The Cat in the Bag: Combination Therapy and Complete Metastatic Ablation

In prior posts of this blog, we have approached the story of metastatic cancer from a number of different angles. We discussed what metastatic cancer is, and why it is a deadly disease. We discussed in depth that drugs such as chemotherapy and immunotherapy are the most common treatment for metastatic cancer because they can attack both visible tumors and microscopic cancer cells. We also reviewed the numerous, devious ways that cancer can escape these same drug therapies. Finally, the last two posts introduced a different class of treatment: Radiotherapy. Because external radiotherapy consists of a beam of fast-moving particles that is directed only at visible tumors, we discussed that its role in metastatic cancer has been mostly limited to the palliative situations where a single, troublesome tumor is treated to relieve symptoms. Said differently, a beam directed only at visible tumors should not be able to address the microscopic cancer cells floating elsewhere beyond the beam’s reach.

In this post, I want to tie all of these different threads together into a single provocative question: Is there an opportunity to improve metastatic cancer treatment by combining radiotherapy with drugs in a more definitive way? In other words, can a marriage between drug therapy and definitive – not palliative – radiation therapy create synergies that overcome the individual deficits of each treatment by itself? I think the answer is “Yes” and there is already emerging evidence from clinical trials that lends support to this conclusion.

To think about the power of combination therapies in metastatic cancer, we can start by taking a step back from the stage 4 setting and reviewing our understanding of stage 3 cancer. Stage 3 cancer means that a tumor has spread extensively in the local and regional anatomy but has not yet metastasized to distant organs. One example is a lung cancer starting out in the right upper lobe that has spread to lymph nodes in the middle of the chest. Another example is a breast cancer which has spread from the breast to the lymph nodes in the armpit and above the collarbone. Decades of study have revealed that cancer at this stage usually consists of a large, visible component in addition to microscopic cells that have already reached the blood circulation, bone marrow, and lymphatic channels. In fact, although this was not possible in prior eras, we can now detect these microscopic cells using simple blood tests in some cancer types. The main difference between these stage 3 cancers and stage 4 cancers is that in the latter, one or more of these microscopic cells have become macro-scopic; that is, one or more microscopic cells have landed in a distant organ and have grown a large enough colony to become visible.

What kind of treatment approach works best in stage 3 cancer? It turns out that many clinical trials have attempted to answer this question since the 1960s, and although there are exceptions to nearly every rule in medicine, the general trend in these studies is clear. Stage 3 cancer patients do best when we combine a local treatment (surgery, radiation) that kills or removes the visible tumor with a drug therapy (chemotherapy, immunotherapy) that addresses the microscopic cells that are elsewhere. In stage 3 breast cancer, this usually looks like an aggressive local treatment of surgery and radiation directed at the affected breast and axilla (armpit) followed by chemotherapy and/or hormone therapy. In stage 3 prostate cancer, local radiation or surgery is typically used to either ablate or remove the prostate, and then anti-androgen drugs are given afterward to starve remaining microscopic cells of the testosterone they need to survive.

In fact, this combination of local therapy and drug therapy is used in nearly all the common solid tumors that have reached stage 3, including colon cancer, lung cancer, pancreatic cancer, esophageal cancer, and so on. However, in the not-too-distant past, there was a notable challenge to this paradigm, which I have always considered one of the most interesting cancer clinical trials ever done (1). This study – which was conducted in Sweden in the late 1990s and early 2000s – took patients with non-metastatic prostate cancer at high risk for microscopic cancer cells beyond the prostate and asked, “Does local therapy directed at the prostate add any benefit to drug therapy by itself?” The hypothesis was that effective drug therapy would control both the visible disease in the prostate and the invisible microscopic disease throughout the body, and so therefore, radiation to the prostate might be unnecessary. Another way of thinking about the hypothesis is that the same “cat is already out of the bag” argument was being made then against local therapy in stage 3 cancer that we hear now when discussing local therapy in stage 4 cancer.

The investigators tested their hypothesis by randomizing the study participants to receive either drug therapy alone or drug therapy combined with radiation to the prostate. The results of the study were stunning. At 10 years, about 75% of the men who received only drug therapy had a progression or relapse of their prostate cancer, compared to only 25% of the patients who received combination therapy. Likewise, about 1 in 4 men who received drug therapy alone had died of prostate cancer during the 10-year follow-up period compared to only 1 in 9 men who received the combination of radiation and drug. Such an extreme difference in outcome between two groups in a clinical trial is incredibly rare in oncology, and to this day, this study remains one of the most lopsided results favoring one intervention over another in the history of cancer clinical trials. Following publication of this study, there was little doubt that a combination of radiation and drug therapy was the standard of care for best outcomes for prostate cancer that had advanced to what we call stage 3 disease in today’s language.

Although this study could not be clearer that drug therapy alone was inferior to combination treatment, let’s remember that the study was conducted by thoughtful, well-intentioned individuals. When the trial started, the idea of using drug therapy alone in one of the two study groups was felt to be reasonable and ethical, and the investigators may have hoped that drug therapy alone would do well enough to spare patients the inconvenience and side effects of undergoing a local therapy too. What can we learn by re-examining these thought processes, which ultimately were misplaced?

For one thing, the hope of a single drug doing all the heavy lifting in treating advanced stages of cancer, including stage 3 and stage 4 disease, is likely to fall short. This should not be surprising since in a previous blog post we discussed all the ways that cancer can escape the effects of drug therapy given enough time. The second assumption we should challenge is the old metaphor of dismissing local therapies like radiation once “the cat is out of the bag.” Perhaps the metaphor needs to be updated to acknowledge that the cat never leaves the bag; its kittens do. Therefore, if the cat – the visible component of the overall cancer burden — is still “in the bag” as it was in these prostate cancer patients, then there may be a benefit to eradicating this large portion of the disease with an effective local therapy and letting the drug therapy address the microscopic leftovers (the kittens).

Now, let’s extend this metaphor to go from stage 3 to stage 4 cancer…with all due apologies to cat lovers! Let’s start with the original cat in the bag. Let’s also assume that a couple of its kittens have grown up to be young adult cats too and that they have kittens of their own. This metaphor describes the early stage 4 situation where we have the original tumor in the prostate (cat in the bag), a couple of visible metastases elsewhere in the body (young adult cats), and invisible microscopic disease elsewhere (kittens roaming around). Can we still expect a benefit if we use a combination approach of local and drug therapies? Or is this the point at which the situation is too far gone for a local treatment like radiation to have an effect?

It turns out that this question in prostate cancer has also been answered by another randomized clinical trial that was published just this year (2). In this clinical trial from the United Kingdom, about a thousand patients with prostate cancer fitting the description above were randomized to receive either drug therapy by itself or drug therapy with radiation directed at the prostate, just like in the Swedish stage 3 study. Using our metaphor, in one group the original cat, the young adults, and the kittens were all treated drug therapy, which consisted mostly of hormone drugs with some also receiving chemotherapy. In the other group, the drugs were the same, but the treatment directed at the original cat (not the young adult cats) also included radiotherapy.

Echoing the Swedish study, patients who fit the description above (prostate tumor, a small number of metastases, and microscopic disease) did better if they were in the group that received radiotherapy to the prostate in addition to drug therapy. Both the rate of relapses and the rate of death were lower in patients treated with a combination approach. This result made a lot of waves and genuinely surprised a lot of prostate cancer specialists. After all, in the Swedish stage 3 study, radiation directed at the prostate was covering *all* of the visible disease. In this stage 4 study, it was truly unexpected to discover that radiation directed only at *some* of the visible disease (just the grandpa cat in the prostate) could contribute to a better outcome.

This remarkable result has prompted the oncology community to push the boundary even further. The very same group that conducted the stage 4 study above is moving on to the question that naturally follows: Can we push survival rates in stage 4 prostate cancer even higher by treating *all* of the visible disease with radiation rather than just the visible disease in the prostate itself? Going back to our metaphor, this means radiating the cat in the bag and, now, also radiating the young adult cats. If this study turns out to be positive — meaning that the experimental arm outperforms the control arm of usual standard of care — then we will get to a place where stage 4 patients are treated using the same combination of drug therapy and local therapy directed at all visible disease that stage 3 patients routinely receive today. Said differently, such a result would eliminate the bright line that has separated how we treat stage 3 and stage 4 cancer.

This idea of ablating all of the visible disease throughout the body in a stage 4 cancer patient needs a label, so let’s call it “complete metastatic ablation” or “CMA” for short. It’s hard to overemphasize what a radical shift in thinking CMA represents. As we have discussed, the very concept challenges deeply held assumptions around how we have understood and treated metastatic cancer for generations. And one can be forgiven for wondering whether there will be some stage 4 patients who are genuinely cured of their disease with a combination approach, just as in stage 3 cancer.

Although these treatment combinations are very exciting, it is too early to celebrate because the evidence to support CMA continues to mature and accumulate. Nonetheless, there is a palpable anticipation for the results of new trials that test CMA in both prostate cancer and other stage 4 cancers. Importantly, we owe a tremendous debt to the patients who enroll in these studies, without whom we could neither ask nor answer these critical questions.

Refs.

(1)  Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JÅ, Tasdemir I, Hoyer M, Wiklund F, Fosså SD. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. The Lancet. 2009 Jan 24;373(9660):301-8.

(2)  Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, Ritchie AW, Attard G, Chowdhury S, Cross W, Dearnaley DP. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. The Lancet. 2018 Dec 1;392(10162):2353-66.