Tumor Hypoxia

The equally intriguing phenomenon of tumor hypoxia has been documented to occur in a number of tumor types including cancers of the uterine cervix , head and neck , bladder as well as in soft tissue sarcomas . This is the result of inadequate blood supply to tissues that leads to the compromise of biological function and in the case of cancers this is usually related to abnormal or inadequate blood vessels, anemia, or the formation of methemoglobin or carboxyhemoglobin that will reduce the oxygen carrying capacity of the blood in smokers. 

There have been several observations collected over the last few decades that suggest that tumor hypoxia plays a key role in outcome. These observations are as follows: tumors often have lower median partial pressures of oxygen than their tissues of origin ; the presence of tumor hypoxia cannot necessarily be reliably predicted by factors like stage, size, histology, or grade; tumor-to-tumor oxygen variability is often greater than intratumor oxygenation 

differences , and recurrent tumors often are more poorly oxygenated than their corresponding primary tumor.

While the controversy about the exact role that anemia plays in determining outcome from radiation therapy is age old, i.e., big tumors bleed more and are more likely to spread vs tumors in anemic patients tend to be more hypoxic and hence more resistant to therapy, evidence is accumulating to suggest that reality is firmly rooted between both views. Radiosensitivity is known to be significantly limited when the partial pressure of oxygen is less than 25–30 mmHg. 

It has been known for years that molecular oxygen will increase radiation-induced DNA damage through the formation of oxygen free radicals that act to inflict “indirect” damage beyond the “direct” effects of radiation on DNA . There is also substantial evidence obtained over the last few years that tumor hypoxia induces genomic changes with subsequent upregulation of genes that are linked to radiation resistance . Equally compelling are the experiments that have revealed that presence of tumor hypoxia is linked to an increased incidence of metastatic disease .
The microenvironmental signals in a hypoxic tumor environment are such that there is greater genomic instability and selection pressure to maintain those cells with increased angiogenic potential and decreased apoptotic potential. Improved understanding of this interesting phenomenon will ultimately lead to improved potential for therapeutic targeting of tumors.

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Chemoradiation In Cancer Therapy

The medical uses of ionizing radiation have expanded dramatically since Wilhelm Roentgen first discovered it at the end of the last century. In particular, it has proven to be an effective agent in the ongoing battle against cancer. It is presumed that the essential target for radiation is cellular DNA where it acts through the formation of free radicals to directly or indirectly cause double-stranded breaks. It is these doublestranded breaks in the DNA that are felt to be the lethal lesion that malignant cells sustain from therapeutic radiation.
It was in the period of World War II that it was possible to induce lasting remissions
and potential cures of hematological malignancies with nitrogen mustard (1), which was
really the first chemotherapeutic agent put to widespread use in the treatment of malignant
disease. Since that time, a multitude of other drugs have come and gone in the search
for a cure. A few drugs appear to have found a more lasting place in the therapeutic
armamentarium, including doxorubicin, cisplatinum, cyclophosphamide, and 5-fluorouracil.
A new generation of drugs with varied mechanisms of action has appeared in
the last decade and also has the potential to remain as key in the treatment of cancers.
These agents include paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine.
Although oncologists and researchers have often tried to cure cancers with radiation
alone or with various chemotherapeutic strategies, in general these have been met with
limited success for any number of reasons, which will be outlined below. The strategy of
integrating different treatment modalities into a more comprehensive approach to both
local control and the treatment of micrometastatic disease, often referred to as combined
modality therapy, has been met with some success. Although the delivery of neoadjuvant
and adjuvant chemotherapy may contribute to improved local control, it is less clearly
demonstrable than with concurrent therapy. This chapter will focus on combined modality
therapy with an emphasis on concurrent chemoradiation. It will attempt to set the
background with an examination of the rationale and the difficulties that are inherent with
concurrent therapy from the point of view of both the delivery of radiation and of chemotherapy.
Beyond this it will illustrate some of the gains achieved in therapy using a
concurrent treatment approach. Finally it will focus on the potential for the future that lies
in an increased understanding of the molecular players in neoplastic processes as well as
the response of malignant cells to therapy with radiation and chemotherapy. The integration
of new agents that are aimed against more specific cellular targets than either
radiation or traditional cytotoxic chemotherapy may significantly influence the success
of combined modality therapy in the future.

TREATMENT PARADIGMS
Surgical therapy as a sole modality often fails because micrometastatic disease is
already present at the time of surgery or because malignant cells are present beyond the
surgical margins of the resection. Radiation therapy is sometimes added before or after
surgical resection to decrease the possibility of local recurrence when it is felt that there
is a high enough probability of residual malignant cells being present after surgery.
However, radiation therapy as both a sole modality of treatment or as an adjuvant or
adjunctive therapy may fail to sterilize tumors because of micrometastases or because the
dose of radiation that can be safely delivered is limited by the tolerance of the surrounding
normal tissues. Certainly the explosion of new technology in the current computer age
has improved our ability to deliver further radiation in a more conformal fashion. However,
in those malignancies that have a high propensity for distant spread of disease,
delivery of higher doses of conformal radiation may not prove to be a satisfactory approach
to the problem. Unfortunately chemotherapy rarely proves to have a curative role on its
own in the treatment of solid tumors.

 

BIOLOGY COMPLICATES THE DELIVERY OF RADIATION
The delivery of therapeutic radiation is limited by the tolerance of the surrounding
normal tissues. Data have been compiled over many years that suggest which structures
are able to tolerate certain doses with acceptable amounts of toxicity (2). This model for
thinking about how to plan the delivery of radiation has changed considerably with the
advent of new computer- and automation-driven technologies that allow for the more
conformal delivery of dose to the gross tumor and to the clinical target volume. New
analytical tools called dose volume histograms, which allow for a definition of the dose
delivered to a percentage of an organ, have begun to replace more traditional concepts of
normal tissue tolerance. Although these technology-related advances allowfor the delivery of higher doses of radiation, this may only be an effective strategy in those
tumors whose biology makes them amenable to a local therapy as the sole modality of
treatment. Those tumors that have a predilection for the early dissemination of
micrometastases cannot be effectively treated by a local therapy alone. However, those
tumors that tend to remain localized for longer periods of time may have several biologic
reasons that underlie their resistance to radiation.

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