Nontoxic, fiscally responsible, future of oncology: could it be beginning in the Third World?

In this issue of the journal, a prospective pediatric study by Fousseiny et al 1 evaluating a multidrug metronomic regimen in children with difficult-to-treat malignancies in Mali, is presented. It examines, for the first time in a prospective manner, the applicability of using established, off-patent agents in an alternative ‘‘metronomic’’ regimen. The authors, indirectly, make the case, that attainment of stable disease may be a valid alternative in places in which tertiary care necessary for the use of more toxic therapies may be difficult to provide, or in places where cost of novel biological response modifiers is prohibitive. The work suggests that even when there are no limitations or constraints on resources, a complete remission does not always translate to an increased overall survival, and the paradigm of disease control with less toxicity is worth pursuing. The concept of ‘‘cancer without disease’’ seems to be growing in acceptance. Unless a significant change in international health care policies occurs, experimental therapeutics are unlikely to make a significant impact in Third World countries and alternatives are badly needed. The authors suggest that the use of inexpensive, widely available agents in a minimally toxic metronomic chemotherapy setting should be explored, and provide the first example of such an effort. We agree that a well-designed metronomic chemotherapy regimen combining drugs with nonoverlapping toxicities may provide a viable option for the care of children with malignancies in countries where access to medical care and resources is limited. For one, it may change the still prevalent perception in these countries that cancer is always an incurable disease and causes rapid demise. Metronomic therapy may also create an option of keeping children alive longer with nontoxic therapies and good quality of life. As discussed below, even when resources are less limited and the ‘‘more is better’’ mentality is the prevailing public perception, a more rational use of information may lead to less expensive and better anticancer therapy. The concept of metronomic chemotherapy was introduced in 2000, but the general acceptance of the model has been hindered by inconsistencies in its definition. Since the initial introduction, the meaning of metronomic chemotherapy is continuously being redefined. Although almost everyone understands it to mean combination therapy using continuous, frequent, low doses of chemotherapeutic agents with an angiogenic, stromal, or more recently, immunologic target, most clinicians interpret this to simply mean frequent administration of established chemotherapeutic drugs at doses below the maximal tolerated dose (MTD). Thus, what constitutes ‘‘low’’ dose, how ‘‘frequent’’, or what agent, is continuously being renegotiated, redefined, and revised. The historical understanding of chemotherapeutic goals, that is a remission induction through the use of MTDs, often leads investigators to simply divide the MTD of the usual agent used to treat a particular tumor into weekly doses. It is unclear why weekly, but the most likely explanation is that weekly may be the highest frequency that a patient can be reasonably expected to attend the clinic for intravenous therapy. Rarely, frequency is based on the half-life of the agent used or on the inhibition of the target (generally an enzyme or another protein). This leads to a random and very erratic manner in which doses and frequencies are chosen. Unfortunately, until more information is available and until new oral agents are developed, the manner in which metronomic chemotherapy is applied is unlikely to change. Until this happens two main guiding principles should be observed. The intensity of a therapy should be based on the number of days rather than the total amount per dose. We should strive for the ‘‘minimally effective concentration’’ that will give the desired outcome, rather than a standard cumulative dose. Comparing and contrasting the field of oncology with other fields of medicine, the treatment of patients with infectious diseases, hypertension, and seizures