Update on Metastatic Cancer

CANCER IS A two-headed monster, and it’s hard to say which is the more lethal. The malignancy itself can, depending on where it forms, quickly become life-threatening since the out-of-control growth of cancer cells can interfere with core bodily functions. But, the other threat is perhaps even more dire: Individual cancer cells can break away from the original growth and spread to other parts of the body, where they start new tumors in a process known as metastasis.

Having malignant tumors spread throughout the body is obviously a much more challenging situation to treat. In fact, the National Cancer Institute reports cancer overall is the second leading cause of death in the Western world, trailing only cardiovascular disease, with most cancer deaths caused by metastatic cancer.¹ In 2016, there were approximately 1.7 million new cases of cancer diagnosed in the United States (out of a population of roughly 326 million), and 596,000 cancer-caused deaths.² The most prevalent forms of cancer in this country are breast, lung and prostate cancer.³

What Is Cancer Metastasis?

Metastatic cancer is any cancer that has spread to a distant part of the body through the blood or lymphatic systems.⁴ Metastasis is understood to be a different process than the one observed when cancer spreads from its original location to contiguous tissue.⁵

Cancer has been known since antiquity. The Edwin Smith Papyrus, an Egyptian artifact dated to about 3,000 B.C., describes tumors of the breast and notes there was no effective treatment. Two and a half millennia later, Hippocrates used the word “carcinoma” (crab) to refer to ulcer-causing tumors, the name likely based on the pattern that noticeable tumors made under the skin of patients.⁶ In the Middle Ages and Renaissance, autopsies (often illegal) helped further our understanding of many diseases, including cancer. In this last century, there have been dramatic advances in our knowledge of what cancer is and how it operates on cellular and molecular levels. Today, physicians and researchers have identified some 200 different types of cancer.

Despite all this, many of the specific mechanisms of metastasis have not yet been discovered.⁵ And, in spite of all our advances in knowledge, diagnosis and treatment, cancer continues to be the second-leading cause of death in the United States. However, a recent study did show cancer survival rates are increasing. Since 1990, cancer deaths in this country have fallen by 25 percent. And, more recently, from 2004 to 2013, cancer deaths for men declined by 1.8 percent, and for women and children by 1.3 percent.²

Survival rates vary widely from one form of cancer to another, and the National Cancer Institute emphasizes that statistics have little bearing on any individual patient. Breast cancer five-year survival rates from 1975 to 2012 increased from 75 percent to 91 percent, while lung cancer rates increased from 12 percent to 19 percent. Other forms such as bladder, prostate and colon cancers improved at a rate somewhere in between.⁷

Once cancer has spread, however, survival rates go down — often significantly. Those diagnosed with early stage lung cancer have an overall five-year survival rate of 56 percent; those whose lung cancer has spread have only a 5 percent five-year survival rate.⁸ The good news is even those with metastatic cancer are seeing improved long-term survival as treatment improves.⁷ Nevertheless, researchers estimate 90 percent of all cancer deaths result from metastatic tumors, not the original tumor.⁹

Causes of Cancer Metastasis

While today we have a more complete picture of how and why cells become cancerous (i.e., damage to the genetic codes that regulate cellular reproduction), the exact how and why of metastasis are not as well understood. The reasons some malignant cells break away from their tumor are not known. And, while scientists know these rogue cells penetrate the walls of blood and lymphatic vessels, the specific method used is not entirely understood, nor is it known how some of these cancer cells in the bloodstream and lymph nodes evade elimination by the body’s immune system.⁵ Researchers are also unsure what causes the cells to eventually stop their journey and once again begin their unregulated division and growth, although certain types of cancers have shown a tendency to metastasize in the same places (i.e., breast cancer metastasizing in the liver and testicular cancer in the bones).¹⁰

Symptoms and Progression of Metastatic Cancer

As with primary tumors, or even non-tumor-causing cancers such as leukemia and lymphoma, metastatic cancer does not always cause immediate symptoms. Symptoms vary depending on where the tumors develop. In fact, symptoms of a metastatic (or secondary) tumor are no different from those of a primary tumor:

• Sudden change in weight
• Noticeable lump or thickening of tissue under the skin
• Change in bowel movements
• Change in frequency or ease of urination
• Persistent indigestion
• Persistent joint or abdominal pain
• Difficulty breathing or swallowing
• Unexplained bleeding
• Fatigue
• Bone fractures
• Seizures or headaches
• Unexplained skin changes, including sores

Patients should be coached to report any of these symptoms to their physician.¹¹

As with a primary tumor, secondary tumors have a wide range of growth rates. Some can be dormant for years before resuming growth; others spread so rapidly they are basically beyond treatment before they are discovered.⁴

Typically, the progression of metastatic cancer will mirror that of the primary tumor where it originated. A fast-growing cancer that has spread will remain a fast-growing cancer in its secondary tumors as well. Since slow-growing forms are less likely to metastasize than more aggressive types, metastasized cancers are statistically more likely to be of a type that presents a faster progression schedule. Many cases of metastasized cancers will be categorized as advanced cancer due to the seriousness of disease progression and the resistance of malignancy to treatment.¹²

Diagnosing Metastatic Cancer

In most cases, a patient will already have been diagnosed with cancer before being diagnosed with a metastatic tumor. Depending on the type of cancer diagnosed and how far it has progressed, an oncologist may already be regularly testing for metastasization. At other times, it will only be symptoms from the metastatic tumors that alert the physician and patient to the presence of cancer, rather than making a diagnosis until after the malignancy has spread.

Metastatic cancers are known and treated as the original type of cancer. For example, breast cancer that has spread to the liver is still referred to and treated as metastatic breast cancer. A biopsy and examination of the tissue can confirm the secondary tumors are metastasized from the already known cancer. In some cases, the metastatic growths can’t be traced back to a previous tumor. These are referred to as cancer of unknown primary origin.⁴

An initial cancer diagnosis can be made from blood work looking for specific markers, or from an imaging procedure such as a CT scan, MRI or X-ray. However, a biopsy is generally considered the only definitive method to confirm a diagnosis as serious as cancer.¹³

Treating Metastatic Cancer

Until recently, treatment for a metastatic cancer almost always took the form of a continuation of the regimen being used to treat the primary tumor, although the the urgency related to treatment increased significantly.

However, researchers are finding metastasized cancer cells are often resistant to drugs used to successfully attack primary tumors. The cells found in secondary tumors are often even less genetically stable than primary malignancy cells, with wildly different membrane properties, making existing drugs ineffective against them.⁵ (And, in one recently reported case, a lung cancer tumor whose cells had lost the NKX2-1 gene that acts as master switch had grown into a miniature stomach and duodenum, reflecting the genetic instability researchers and physicians face in treating all malignancies.¹⁴)

Depending on how broadly the cancer has spread, treatment may consist primarily of systemic therapy: chemotherapy drugs that move through the bloodstream to attack cancer cells throughout the body. Surgery, ablation or radiation therapy may be used to try to remove or reduce new growths, or to provide pain relief in affected areas.¹² In other cases, because the metastasized cancer can be so different from the primary cancer that created it, new treatments specifically targeting metastasized tumors are being introduced.

One new treatment that has shown promise in the past few years in treating metastatic melanoma and non-small cell lung cancer is immunotherapy in which the body’s own immune system is harnessed to help attack cancer:

– One class of drugs known as PD-1 inhibitors (pembrolizumab [Keytruda]; nivolumab [Opdivo]; ipilimumab [Yervoy]) allow the body’s immune system to recognize malignant cells more easily by suppressing a specific protein on T cells that normally prevent those cells from targeting other cells.¹⁵ However, patients being administered these drugs must also be monitored for side effects that can be caused by the immune system — now unleashed — attacking healthy, noncancerous cells. Because of this, certain pre-existing conditions such as colitis, hepatitis, diabetes and others may preclude use of PD-1 inhibitors.

These drugs are administered intravenously every three to four weeks on an outpatient basis, and regular blood tests are conducted to check for possible side effects.¹⁶ Treatment typically continues until the tumors shrink beyond detection, or there is an adverse reaction. A newly released study shows Keytruda showed improved survival rates in half of lung cancer patients, and delayed the development of advanced cancer.¹⁷

-Stereotactic radiosurgery, performed by aiming multiple, highly focused radiation beams directly at tumors, is now being used to treat brain and spinal metastases.¹⁸ The radiation beams destroy the DNA in the nucleus of the targeted cells, preventing them from reproducing.¹⁹ When multiple beams meet at the tumor, the healthy tissue through which all the beams pass is relatively unscathed, whereas the tumor receives a high dose of radiation that can not only destroy the DNA of the malignant cells, but also cause blood vessels to shrivel and close, denying the malignancy needed nutrients.¹⁸

During stereotactic radiosurgery, a head frame or specialized mask immobilizes the patient’s head to assist in maintaining high accuracy of the beams so only malignant cells are struck and damaged by the radiation. Two main types of machines are used. Linear accelerators use X-rays, and require only a single session for a small tumor or several visits for larger growths or multiple tumors, and they are used to treat tumors throughout the body. Gamma Knife machines use gamma rays, which are even higher energy photons than X-rays, and are generally limited to treating conditions in the brain, including secondary malignancies. Treatment consists of one to several visits depending on the size and number of growths.¹⁸ Follow-up care includes blood tests and radiological imaging to see if the treatment was successful in shrinking the secondary growths, and monitoring of the patient with possible chemotherapy or follow-up radiation treatment.

-Proton therapy is similar to stereotactic radiosurgery, but rather than using highly charged photons (the same particles as in visible light or radio waves), much heavier protons are used. Where an X-ray or gamma ray beam continues on after hitting the tumor, a proton beam stops at its target, doing no further damage to the tissue behind the tumor. With increased accuracy and less secondary damage to nearby healthy tissue, proton therapy is preferred for malignancies in the brain and spinal cord, as well as in children.²⁰

The proton therapy treatment regimen is much the same as radiation therapy: One or more visits to the radiation center, depending on the size and number of tumors. Follow-up care includes blood tests and subsequent imaging to determine the effectiveness of treatment.

Additional care to any of the above three treatment regimens includes long-term monitoring by an oncologist and primary care physician, and may include additional chemotherapy tailored to the original cancer.

The newest treatment is not yet available for most metastasized cancers, but its implications for all cancers are revolutionary. Last summer, the U.S. Food and Drug Administration approved Novartis’ CAR-T therapy, the first anti-cancer gene therapy approved in the U.S., to treat acute lymphoblastic leukemia. With CAR-T therapy, a physician extracts T cells from the patient, freezes them cryogenically and sends them to Novartis. At the company’s lab, the patient’s T cells are reprogrammed to produce a new protein called a chimeric antigen receptor. This protein causes the T cells, which are refrozen and shipped back to the physician for injection into the patient, to identify and kill any cells with that specific antigen, which is unique to this type of leukemia, on their membrane. Early studies showed more than 80 percent of patients in a CAR-T study had their cancer enter remission within three months of treatment.²¹

Whether the care plan is to eliminate the cancer, slow its growth or provide palliative relief to the patient, the American Cancer Society recommends the patient must always know what the goal of each step is in the treatment plan, what the options are and be included in decisions regarding treatment.¹²

When a cure is no longer an option, the oncologist and primary care physician will work with the patient and his or her family or other inner circle to ensure the highest quality of life. Pain relief, mobility and mental acuity are all goals to be balanced in planning the best course of treatment.¹²

Preventing Metastatic Cancer

Since the triggers that cause some tumors to metastasize are not fully understood, there is no way to prevent an existing cancer from metastasizing other than successfully treating it — whether through surgery, radiation or chemotherapy. Preventing the initial development of cancer is the best method to preventing cancer metastasis.

Healthy eating, avoiding tobacco use and maintaining an active lifestyle remain the best, most widely accepted methods of reducing the risk of developing a malignancy in the first place.

Ongoing Research

Cancer is likely the most-studied medical condition on Earth. Of the more than 60,000 studies listed on ClinicalTrials.gov, there are quite a few focusing specifically on cancer metastasis. Given that there are more than 200 types of cancer, and that it is likely each of them is capable of metastasis, it is not surprising there are more than 9,000 studies on cancer metastasis listed.

Among the thousands of studies listed, these are some of the more intriguing:

• A 2017 study conducted at Samsung Medical Center in South Korea is building a database of genomes of metastatic cancerous cells to cross-reference them against all registered drugs that target specific cellular molecules.²²
• The Mayo Clinic’s Jacksonville, Fla., facility is expected to issue its findings this fall on a 10-year study it is conducting in conjunction with the National Cancer Institute on stereotactic radiation therapy on patients with liver metastases. While stereotactic radiation therapy is already being clinically employed, it remains a young technology. This study is looking at determining ideal dosage to balance effectiveness versus side effects in a field of 18 participants, and the final report will include post-treatment measurements of both survival rates and the patients’ reported quality of life.²³
• At the Moores Cancer Center at the University of California, San Diego, researchers are roughly two years into a five-year study comparing survival and quality of life rates among patients whose metastatic cancers are treated with checkpoint blockade immunotherapy (CBI) alone versus those whose CBI treatment is supplemented by stereotactic body radiation therapy. The 146 participants were randomly assigned to two treatment regimens. Half will have their advanced metastasized cancer treated with an anti-PD-1/PD-L1 immunotherapy only, and the other half will receive immunotherapy plus have their metastasized tumors treated with SBRT at 9.5Gy x3 fractions within three weeks of the beginning of immunotherapy. Results are expected to be posted in January 2021.²⁴
• Eli Lilly is in the midst of a three-year study set to conclude in September 2018 studying the efficacy of a new fibroblast growth factor receptor 3 (FGFR3) antibody-drug, LY3076226, in both advanced cancer and metastatic cancer patients. The 37 study subjects receive an intravenous dose of the drug every three weeks, with follow-up study measuring residual amounts of the drug in the bloodstream, and its effectiveness in treating the tumor(s).²⁵
• Massachusetts General Hospital and Merck Sharp and Dohme Corp. are collaborating on a study investigating whether pembrolizumab (Keytruda) is effective in fighting metastases in the central nervous system. The 102 participants are currently fighting either a previously untreated brain metastasis, a progressive brain metastasis, multiple brain metastases from melanoma, or a neoplastic meningitis with a solid malignancy. Patients will be examined with a cranial MRI every six weeks to study the efficacy of the treatment. The study began in 2016, and is expected to be completed in 2024.²⁶

Looking Ahead

Curing cancer has been the No. 1 goal of the Western medical profession for nearly a half century, with massive government subsidies since at least the Nixon administration with the signing of the National Cancer Act of 1971. While tremendous progress has been made, cancer remains the second-leading cause of death in the developed world. Some studies suggest that as advances in treating and preventing cardiovascular disease continue to show results, cancer will become the leading cause of death in North America and Western Europe.

Metastasis seems to be endemic to what cancer is. Since cancer will sadly remain with us for the foreseeable future, physicians will continue to work with patients to attack these diseases when possible, and provide quality-of-life care when it is not.