Part II

Last week we discussed how and when clinical trials are recommended in the management of patients with cancer. Because so many cancer patients, unfortunately, have or develop a poor prognosis and exhaust the effective treatments available, they frequently resort to experimental therapies if they wish to continue to be aggressive in prolonging their survival.

I noted last week that 3%-8% of patients with advanced disease do avail themselves of a trial at some point in the course of their disease. Many others may wish to do so but don’t have a trial available to them or are not eligible for one reason or another.

It is worth bearing in mind the true purpose of trials. Here I provide my own perspective, so some may disagree, but trials are not fundamentally conducted for the benefit of the individual patient who seeks to enter the trial. Rather, a trial is conducted by the scientific investigators to answer a scientific question. There may be significant input/interest of a pharmaceutical company, the National Cancer Institute, and by the cancer centers hosting the study.

The goal is to develop new treatments that may ultimately benefit many patients. It is certainly an important by-product that the subjects who participate in the trial benefit as well, but that is not the primary objective of the study. The decisions made in the trial—who can enter, how long they can stay on study, how the doses are modified—will appropriately reflect the scientific demands and may be different than would transpire if the patient were under the care of his/her personal physician.

There are three types of trials. When a drug or treatment regimen is first introduced to people, it undergoes phase I testing. A phase I trial has two purposes—to determine the best dose at which to administer the drug and to identify common adverse effects. Its purpose is not to determine if the drug actually helps with cancer. The drug is given to a few patients at a dose that is lower than it is expected will be the ultimate safe dose. If these patients tolerate the drug at that dose without undue side effects, then the trial moves on to a higher dose of the drug and a few more patients are treated. Again, if no significant toxicities are found, the trial goes to a higher level and so on. Ultimately there is a highest pre-set dose level at which the trial stops.

Phase I patients are monitored closely for their renal, cardiac, hepatic and other physiologic functions to see if any undue toxicities are identified, or if there is significant nausea, diarrhea, etc. If truly severe side effects occur, particularly if they are life-threatening, a drug may be deemed too dangerous to be utilized and that may end its career.

It is not uncommon for some treatment responses to occur in a phase I trial, but this is not its primary objective. A drug that shows responses in a phase I trial is considered truly promising, and it certainly does happen. A recent analysis of several hundred phase I trials estimated that overall 4% of patients on phase I oncology trials had a significant clinical response. A similar result was found in a prior study published in the New England Journal of Medicine years ago that also estimated around 5%.

Once a new drug completes phase I testing, it moves on to phase II trials. The purpose of a phase II trial is to determine the efficacy of the drug against a specific tumor. So a phase II trial tests the drug (at the dose that was determined in the phase I trial) against a number of patients with a specific tumor, e.g., advanced pancreatic cancer. Thus, it may treat 25 patients with metastatic pancreatic cancer and see in how many of them the tumor shrinks or how long it takes before the tumor progresses (called progression-free survival). A promising drug may undergo several phase II trials, one each for several tumor sites. It is not uncommon for there to be no responses in a phase II trial, thus dooming the drug for that indication. If there are a couple of responses, the recent trend has been to expand the phase II trial to include more patients so as to obtain a better statistical estimate of how many responses there really are.

Finally, there is the phase III trial. This is what we all recognize as the randomized trial, a large study that randomizes patients to receive either the new therapy or the standard conventional therapy. The goal here is to determine whether the new treatment is superior to what is currently given to patients. If there is no standard therapy, the comparison arm may be a placebo or “best supportive care.” Patients in a randomized trial almost uniformly enter the trial with the desire to obtain the new experimental agent, and thus are disappointed if they are randomized to the other arm. But there may be no access to the experimental drug in the absence of entering the trial.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

By Alfred I. Neugut