Although legitimate questions have been raised over the years regarding the generalizability of clinical study results in the nonresearch setting, patients with cancer have benefited greatly from the appropriate conduct, completion, and ultimate reporting of such trials in the peer-reviewed medical literature.
Maurie Markman, MD
The major role played by phase III randomized trials in the development of evidence- based cancer medicine is appropriately well acknowledged. Although legitimate questions have been raised over the years regarding the generalizability of clinical study results in the nonresearch setting, including the unfortunate exclusion of elderly patients and individuals with highly relevant comorbidities (eg, pre-existing cardiac, pulmonary, hepatic, and renal disease), patients with cancer have benefited greatly from the appropriate conduct, completion, and ultimate reporting of such trials in the peer-reviewed medical literature.
The question now is whether that established model can carry cancer care forward in an era of fast-paced innovation and long-term survivorship. As cancer becomes a more chronic condition to be managed over extended periods of time, the fundamental limitations of trials examining the utility of individual drugs or combination strategies at a single point in the natural history of a given malignancy will become increasingly—and likely painfully—obvious. Restrictions on Patient Populations First, let us consider the limits of the current clinical trial protocols concerning patient populations. Of necessity, clinical studies examining new antineoplastic strategies require specific eligibility for patient entry. Justification for limitations regarding who may, or may not, be permitted to be treated on a given clinical trial include concerns regarding the toxicity profile of a particular strategy or evidence that a specific approach may only be clinically active in certain conditions such as a particular tumor type or the presence of a validated biomarker.
In general, early-phase studies (ie, phase I) may be more restrictive in the exclusion of potential comorbidities due to many unknowns regarding the agent’s adverse event profile and less restrictive regarding tumor type or number of prior lines of treatment, compared with later stages (phase II, III) in the drug developmental pathway. In fact, it is in the evidence-based studies employed to obtain regulatory approval where one generally encounters the most restrictive eligibility criteria. As previously noted, the reasons for a variety of entry barriers are fairly obvious. These include concerns for excessive toxicity due to the unique adverse event profile of the agent observed in prior trials using the drug and the presence of particular comorbidities that may potentially negatively impact the ability to define the favorable effects (toxicity, efficacy, or both) of the new product.
Of course, such restrictions, while likely permitting a more focused examination of the experimental agent in question, may quite seriously limit the clinical applicability of data relevant to patients treated in the real world where comorbidities are very common. This issue is especially relevant in the more elderly population most likely to develop the majority of malignant disease.Although the substantial concerns over the value of evidence-based regulatory agency— approved trial data that exclude patients with common and clinically meaningful comorbid conditions are increasingly recognized, there is an additional potential impact of specific restrictions associated with the large majority of the study designs employed to gain permission for a drug to be sold commercially.
That is the impact of restricting clinical trial enrollment based upon the nature of the prior therapies the potential participants have received. Knowledge of the compiled evidence supporting potential indications for a new drug as well as the existing standard of care in particular clinical settings will dictate the specific patient populations where the evaluation of efficacy of a new antineoplastic agent or combination regimen should be undertaken. Further, there is a logical desire to restrict as much as possible the heterogeneity of the patient population entered into a given study in an effort to optimize the potential that a favorable signal specifically related to the drug’s effect will be observed, assuming it actually exists.
As a result, it is routine that a study of “Drug A” versus “Drug B” in patients with “metastatic cancer C” will narrowly define the study eligibility, including the prior number of chemotherapy regimens permitted. For example, a given trial may permit one prior chemotherapy regimen for metastatic disease, may state the only previous chemotherapy allowed is for adjuvant treatment, or may even state that no prior drug therapy or radiation therapy is permitted for study entry.Assuming that the substantial regulatory approval hurdles are overcome and the new antineoplastic agent enters the market to be employed by cancer specialists in nonresearch care, the critical question concerns the fundamental relevance of such prior treatment restrictions to the routine practice of oncology.
It would be very difficult to argue that a new antineoplastic agent approved for use in metastatic disease should simply be utilized in the adjuvant setting in the absence of a trial demonstrating its utility in this patient population. This would be particularly true if there were an existing alternative approach whose efficacy for the clinical indication had previously been documented in an evidence-based phase III randomized trial.
Perhaps even more relevant in this stated restriction regarding the assumption of clinical utility is that the basic goals of therapy in most metastatic cancers are quite different from those of adjuvant therapy. Although extension of survival with an acceptable adverse event profile is an important aim of therapy in the metastatic setting, the goals are different for adjuvant therapy.
In the adjuvant setting, an increase in the opportunity for “cure” or at a minimum very long-term disease-free survival would be required to justify the delivery of a regimen with known serious toxicities in the absence of direct evidence that the cancer persists in a particular patient. Thus, in view of the fundamental differences in required outcome, it would be inappropriate to simply conclude that a drug that modestly— even if statistically significantly—extends survival in the metastatic setting in a particular cancer type should be employed as adjuvant treatment in the same malignancy.However, the specific question being addressed in this discussion is not the differences between metastatic versus adjuvant therapy, but rather the increasingly realistic possibility that there may be several therapeutic options available in a given tumor type and specifically in the metastatic setting. If both “Drug A” and “Drug B” have been shown to be active in “Metastatic Cancer C” in the firstline metastatic setting, but neither has specifically been examined in a phase III randomized trial when delivered as second-line or third-line therapy, is there any reason to believe that if one initially employed “Drug A” there is anything wrong with subsequently delivering “Drug B”?
And what if three, four, or more anticancer agents were available to consider for use in the metastatic setting? Is there a problem with examining these drugs in sequence in an individual patient if that is the patient’s desire, even if randomized trials have never been performed to specifically address the clinical utility of the individual drugs in the third-, fourth-, or fifth-line settings? An excellent example of the relevance of this question is the experience in advanced ovarian cancer where an increasing number of single cytotoxic agents, and now several single cytotoxic agents combined with the antiangiogenic agent bevacizumab, have demonstrated biological and clinical activity when utilized in the setting of platinum-resistant ovarian cancer.1,2 It should be noted that there is no randomized controlled trial evidence in platinum-resistant ovarian cancer that suggests an optimal sequence of drug delivery or the absence of activity if one particular cytotoxic drug is employed prior to another agent in disease management.
Of course, it is well recognized that cancers tend to become more resistant to the effects of cytotoxic therapy as they are treated with such agents during the natural history of a given malignancy. However, while oncologists are frequently left to use their own best judgment in the absence of definitive data in these settings, there is no inherent reason to believe that an individual anticancer agent demonstrated to be active when delivered in an earlier metastatic setting might not also be active when employed at a later point during the course of the illness. And by “active,” one is referring to the potential that administration of the drug may produce meaningful clinical benefit in an individual patient.
The question posed in this commentary becomes even more relevant with the increasingly rapid introduction of novel anticancer agents into the oncologist’s armamentarium. A given drug approved for commercial use for a particular indication is quite likely to have clearly specified clinical indications, which include the number of previously received antineoplastic regimens. These indications will be based on the criteria employed in the definitive clinical trials that result in regulatory approval.
Considering the fact that many new drugs are compared with a placebo, best supportive care, or a now completely out-of-date standard-of-care study “control arm,” how should an oncologist select an optimal therapy when several reasonable choices exist?
Again, if “Drug A,” newly FDA-approved for first-line treatment of “Metastatic Cancer C,” is delivered, is it acceptable to subsequently administer recently approved “Drug B” in the second-line setting even though the “Drug B” was also specifically tested only as a first-line treatment option in metastatic disease? The recent regulatory approval of several novel highly biologically and clinically active antineoplastic agents in the management of metastatic malignant melanoma demonstrates the problem that will likely become commonplace in an increasing number of tumor types in the future.3-7
Until there is evidence that it is possible to safely combine these drugs and that such a strategy is shown to favorably impact a survival outcome, the optimal use of these drugs will surely be sequential delivery. And, unfortunately, in the absence of clinical trials revealing how to accomplish this goal, oncologists will be required to use their own judgment regarding how to give individual patients their best opportunity to achieve meaningful clinical benefit without experiencing excessive toxicity.
Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. email@example.com.