Platinum chemotherapy, particularly cisplatin, is commonly associated with electrolyte imbalances, including hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia and hyponatremia. The corpus of literature on these dyselectrolytemias is large; the objective of this review is to synthesize the literature and summarize the mechanisms responsible for these particular electrolyte disturbances in the context of platinum-based treatment as well as to present the clinical manifestations and current management strategies for oncologists and primary care physicians, since the latter are increasingly called on to provide care for cancer patients with medical comorbidities. Correct diagnosis and effective treatment are essential to improved patient outcomes.

The first tenet of medicine, “primum non nocere” or “first, do no harm”, is not always compatible with oncological interventions e.g., chemotherapy, targeted therapy and radiation, since they commonly result in significant toxicities. One of the more frequent and serious treatment-induced toxicities is mucositis and particularly oral mucositis (OM) described as inflammation, atrophy and breakdown of the mucosa or lining of the oral cavity. The sequelae of oral mucositis (OM), which include pain, odynodysphagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions and discontinuations that not only negatively impact quality of life but also tumor control and survivorship. One potential strategy to reduce or prevent the development of mucositis, for which no effective therapies exist only best supportive empirical care measures, is the administration of agents referred to as radioprotectors and/or chemoprotectors, which are intended to differentially protect normal but not malignant tissue from cytotoxicity. This limited-scope review briefly summarizes the incidence, pathogenesis, symptoms and impact on patients of OM as well as the background and mechanisms of four clinical stage radioprotectors/chemoprotectors, amifostine, palifermin, GC4419 and RRx-001, with the proven or theoretical potential to minimize the development of mucositis particularly in the treatment of head and neck cancers.

As early as the 1920s, the eminent physician and chemist, Otto Warburg, nominated for a second Nobel Prize for his work on fermentation, observed that the core metabolic signature of cancer cells is a high glycolytic flux. Warburg averred that the prime mover of cancer is defective mitochondrial respiration, which drives a switch to an alternative energy source, aerobic glycolysis in lieu of Oxidative Phosphorylation (OXPHOS), in an attempt to maintain cellular viability and support critical macromolecular needs. The cell, deprived of mitochondrial ATP production, must reprogram its metabolism as a secondary survival mechanism to maintain sufficient ATP and NADH levels for macromolecule production, membrane integrity and DNA synthesis as well as maintenance of membrane ionic gradients. A time-tested method to identify and disrupt criminal activity is to "follow the money" since the illicit proceeds from crime are required to underwrite it. By analogy, strategies to target cancer involve following and disrupting the flow of ATP and NADH, the energetic and redox "currencies" of the cell, respectively, since the tumor requires high levels of ATP and NADH, not only for metastasis and proliferation, but also, on a more basic level, for survival. Accordingly, four broad ATP reduction strategies to impact and potentially derail cancer energy production are highlighted herein: 1) small molecule energy-restriction mimetic agents (ERMAs) that target various aspects of energy metabolism, 2) reduction of energy 'subsidization' with autophagy inhibitors, 3) acceleration of ATP turnover to increase energy inefficiency, and 4) dietary energy restriction to limit the energy supply.

RRx-001 is a cysteine-directed anticancer alkylating agent with activity in a Phase II study in platinum refractory small cell lung cancer. Here, we describe the design of REPLATINUM, an open-label, Phase III trial. 120 patients with previously platinum-treated small cell lung cancer in third line will be randomized 1:1 to receive RRx-001 followed by four cycles of a platinum doublet, and then alternating cycles of RRx-001 and single agent platinum until progression versus four cycles of a platinum doublet. At radiologic progression on the platinum doublet, patients may cross over to the RRx-001 arm. Primary objective: to demonstrate superior progression-free survival in the RRx-001 population. Secondary objectives: to demonstrate superiority for overall survival and objective response rate. Clinical Trial registration: NCT03699956

Overall survival (OS) has emerged as the definitive regulatory “be-all, end-all” for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a “test of time,” OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of clinical trials. Second, OS captures the impact of subsequent therapies, both beneficial (i.e., active) and detrimental, on survival but it does not take into account the contribution of subsequent therapies by treatment arm; the postprogression period is treated as an unknown black box (no information about the potential influence of next-line therapies on the outcome) under the implicit assumption that the clinical trial treatment is the only clinical variable that matters: what OS explicitly measures is the destination, that is, the elapsed time between the date of randomization (or intention to treat) and the date of death, not the journey, that is, what transpires in-between.In long-term maintenance strategies, patients receive treatment in temporally separated but mutually interdependent and causally linked sequences that exert a “field of influence” akin to action-at-a-distance forces like gravity, electricity, and magnetism on both the tumor and each other. Hence, in this setting, a new end point, PFS2, is required to measure this field of influence. This article reviews the definition and use in clinical trials of PFS2 and makes the case for its potential applicability as a preferred end point to measure the mutual influence of individual regimens in long-term maintenance strategies with resensitizing agents in particular.