Abstract
BackgroundA select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years. However for the more common metastatic malignancies chemotherapy treatment frequently brings clinical benefits but cure is not expected. Clinically this clear divide in outcome between the tumour types can appear at odds with the classical theories of chemotherapy sensitivity and resistance that include rates of proliferation, genetic development of drug resistance and drug efflux pumps. We have looked at the clinical characteristics of the chemotherapy curable malignancies to see if they have any common factors that could explain this extreme differential sensitivity to chemotherapy.DiscussionIt has previously been noted how the onset of malignancy can leave malignant cells fixed with some key cellular functions remaining frozen at the point in development at which malignant transformation occurred. In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma. These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage. To investigate this hypothesis we have examined the natural history of the healthy cells during these processes and the chemotherapy sensitivity of malignancies arising before, during and after the events.SummaryTo add to the debate on chemotherapy resistance and sensitivity, we would argue that malignancies can be functionally divided into 2 groups. Firstly those that arise in cells with naturally heightened apoptotic potential as a result of their proximity to the unique genetic events, where the malignancies are generally chemotherapy curable and then the more common malignancies that arise in cells of standard apoptotic potential that are not curable with classical cytotoxic drugs.
Highlights
A select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years
Those that arise in cells with naturally heightened apoptotic potential as a result of their proximity to the unique genetic events, where the malignancies are generally chemotherapy curable and the more common malignancies that arise in cells of standard apoptotic potential that are not curable with classical cytotoxic drugs
Summary and therapeutic implications The historical explanations for chemotherapy sensitivity and resistance usually include the concepts of rates of growth, mathematical risks of the development of resistance, drug efflux pumps and changes in DNA repair mechanisms
Summary
Review of metastatic malignancy chemotherapy curability In 2015 it is perhaps challenging to understand quite the impact produced by the early success of cytotoxic chemotherapy treatment. The revolution in care that took place from 1955–1980 is perhaps the most dramatic that will be seen in cancer treatment development. In this period a number of malignancies that predominantly affected younger patients and were previously nearly uniformly fatal moved to becoming routinely curable, both in the major academic centres and in routine clinical care [3,28]
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