Is it time for a new paradigm for systemic cancer treatment? Lessons from a century of cancer chemotherapy

Abstract

U.S. SEER (Surveillance Epidemiology and End Results) data for age-adjusted mortality rates for all cancers combined for all races show only a modest overall 13% decline over the past 35 years. Moreover, the greatest contributor to cancer mortality is treatment-resistant metastatic disease. The accepted therapeutic paradigm for the past half-century for the treatment of advanced cancers has involved the use of systemic chemotherapy drugs cytotoxic for cycling cells (both normal and malignant) during DNA synthesis and/or mitosis. The failure of this therapeutic modality to achieve high-level, consistent rates of disease-free survival for some of the most common cancers, including tumors of the lung, colon breast, brain, melanoma, and others is the focus of this paper. A retrospective assessment of critical milestones in cancer chemotherapy indicates that most successful therapeutic regimens use cytotoxic cell cycle inhibitors in combined, maximum tolerated, dose-dense acute treatment regimens originally developed to treat acute lymphoblastic leukemia and some lymphomas. Early clinical successes in this area led to their wholesale application to the treatment of solid tumor malignancies that, unfortunately, has not produced consistent, long-term high cure rates for many common cancers. Important differences in therapeutic sensitivity of leukemias/lymphomas versus solid tumors can be explained by key biological differences that define the treatment-resistant solid tumor phenotype. A review of these clinical outcome data in the context of recent developments in our understanding of drug resistance mechanisms characteristic of solid tumors suggests the need for a new paradigm for the treatment of chemotherapy-resistant cancers. In contrast to reductionist approaches, the systemic approach targets both microenvironmental and systemic factors that drive and sustain tumor progression. These systemic factors include dysregulated inflammatory and oxidation pathways shown to be directly implicated in the development and maintenance of the cancer phenotype. The paradigm stresses the importance of a combined preventive/therapeutic approach involving adjuvant chemotherapies that incorporate anti-inflammatory and anti-oxidant therapeutics.

Keywords: adjuvant; anti-inflammatory; anti-oxidant; chemotherapy; drug resistance; neoplasm; tumor microenvironment.

FIGURE 1

Age-adjusted mortality rates for all cancers combined, US SEER data (Howlader et al., 2011).

FIGURE 2

Age-adjusted mortality rates for specific cancer types in males and females, all races combined, US SEER data (Howlader et al., 2011).

FIGURE 3

Age-adjusted mortality rates for specific cancer types in females, all races combined, US SEER data (Howlader et al., 2011).

FIGURE 4

Age-adjusted mortality rates for specific cancer types in males, all races combined, US SEER data (Howlader et al., 2011).

FIGURE 5

Development of a successful combined chemotherapy approach for childhood acute lymphoblastic leukemia (ALL) that ultimately became a therapeutic model for the treatment of systemic cancers of many types. In 2012 the cure rate for childhood ALL is 90%. (Photo: Archive St. Jude’s Hospital). “November 12, 1970 – Dr. Rhomes J. A. Aur, of St. Jude Children’s Research Hospital, with Steven Ray of Jackson, Miss. who has been receiving treatment for leukemia for 2 years. Announcement of a 17% cure rate in leukemia was made at the hospital today.”

FIGURE 6

dUS SEER data on mortality rates of several leukemias and Hodgkin’s lymphoma that have seen a precipitous decline since 1975 resulting from dose-dense combined chemotherapy MTD therapies (Howlader et al., 2011).

FIGURE 7

Growth fraction model suggests that tumors consist of pools of both proliferating and non-proliferating cells, with only the former category possessing the intrinsic biological capacity to respond to drugs that specifically target dividing cells. Differential localization of cells within a solid tumor give rise to marked gradients in the rate of cell proliferation as a result of decreasing diffusion rates for oxygen, nutrients, and growth factors-associated abnormal vascularization of the solid tumor interior. Intrinsic chemotherapy resistance results when non-dividing cancer cells do not respond to S- and M-phase chemotherapy drugs that block cell proliferation by virtue of the fact that they are not in either the S- or M-phase of the cell cycle at the time of treatment (Komarova and Wodarz, 2005).

FIGURE 8

Physiological connections that may link cancer prevention and treatment. Excessive ROS (reactive oxygen species) due to aging or environmental exposure damage mitochondria and promote glycolytic switch characteristic of tumor cells. Inflammation and ROS activate NF-kB and other transcription factors that drive tumor progression. Anti-inflammatory agents and anti-oxidants prevent cancer by blocking systemic and microenvironmental changes that promote incipient tumor development and systemic disease progression. In the therapeutic setting, their long-term use restores systemic environment that blocks disease progression and/or recurrence.