Ten Best Readings
Ten Best Readings in Combined Radiation and Chemotherapy
Henry Wagner, Jr, MD
Thoracic Oncology Program,
H. Lee Moffitt Cancer Center & Research Institute
Haimovitz-Friedman A, Kan CC, Ehleiter D, et al. Ionizing radiation acts on cellular
membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994;180:525-535.
The classic radiobiologic teaching of 20 years ago instructed that the direct or
indirect effects of ionizing radiation on DNA were responsible for cell death. This
investigation demonstrates that radiation of bovine aortic endothelial cells or cell
membranes in a nuclei-free system can activate portions of a signal transduction pathway
involving hydrolysis of the membrane lipid sphingomyelin to yield ceramide, which
activates a downstream serine-threonine protein kinase. This radiation-activated pathway
leading to apoptosis was blocked by activation of protein kinase C, suggesting points for
possible pharmacologic modulation of radiosensitivity.
Perego P, Giarola M, Righetti SC, et al. Association between cisplatin resistance
and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer
Res. 1996;56:556-562.
Studies demonstrate a mechanism of resistance to radiation and a chemotherapeutic
agent based on a lack of intact downstream biochemical pathways leading to apoptosis
rather than a failure to register initial damage or efficiently repair damage.
Powell SN, DeFrank JS, Connell P, et al. Differential sensitivity of p53(-) and
p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer
Res. 1995;55:1643-1648.
The authors suggest a therapeutic strategy of identifying agents that at clinically
achievable levels are able to override the G2-M division checkpoint and using these agents
in conjunction with ionizing radiation (and possibly also agents such as cisplatin) in
tumors with impaired p53 function. Methylxanthines with little stimulation to the central
nervous system and other checkpoint inhibitors have promise as genome-specific
radiosensitizers.
Huschtsacha LI, Bartier WA, Ross CE, et al. Characteristics of cancer cell death
after exposure to cytotoxic drugs in vitro. Br J Cancer. 1996;73:54-60.
Morphologic and biochemical manifestations of cell death were observed in acute
leukemia cells following treatment with a variety of cytotoxic agents of diverse
mechanisms of action. Perturbations in the cell cycle were the first changes seen with all
agents. Morphologic changes associated with apoptosis was seen with all agents, but the
pattern and timing varied with different agents. The authors recommend that investigations
of the mechanisms of cell death use several different methodologies (eg, morphology, DNA
electroph-oresis, flow cytometry, clonogenic survival) rather than rely on a single
parameter.
Rubin P, Johnston CJ, Williams JP, et al. A perpetual cascade of cytokines
postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys.
1995;33:99-109.
Two competing models for radiation damage to normal tissue have been the depletion of
clonogens in the relevant normal tissue and the disruption of normal vascular supply to
the organ by radiation killing of endothelial cells. Fibrosis was considered to be a
secondary - and largely passive - phenomenon. Using mice that were genetically prone to
developing radiation fibrosis, the authors showed that a single radiation fraction was
followed by prolonged elevations of inflammatory cytokines such as interleukin 1-alpha,
proliferative cytokines such as transforming growth factor-beta, and the expression of
collagen mRNA. Radiation-induced cytokines and other proteins in radiation effects, to
normal tissues as well as to tumor clonogens, are important additions to our understanding
or radiation biology.
West CM, Elyan SA, Berry P, et al. A comparison of the radiosensitivity of
lymphocytes from normal donors, cancer patients, individuals with ataxia-telangiectasia
(A-T) and A-T heterozygotes. Int J Radiat Biol. 1995;68:197-203.
It has long been recognized that some patients have severe acute or late complications
following radiation therapy. While most of these are idiosyncratic, several syndromes,
such as ataxia-telangiectasis (A-T), predictably lead to these outcomes. Since
heterozygosity for the A-T gene is common, complications seen in these individuals may
impact significantly on our impression of overall radiation-tolerance doses.
Radiation-toleration doses generally are based on uncommon but severe complications. If it
can be shown that these are predictable on this or other genetic bases in most cases, it
may be possible to safely increase doses to individuals not genetically predisposed to
such complications, thus improving the likelihood of local tumor control.
Graf WD, Chance PF, Lensch MW, et al. Severe vincristine neuropathy in
Charcot-Marie-Tooth disease type 1A. Cancer. 1996:77;1356-1362.
The theme of this article parallels that of the preceding article, but the focus is on
toxicity of chemo-therapy rather than radiation therapy. Individuals who sustained severe
and persistent sensory and motor neuropathy following modest individual and cumulative
doses of vincristine are described. All had a 19p11.2-12 duplication, which is associated
with a hereditary motor-sensory neuropathy (Charcot-Marie-Tooth) disease. The authors also
raise the possibility that other pre-existing (albeit subclinical) neurologic disorders
may predispose individuals to severe drug complications.
Komaki R, Meyers CA, Shin DM, et al. Evaluation of cognitive function in patients
with limited small cell lung cancer prior to and shortly following prophylactic cranial
irradiation. Int J Radiat Oncol Biol Phys. 1995;33:179-182.
The controversy regarding the role of prophylactic cranial irradiation (PCI) for
patients with small cell lung cancer hinges on its efficacy and toxicity. There is concern
that benefits are counterbalanced by neurologic toxicity that has been attributed to
cranial irradiation when administered alone or particularly when given in association with
concurrent chemotherapy. This trial suggests no change in psychometric measurements
occurred in patients receiving PCI. Thus, late events should not be attributed solely to
treatment without knowledge of the patient's pretreatment status and the natural history
of the disease process.
Ahles TA, Silberfarb PM, Rundle AC, et al. Quality of life in patients with limited
small-cell carcinoma of the lung receiving chemotherapy with or without radiation therapy,
for cancer and leukemia group B. Psychother Psychosom. 1994;62:193-199.
The findings reported in this study support the importance of using measures of
quality of life in addition to measures of physical toxicity so that patients can make an
informed choice regarding treatment options.
Aaronson NK, Visser-Pol E, Leenhouts GH, et al. Telephone-based nursing intervention
improves the effectiveness of the informed consent process in cancer clinical trials. J
Clin Oncol. 1996;14:984-996.
The authors demonstrate that telephone-based nursing interventions can enhance patient
education. This technique could assist management of the toxicities from combined
radiation and chemotherapy for intrathoracic neoplasms.
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Journal Volume 3 Number 4