prevention or early detection, but not prolong the lives of patients with advanced disease. I want us to do both, and certainly as a clinical trialist I would have been delighted to present a positive Phase III trial at my society's premiere event.
But the two trials showed the difference between what medical oncologists consider important (introducing new targeted therapies that improve outcome for patients with advanced disease) and what rational health care systems consider cost-effective and valuable. The difference between the two is rarely thrust in our faces as it was by the plenary session, but it is always there in the background.
Should we spend money on smoking cessation, on CAT scans for smokers, or for therapy for Stage IV adenocarcinoma of the lung with the latest targeted ALK inhibitor? All of these approaches “work,” depending on what you mean by “work,” but they all mean something different, and all require something different of the health care system in terms of access, expense, and ultimate value. The answer different systems will come to will depend on economic and political calculations as much as medical and scientific formulations.
The other emerging theme at ASCO involved immunotherapy. Here, as two years ago, melanoma led the way. If you had told me a few years ago that I would soon attend an ASCO meeting where the breast cancer researchers were bored to tears, while the melanoma docs walked around with goofy smiles on their faces as new drugs rained down on them from the Pharma heavens, I would have thought you nuts. But this has come to pass, not once but twice in the past three years.
The star here was anti-PD-1 therapy. Tony Ribas of UCLA presented the results of a study with lambrolizumab in advanced melanoma, and showed an overall response rate of 38 percent, with many durable responses. Jedd Wolchok of Memorial Sloan-Kettering presented a combination of the anti-PD-1 agent nivolumab with ipilimumab, and demonstrated responses in more than half of treated patients. The anti-PD-1 drugs look like stars: less toxic than ipilimumab, combinable with other agents, employing a novel target, and exportable to other disease types.
Cancer immunotherapy has finally arrived, after decades of false starts. Future ASCO meetings will see a flood of Phase III trials with these agents, alone or in combination with other immunotherapeutics and targeted therapies.
One gets the real sense from these studies that melanoma has turned the corner and headed off into a new and quite promising direction. But even more, immunotherapy is here to stay, and oncologists will need to dust off their old textbooks and learn the mysteries of CTLA-4, PD-1, PDL-1, Tregs, and other terms we have forgotten in the years since medical school. Or, in my case, learn for the first time, since these pathways were undiscovered when I was in medical school. But I age myself.
As always I had two feelings about ASCO: anticipatory exhaustion as my plane landed in Chicago, and delight at learning new things and seeing old friends. I routinely feel, on leaving the meeting, that I belong to a vibrant community of dedicated researchers and physicians. That sense of community, that belief in progress, brings me back year after year.
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