Published on November 4, 2024 10:50 PM GMT
Metastatic Cancer Is Usually Deadly
When my mom was diagnosed with cancer, it was already metastatic; her lymph nodes, said the nurse, “lit up like a Christmas tree.”
Most people with any kind of metastatic cancer — that is, instead of a single tumor, a cancer that has spread to multiple locations in the body — die within the year.
You’ve probably heard of people “surviving” cancer, saved by chemotherapy or surgery or radiation or a new high-tech drug.
If you know more about cancer, you’re aware that “survival” is relative; when there are no observable signs of cancer, you’re considered to be “in remission”, but you’ll always be at elevated risk of the cancer coming back. Still, years-long or even lifelong remissions are possible, and for some cancer types are even now the norm after treatment.
Mostly that’s for cancers caught early, though. Once the cancer is metastatic1, lasting remission is uncommon.
…So Eradicating Metastatic Cancer is Especially Impressive
There are cases where metastatic cancers go into complete remission, however. They’re not common, and it’s an exceptionally high bar for a cancer treatment to clear.
Historically, this was usually only possible in cases where there was a strongly immunogenic cancer (like melanoma) and one of the older forms of immunotherapy was available (like injecting tumor-infiltrating lymphocytes, or a toxic pro-inflammatory signaling agent like IL-2, directly into the tumor to stimulate a strong immune response.)
Now, though, we’re living in a golden age of immunotherapy, and seeing a variety of new approaches to cancer treatment reach the clinic — so it’s worth looking back over the past 15 years to see what treatments have succeeded on the “hardest of hard mode” tests: effectiveness on metastatic (or refractory/relapsed) cancers.
Methodology
I looked through Google Scholar using search terms like “metastatic” and “complete response.”
In cancer clinical trial lingo, a “partial response” refers to some shrinkage of the tumor(s)2, or (in hematological cancers), a decrease in the number of cancer cells.
A “complete response” refers to the total elimination of (detectable) tumors or cancer cells.
Every remission requires a complete response; but it’s possible for a complete response not to last very long before the cancer comes back.
I included studies in which >20% of cancer patients with metastatic solid tumors, or relapsed/recurrent hematological cancers, had complete responses to therapy.
This includes a lot of uncontrolled studies, and some case studies.
Obviously, if a single patient in a case study has a complete response that’s technically “100%”, but that shouldn’t give you the impression that the true complete response rate for that treatment is anywhere near 100%. Case studies are selected for being remarkable. Still, I included n=1 case studies because they’re intriguing and instructive, in a separate section from n>1 case series and studies.
Most studies included here are uncontrolled — they’re retrospective analyses of cases at one or more clinics, or they’re single-arm studies, that tell you the performance of a given treatment but don’t compare it to a “control.”
Because spontaneous regressions of metastatic cancers are almost unknown, virtually any case of a “complete response” from a treatment indicates the treatment works better than no treatment at all, even in the absence of a control group. On the other hand, without a control group it’s much less certain whether some New Treatment + Baseline Treatment is better than Baseline Treatment alone, where the “baseline” standard of care would differ a lot based on the exact cancer type and patient characteristics. Oncologists rarely give any cancer patient literally no treatment unless the patient insists.
Single-Patient Case Studies
Here’s a link to the spreadsheet.
Stats
84 cases, published between 2010 and 2024
33% gastrointestinal cancers, 20% other cancers, 12% kidney cancers, 9% lung cancers, 8% breast cancers, 6% skin cancers
42% include an immune checkpoint inhibitor, 30% include chemotherapy, 26% include other targeted therapy, 9% include radiotherapy, 7% include cell immunotherapy
Takeaways
The newish immune checkpoint inhibitor drugs (nivolumab, pembrolizumab, ipilimumab, and others) are clearly the most common category of treatment in this set of case studies.
These drugs “unblock” the immune system by inhibiting the “checkpoint” genes PD-1 and CTLA4 (or their receptors), allowing the immune system to more effectively attack cancers. This mechanism is what won James Allison and Tasuku Honjo the 2018 Nobel Prize, and kicked off the cancer immunotherapy era we’re living in.
Over the past two decades, they’ve been FDA-approved for a really wide range of solid tumor types and produce tens of billions of dollars a year in revenue. They’re among the biggest success stories of 21st-century oncology.
Older methods (chemotherapy, radiotherapy, growth-factor-targeting drugs, hormone therapy for hormone-dependent cancers), alone or in combination, have also been observed to cause complete responses in cases of metastatic cancer.
One unusual example is a case where restriction of the amino acid methionine, via a low-methionine diet and a methionine-depleting enzyme, caused a complete response in metastatic breast cancer; some cancers are unusually methionine-dependent, a phenomenon known as the Hoffman Effect.
Another weird example is a case where heat-killed bacteria, used as an immunostimulant alongside chemotherapy, caused a lasting remission in metastatic pancreatic cancer (which is usually incurable).
Larger Studies and Case Series
Here’s a link to the spreadsheet.
Stats
59 studies, published between 2010 and 2024
39% skin cancers, 26% hematological cancers, 10% breast cancers, 8% lung cancers
29% include cell immunotherapies, 19% include immune checkpoint inhibitors, 19% include other targeted therapies, 15% include other immunotherapies, 8% include chemotherapy
Takeaways
CAR-T and other cell immunotherapies really, really work on refractory/relapsed hematological cancers.
Complete response rates are often >50%, which was unheard of before the 21st century. This is genuinely awe-inspiring.
These are treatments where immune cells — usually the patient’s own — are extracted, sometimes genetically modified or screened to target the patient’s cancer type, and reintroduced to attack the cancer.
CAR-T is mostly — not entirely — used for leukemias and lymphomas, but there’s also an incredible 2011 study where it was used to produce 27% complete responses in pediatric brain cancers. Solid tumors, here we come!
Immunotherapies for metastatic melanoma, particularly including the newer immune checkpoint inhibitors (nivolumab, ipilimumab), also perform well.
Complete response rates tend to be in the 20-30% range in the successful trials.
While immune checkpoint inhibitors can work on lots of things, they’re most effective on highly immunogenic cancers like melanoma.
Treatments that physically localize cancer-killing treatments to tumors (intralesional IL-2, isolated limb perfusion with TNF-alpha, intratumoral electrochemotherapy) are only possible in special cases but seem to have exceptionally high success rates.
These chemicals, several of which are produced by the innate immune system, are too toxic to spread throughout the bloodstream, but if you can confine them to the tumor, you can kill the cancer without killing the patient.
Usually intralesional/intratumoral approaches are only feasible for skin metastases, or for tumors exposed during surgery but impossible to surgically remove.
This is intriguing as an area of research to expand on — to what extent can we develop delivery mechanisms to physically localize toxins to a tumor when it’s not so conveniently in reach?
A couple of uncommon or new approaches have at least one successful example:
oncolytic viruses
i.e. viruses that attack cancers
antibody-drug conjugates
i.e. a cancer-killing drug attached to an antibody that targets the cancer
peptide vaccines
i.e. enticing immune cells to attack cancers by administering the antigens that activate them
proteasome inhibitors
i.e. drugs that prevent cells from disposing of defective proteins, leading to cell death
high-intensity focused ultrasound
i.e. ablating tumors by ultrasound-induced heating
What are the takeaways, for patients, researchers, and the general public?
First of all, this is real progress, not stagnation. I looked for examples of >20% complete responses in metastatic cancers a decade ago, and there’s a lot more out there now than there used to be, mostly due to the results from the new immunotherapies coming in. In some types of advanced cancer, lasting remissions are now a real possibility for nontrivial numbers of people.
Secondly, I think there’s probably a lot more room to improve and expand upon these immunotherapy successes. There are a lot of variables to tweak. Remember that it took a few decades between the first discovery of chemotherapy in the 1940s to the development of effective chemo regimens for solid tumors like breast cancers in the 1970s. Figuring out drug cocktails, dosing strategies, etc, makes a big difference in effectiveness and applicability. Now notice that now, unlike in the mid-20th century, we have the whole molecular biology and immunology toolbox to play with. The range of possible “CAR-T therapies”, for instance, is almost infinite. The optimization process is not done.
I have a good feeling about “old-fashioned” immunotherapy angles — oncolytic viruses, heat-killed bacteria, innate-immune inflammatory toxins like IL-2 and TNF-alpha. This zone was where researchers first started to notice that the immune system might fight cancer; these are simpler, cruder techniques with fewer moving parts than the new hyper-personalized stuff.
And, of course, antibody-drug conjugates are going to hit the clinic in much bigger numbers in the coming years, and we should be pretty hopeful about them; it’s yet another way of putting your cytotoxic drugs where you want ‘em and not where you don’t.
Hematological (=blood) cancers are already disseminated throughout the bloodstream rather than lumped up in tumors, so “metastatic” isn’t really a meaningful term there. But an equivalent concept is “refractory” or “relapsed” hematological cancer — a cancer that keeps coming back after multiple rounds of chemo. Like metastatic cancers, refractory/relapsed hematological cancers usually have survival times measured in months.
in the often-used RECIST criteria, a partial response requires at least a 30% decrease in the sum of the diameters of all tumors.
Discuss
