Learn rationale for adjuvant therapy.Trials of adjuvant
Learn About Phase III Trials First!Most adjuvant trials are a special type of Phase III trial. To get the most out of this article, please read Steve’s Strategic Guide to Phase III Clinical Trials first! To get a general background on the rationale for adjuvant therapy, see Understanding Adjuvant Therapy by Dr. Kevin Murphy.Adjuvant therapy is additional treatment that is given after primary treatment for apparently localized cancer. The primary treatment is usually surgery and the adjuvant therapy is usually drug therapy or radiation therapy. The idea is to prevent recurrence by wiping out any metastases which are presently too small to detect. See Understanding Adjuvant Therapy by Dr. Kevin Murphy, for more on the rationale for adjuvant therapy.Trials of adjuvant therapy are intended to improve on the current best standard adjuvant therapy, or to establish the effectiveness of adjuvant therapy where none is yet proven. Because you can’t measure the effect of adjuvant therapy in any individual patient, conclusions about the effectiveness of adjuvant therapy rely more strongly on statistical evidence than is the case for other cancer therapy, and the case for very carefully controlled randomized trials is at its strongest.Adjuvant Trials: Primary ObjectivesAdjuvant trials compare survival of two adjuvant treatments or, where no adjuvant therapy is standard, the adjuvant therapy under test is compared to no additional treatment. Often Disease Free Survival (DFS) is used instead of Survival, or in addition to it. DFS is the length of time from initial treatment until recurrence is detected – the length of time the patient is disease free. DFS has the advantage that it doesn’t depend on the efficacy of treatments for advanced disease which may vary from patient to patient since such treatment is not part of the trial, but at the same time while DFS tells you whether the treatment affected the risk of recurrence increased DFS doesn’t quite equate to benefit if advanced disease is very curable or treatable. I think in most cases DFS is a very reasonable surrogate for total benefit since with most cancers, the prognosis is poor after a recurrence.As with other Phase III trials, comparing Quality of Life (QOL) is also a typical and important endpoint. Considering that some patients in most adjuvant trials are already cured by the primary treatment, and that all patients in these trials are already clinically disease free and symptom free, assessment of QOL seems particularly important to me, despite its subjective nature.Adjuvant Trials: Standard DesignLike Phase III trials, adjuvant trials are usually randomized trials, and may be called Phase III trials in some of the databases, though the word “adjuvant” is usually in the title. If your cancer is localized and operable, these may well be the only trials you might qualify for! If there is already a standard adjuvant therapy, the proposed new adjuvant therapy will be compared to the standard. In some cases, more than one adjuvant therapy is in common use and the trial compares two different standard adjuvant therapies. If there is no standard adjuvant therapy for your cancer, the control group will probably get observation only. This is the situation in which no treatment groups or even placebo control groups are most common in cancer clinical trials!Adjuvant Trials: VariationsIn neoadjuvant therapy, the secondary therapy is given before surgery. Neoadjuvant therapy is typically used in locally advanced disease. The idea is to shrink large tumors to make surgery possible or to make the required surgery less drastic. It appears that in some situations, giving the systemic therapy earlier is more effective in treating micrometastases and preventing recurrence. There have been major successes with neoadjuvant therapy in locally advanced breast cancer and stage IIIa non-small cell lung cancer. Sometimes additional therapy is given after the surgery as well as before.Pilot Studies: There are a significant number non- randomized adjuvant pilot trials. Adjuvant pilot studies are likely to be called Phase II studies in the databases, but like randomized adjuvant trials, the word “adjuvant” is likely to appear in the trial’s title. I am frankly less than sure of the purpose of such trials but I believe they are intended to establish the feasibility of a new adjuvant therapy, and perhaps provide a rough check that the results are reasonable compared to historical norms or matched concurrent patients who are not part of the trial. If the results from the pilot study are acceptable then it should be followed by a regular randomized adjuvant study. Adjuvant pilot trials do offer the chance to get a new adjuvant therapy without randomization. The question is how to evaluate the trial to see if it is more desirable than the standard adjuvant therapy, or the best adjuvant therapy in randomized trials.Adjuvant Trials: Key Eligibility RulesTiming Is Everything!: If you have apparently localized disease, it is critical to investigate adjuvant trials before surgery, or if you have just had surgery, then just as soon as possible!Almost all adjuvant trials have a time limit on how long you can wait after surgery to enroll in the trial. The limit is typically two or three months.Some new biological therapies use the resected tumor to make a vaccine. In this case you need to enroll in the trial before surgery.Obviously you need to enroll in trials of neoadjuvant therapies (see below for an explanation of neoadjuvant therapy) before surgery!You Only Get One Crack at Adjuvant Therapy: Patients are normally treated with at most one adjuvant therapy. There is no basis to try a second adjuvant therapy if the first one didn’t work because it impossible to know in any individual case whether an adjuvant therapy worked unless the patient relapses. In that case, therapy for advanced disease is needed rather than another adjuvant therapy. Therefore, patients in adjuvant trials must not have had any prior adjuvant therapy. Again, if you are to participate in an adjuvant trial, you must research and decide on adjuvant trials before starting any standard adjuvant therapy!Staging: Most adjuvant trials require that your cancer be a particular stage or one of a few stages. Typically the testing of an adjuvant therapy starts with patients who are at the highest risk of recurrence, and who are most likely to benefit. Once the benefit of a particular adjuvant therapy is proven in high risk patients, later adjuvant trials may test the therapy with lower stage patients who are less likely to have a recurrence.Adjuvant Trials: StrategiesRisk of Recurrence and Toxicity: Depending on the type of cancer and stage, and other factors, your risk of recurrence may range from almost zero to nearly 100%. Unless your risk of recurrence is 100%, there is some chance you will be cured by the surgery alone, maybe even a good chance. That means that if you take adjuvant therapy you may endure the side effects of treatment but get no benefit because you are already cured. Of course, like almost any cancer treatment, adjuvant therapy does not work all of the time, so it might be that you relapse in spite of adjuvant therapy. Despite these drawbacks adjuvant therapy can reduce the risk of recurrence although in some situations where adjuvant therapy been proven, the reduction in the risk of recurrence is only modest. Finally, if your cancer is potentially curable even after it recurs, this decreases the overall benefit of adjuvant therapy. Most cancers are only rarely cured if they recur, but there are certainly exceptions.The potential benefit of adjuvant therapy trades off against the side effects and inconveniences of treatment and consequent loss of quality of life. Whether any decreased risk of recurrence is worth the side effects of adjuvant therapy in any given case is a personal decision, but presumably the greater the likely benefit, based on the evidence, the more side effects you would be willing to tolerate. (Keep in mind that not all side effects are created equal! My article on thinking rationally about side effects will help you organize your thoughts.) If you are considering adjuvant therapies or trials, your first job is to learn your risk of recurrence based on your stage, grade, pathologic subtype, and other factors. If your risk is high, and the cancer is difficult to cure after a relapse, you’ll be highly motivated to seek adjuvant therapy. If it’s low, or your cancer would be highly curable even after a relapse, you’re likely to be much less interested in undertaking adjuvant therapy, especially if its difficult or toxic.Randomization and Adjuvant Therapies: If you are uncomfortable with being randomized because you have a preference for one arm of the trial, you should know that many adjuvant therapies use drugs and combinations that are approved and established for metastatic disease, or for other purposes. In my case, I was offered an adjuvant trial of interferon versus observation, after my surgery, and before I was diagnosed with metastatic disease. I thought of interferon as almost science-fiction – I had no idea it was an approved drug (though not for my cancer) which I could, at least in theory, get off protocol, and my doctor didn’t tell me. My attempts to convince a doctor to prescribe it were cut short by the discovery of metastatic disease, and later trials showed it to be ineffective as adjuvant therapy for renal cell cancer. The point is that you may be surprised at what is potentially available off-protocol. Take the time to investigate.A Special Case: If there is no proven adjuvant therapy for your cancer, and the therapy under test has minimal to no side effects it would seem there is nothing to lose by enrolling in the trial! Many less toxic therapies are innovative biological therapies which are only available in clinical trials so you may have to accept randomization with a no-treatment arm.Evidence for Adjuvant TherapyIt’s uncommon for treatments to be tried for the first time as adjuvant treatment. Normally, they are tested in advanced disease first. If a treatment shows some effectiveness in advanced disease, it is a candidate for trial as an adjuvant therapy. The hope is that the treatment will be more effective in wiping out tiny micrometastases than in dealing with the large tumors of overt advanced disease. In some cases, treatment which is only very modestly beneficial in advanced cancer has proven to be more beneficial as adjuvant treatment. Colon cancer is one example. 5-FU based chemo for metastatic colon cancer, produces only relatively few responses and those tend to be brief, yet some of these same chemotherapies, when used as adjuvant therapies, significantly reduce the risk of recurrence.As I explained above, sometimes the first test of an adjuvant therapy is in an adjuvant pilot study. This means that the evidence may include results from such a study. Interpreting results of uncontrolled studies is fraught with difficulties and uncertainties, but in my opinion, a strikingly better result in the pilot study compared to a historical control, or the expected prognosis, suggests that the therapy is promising. I think a trial with this kind of evidence is well worth considering, especially if there is no proven adjuvant therapy for your cancer.Normally, when a treatment is first tested in the adjuvant setting it is tested on patients who are at very high risk of recurrence. These patients have high stage local or regional disease. Once the therapy has already been proven effective as an adjuvant therapy in higher risk disease, it is tested in patients with lower risk disease to see if the benefits can be extended to those patients. I think a trial of this type is a relatively good bet in terms of the chances that a benefit will be found. The downside is that the trade-off with the side-effects of the treatment, which remain the same regardless of your risk of recurrence, is not as favorable since the chance that you are already cured is higher.