Monday, April 29, 2019

Is there an oligometastatic state for prostate cancer?

The concept of an "oligometastatic state" is that there exists an early stage where 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 in reservoirs like bone, nerve cells, lymph nodes and other organs. If such a state exists, the cancer can 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 "seed and soil." 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.

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 in its original tissue; they are phenotypically different.

Are all cancers alike?

There are certain "hallmarks of cancer." To qualify as a cancer, it 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. 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 originally multifocal in the prostate. While some cancers can be cured by surgically removing 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 signalling 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. Unlike other cancers, prostate cancer metastatic 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.

Iyengar et al. reported the results of a small trial where 14 patients with non-small cell lung cancer (NSCLC) with a small number of distant metastases were treated with SBRT to the lung and distant lesions ("consolidative therapy") and chemotherapy. 15 patients only received chemo. There was a significant increase in progression-free survival: 9.7 months vs 3.5 months. Larger trials (NRG LU002 and SARON) will investigate overall survival.

(update 12/6/23) NRG LU002 will not move to a Phase III trial because the Phase II Progression-Free Survival failed to meet its prespecified goal.

(update 6.2.22) Steven Chmura reported at the 2022 ASCO meeting (J Clin Oncol 40, 2022 (suppl 16; abstr 1007) that the randomized trial (NRG BR-002) of SBRT (+ standard of care (SOC)) to oligometastatic breast cancer failed to slow progression or increase survival over SOC alone. There were 125 patients (65 SBRT+SOC, 60 SOC). An expanded trial was canceled due to futility.  Clearly then, there is no oligometastatic "state" that applies to all cancers.

The SABR-COMET Phase 2 Trial

Palma et al. recruited 99 patients at 10 hospitals in Canada, Scotland, Australia and the Netherlands from 2012-2015. Patients had 1-5 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 had 1-3 metastases: 94% in the control group, 93% in the SABR group
  • SABR dose was most commonly 35 Gy in 5 treatments,  60 Gy in  8 treatments, and 54 Gy in 3 treatments
  • 12% received additional SABR for disease progression

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

  • Overall mortality was 36% for SABR, 48% for control (Hazard Ratio = .75)
  • Overall survival (median) was 41 months for SABR, 29 months for control (Hazard Ratio = 0.57; p=0.09) Note: they prespecified that anything above 80% confidence would be sufficient to expand to a Phase 3 study.
  • 39% had metastatic progression in the SABR group, mostly new metastases
  • 61% had new metastases in the control group
  • Grade ≥2 adverse events: 9% in the control group, 29% in the SABR group
  • 5% of the SABR group died as a result of treatment: radiation pneumonitis, pulmonary abscess, and subdural hemorrhage from 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 have already announced two Phase 3 randomized clinical trials for people with 1-3 metastases and 4-10 metastases.

Skewed Distribution of Cancers Accounts for the Purported Benefit

The distribution of cancer types was vastly different in the SABR and control groups. Metastatic colorectal cancer, which has an 70% 2-year mortality rate, is twice as likely to appear in the control group as the SABR group; while metastatic prostate cancer, which has a 10% 2-year mortality rate is more than 3 times as prevalent in the SABR group. This skewed distribution accounts for almost all of the difference that the authors attribute to a treatment effect.

Type of CancerControlSABR
expected 2-year survival (approx)
n% of totaln% of total
Breast515%1320%50% (1)
Colorectal927%914%30% (2)
Lung618%1218%10% (3)
Prostate26%1421%90% (4)

Expected 2-year survival due to distribution35%48%
Expected 2-year mortality due to distribution65%52%
Hazard Ratio due to skewed distribution80% 
Reported Hazard Ratio75%

Because of the uneven distributions in the treatment and control, the hazard ratio does not reach 80% confidence and the hypothesis should be rejected. The authors believe that just eliminating prostate cancer patients from both groups would correct the flaw, but they would have to eliminate colorectal cancer as well - I doubt the result would be significant with even 80% confidence. I believe the authors of the study erred in accepting the results even with 80% confidence for forging ahead with a Phase 3 randomized trial. The treatment effect, if any, is so small that their Phase 3 trial as specified is 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 attributable to SABR of metastases. 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.

(update 05/25/2022) SABR-COMET was updated with 8-year results. They report:

  • 8-yr overall survival was 26.2% in the SABR arm vs 13.2% in the control arm (HR=0.50)
  • 8-yr progression-free survival was 21.6% in the SABR arm vs 0.0% in the control arm (HR=0.45)
  • Rates of acute or late Grade 2+ toxicity were 30.3% in the SABR arm vs 9.1% in the control arm

The Kaplan-Meier survival curves showed a large drop-out of participants after 4 years in the control group. This is consistent with the relative lack of prostate cancer patients and the relatively large presence of colorectal cancer patients in the control group. 

There was no difference between arms in time to new metastases. So, the larger progression-free survival in the SABR arm is entirely due to local control. The cancer continued to seed new metastases at the same rate in both arms.

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