Evaluation of Chemotherapy Treatment

First and second line treatment regimens

Selecting cancer treatment regimens are among the most complex decisions in medicine. While treatment protocols have been established by oncologists and validated in clinical trials, there is remarkable variability in how patients respond to a particular therapy. The histology of tumors vary, as does the biology of the patient, and the successes of interventions in clinical studies does not necessarily mean the same interventions will work on any particular patient.

Nonetheless, standard first line treatment protocols exist for virtually every common cancer type. First line therapy, in essence, is the treatment deemed most likely to lead to a cure or significant resolution of cancer symptoms for a particular tumor. These protocols are somewhat individualized to account for neoplasms of various stages, grades, and molecular composition (e.g. does the tumor possess a particular receptor that could be targeted?). Second line therapeutic regimens, that is, therapies instituted when first line therapy has failed, are often less well-defined.

First line therapy is considered finished if there is evidence of disease progression, recurrence, or treatment failure. If none of these has occurred by one year after diagnosis, any subsequent treatment would be considered second line. After a period of time without disease, if the initial tumor grows or if the affected organ develops another tumor, it would be labeled disease recurrence. Importantly, first line therapy may be extended for several cycles, perhaps even beyond the initial prescribed course. If the same type of chemotherapy is used, but for more cycles than originally proposed, it is still first line treatment.

Treatment success is relative

Success and failure in chemotherapy are largely related to prognosis. On one end of the spectrum, consider a type of cancer with an 80% cure rate, such as bladder cancer. The reasonable goal of therapy might be cancer-free survival at five years after diagnosis. Thus success of the treatment can be assured if the patient continues to live without disease recurrence at five years. On the other end, if the cancer his highly and rapidly lethal, such as in advance lung cancer, the goal of chemotherapy is generally palliative. Thus reducing the size of a tumor, for example, to the point that it improves the patient’s inspiratory volume or oxygenation, would be a treatment success. Defining treatment success requires a reasonably accurate prognosis so that treatment goals are realistic and attainable.

Somewhere along this spectrum is the concept of “marginal benefit.” Generally speaking, “marginal” means an additional benefit, though not necessarily small. A marginal benefit may be an additional life expectancy of a few years with certain treatments, though it may not provide a cure or a return to an average life span.

Defining treatment failure

The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program has set the operational definition of treatment failure as “The treatment modalities did not destroy or modify the cancer cell. The tumor either became larger (disease progression) or stayed the same size after treatment.” This definition is more easily understood with solid tumor cancers. Part of cancer diagnosis and treatment planning is excellent imaging of the neoplasm. This usually means a computerized tomography (CT) scan of the affected region and perhaps magnetic resonance imaging (MRI), especially for surgical planning. The imaging modalities allow the radiologist to make incredibly precise measurements of a tumor that are comparable across time. Thus if the tumor is of a particular size before first line treatment and the same afterwards, this would meet the definition of treatment failure. Likewise, if the tumor increased in size, this would mean both treatment failure and disease progression.

Nuclear medicine imaging techniques

While some primary tumors may present as a discrete or even encapsulated mass, other cancer types and metastases may be below the resolution of CT or MRI. In these cases, physicians may turn to nuclear medicine for help. Nuclear medicine studies uses small amounts of radioactive material (tracer) to “stain” abnormal cells and tissues in the body. A classic example is the radioactive iodine uptake study for diagnosing metastatic thyroid cancer. Patients are given a small amount of radioactive iodine (I-123) which is absorbed and concentrated by thyroid tissue. The patient’s entire body is scanned with the a specialized radiation detector, looking for areas of uptake (tracer). The primary thyroid cancer may show abnormalities in the thyroid gland, but tracer in other locations may indicate metastatic disease. After treatment, this nuclear medicine study may be used to verify disease recurrence.


Tumor markers

Cancer cells are human cells that have undergone a series of mutations that make them cancerous. Some of the original cellular functions may continue after the cell has turned cancerous, but often the cell produces a number of abnormal substances, like glycoproteins. Fortunately, these abnormal cellular products allow one to differentiate between normal cells and cancer cells. CA-125, for example, is produced by some ovarian tumors. The level of CA-125 can be tracked throughout treatment as a means of determining treatment success or failure. One would expect that a successful treatment regimen would result in a dramatic reduction in CA-125. The level should stay at post-treatment levels—a lack of a drop or a subsequent rise in CA-125 may indicate treatment failure, progression or recurrence.

When to adjust first line therapy

Treatment failure and disease progression are fairly straightforward endpoints for considering second line therapy. What is less straightforward is the decision to continue first line therapy beyond its original dosing schedule by adding additional cycles. By the same token, certain chemotherapeutic regimens may be halted before the original number of cycles is administered if the treatment is not working. This is guided by a combination of published randomized clinical trials and the objective effects within the specific patient.

In essence, physicians are looking for signs that the chemotherapy is having an effect on the cancer. In some cases, the chemotherapy may not have a detectable effect on the tumor until all of the initial cycles are complete. Thus a standard number of cycles are given and then, after a certain period of time, the physician will employ one of the above technologies to assess the degree of effect.

In some cases there is a demonstrable effect on tumor size within the course of first line chemotherapy treatments. If the tumor is smaller or the extent of spread is less (by some amount generally accepted for that cancer type), the physician may reduce the total number of cycles or, more often, maintain the course until complete. If the tumor is unaffected or affected to only a very small degree, additional cycles may be added.

One example of how this occurs in practice is in the treatment of bladder cancer. Response rates to standard chemotherapy vary from 40% to 72%, with 13% to 36% complete responses.  Unfortunately, the drugs given to treat the disease have fairly intense adverse effects. Six cycles of chemotherapy is the standard first approach (if patients can tolerate the drugs’ toxicities). The traditional criterion for treatment success was a reduction in tumor size, which is usually evident by CT or MRI within the first two of six chemotherapy cycles. It has been argued that treatment should begin with two cycles of treatment and then an assessment made using a particular MRI technology (Fast Dynamic Contrast-enhanced MR Imaging).  If there is no demonstrable effect after two cycles, the chemotherapy should be halted. If there is a quantifiable effect, the additional four cycles should be given.

Bigger Picture

The Institute of Medicine promulgated a framework to guide development of health initiatives and what’s important.  They include six values to shoot for: safe, effective, timely, efficient, patient-centered, and equitable.

See also: Endpoints

Response Evaluation Criteria in Solid Tumors