2 Keys to Improving Treatment Effectiveness in Stage 4 Cancer: Performance Status & Genetic Testing

A cancer patient's general performance status (performance status, PS) and molecular / genetic test results are key tools for patients with newly diagnosed metastatic (stage 4) solid tumors (organ cancers) in determining prognosis (the course of disease).

A patient's performance status is a score estimating the patient's ability to perform certain activities of daily living without help from others. These include basic activities such as dressing, eating and bathing, as well as more complex activities such as cleaning the home and doing regular work.

Performance status scale

1. Fully active and able to maintain predisease performance without restrictions
2. Restricted in physically strenuous activities but ambulatory and able to perform light, sedentary work, such as light housework or office work
3. Up and about > 50% of the time and capable of all self-care, but unable to carry out any work activities
4. In bed or a chair > 50% of the time, capable of only limited self-care

Oncologists have a large and continually growing body of clinical trial data to help determine a cancer patient's prognosis. Yet physicians also make little use of tools predicting the course of disease. One such tool is the ECOG performance score.

A criterion for inclusion in clinical trials is a good ECOG Performance Score (0 or 1). Clinical trials almost never enroll patients with ECOG status 3 or 4. Yet most hospitalized patients with metastatic cancer have an unfavorable ECOG score (3 or 4). It is therefore difficult to say that trial results cover this substantial patient group.

The distinction between ECOG 2 and 3 is very important in oncology

When treatment options are discussed with hospitalized patients who have poor performance status (ECOG 3 or 4) and metastatic cancer, their doctor often says: "Assuming you feel better and can go home, these clinical trial data may then be more relevant to you."

When hospitalized patients with advanced cancer ask about their life expectancy, United States or worldwide 5-year overall survival data should not be quoted. These 5-year overall survival figures are not an individualized assessment. Furthermore, oncology is a rapidly evolving field in which important treatment advances occur all the time. Cancer statistics have lagged far behind this. For example, for stage 4 non-small-cell lung cancer (KHDAK), United States statistics put 5-year survival in 2009-2015 at around 5%, whereas this rate is now known to have reached 20% with immunotherapies.

Indeed, it is no longer true that average survival for patients with metastatic KHDAK is less than one year. In the KEYNOTE-189 clinical trial, which recruited participants in 2016-2017 and changed the standard treatment approach, the immunotherapy pembrolizumab (Keytruda) plus chemotherapy produced a median overall survival of 22 months, compared with 11 months in patients receiving standard chemotherapy.

Consequently, combination treatment using pembrolizumab immunotherapy with chemotherapy is now used where targetable mutations are absent in metastatic non-small-cell lung cancer patients, as standard practice.

Deciding whether to offer patients with advanced metastatic cancer and poor performance status palliative systemic treatment is difficult. It is necessary to determine whether this status is caused by the cancer itself or another cause, such as liver failure, that cannot easily be reversed.

Consider, for example, a hospitalized patient with another type of lung cancer, small-cell lung cancer (KHAK). This is an aggressive, chemosensitive (drug-sensitive) cancer. If poor performance status in a patient with advanced KHAK is caused by the cancer itself, immediately starting inpatient chemotherapy is vital, and chemotherapy can rapidly help the patient recover. Conversely, if poor performance status is caused by organ failure or another problem that cannot easily be improved, for patients with no chance of cure (complete recovery), palliative care may be a more appropriate option.

What characterizes small-cell lung cancer over time is that, despite responding to treatment, it inevitably undergoes recurrence (relapse). However, chemotherapy can give people in this situation months of quality time, so we generally try to treat such patients.

Advanced small-cell lung cancer (KHAK) is not the only metastatic cancer that is chemosensitive (sensitive to chemotherapy). Many oncologists believe aggressive chemotherapy should be offered even in the face of poor patient performance status attributable to the cancer itself.

Consider, for example, colorectal (large bowel) cancer with no more than 5 metastases to the lung or liver, provided that these metastases can be surgically removed or undergo radiation treatment. These patients can actually be treated at a high rate. Patients with colon and rectal cancer with isolated / few metastases have substantial 5-year survival rates (up to 30-40%). Even if their performance status is poor, we therefore generally try to treat these patients intensively if we can prepare them for surgery or radiotherapy.

There are many other chemoresponsive (responding to chemotherapy) metastatic cancers for which oncologists frequently recommend intensive treatment to improve quality of life in patients with poor performance status. These include aggressive lymphomas, which can actually often be treated; multiple myelomas; testicular and germ cell cancers; non-small-cell lung cancers (KHDAK) with a targetable mutation that usually respond to oral drugs; prostate cancers; and thyroid cancers that can be treated with hormone- or iodine-based drugs rather than chemotherapy.

The effect of inpatient palliative chemotherapy in patients with poor performance status and other advanced solid / organ cancers not included in the short list of chemosensitive cancers has not been well studied.

A recent retrospective study of 228 such patients receiving inpatient chemotherapy at a large academic medical center in Brazil provided little reason for encouragement about giving chemotherapy to patients with poor general performance status. Reported survival was short, with 30- and 60-day survival rates of 56% and 39%, respectively. In addition, 30% of patients were admitted to intensive care, where they received intensive and costly end-of-life care. The researchers found that these results suggested overprescribing of inpatient palliative chemotherapy.

In a multivariable analysis, the researchers found that elevated bilirubin (a jaundice measure) was associated with a 217% increase in 30-day mortality (death) risk, and hypercalcemia (elevated calcium) with a 119% increase in risk. These factors should therefore be considered when deciding on treatment for patients with advanced cancer and poor general performance status.

Patients and their relatives often appear overly optimistic about prognosis and have high expectations. Disagreement between oncologists and patients or relatives over aggressive treatment for a hospitalized patient with advanced cancer is quite common.

Molecular / genetic testing has now become standard in metastatic cancers!

Today, oncologists assess eligibility for drugs directed at genetic targets and clinical trial participation, help determine prognosis and, if unclear, the cancer's origin by requesting molecular genetic tests for most patients with metastatic cancer.

Trucut (core needle) biopsy does not provide sufficient tissue for molecular tests. It is therefore important to prefer trucut biopsy initially to avoid repeat biopsies, which cause discomfort and can delay diagnosis and treatment.

Targetable mutations may be present in metastatic cancer patients, so molecular test results can be awaited before attempting to determine prognosis. Survival rates may vary greatly according to these results. For example, consider metastatic non-small-cell lung cancer (KHDAK): clinical trials published last year reported, for treatable mutations in the epidermal growth factor receptor (EGFR), 39 months; for anaplastic lymphoma kinase (ALK) mutations, 42 months; and for a ROS1 mutation, 51 months of overall survival, compared with 22 months without targetable mutations in the KEYNOTE-189 study.

In conclusion, there is considerable heterogeneity (a mixed picture) in how metastatic tumors behave and respond to treatment. Not all metastatic cancers are the same. When planning treatment for a patient with advanced disease, a decision should take account of general performance status, tumor chemosensitivity, whether the current condition stems from the cancer itself or other problems, and the tumor's genetic makeup.