Is there an “oligometastatic state” for prostate cancer?

The concept of an “oligometastatic state” is based on the idea that there is an “early advanced” stage of cancer during which metastases are few in number and are in some way different from metastases that develop later. It also means that there are no micrometastases in systemic circulation (in bone and lymph) and/or in reservoirs like bone, nerve cells, lymph nodes, and other organs. If such a state exists, the cancer can — at least theoretically — be picked off, like dandelions in a lawn, and the person can be cured.

The alternative concept is that cancer spread is always polymetastatic. Thousands of cells are released from the primary tumor. They find their way to sites where they change the tissue they land in, making it amenable to future growth. This is called the “seed and soil” hypothesis. A metaphor might be mushrooms growing at the base of an oak tree. The mycelium extends everywhere throughout the soil and into the roots of the tree. Occasionally, a mushroom crops up. You can pick all the mushrooms you want, but the fungus is never destroyed. There is no way to destroy the fungus short of destroying the roots of the oak tree and sterilizing the soil. This is what “systemic” means when we refer to metastatic forms of cancer as a systemic disease.

It is well known that tumor cells must undergo a genomic change called epithelial-to-mesenchymal transition (EMT) before they are capable of traveling and living outside of their original environment. Metastasized cells do not look like or behave like the original tumor cells in its original tissue; they are phenotypically different.

Are all cancers alike?

There are certain, specific “hallmarks of cancer.” To qualify as a cancer, a tumor must be malignant, destroying healthy tissue. Most cancers multiply rapidly, losing the ability to self-destruct when its DNA goes awry (apoptosis). They are usually immortal and evade destruction by the immune system. They can travel from one place to another in the body. Solid tumors change the structure of their host tissue and usually generate their own blood supply and nerve innervation (see cancer as a tissue-based disease).

But all cancers are different. Unlike most other solid tumors, prostate cancer is usually, initially multifocal within the prostate. While some cancers can be cured by surgically removing just the original tumor, the whole organ must be removed (or irradiated) for prostate cancer. Foci may be a centimeter or more apart, so it is known to have a strong signaling mechanism that changes host tissue. It has a predilection for lymph nodes and bone, where it usually creates osteoblastic lesions (bone overgrowth). It is activated by an androgen receptor, which eventually becomes impervious to androgen deprivation. Tumors tend to be hypoxic, and have low immune-cell infiltration. They are relatively radioresistant, and are not appreciably killed off by non-taxane chemotherapy. There are multiple growth pathways — block one and others predominate. It is also abnormally slow growing. It may take many years for EMT cells to originate. The time from the first detectable metastasis to the second may be years apart. In contrast to other cancers, metastatic prostate cancer cells generate energy for reproduction from lipid metabolism at first. Many years later, glycolysis may come to predominate (as it does in most other cancers).

To determine if there is such a thing as an “oligometastatic state” it is therefore necessary to show that such a state exists for every kind of cancer. The first step is to show plausibility. With high throughput sequencing it may be able to distinguish the genomics of early metastases from later ones. However, because genetic breakdown is a characteristic of cancer, it is also necessary to show that the early clones are phenotypically different from later clones. If early clones lack the ability to disseminate and prepare the “soil” for metastatic progression, that would create a case for an oligometastatic state.

It is also necessary to show that such a state exists for every type of cancer, or at least to find the cancers in which such a state exists. One cannot just assume that all cancers are alike in this regard.

The SABR-COMET Phase II Trial

Palma et al. recruited 99 patients with oligometastatic cancers of different types at 10 hospitals in Canada, Scotland, Australia, and the Netherlands between 2012 and 2015. Patients had at least one and up to five metastases, and were randomly assigned to high-intensity metastasis-directed radiotherapy (SABR or SBRT) or systemic standard of care. After 2 years median follow-up, there were:

  • 66 patients in the SABR group
  • 33 patients in the control group
  • Most patients had between one and three metastases:
    • 94 percent in the control group
    • 93 percent in the SABR group
  • The SABR dose was most commonly 35 Gy in 5 treatments,  60 Gy in  8 treatments, and 54 Gy in 3 treatments
  • 12 percent received additional SABR for disease progression

After a median follow-up of 25 to 26 months:

  • Overall mortality rates were 36 percent for the SABR group and 48 percent for the control group (hazard ratio [HR] = 0.75)
  • Median overall survival was 41 months for the SABR group and 29 months for the control group (HR = 0.57; p = 0.09).
  • The rates of metastatic progression were 39 percent in the SABR group (mostly new metastases) and 61 percent in the control group (all new metastases).
  • Adverse events  of Grade ≥2 occurred in 29 percent of patients in the SABR group and 9 percent of patients in the control group.
  • 5 percent of patients the SABR group died as a result of treatment: from radiation pneumonitis, pulmonary abscess, and subdural hemorrhage after surgery to repair a perforated gastric ulcer

The authors are cautious about the toxicity, but optimistic that their study provides proof of an “oligometastatic state.” They had originally prespecified that anything above 80 percent confidence in a survival difference in this Phase II trial would be sufficient to expand to a Phase III study. Consequently, they have already announced two Phase III randomized clinical trials: one for men with one to three metastases; another for for men with four to 10 metastases.

However, …

Skewed Distribution of Cancers Can Account for the Purported Benefit

The distribution of cancer types was vastly different in the SABR and the control groups of the SABR-COMET Phase II trial.

Metastatic colorectal cancer, which has a 70 percent 2-year mortality rate, was twice as likely to appear in the control group as the SABR group; while metastatic prostate cancer, which has a 10 percent 2-year mortality rate was more than three times as prevalent in the SABR group, as shown in the first of the tables below:

Reference sources: 1. Lobbezoo et al. (2015). 2. Oh et al. (2007). 3Cetin et al. (2011). 4Parker et al. (2018).

This skewed distribution can clearly account for almost all of the difference that the authors attribute to a treatment effect:

I believe the authors of the study have erred in accepting the results — even with the prespecified 80 percent confidence for forging ahead with a Phase III randomized trial. The treatment effect, if any, is so small that their Phase III trials, as specified, are insufficiently powered to detect a treatment effect. They do not propose to stratify by type of cancer. Also, much longer follow-up is needed for prostate cancer.

On top of that, they have not made the case for an oligometastatic state, which would have to be true for every cancer type and not just a weighted average sum of them. They would also have to include genomic and phenotypic analysis of biopsied tissue when there are both few metastases and many in order to demonstrate plausibility.

Patients should note the mortality rate of metastases attributable to SABR treatment. There is little risk in irradiating metastases occurring in safe locations, like the pelvic bones. There may be unacceptable risk in irradiating metastases near the heart, lungs, or digestive tract. Since there is no evidence that metastasis-directed therapy for prostate cancer improves survival, patients should not avoid systemic therapy (for which there is convincing evidence). Patients who are interested in SABR of metastases should talk to experienced radiation oncologists in large tertiary-care facilities.

Editorial comment: This commentary was written by Alan Edel for The “New” Prostate Cancer InfoLink.

2 Responses

  1. Before everyone starts to say that “but oligometastatic radiation has worked for me”, your sitemaster would carefully point out that Allen’s analysis does not deny that possibility — for the simple reason that some men with one or two evident, slowly growing metastases can quite certainly be placed back into long-term remission as a consequence of such therapy, especially if their targeted radiation was being given in concert with some type of systemic therapy.

    The issue that Allen is addressing is a different one, which is whether for the vast majority of men with early metastatic prostate cancer (in a hypothetical “oligometastatic state” as described in his commentary) one could reasonably expect to observe a prostate cancer-specific survival benefit from targeted radiation therapy without adjunctive, systemic therapy of some sort.

    Your sitemaster has for some time been (at best) somewhat disturbed by the very structure of the COMET-SABR Phase II trial. In his mind it is rather like putting different amounts of four different foods into the bowls for 50 different hungry dogs at breakfast time and then, when 95% of the dogs wolf down all the food, claiming that they liked all of the foods as much as each other. Anyone who has spent much time around dogs will recognize the fallacy of that claim!

  2. Given that — as stated — prostate cancer differs in many respects from other solid tumors, it is hard to understand the point of the COMET-SABR trial that lumps several diverse types of cancer into one trial.

    The number of published studies on our cancer are rather overwhelming — more than 5,000 per year. The structure and conclusions of too many are underwhelming! The analyses on this blog do help to separate the “wheat from the chaff”.

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