Principles of Chemoradiation: Theoretical and Practical Considerations (2023)

Chemotherapy agents known to potentiate the effects of radiation in preclinical studies have been used alongside radiation therapy in several clinical trials with the prospect of further potentiating radiation-induced

ABSTRACT: Chemotherapy agents known to potentiate the effects of radiation in preclinical studies have been used concurrently with radiation therapy in several clinical trials with the prospect of further improving radiation-induced local tumor control. While some success in several tumor histologies has been achieved using this approach, a major concern has been enhancement of normal tissue toxicity. This brief review addresses both theoretical and practical issues regarding clinical trials of chemoradiation. Recommendations for clinical trials are provided which, if implemented, may increase our understanding of basic mechanisms (in patients) and provide a more rational approach to future trials.[ONCOLOGY 13(Suppl 5):11-22,1999]


Despite advances and refinements in cancer treatment and an emphasis on early detection, the vast majority of malignancies are not effectively treated. Knowledge of the complex nature of human cancer is growing exponentially as modern molecular biology and genetics reveal potential targets to combat and perhaps one day prevent this terrible disease. Nevertheless, there is still a need to fully develop and optimize combined modality cancer treatment to help patients who will not have the opportunity to benefit from the molecular biology revolution.

The combined use of radiotherapy and chemotherapy in cancer treatment is a logical and reasonable approach that has already been shown to be beneficial for several malignancies. Local control of the primary tumor mass (which can often be achieved by high-dose radiation), combined with systemic chemotherapy to control metastatic disease, should provide effective means of combating such a highly complex disease. Furthermore, the discovery that many chemotherapy drugs potentiate the effects of radiation provides even more impetus to integrate both modalities.

The emergence of concurrent chemoradiation dates back to the 1950s, when investigators began searching for chemical agents that could enhance the effects of radiation.[1,2] In 1958, Heidelberger et al. potentiation of activity by combining fluorouracil with radiation in a preclinical study.[3] They treated transplanted murine tumors with fluorouracil 20 mg/kg/day for 7 days and radiation doses of either 15 or 20 Gy. These pioneering studies were later translated into clinical trials, often with conflicting results, such as those observed in the treatment of lung cancer.[4,5] However, a major breakthrough was achieved in the early 1970s, when the were encouraged by the results obtained with chemoradiotherapy at the Mayo Clinic on gastrointestinal cancers[6,7] Nigro and colleagues used a combination of fluorouracil and mitomycin concurrently with radiation as neoadjuvant therapy in patients with rectal cancer. They reported that three out of three patients achieved complete responses.[8] In two of the three patients, an abdominoperineal resection was performed 2 months after treatment. Histological examination of tissue samples confirmed a pathological complete response. The other patient refused surgery but was alive and clinically free of disease 14 months after treatment. Although the study included only a small number of patients, the results of this initial pilot study (and subsequent clinical trials) were so dramatic that they led to a paradigm shift in oncologists' thinking away from exonerative surgery for anal cancer. Since the 1970s, several chemoradiation trials have been performed with varying degrees of success in a variety of cancer histologies.

It is most reasonable to consider why chemoradiation is so successful in the treatment of one cancer histology and yet produces only varying levels of success in others. Furthermore, it is also reasonable to explore the limitations of chemoradiation. The major limitation of combining two modalities has been cumulative normal tissue toxicity. Both modalities, when used alone, can cause severe toxicity in normal tissue, which in some cases can be life-threatening. The onset of normal tissue toxicity limits the dose that can be achieved by either modality alone and thus compromises the administration of the drug or radiation dose. Most experimental models and a number of clinical trials with combined medicine and radiation simultaneously show that the toxicity in the normal tissue can be further enhanced.[9,10] Thus, a major barrier in the use of radiation or chemotherapy for the treatment of cancer is either alone or in combination is lack of specificity.

A photon beam, no matter how well shaped or adapted to the dimensions of the tumor, will undoubtedly irradiate some normal tissue. The radiosensitivity of tumor and normal tissue is often similar, or in some cases the tumor cells may unfortunately be more resistant than surrounding normal tissue. Radiation alone can and does damage normal tissue if threshold doses are exceeded. Systemic drug therapy theoretically exposes all tissues, both normal and tumors, to cytotoxic action. Normal tissue toxicity often exceeds tumor cytotoxicity, or effective tumor cell cytotoxicity is compromised by reducing the dose to reduce normal tissue toxicity to an acceptable level. During chemotherapy, patients often relapse after initial treatment and become progressively less responsive to second- or third-line therapies.[11] Combined modality therapies further complicate these issues. It is the harsh realities of combined modality therapy that must be addressed if cancer care is to be improved using multimodality approaches.

Rational and systematic collaboration between basic researchers and clinicians makes it possible to create treatment methods that work. This article will focus on several aspects of combined modality therapy that should be considered. Space does not permit review of every single radiation dose modifying agent in current use; however, the reader is referred to several fine reviews that provide more detail, particularly regarding specific drugs and radiosensitization.[12-14]

The Ideal Radiation Modifier

When considering the combination of one or more chemotherapy drugs (or radiation modifying agent(s)) with radiation, it is important to understand the mechanisms of action of each modality, how these mechanisms may overlap to enhance one or the other, and how one effectively times each agent to provide maximum benefit. It is perhaps worth asking the question, If one could design an ideal radiation modifier, what would its properties be? Table 1 highlights the characteristics of an ideal radiation modifier.

Considering an ideal modifier may be a lofty ambition, but it nonetheless provides a standard to aim for. In principle, the ideal radiation modifier shown in Table 1 allows to deliver more radiation dose to the tumor (in the case of a protector) and more effective dose (in the case of a sensitizer). Most experimental tumors and most human primary tumors respond to radiotherapy in a dose-dependent manner in terms of response and cure. The more dose delivered to the tumor, the greater the likelihood of tumor cure. Likewise, an ideal radiation sensitizer has effective antitumor activity against metastatic disease, a major determinant of long-term, disease-free survival. In reality, an ideal radiation modifier does not yet exist, but we can use the properties of an ideal radiation modifier as a standard as new chemoradiation agents become available.

Radiation sensitizers

The main reason to consider the use of a radiation sensitizer is to improve local control of the disease. A radiosensitizer may not have a direct anticancer effect (as is the case for some hypoxic cell radiosensitizers), or it may be one of a number of anticancer drugs that, in addition to radiosensitization alone, exhibit antitumor effects. Understanding the mechanism of action of a specific radiosensitizer can influence the way it is used in the clinic. In general, the mechanism by which agents sensitize cells to radiation can be categorized into three broad areas, as discussed below.

Increase in initial damage

Radiation-induced cellular effects result from the production of free radicals and/or direct ionization of target molecules. The exact identification of critical cellular structures or molecules and the specific type of damage caused by radiation is not completely known. However, considerable evidence points to DNA as the critical target of radiation damage,[15] with DNA double-strand breaks as the lethal lesion.[16] Cells die after radiation treatment by mitotic-linked death and/or programmed cell death (apoptosis). An agent that causes more initial damage to critical cellular targets would be expected to potentiate the cytotoxic effects of radiation if repair systems become saturated. Halogenated pyrimidines, which enhance the radiation response in part by increasing damage, have been used in chemoradiation studies. Incorporation of halogenated pyrimidines into cellular DNA has been shown to increase DNA damage[17] as well as compromise repair systems[18], as discussed below.

Repair inhibition

The ability to repair radiation damage is a vital and necessary cellular function. Repairs in this context fix or undo the damage to a structure or molecule that is necessary for viability and function. There are several likely ways in which cells can achieve this goal. First, molecules that chemically repair damaged molecules may be present in cells. An example would be a reducing species that could donate electrons to oxidized (damaged) substrates. Second, there may be a variety of enzymatic systems that can recognize and repair damaged substrates through a set of complex, ordered reactions. Finally, in a very loose sense of repair, there may be cellular systems that prevent damage before it occurs. Such systems would involve detoxification of toxic species by either chemical or enzymatic means.[19,20] Much is being learned about the specific enzyme(s) responsible for the repair of radiation damage; undoubtedly in the future specifically targeting these enzymes will provide another opportunity for chemoradiation studies.

The radiation dose-response curve for most human tumor cell lines derived from solid tumors is characterized by a shoulder in the low-dose region of the curve.[21] The implication of the shoulder region of the curve is that cells have the capacity to repair radiation damage, especially for radiation doses delivered in radiotherapy (~2 Gy). Extensive studies show that the time required for maximum radiation damage repair varies between 3 and 6 hours.[22] The extent of repair depends on the particular cell type and can be quite significant, especially in tumors that do not respond well to radiation, such as melanoma and glioblastoma. Normal tissue can also repair radiation damage to varying degrees. Time-dependent repair of normal tissue is the main reason why the radiation dose is fractionated. Thus, cells of tissue treated with 2 Gy on Monday morning will have repaired all the damage they are capable of repairing when the next fraction is given on Tuesday, and so on. Ideally, agents that inhibit repair of radiation damage (in the tumor) should be present daily while radiation is administered. Due to the lack of specificity of most agents currently used, normal tissue may also be radiosensitized.

Cell-cycle redistribution

Tumor growth is governed by (1) the fraction of cells in the tumor that are actively dividing (cycling vs resting cells); (2) the duration of the cell cycle; and (3) the cell loss factor.[23] It has been known for more than 30 years that cells vary in their response to radiation as a function of their position in the cell cycle;[24] cells in G2/M at the time of irradiation are approximately three times more sensitive than cells in late S phase/early G1. The exact reason(s) for the variation in sensitivity to ionizing radiation throughout the cell cycle is not known. An agent that selectively blocks tumor cells in a radiosensitive phase may provide a means of significant radiosensitization.

Many chemotherapeutic agents are capable of inflicting cell cycle blocks with subsequent radiosensitization.[25] For example, preclinical studies have shown that paclitaxel (Taxol), a drug currently being evaluated in chemoradiation clinical trials, imposes a significant G2/M blocks and radiosensitizes many human tumor cell lines[26,27] and murine tumor models.[28] Figure 1 shows the dependence of G2/M block for radiosensitization of MCF7 breast cancer cells. Note that radiosensitization did not occur until cells were depleted from S phase into G2/M.

Armed with encouraging preclinical results, a number of institutions are evaluating the combination of paclitaxel and radiation in a variety of tumor types. Will the preclinical information and enthusiasm be translated into benefits for cancer patients? The answer to this question must await the results of the experiments. But are the trials combining paclitaxel and radiation properly designed for success, and perhaps just as importantly, if the trials fail, will we know why? These are difficult questions to answer.

Clinical trials are traditionally launched with the assumption that the results and possibly the mechanisms observed using in vitro and in vivo laboratory models will translate to the human model. This is a minimal assumption. Unfortunately, few clinical studies are designed to actually determine whether anticipated mechanisms are operational in the human model. Preclinical studies showed that for paclitaxel to radiosensitize, cells must move through the cell cycle to block in G2/M.[27] Celler i plateaufase (G0) are not radiosensitized by paclitaxel.[27] Therefore, tumors with a low growth fraction (few cells cycling) are not expected to be radiosensitized to the same extent as tumors with high growth fractions. Considerable data are available regarding the growth kinetics of human tumors;[29] therefore, phase II trials should initially be conducted to treat those tumors that have the best chance of response.

Dose effect factor/therapeutic benefit

In order for an agent to be considered for use in chemoradiation, preclinical studies are usually performed. Radiation dose-response curves are generated for a variety of tumor cell types in the absence and presence of the drug. Depending on what is known about the drug's mechanism of action, different concentrations and exposure durations are investigated either before, during or after radiotherapy. After the cytotoxicity of the drug treatment alone is normalized, the effect of the drug on radiosensitivity can be assessed for a given endpoint.

For cell survival curves, the dose-effect factor is calculated at a given survival level. The dose of radiation alone required to produce a given level of survival is divided by the dose to produce the same level of survival for the radiation/drug combination. If the ratio gives a number > 1, the radiation response amplifies; similarly, if the agent gives a ratio < 1, the agent protects. Dose-effect factors can be determined not only for cells in culture, but also for tumor and normal tissues in animal models.[14] Determination of dose-effect factors in animal models allows determination of the therapeutic benefit, which is calculated by dividing the dose-effect factor for the tumor by the dose-effect factor for the normal tissue. For chemoradiation to be successful, a therapeutic gain > 1 is the goal.

In reality, however, the determination of a meaningful therapeutic benefit in experimental models is both arduous and difficult to interpret. It is cumbersome in the sense that combined chemoradiation studies in animals are time-consuming, expensive, and may involve numerous permutations of drug concentrations and timings. It is difficult to interpret because most rodent tumor models, with their rapid growth kinetics, do not reflect human tumors. Human tumor xenografts in immunocompromised mice are an alternative to rodent tumors; however, these are human tumors that grow under the control of mouse physiology. On the other hand, the radiation response of normal tissue in mice closely corresponds to the response seen in humans,[14] and can give the clinician an idea of ​​which and to what extent normal tissue is vulnerable.

Because of the problems discussed above, new agents are often brought to clinical trials with chemoradiation without information on preclinical therapeutic benefit. Commonly, dose-effect factors are determined for cell lines (human tumor), and perhaps a few studies have been performed in mice regarding the effectiveness of tumor response with combination therapy. Murine normal tissue dose effect factors are rarely determined. It can be rationalized that most new agents being considered for chemoradiation have already undergone clinical trials as single agents and much is already known about their toxicity profiles. What is not known, however, is the extent to which radiation will exacerbate these toxicities. Given these realities, what dose-effect factor value (primarily derived from in vitro studies) warrants the introduction of a new agent for chemoradiation evaluation (ie, 1.1, 1.5, 2.0, or higher)? This question is actually difficult to answer.

A dose-effect factor of 1.1 means that a radiation dose will be increased by 10%, a seemingly modest amount. However, if one assumes that the radiation response will be enhanced by the agent foreveryradiation fraction, over the course of 30 fractions this could constitute a significant improvement, even for a dose-effect factor of 1.1. Of course there are qualifications. For example, the intrinsic radiosensitivity of the tumor cells can greatly influence the net response of an agent that produces a dose-effect factor of 1.1.

Figure 2is a theoretical plot of the number of 2-Gy fractions required (out of a normal 30-fraction course) to achieve a 90% tumor cure as a function of the dose-effect factor for three different initial surviving fractions at 2Gy (SF2Gy(0.5, 0.6, 0.7). A number of assumptions are made in generating this plot, including (1) a 1-g tumor (1 cm diameter, 109cells); (2) a 90% tumor cure, a probability that requires a total radiation dose to reduce survival to < 1 × 10-11; (3) no repopulation during treatment; (4) a completely aerobic tumor; (5) SF2Gydetermined using the a/b model, with an a/b ratio = 10; (6) uniform radiosensitivity of all cells in the tumor; and (7) complete radiation repair for each fraction. Increase is calculated by multiplying the effective dose per fraction with the dose-effect factor. As shown in Figure 2, the intrinsic radiosensitivity of the cells in the tumor is a major determinant of an agent's ability to reduce the number of fractions required for a 90% cure. For relatively sensitive tumors (SF2Gy£ 0.5), dose-effect factors in the range of 1.2 to 1.5 can be effective if the modifier is given in about 30% to 70% of the total number of fractions. For less sensitive tumors (SF2Gy> 0.6), the modifier should have a dose-effect factor greater than 1.9 if an effect of 90% tumor cure level is to be achieved. Whether a tumor dose-effect factor of 1.1 for a particular agent can be achieved in the clinic depends on numerous factors.

Potential barriers to effective use of chemoradiation Normal-tissue toxicity

As discussed above, increased radiation-induced toxicity in normal tissue due to concurrently administered chemotherapy agents is a major problem. The use of three-dimensional treatment planning and conformational delivery of the radiation beam to the tumor to minimize dose to normal tissue offers some promise to further improve the efficacy of chemoradiation. Theoretically, use of radiation shields should also be a beneficial addition to a chemoradiation protocol. As shown in Table 1, an ideal radiation shield should only protect normal tissue; if the tumor was also protected, there would be no therapeutic benefit. In the 1970s, Yuhas and colleagues showed that an agent developed by the US military, WR-2721 (amifostine), could preferentially radioprotect normal tissues in mice.[30] But other laboratories believed that the agent also protected the tumor.[31]

Amifostine has been used in several clinical trials and has recently been used in a chemoradiation setting. Amifostine was used in a study involving combined radiotherapy and carboplatin (Paraplatin) in patients with head and neck cancer.[32] Amifostine was given daily during the two cycles of carboplatin (days 1–5 and days 21–26); radiotherapy was administered in daily fractions of 2 Gy, beginning on day 1. Amifostine was shown to significantly reduce mucositis, xerostomia, thrombocytopenia, and leukopenia. Tumor response was essentially the same in patients receiving amifostine compared with those not receiving amifostine; thus, the drug did not protect the tumor. The study is encouraging in that not only did amifostine protect normal tissue within the treatment area, but toxicities secondary to carboplatin treatment were also reduced.

Another new class of radioprotective agents, the nitroxides, is currently being investigated preclinically.[33] Studies have shown that nitroxides exhibit selective radioprotection of normal tissue.[34] Additionally, these agents can be imaged non-invasively in vivo using electron paramagnetic resonance imaging approaches.[35]

Drug delivery

Technical innovations in radiation dose delivery over the past 30 years have enabled radiation oncologists to determine the precise radiation dose (within a few percentage points) delivered to a tumor treatment volume. Unfortunately, this is not the case for the delivery of systemic drugs. A drug administered systemically to a tumor-bearing patient may encounter several barriers or obstacles that can reduce the drug concentration before it reaches its final destination, which is the tumor cell, and more precisely the target within the cell. While drug pharmacokinetic profiles in the blood are useful, such studies do not directly measure the effective concentration reaching the tumor cells. As a chemotherapeutic drug crosses the vascular system, it can be metabolized/detoxified by various organs. Likewise, given the altered, compromised vascularization that often accompanies cancerous masses, uniform drug delivery within a tumor can be difficult. Factors, such as tumor interstitial fluid pressure[36] and compromised blood flow,[37] may also affect drug delivery. In addition to compromised drug delivery to the tumor, there may also be intrinsic or evolved drug resistance[38], which may result from an overabundance of specific intracellular detoxifying enzymes.[39]

A recent study compared the plasma level of methotrexate in nine breast cancer patients with the methotrexate level in the tumor interstitial space (as determined by inserting a microdialysis probe into the tumor).[40] In none of the patients did the plasma methotrexate level agree with the tumor interstitial level. The mean area under the concentration-time curve (AUC) values ​​for the interstitial tumor space were approx. 50% of the AUC values ​​of the drug in plasma. Saying that achievable plasma levels of a particular drug are in the range needed to kill tumor cells (based on preclinical in vitro data) can therefore be completely misleading, the actual level in and within the tumor cell is critical.

The issue of drug delivery is further complicated by the effect of daily radiation doses delivered to the tumor and the possible effect on tumor vasculature. Radiation therapy can result in damage to tumor vasculature, the consequences of which can be the development and increase of compromised drug delivery as the radiation dose accumulates. Given this, an important question to ask is: Does the drug actually get to the tumor cells at a sufficient concentration to (1) kill the tumor cell or (2) in the case of chemoradiation, enhance the radiation response? Although this is a rational and reasonable question, few studies have been conducted to answer it because the task is quite difficult. Taking multiple tumor biopsies is inconvenient, increases the cost of the study and may pose certain risks to the patient. The location of the tumor for biopsies is often problematic, as is the concern of multiple biopsies in an irradiated field. The interpretation of drug concentration in tumor biopsies can be complicated by the infiltration of host cells into the tumor mass, as discussed below. Finally, the availability of suitable assays for the drug and its metabolites is not always straightforward. These concerns can be partially addressed for agents whose mechanisms of action are known because in this setting functional biological assays can be performed. For example, paclitaxel treatment results in a G2/M arrest in cells in culture. If the arrest of cells in G2/M is required for paclitaxel-mediated enhancement of radiation toxicity, after which determination of cell cycle parameters from biopsy material taken from the patient's tumor as a function of time after paclitaxel administration should reveal whether the drug reaches the tumor cells at a concentration sufficient to reach the target.

In a National Cancer Institute pilot clinical trial evaluating continuous paclitaxel infusion with concurrent radiation therapy for head and neck cancer, tumor biopsies were taken before and 48 to 96 hours after paclitaxel infusion. The tumor samples were analyzed by flow cytometry (Figure 3). Seven of nine patients showed no cell cycle arrests as a result of the 48- to 96-hour continuous infusion of paclitaxel (started at 105 mg/m² to 120 mg/m²). Figures 3A and 3B show pre-paclitaxel and post-paclitaxel treatment DNA flow cytometry profiles from a patient's tumor that did not show a treatment-related cell cycle block in G2/M. One patient's tumor showed some modest cell cycle rearrangement as a result of the paclitaxel treatment (Figures 3C and 3D).

The reason(s) why paclitaxel in this study did not arrest cells in G2/M is most likely more. First, the concentration of infused paclitaxel may not have been sufficient. Second, if drug-resistant phenotypes are present or due to the continuous paclitaxel treatment, one would not expect to see cell cycle redistribution. Third, the biopsy taken represents only a small portion of the total tumor mass; perhaps the biopsies were taken from areas where the cells were quiescent and not cycling. Fourth, 48 to 96 hours of continuous drug infusion may not be long enough to detect significant changes in cell cycle distribution. Finally, currently unidentified factors could contribute to the lack of G2/M arrest. This example highlights the complexity of asking the simple question of whether a drug reaches and affects a tumor; nevertheless, attempts should be made to obtain this type of important information. If a drug is not an effective radiation modifier, it is important to know why.

Knowledge of Optimal Timing of Agents

Preclinical in vitro studies can contribute significant information to define the optimal timing of a drug and radiation in clinical protocols. Indeed, timing considerations in clinical chemoradiation protocols are often based in part on scheduling data derived from preclinical in vitro studies. However, there can be a big difference between controlled in vitro studies and the in vivo situation.

Most in vitro chemoradiation studies are performed with a single radiation dose with drug therapy occurring before, during, or after radiation therapy. Radiation is delivered in daily fractions (often twice a day). But if the drug is administered as a weekly bolus, will there be sufficient concentrations of the drug present to increase the radiation doses administered by the end of the week? Also, will the radiation doses given in the first week influence the drug given in subsequent treatment weeks to enhance the radiation effects? In the case of cell cycle-specific drugs, does radiation therapy (which alone can induce cell cycle block) inhibit the drug's ability to affect cell cycle distribution? For example, numerous investigators have shown that paclitaxel given before radiation results in radiation enhancement of cytotoxicity.[26,27] However, treating cells first with radiation has been shown to antagonize the cytotoxic effects of paclitaxel.[41] One wonders if this is a problem in current clinical protocols combining paclitaxel and radiation.

There is substantial data for certain tumor types suggesting that after the first 3 to 4 weeks of fractionated radiotherapy, the surviving tumor cell clonogens have an increased growth rate.[42] To compensate for this accelerated tumor cell growth/repopulation, additional radiation doses will be required if the radiation course is extended beyond the planned time. For oropharyngeal tumors, it is estimated that an additional 0.6 Gy/day would need to be added to compensate for repopulation.[42] If true, the use of cell cycle-specific radiation enhancing agents may be more effective if given at the end of the normally planned radiation protocol rather than at the beginning. Similarly, it may be interesting and effective to use halogenated pyrimidines towards the end of radiotherapy when tumor cell growth is accelerated. The disadvantage of this approach is that radiotherapy can stimulate the repopulation of certain normal tissues.

It is not entirely obvious exactly how the question of timing should be approached in clinical trials. This is why it is important to know the mechanism of action of an agent being taken into clinical trials and how the agent interacts with radiation, at least at the cellular level. With this information, tumor material could be biopsied during the trial to determine whether the basic mechanisms presumed to be operative are actually operating in the patient's tumor. If this does not work, alternative timing protocols should be considered.

Physiological considerations

A number of physiological factors, some unique to the tumor, can influence a tumor's response to drugs and radiation. Such factors include tumor blood flow,[37] oxygen transport,[43] hypoxia,[44] interstitial fluid pressure[36,45] and tumor pH.[46] In radiobiology, considerable research has gone into determining the effect of hypoxia on the radiation response. The existence of hypoxic regions in human tumors was hypothesized in the mid-1950s,[44] and over the past several years the presence of hypoxic regions in human tumors has been verified by oxygen electrode studies.[47]

The significance of hypoxic areas (both chronic and acute) in tumors for oncology is that (1) hypoxic cells may be viable and able to proliferate if oxygen becomes available; (2) hypoxic cells are approximately three times more resistant to radiation than aerobic cells, and (3) the presence of hypoxic cells in a tumor is an unfavorable prognostic indicator for local control of tumors treated with either radiation therapy or surgery.[47 ] In the context of chemoradiation, the presence of hypoxic areas in tumors may mean that drug delivery to these areas is compromised. If oxygen cannot easily reach these areas, a low molecular weight drug is also unlikely to reach the areas. Research is ongoing to identify a means of increasing oxygen levels to hypoxic areas[48] and to develop new sensitizers or cytotoxins from hypoxic cells.[49,50]

Drug resistance

The development of drug resistance during chemotherapy is a formidable problem. While much has been learned about the cellular/molecular mechanisms of drug resistance, methods to circumvent this problem have not yet been identified. Drug resistance in tumor cells can effectively reduce the dose of drug available for radiosensitization. Several studies have convincingly shown that drug-resistant cells are not radioresistant[51], but to our knowledge, no information exists on whether drug-resistant cells can be radiosensitized by the drug(s) to which they are resistant. Stated differently, it is not known whether a cell's cytotoxicity detoxification mechanism results in loss of radiosensitization.

Host cell infiltration of tumor

As early as 1863, tumor infiltration by leukocytes was noted, and based on this observation, Virchow concluded that tumors arise in areas of chronic inflammation.[52] More recently, the presence of leukocytes has been linked to the idea of ​​immune surveillance, which proposed that tumor cells are recognized as antigenically different from normal host cells and thus prompt an immune response.[53] In their reports, pathologists rarely mention the presence of reactive cellular infiltration.[54] In an analysis of breast carcinoma, Underwood found that the average total tumor cell volume of two medullary carcinomas was 64.5%, while the tumor cell volume of ten scirrhous carcinomas was only 21.5%.[55] It is thus possible that a significant part of the tumor cell mass may be composed of cells other than malignant cells.

We have evaluated the extent of tumor infiltration by normal host leukocytes from biopsies of 26 human tumors from the lung, including both primary and metastatic lesions. Delineation of leukocyte infiltration was achieved by double staining of tumor sections with a pan-anti-leukocyte monoclonal antibody (HLE-1) and propidium iodide. Images of the staining patterns of both the total nuclei (stained by propidium iodide) and leukocytes (labeled with a biotinylated anti-mouse secondary antibody and FITC-streptavidin) examined under low magnification were acquired and stored using a laser scanning microscope and computer-based image analysis system. The staining pattern of individual leukocytes varied markedly throughout all tumor sections examined. In general, the leukocytes were seen either in clumps of varying size or as individual leukocytes scattered throughout the tumor section.

Representative samples are shown in Figure 4. The pattern in Figure 4A, which contains a moderate infiltration of leukocytes, is representative of many samples analyzed, while in Figure 4B the leukocytes appear randomly distributed throughout the section. Figure 4C shows an island of cells surrounded by leukocytes in a section with a high degree of leukocyte infiltration. The percentage of tumor leukocyte infiltration was quantified by taking the ratio of leukocyte staining to nuclear staining for each section. The proportion of leukocytes in the individual tumors varied from 4% to 90%, with an average of 40% (Figure 5). In 15 of 26 samples, the leukocyte fraction was equal to or greater than 40% of the entire tumor sample. In addition, we also attempted to classify the types of leukocytes present in 15 out of 26 patients using antibodies specific for monocytes/macrophages, granulocytes, T-cell lymphocytes, and B-cell lymphocytes. A majority of the samples analyzed contained both macrophages and granulocytes (12 out of 15 samples), while only two samples had T cells above 19%.

The reason(s) for the extensive infiltration of host cells in these tumor samples and whether their presence constitutes a barrier to effective chemoradiation (or chemotherapy alone) is not known. Undoubtedly, the presence of these cells in a tumor biopsy complicates accurate determination of tumor cell drug uptake and functional cellular/molecular assays specific for drug therapy. Are these cells activated/inactivated for tumoricidal activity? Do these cells represent a means of drug detoxification that would effectively reduce the drug concentration ultimately delivered to tumor cells? Does the response of these hematopoietic cells to different treatment protocols have an important impact on what is perceived as a partial or complete tumor response to cytotoxic therapies? The answers to these questions require further confirmation and an understanding of their significance for tumor growth behavior and response to therapeutic modalities.


This review has raised more questions than answers. The combined use of radiation modifiers to effectively enhance the radiation response is indeed complex. It should be understood that despite the myriad problems and concerns regarding concurrent chemoradiation, under certain circumstances, the approach works in that better local control can be achieved with acceptable normal tissue toxicity. Chemoradiation trials can be designed not only to study possible efficacy for the cancer patient, but to gain more information about the mechanisms of action (in the patient) and the pharmacokinetics/pharmacodynamics of drug uptake and action in the tumor/tumor cell.

Based on concepts advanced in this review, Table 2 shows several possible considerations for chemoradiation trials. Although it is recognized that designing clinical trials to address specific basic science questions is a more difficult task than encountered in the research laboratory, failing to turn the trial leaves empirical permutations. There is nothing particularly wrong with empirical approaches; however, teamwork between basic scientists and clinicians can add a new dimension of scientific information that will undoubtedly advance the field. If, for example, the drug(s) do not reach the target in the patient's tumor in sufficient concentrations to enhance the radiation response, research must focus on a means to enhance drug delivery.


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