3 Clinical Principles and Applications of Chemoirradiation

3 Clinical Principles and Applications of Chemoirradiation

Dan P. Garwood, L . Chinsoo Cho, and Hak Choy

D. P. Garwood, MD; L. C. Cho, MD; H. Choy, MD

Department of Radiation Oncology, UT Southwestern Medi- cal Center at Dallas, 5801 Forest Park, Dallas, TX 75390-9183, USA

drugs – in the treatment of cancer. From the initial use of fluorinated pyrimidines (e.g., 5-fluorouracil;

5-FU) in the late 1950s (Heidelberger et al. 1957) to the recent application of vascular endothelial growth factor (VEGF) (Willett et al. 2004) and epidermal growth factor receptor (EGFR) inhibition (Bonner et al. 2004), chemoradiation holds great promise for the future.

This chapter will first examine the biological basis for combining chemotherapy with ionizing radiation and then look briefly at some of the spe- cific agents involved. Lastly, a limited tour will be taken through some of the clinical experience in specific sites of malignancy.

3.1

Clinical Principles

Both radiation and chemotherapeutic drugs are cytotoxic to tumor and normal tissue cells, a lack of specificity which is a major limitation in their use when applied either as individual treatments or in combination. Toxicity is often accentuated when the two agents are combined and when they affect the same tissue. The goals of combining chemo- therapeutic drugs with radiotherapy are to increase patient survival by improving local-regional tumor control, decreasing or eliminating distant metas- tases, or both, while preserving organ and tissue integrity and function. Combined modality treat- ment can further improve positive therapeutic out- come of individual treatments through a number of specific strategies, which Steel and Peckham (1979) classified into four groups: “spatial coopera- tion”, independent toxicity, enhancement of tumor response, and protection of normal tissues.

1. “Spatial cooperation” was the initial rationale for combining chemotherapy with radiotherapy, where the action of radiation and chemotherapeu- tic drugs is directed toward different anatomical sites. Localized tumors would be the domain of

CONTENTS

3.1 Clinical Principles 39

3.2 Specific Chemotherapeutic Agents 43 3.3 Clinical Use of Chemoirradiation in Specific Sites 44

3.3.1 Small Cell Lung Carcinoma 44 3.3.2 Non-Small Cell Lung Cancer 44 3.3.3 Head and Neck 45

3.4 Uterine Cervix 47 3.5 Urinary Bladder 47 3.6 Anus 48

3.7 Esophagus 48 3.8 Rectum 49

3.8.1 Central Nervous System 51 3.9 Conclusion 51

References 51

For more than a century, ionizing radiation has

been used as an effective local agent against neo-

plastic disease. Increasing sophistication in com-

puter-assisted treatment planning and delivery has

brought vast strides in the accuracy and distribution

of radiation dose; even so, local control of malig-

nant tumors often still remains elusive. In paral-

lel to the modern development of radiotherapy, the

use of systemic chemotherapeutic agents has blos-

somed since it was first possible to produce signifi-

cant clinical impact on hematological malignancies

using nitrogen mustard around the time of World

War II (Gilman 1963). Since that time, an increas-

ingly broad array of chemotherapeutic agents have

entered the clinical armamentarium. It is only natu-

ral that researchers have sought to combine the two

approaches, in hopes of building upon the strengths

of each and achieving more than can be reached

by either modality alone. Chemoirradiation is the

science of applying combined modality therapy –

local irradiation with the concurrent use of systemic

radiotherapy, and chemotherapeutic drugs would likely be more effective in eliminating dissemi- nated micrometastases than in eradicating larger primary tumors. Thus, the cooperation between radiation and chemotherapy is achieved through the independent action of two agents. “Spatial cooperation” is the basis for adjuvant chemora- diotherapy, where radiation is given fi rst to control the primary tumor, and chemotherapy is given at a later time to cope with micrometastases. The concept of “spatial cooperation” is also applied in the treatment of hematological malignancies that have spread to “sanctuary” sites, such as the brain, poorly accessible to chemotherapeutic agents.

2. Independent toxicity is another strategy to increase the ratio of effi cacy to toxicity of chemo- radiotherapy. Combinations of radiation and drugs would be better tolerated if the drugs were selected such that there was no overlap of toxici- ties to specifi c cell types and tissues from each modality, or minimally so. Careful drug selection based on knowledge of mechanisms of drug tox- icity, mode of action, and drug pharmacokinet- ics may minimize normal tissue damage while retaining antitumor effi cacy when combined with radiotherapy.

3. Another strategy in chemoradiotherapy is exploi- tation of the ability of chemotherapeutic agents to enhance tumor radiation response. The enhance- ment denotes the existence of some type of interac- tion between drugs and radiation at the molecular level, resulting in an antitumor effect greater than would be expected on the basis of additive actions.

The enhancement must be selective or preferential to tumors compared with critical normal tissues in order to achieve therapeutic gain. The ability of chemotherapeutic agents to enhance tumor radi- ation response by counteracting determinants associated with tumor radioresistance is a major rationale for concurrent radiotherapy.

4. In addition, protection of normal tissues in order to deliver higher doses of radiation to the tumor is important. This can be achieved through technical improvements in radiation delivery or administration of chemical or biological agents that exert selective or preferential protection of normal tissues against the damage by radiation or drugs.

Any drug considered for use in combination with radiotherapy needs to undergo preclinical evalu- ation for its interaction with radiation both in in

vitro cell culture systems and in vivo, with the aim of assessing antitumor activity and normal tissue toxicity. The interaction between two agents is more easily defined and quantified in vitro because com- plete cell survival curves are readily obtained. Cell survival is determined after treatment with a drug or radiation alone, given at different doses, or after treatment with both agents, in which case the cells are exposed to the drug before, during, or after irra- diation.

In vitro testing is often followed by in vivo explo- ration of drug–radiation interactions, which allows assessment of the combined treatment on both tumors and normal tissues. The efficacy of the treat- ment is determined by the extent of tumor growth delay or the rate of tumor cure. In normal tissues, the effect of chemotherapeutic drugs on radiation response of acutely and late responding tissues can be assessed using a variety of available assays. Some of these assays are clonogenic, such as the jejunal crypt assay, where the endpoint depends directly on the reproductive integrity of individual cells. More frequently, however, dose–response relationships for normal tissues are based on functional end- points (such as breathing rate in lung damage and paralysis in spinal cord damage).

Radiation induces many different lesions in the DNA molecule, which is the critical target for radia- tion damage. DNA double-strand breaks (DSBs), and chromosome aberrations that occur as a con- sequence, are generally considered to be the prin- cipal damage that results in cell death (Radford 1986). Any agent that makes DNA more susceptible to radiation damage may enhance cell killing. Cer- tain drugs, such as halogenated pyrimidines, incor- porate into DNA and make it more susceptible to radiation damage (Kinsella et al. 1987).

Both sublethal (Elkind and Sutton 1959)

and potentially lethal (Little et al. 1973) damage

inflicted by radiation can be repaired. While sub-

lethal damage repair (SLDR) denotes the increase

in cell survival when radiation dose is split into two

fractions of radiation separated by a time interval,

potentially lethal damage repair (PLDR) desig-

nates the increase in cell survival as the result of

post-irradiation environmental conditions. SLDR is

rapid, with a half time of about 1 h, and is complete

within 4–6 h after irradiation. This time between

two radiation fractions allows radiation-induced

DSB in DNA to rejoin and repair. SLDR is expressed

as the restitution of the shoulder on the cell survival

curve for the second dose. PLDR occurs when envi-

ronmental conditions prevent cells from dividing

for several hours, such as keeping in vitro growing cells in plateau phase after irradiation. Preventing cells from division allows completion of the repair of DNA lesions that would have been lethal had DNA undergone replication within several hours after irradiation. PLDR is considered to be a major determinant responsible for radioresistance in some tumor types, such as melanomas.

Many chemotherapeutic agents used in chemora- diotherapy interact with cellular repair mechanisms and inhibit repair; hence, they may enhance cell or tissue response to radiation. The above-mentioned halogenated pyrimidines enhance cell radiosen- sitivity not only through increasing initial radia- tion damage but also by inhibiting cellular repair (Kinsella et al. 1987; Wang et al. 1994). Nucleoside analogs, such as gemcitabine, are a class of chemo- therapeutic agents potent in inhibiting the repair of radiation-induced DNA and chromosome damage (Plunkett et al. 1995; Lawrence et al. 1997;

Gregoire et al. 1999). They have been shown to strongly enhance tumor radiation response in pre- clinical studies and are at present being extensively investigated for such activity in cancer patients (Gregoire et al. 1999; Milas et al. 1999a).

Both chemotherapeutic agents and radiation are more effective against proliferating than non- proliferating cells. Their cytotoxic action further depends on the position of cells in the cell cycle.

Cell-cycle dependency in response to radiation was first reported almost 30 years ago (Terasima and Tolmach 1963). Terasima and Tolmach (1963) reported that radiosensitivity of cell response to radiation widely varied depending on which phase of the cell cycle the cells were in at the time of irradi- ation, and that cells in the G

and M cell-cycle phases were about three times more sensitive than cells in S phase.

The influence of cell cycle on cell response to cytotoxic agents can be therapeutically exploited in chemoradiotherapy using cell-cycle redistribution strategies. For example, some chemotherapeutic drugs, such as taxanes, can block transition of cells through mitosis with the result that cells accumu- late in the radiosensitive G

and M phases of the cell cycle. Radiation delivered at the time of significant accumulation of cells in both the G

and M phases results in an enhanced radiation response of cells in vitro (Tishler et al. 1992; Choy et al. 1993) and of tumors in vivo (Milas et al. 1995, 1999b). How- ever, this cell-cycle mechanism of taxane-induced enhancement of tumor radiation response is domi- nant only in tumors that are resistant to paclitaxel

or docetaxel as a single treatment. Although tumor growth in taxane-resistant tumors is not substan- tially affected by the drug, tumors do exhibit sig- nificant transient accumulation of cells in mitosis 6–12 h after the treatment (Milas et al. 1999b).

Elimination of the radioresistant S phase cells by the chemotherapeutic agents may be another cell-cycle redistribution strategy in chemoradio- therapy. Nucleoside analogs, such as fludarabine or gemcitabine, are good examples of the agents that become incorporated into S phase cells and elimi- nate them by inducing apoptosis (Gregoire et al.

1999; Milas et al. 1999a). In addition to purging S phase cells, the analogs induce the surviving cells to undergo parasynchronous movement to accu- mulate in G

and M phases of the cell cycle between 1 day and 2 days after drug administration, a time when the highest enhancement of tumor radia- tion response was observed (Milas et al. 1999a). It should be noted that tumors with a high cell growth fraction are likely to respond better to the cell-cycle redistribution strategy in chemoradiotherapy than tumors with a low cell growth fraction.

Solid malignant tumors are generally character- ized by defective vascularization, both in the number of blood vessels and vessel function. Because of this, blood supply to tumor cells is inadequate, cells lack oxygen and nutrients, and multiple tumor micro- regions become hypoxic, acidic, and eventually necrotic. Hypoxic cells are 2.5–3 times more resis- tant to radiation than well-oxygenated cells. Com- bining chemotherapeutic agents with radiotherapy can reduce or eliminate hypoxia or its negative influence on tumor radiation response. Most che- motherapeutic drugs preferentially kill proliferating cells, which are primarily found in well-oxygenated regions of the tumor. Since these regions are located at a close proximity to blood vessels, they are easily accessible to chemotherapeutic agents. Destruction of tumor cells in these areas will lead to an increased oxygen supply to hypoxic regions and hence re-oxy- genate hypoxic tumor cells. It was recently shown that tumor reoxygenation is a major mechanism underlying the enhancement of tumor radiation response induced by taxanes in tumors sensitive to these drugs (Milas et al. 1995).

The constant balance between cell production

and cell loss maintains the integrity of normal tis-

sues. When this balance is perturbed by cytotoxic

action of chemotherapeutic drugs or radiation, the

integrity of tissues is reestablished by an increased

rate of cell production. The cell loss after each

fraction of radiation during radiotherapy induces

compensatory cell regeneration (repopulation), the extent of which determines tissue tolerance to radiotherapy. Chemotherapeutic drugs, due to their cytotoxic or cytostatic activity, can reduce the rate of proliferation when given concurrently with radio- therapy and, hence, increase the effectiveness of the treatment. Caution must be taken to select drugs that preferentially affect rapidly proliferating cells and preferentially localize in malignant tumors.

However, the main limitation of concurrent chemo- and radiotherapy is the enhanced toxicity of rapidly dividing normal tissues, because most available chemotherapeutic agents show poor tumor selectiv- ity. Moreover, accelerated repopulation induced by chemotherapeutic drugs may have a negative influ- ence on the outcome of tumor response to radiation when drugs are used in induction or neoadjuvant chemotherapy protocols. Using this strategy, che- motherapy precedes radiotherapy. Treatment out- comes following induction chemotherapy followed by radiotherapy have not been overly encouraging in terms of both local tumor control and patient survival, even if a large proportion of tumors ini- tially responded with total or partial clinical regres- sion by the time of radiotherapy implementation.

Some experimental evidence suggests that the drug- induced accelerated cell repopulation can actually make the tumor more difficult to control with radia- tion (Stephens and Steel 1980; Milas et al. 1994).

Most clinical chemoradiotherapy regimens evolved empirically: drugs known to be active against a tumor type were combined with radiation, and the doses of both agents and their administra- tion schedules were selected for safety. Increasingly,

however, information from preclinical studies is being considered in planning optimal timing of drug administration in relation to radiotherapy. Depend- ing on the principal aim of the therapy, drugs are administered before (induction or neoadjuvant chemotherapy), during (concurrent or concomitant chemotherapy), or after (adjuvant chemotherapy) the course of radiotherapy. The advantages and disadvantages of each approach are summarized in Table 3.1.

Induction (neo-adjuvant) chemotherapy is aimed at both the disseminated disease and the primary tumor. It is initiated soon after tumor diagnosis to cope with metastatic foci, while these still con- tain a small number of tumor cells. With regard to the primary tumor, induction chemotherapy may reduce the number of clonogenic cells and cause the reoxygenation of the surviving hypoxic cells, both of which render tumors more controllable by radia- tion. Additionally, chemotherapy-induced tumor shrinkage may allow the use of smaller radiation fields, in which case less normal tissue is exposed and damaged by radiation. This treatment approach is often used in therapy of solid tumors in children and of lymphomas. Induction chemotherapy pre- cedes radiotherapy for a few weeks to a few months, which improves tolerability of the combined treat- ment.

Induction chemotherapy has resulted in thera- peutic improvement in a number of clinical trials when compared with radiotherapy; but, in general, the therapeutic benefits are below expectations. A number of factors could account for this, including accelerated proliferation of tumor cell clonogens

Table 3.1. Advantages and disadvantages of different chemoradiation sequencing strategies

Strategy Advantages Disadvantages

Sequential chemoradiation • Least toxic • Increased treatment time

• Maximize systemic therapy • Lack of local synergy

• Smaller radiation fields if induction shrinks tumor

Concurrent chemoradiation • Shorter treatment time • Compromised systemic therapy

• Radiation enhancement • Increased toxicity

• No cytoreduction of tumor Concurrent chemoradiation and

posterior chemotherapy

• Maximize systemic therapy • Increased toxicity

• Radiation enhancement • Increased treatment time

• Both local and distant therapy delivered up front

• Difficult to complete chemotherapy after chemoradiation

Induction chemotherapy and concurrent chemoradiation

• Maximize systemic therapy • Increased toxicity

• Radiation enhancement • Increased treatment time

• Difficult to complete chemoradiation after induction therapy

and selection or induction of drug-resistant cells that are cross-resistant to radiation. The preclini- cal findings provide solid evidence for the existence of accelerated repopulation in tumors treated with chemotherapeutic agents. However, although devel- opment of drug resistance is a significant problem in chemotherapy, the evidence that cells that acquire drug resistance are also resistant to radiation is not convincing.

The treatment approach in which chemothera- peutic agents are given during a course of radio- therapy is referred to as concurrent chemotherapy.

This form of treatment is intended to cope with both disseminated lesions and the primary tumor, but it takes the advantage of drug–radiation inter- actions to maximize tumor radiation response. The drug scheduling in relation to individual radiation fractions is highly important, and the selection of optimal timing of drug administration must be based on mechanisms of tumor radioenhancement by a given drug, the drug’s normal tissue toxicity, and conditions under which the highest enhance- ment is achieved. The data from preclinical stud- ies can greatly contribute to the selection of the most optimal schedules. For example, it has been demonstrated that murine tumors sensitive to tax- anes show enhanced radiation response, but the best effect is achieved if drug treatment precedes radiation by 1–3 days (Milas et al. 1995). A major mechanism for tumor radioenhancement was reox- ygenation of hypoxic cells. Based on this preclinical information, one would anticipate that in clinical protocols such tumors would best respond to a bolus of a taxane given once or twice weekly during radio- therapy. In contrast, tumors resistant to taxanes on their own would call for daily administration of a taxane, since they show accumulation of radiosen- sitive G

and M cells 6–12 h after drug administra- tion. If the objective is to counteract rapid repopula- tion of tumor cell clonogens induced by radiation, then administration of cell-cycle-specific chemo- therapeutic agents during the second half of radio- therapy, when accelerated repopulation is more expressed, might be more effective. Optimal sched- uling is essential in concurrent chemotherapy, not only to maximize tumor radiation response but also to minimize increases in toxicity to critical normal tissues. At present, the enhancement in normal tissue complications remains the major limitation of concurrently combining chemotherapy with radiotherapy. Nevertheless, concurrent chemo- and radiotherapy has provided better clinical results in terms of both local tumor control and patient sur-

vival than have other modes of chemoradiotherapy combinations (Munro 1995; Morris et al. 1999;

Eifel et al. 2004).

Adjuvant chemotherapy designates a treatment modality in which chemotherapeutic drugs are given some time after completion of surgery or radiotherapy. The primary objective is to eradicate disseminated disease; however, the control of the primary tumor may also be improved by the ability of drugs to deal with tumor cells that have survived radiation.

Technical improvements in radiotherapy, such as three-dimensional treatment planning and con- formational or intensity-modulated radiotherapy, are other approaches likely to minimize the toxic- ity, consequently enhancing the effectiveness, of chemoradiation (Holloway et al. 2004). Either the use of radioprotective compounds or the implemen- tation of technical advances may enable administra- tion of higher doses of radiation, chemotherapeutic drugs, or both, which may result in superior treat- ment outcome.

3.2

Specific Chemotherapeutic Agents

Many classes of drugs have been used with radiother- apy. Anti-metabolites such as 5-FU were among the earliest radiosensitizers (Bagshaw 1961; Buchholz et al. 1995). A newer nucleoside analog, gemcitabine, is a potent sensitizer (Scalliet et al. 1998). Plati- num-based drugs have been widely used, including cisplatin (Dewit 1987), carboplatin (O’Hara et al.

1986; Begg et al. 1987), and more recently oxalipla- tin (Freyer et al. 2001). The taxanes paclitaxel and docetaxel inhibit the mitotic spindle by promoting microtubule assembly and inhibiting disaggrega- tion (Rowinsky 1997); this leads to cellular arrest in the G

M phase of the cell cycle, a point of increased radiosensitivity (Hall 1994). The camptothecins, such as irinotecan and topotecan, target DNA topoi- somerase I (Hsiang et al. 1985; Hsiang and Liu 1988). Other agents have included mitomycin C91, which targets hypoxic cells which are relatively radioresistant (Bristow and Hill 1998).

Newer strategies of combining systemic ther-

apy with irradiation involve exploiting targets in

the signal transduction pathways of cells, such as

EGFR, or angiogenic factors supporting the growth

of tumor vasculature (Mason et al. 2001). EGFR is

involved in tumor growth and response to cytotoxic

agents, including ionizing radiation, and expression of the receptor in a cancer is often associated with an aggressive neoplasm that is resistant to chemo- therapy (Mendelsohn and Fan 1997; Schmidt- Ullrich et al. 2000). The formation of blood vessels necessary for tumor growth is dependent on angio- genic factors such as VEGF, and inhibitors have been shown to improve the efficacy of irradiation (Teicher et al. 1995; Mauceri et al. 1998).

There are numerous other new, targeted agents that hold the promise of improving outcomes from therapy not discussed above. They will aim to specifically block the action of numerous specific targets, including: cyclin-dependent kinase, mito- gen-activated protein kinase, farnesyl transferases, mitogen-activated protein kinase, PI 3’-kinase, matrix metalloproteinases, and Bcl-2 (Raben et al.

2004).

3.3

Clinical Use of Chemoirradiation in Specific Sites

The combination of chemotherapy and ionizing radiation has increased steadily, with the goal of increasing local control and sometimes overall sur- vival, as well as allowing organ preservation. Some illustrative examples follow.

3.3.1

Small Cell Lung Carcinoma

While the natural history of this malignancy involves early seeding of distant metastases, patients diagnosed with localized or limited stage tumors are potentially curable. Chemotherapy remains the mainstay of therapy, although up to 80% of patients treated solely in this manner suffer a relapse, some of whom have no noted distant disease (Warde and Payne 1992). Meta-analyses that examined the value of thoracic radiation in the limited stage of this disease performed by both Warde and Payne (1992) and Pignon et al. (1992) demonstrated an improvement in 2 to 3-year sur- vivals of 5%. Warde’s analysis showed that thoracic in early limited disease radiation improved local control by 25%. Fried et al. (2004), in a meta- analysis of randomized trials, found that with early administration of thoracic irradiation there was a significant increase in 2-year compared with late

administration when radiation therapy was com- bined with cisplatin. The use of cisplatin and eto- poside in concurrent therapy is generally accepted, as these drugs lack many of the toxicities caused when the cyclophosphamide–doxorubicin–vincris- tine (CAV) regimen is delivered with radiation. A recently published randomized trial has examined the benefit of delivering hyperfractionated radia- tion with the first cycle of chemotherapy and found that the 2-year and 5-year survivals with the hyper- fractionated regimen were 47% and 26% compared with only 41% and 21% with the once daily regi- men (Turrisi et al. 1999). On further analysis, it was found that not only was the local control improved in the group that received hyperfrac- tionated radiation but there was also a decreased incidence of simultaneous local and distant failure.

This suggests that improved local control may lead to improved survival, even with a malignancy that tends to disseminate systemically. The principle of spatial cooperation enters the treatment realm in this disease wherein the value of prophylactic cranial radiation is associated with a decrease in the incidence of brain metastases. This decreased incidence of brain metastases is associated with an increased survival in patients with limited stage disease who have had a complete response to ther- apy (Auperin et al. 1999; Kotalik et al. 2001). As such, prophylactic cranial radiation forms a piece of the standard part of treatment of limited stage small cell lung cancer.

3.3.2

Non-Small Cell Lung Cancer

There are multiple trials that have compared the delivery of standard radiation with chemoradiation in non-small cell lung cancer (NSCLC) (Le Chevalier et al. 1991; Schaake-Koning et al. 1992; Dillman et al. 1996; Sause et al. 2000). The median survival improvement from 9.6 months with radiation alone to 13.7 months with sequential chemoradiation in the original Dillman study is illustrative of the ben- efit of the addition of chemotherapy (Dillman et al. 1996). A meta-analysis confirmed that cisplatin- based chemotherapy in combination with radiation does improve outcome relative to radiation alone in cases of NSCLC at the expense of increased toxicity (Pritchard and Anthony 1996).

Two more recent trials have moved the paradigm

one step further in that they both found a benefit

to delivering radiation and chemotherapy concur-

rently. Furuse et al. presented the results of their Japanese trial, in which MVP (mitomycin C, vin- desine and cisplatin) with 56 Gy were given in both sequential and concurrent fashions (Furuse et al.

1999). There was an improved median survival of 16.5 versus 13.3 months with the concurrent ther- apy. The concurrent therapy was also well tolerated as the radiation was delivered in a split-course fash- ion with comparable rates of esophagitis in both treatment arms. The Radiation Therapy Oncology Group (RTOG) 9410 randomized phase-III experi- ence has confirmed the benefit of concurrent ther- apy (Curran et al. 2000). This trial used cisplatin- based therapy delivered in one of three fashions:

(1) sequentially with vinblastine followed by radio- therapy, (2) concurrently with vinblastine and once daily radiotherapy, and (3) concurrently with etopo- side and twice daily hyperfractionated radiotherapy.

Arm 2 of the trial, during which chemotherapy was delivered concurrently with once daily radiation, revealed a statistical benefit over the sequential administration of chemotherapy and radiation with a median survival of 17 months versus 14.6 months (P=0.038).

Cakir and Egahan (2004) reported on another randomized trial in which 176 patients with stage- III NSCLC were allocated to radiation therapy alone (64 Gy, 2-Gy fractions) or combined with 20 mg/m

cisplatin given 1 h before irradiation on days 1–5 of the 2nd and 6th treatment weeks. The 3-year sur- vival was 10% with combined chemoirradiation and 0% in the group treated with radiation therapy alone (P=0.00001). Many of the current ongoing trials are incorporating new chemotherapies and dose schedules into the treatment of NSCLC. Con- current weekly paclitaxel and carboplatin, a treat- ment which tries to maximize the enhancing effects of both drugs, is based largely on the phase I–II experience of investigators (Choy et al. 1998a,b).

Efforts at including other newer agents including gemcitabine, vinorelbine, irinotecan, and docetaxel are ongoing (Penland and Socinski 2004; Rowell and O’Rourke 2004). Strategies seeking to maxi- mize radiation dose with the delivery of high-dose conformal therapy remain investigational, although preliminary results are encouraging (Bradley et al. 2005). No trials suggest a substantial benefit to post-operative therapy (Dautzenberg et al. 1999;

Keller et al. 2000). Some reports have described a lower incidence and severity of pneumonitis and esophagitis when amifostine is given before admin- istration of chemoradiation in patients with NSCLC (Komaki et al. 2004).

3.3.3

Head and Neck

Traditional management of locally advanced squa- mous cell cancers of the head and neck has involved a combination of surgery and radiation in most cases. Despite aggressive therapy with significant morbidity, treatment often yields poor long-term survivals when there is unresectable disease with 5-year survivals in the range of 30%.

Alternative fractionation schemes that exploit the differential ability of cells to repair radiation- induced damage, thus allowing for delivery of a higher tumor dose, or those that attempt to deliver therapy in a shorter overall treatment time to combat accelerated repopulation of tumors have become more popular therapies due to some trials suggest- ing a benefit (Horiot et al. 1992; Fu et al. 2000).

Approximately 70 randomized trials have been performed to examine the contribution of com- bined chemoradiation on local control and over- all survival. Many studies have been small, with inadequate power to detect a significant benefit to the addition to chemotherapy in a heterogeneous population of tumors. As such, several meta-analy- ses have been undertaken to assess a larger patient population and to help determine the absolute ben- efits of the addition of chemotherapy (Munro 1995;

El-Sayed and Nelson 1996; Bourhis and Pignon 1999; Pignon et al. 2000).

The MACH-NC study, which evaluated 63 trials and a total of 10,741 patients, is the largest of the meta-analyses (Pignon et al. 2000). Individual data, rather than literature-based data, with the inclusion of updated data and unpublished trials were assessed including individual data updated in 66% of the trials as far out as a median follow-up of 6.8 years. Subcategorization into locoregional treat- ment with and without concomitant chemotherapy, induction/adjuvant chemotherapy, and laryngeal preservation with induction chemotherapy rather than definitive treatment for laryngeal and hypo- pharyngeal tumors were reported. No benefit was detected for neoadjuvant or adjuvant chemotherapy, while a trend toward a statistically significant ben- efit (4%) was reported for concurrent or alternating chemoradiotherapy (P=0.23).

At present, the literature does justify the use of

neoadjuvant chemotherapy in the limited setting of

advanced laryngeal or hypopharyngeal primaries

with the dual goals of organ preservation and the

treatment of micrometastatic disease. Induction

chemotherapy has been considered appropriate in

this setting as it does improve laryngeal preser- vation while not compromising overall survival.

The landmark Veteran’s Affairs Laryngeal Study randomized patients into two treatment arms: (1) induction with cisplatin/5-FU for three cycles fol- lowed by radiation or (2) laryngectomy followed by radiation (Anonymous 1991). There were 332 patients entered into the study. An evaluation occurred after two cycles of chemotherapy. Patients with a partial response received a third cycle of che- motherapy followed by radiotherapy. Those patients without an initial response to induction chemother- apy received a laryngectomy followed by radiation therapy. Patients with residual disease following the completion of radiotherapy underwent surgical resection. With a median follow-up of 33 months, an estimated 2-year survival of 68% in both groups failed to demonstrate a difference in overall survival (P=0.9846), while a majority of patients (64%) were able to preserve function of the larynx. Recurrences differed between the two groups with increased local-regional control (P=0.0005) and decreased metastases (P=0.016) in the induction chemotherapy group. Given that there was no compromise of over- all survival, induction therapy is felt to be feasible in the setting of laryngeal carcinoma in order to allow organ preservation without compromise of overall survival. These results have been confirmed by the European Organization for the Research and Treat- ment of Cancer (EORTC) (Lefebvre et al. 1996).

The updated results of the intergroup trial R91-11 add to the picture (Forastiere et al. 2003). A total of 547 patients with stage III and stage IV potentially resectable carcinoma of the larynx were randomized to receive one of three treatments. In arm A, induc- tion with cisplatin 100 mg/m

and continuous infu- sion of 5-FU 1000 mg/m

per day for three cycles was used followed by 70 Gy of radiation in responding patients. In arm B, concurrent cisplatin at 100 mg/

m

was used on days 1, 22, and 43 along with 70 Gy, while in arm C patients received radiation alone.

The rate of loco-regional tumor control was 78%

with concurrent chemoirradiation, 61% with induc- tion by cisplatin followed by radiation therapy, and 56% with radiation therapy alone. The proportion of patients with larynx preservation was 88%, 75%, and 70%, respectively. At 2 years, the laryngectomy- free survival rates for the treatments were: A 58%, B 66%, C 52%. No significant difference in laryn- gectomy-free survival or overall survival was found when comparing arms B or C to the control arm A.

The time to laryngectomy was significantly better for arm B than arm A (P=0.0094). While this study

was not powered to compare arms B and C, a second- ary analysis shows that concurrent therapy yields a superior laryngectomy-free survival (P=0.02). This confirms that concurrent chemotherapy and radia- tion is the preferred therapy for this population when organ preservation is desired.

Al-Sarraf and colleagues have performed a large randomized, prospective, phase-III intergroup trial of 185 patients with locally advanced nasopha- ryngeal cancer randomized to radiation therapy alone or concomitant chemoradiation therapy (Al- Sarraf et al. 1998). All patients received 35–39 frac- tions of daily radiotherapy and were randomized to receive concomitant cisplatin (100 mg/m

on days 1, 22, and 43) followed by three cycles of adjuvant cis- platin (80 mg/m

, day 1) and continuous infusion 5-FU (1000 mg/m

, days 1–4) every 28 days. The superiority of combined treatment was seen in the concomitant chemoradiation therapy arm with a 3-year progression-free survival of 69% versus 24%

(P<0.001) and a 3-year overall survival of 78% versus 47% (P=0.005). Hence, the recommended standard of care in treating patients with more advanced nasopharyngeal carcinoma has become concomi- tant chemoradiotherapy.

The contribution of the newer generation of che- motherapies including the taxanes and gemcitabine continues to be investigated. The early results of a phase-I trial that incorporated C225 – an antibody directed against the extracellular domain of the EGFR – are encouraging, with 9 of 13 patients (69%) who had received greater than 50 mg/m

of C225 along with chemoradiation achieving disease stabili- zation (Baselga et al. 2000). Equally interesting are reports like those from Glaser et al. (2001) suggest- ing that locoregional control benefits when patients are treated with neoadjuvant radiation (50 Gy) and chemotherapy (5-FU and mitomycin C) with human recombinant erythropoietin prior to radical tumor resection. Results of a retrospective comparison of anemic patients (Hb<14.5 g/dl pretreatment) treated similarly with or without erythropoietin reveal that the pathological complete response rate increased from 17% to 61% (P<0.001) with the addition of the drug. This has led to a significantly improved rate of local control (P<0.001) and 2-year survival. The ongoing RTOG phase-III trial is examining this fur- ther.

A phase-III study of the EGFR-blocking antibody

cetuximab in locoregionally advanced squamous

cell carcinoma of the oropharynx, hypopharynx, or

larynx has been reported by Bonner et al. (2004),

with patients randomized to radiation alone or to

radiation plus weekly cetuximab. This trial showed that the addition of cetuximab provided a statisti- cally significant prolongation in overall survival, while showing only a minimal increase in the toxic- ity expected with radiotherapy.

3.4

Uterine Cervix

While the exact indications and the regimen of choice remains controversial, there is convincing evidence from recent studies that concurrent chemo- therapy can improve outcome in patients requiring radiation for locally advanced cervix cancer. While several studies with debatable results have been con- ducted using hydroxyurea and 5-FU, the weight of the data suggests that a cisplatin-containing concur- rent regimen is now the treatment of choice for many patients. There is no evidence to support the use of neoadjuvant or adjuvant chemotherapy at present (Thomas 1999).

A GOG trial in which patients with locally advanced disease who had negative para-aortic nodes at lymphadenectomy were randomized to receive concurrent hydroxyurea plus radiation ther- apy versus concurrent cisplatin and FU plus radia- tion therapy has been completed and has shown a benefit for the cisplatin-containing arm (Rose et al. 1999). In a second trial, two more aggressive cis- platin-containing chemotherapy regimens showed benefit over a hydroxyurea and radiation regimen (Keys et al. 1999). Both cisplatin-containing treat- ments yielded dramatic, highly significant improve- ments in local disease control and survival.

Over the same time period the RTOG designed a trial comparing a combination of cisplatin, 5-FU and pelvic irradiation with extended-field irradia- tion alone in RTOG 90-01 (Morris et al. 1999; Eifel et al. 2004). Patients were required to have nega- tive para-aortic lymph nodes based on a lymphan- giogram or retroperitoneal lymph node dissection.

The radiation alone arm was based on a previous study that found a survival benefit when prophy- lactic para-aortic irradiation was added to standard pelvic irradiation. This trial was published early, after an interim analysis revealed a highly signifi- cant improvement in overall survival, disease-free survival, local disease control, and rate of freedom from distant metastases in the combined modality arm. A later update (Eifel et al. 2004) confirmed the initial observations.

Two further trials (Pearcey et al. 2000; Peters et al. 2000) have demonstrated a survival benefit when cisplatin is added to radiotherapy in the setting of earlier stage disease followed by an extrafascial hys- terectomy or when cisplatin is added to pelvic radia- tion in those patients who have already undergone a radical hysterectomy.

Of the recent trials looking at the addition of cis- platin-based chemotherapy, only the NCI Canada trial has failed to demonstrate a survival benefit to the addition of concurrent chemotherapy (Pearcey et al. 2000). However, the authors of this study main- tain that the optimization of the radiation as it was delivered in their trial may account for the lack of benefit. The issues of how to best integrate newer chemotherapies such as the taxanes, which have considerable radiation sensitization properties, tar- geted biological agents, and agents that may opti- mize the oxygenation status of the tumors are still under investigation. The differences and the pos- sible explanations for them were carefully analyzed by Lehman and Thomas (2001).

3.5

Urinary Bladder

The natural history of muscle-invasive bladder cancer is much more aggressive than superficial dis- ease, with a 5-year survival of only 50%. The strat- egy of using radiation, chemotherapy or a maximal transurethral resection of a bladder tumor in isola- tion to achieve lasting pelvic control pales in com- parison with the modern radical cystectomy. This surgical therapy yields local control in better than 90% of all cases. Issues related to overall survival benefits as well as quality of life endpoints have led to the pursuit of a combined modality strategy that incorporates all elements of therapy in an attempt to preserve organ function (Coppin et al. 1996; Kuczyk et al. 2003).

A randomized trial to show a benefit to the addi- tion of concurrent chemotherapy in the defini- tive treatment of bladder cancer is that of the NCI Canada, which showed a significant improvement in local control (P=0.036) and suggested a survival difference (47% versus 33%, P=0.34), with addition of concurrent cisplatin to local therapy (Kaufman et al. 1993). This study was, unfortunately, small and not adequately powered to show a survival benefit.

In 1993, investigators at the Massachusetts Gen-

eral Hospital published the results of a single-arm

institutional study, which has become the model for several subsequent trials (Dunst et al. 1994); 53 patients underwent maximal TURBT, followed by two cycles of CMV, then 40 Gy with two cycles of concurrent single-agent cisplatin. At this point, they underwent endoscopic re-evaluation, and if they had an incomplete response to therapy they underwent a cystectomy, if medically feasible, while complete responders were consolidated with an additional 24.8 Gy and an additional cycle of cisplatin. A total of 42 patients completed therapy, and there was no chemotherapy-related mortality. Radical cystec- tomy was required in a total of 15 patients, includ- ing 3 that had a salvage surgery. After 48 months of follow-up, 53% of the patients were alive and 42%

had no evidence of disease. An updated report on 106 patients found that 34% of patients ultimately required a salvage cystectomy, with 49% of patients alive, and 43% alive with their native bladders intact (Dunst et al. 1994).

Series from several other centers or groups (Housset et al. 1993; Tester et al. 1993; Shipley et al. 2003) have tested bladder conservation strate- gies with reasonable results and far more patients failing with distant disease than local-only fail- ures. While there is not likely to be a definitive ran- domized trial comparing a bladder conservation approach to radical cystectomy, it would appear that combined modality therapy is not an unrea- sonable option for selected patients (George et al.

2004). Ongoing studies are looking at integrating the taxanes and other biological agents into ther- apy to improve outcome.

3.6 Anus

In the case of tumors originating in this location, the early experience of Nigro et al. (1974) sug- gested that there may not be a need to perform surgery as part of the initial therapy of this cancer, reserving the abdominoperineal resection for local recurrence. Three patients treated with pre-opera- tive radiation, 5-FU and mitomycin C were found to have had a complete pathological response at the time of their surgery. This work has been expanded upon by Cummings et al. (1991) in their series of patients who were treated by various concurrent regimens over time and by several large inter- group studies (Flam et al. 1996; UKCCCR 1996;

Bartelink et al. 1997) that have demonstrated the

value of concurrent chemotherapy and radiation in this disease.

The UKCCCR trial showed that the combined modality arm improved 3-year actuarial local tumor control from 29% to 61% and was significant. This trial did not show a survival benefit to the addition of chemotherapy, and the combined arm had more early grade-4 toxicity. Similar benefit in terms of local control was also seen in the EORTC trial with the addition of 5-FU and mitomycin C (5-year colos- tomy-free survival was 72% versus 40%). However, once again, a survival benefit was not seen. The Inter- group trial, which randomized patients to treatment with or without mitomycin C, confirmed its benefit to therapy with a higher complete response rate (92%

versus 85%) and a significantly lower colostomy rate (9% versus 22%). There was, however, no significant survival benefit. The RTOG 98-11 is ongoing, exam- ining the benefit of two cycles of induction using 5- FU and cisplatin.

The EORTC 22861 trial confirmed that radia- tion chemotherapy combination is the standard treatment for locally advanced anal cancer. The EORTC phase-II study no. 22953 tests the feasibility of reducing the gap between sequences to 2 weeks, to deliver mitomycin C in each radiation sequence and to administer 5-FU continuously. The initial dose was 36 Gy/4 weeks, mitomycin C (10 mg/m

on day 1), and 5-FU (200 mg/m

on days 1–26).

The second sequence consisted of 23.4 Gy/17 days combined with the same doses of chemotherapy. The 3-year results for the above trials are 68% and 88%

local tumor control, 72% and 81% colostomy-free survival, and 70% and 81% survival, respectively (Bosset et al. 2003). Similar results were reported in 305 patients with stage T1–T4 anal cancer treated with external pelvic irradiation and brachytherapy (Deniand-Alexandre, 2003). Further, Chauveire et al. (2003) noted that in 67 patients with anal cancer (24 with T3–4 tumors) chemoirradiation was administered to only 55% of the patients with T3-4 lesions, mostly because they were deemed too old, emphasizing the importance of patient selection.

3.7

Esophagus

While the ideal approach to the management of

locally advanced disease is controversial, the evi-

dence from several randomized trials shows that

chemoradiation is associated with an improved

survival when compared with radiation alone (Al Sarraf et al. 1997; Smith et al. 1998). The Inter- group trial RTOG 85-01 has had a profound influ- ence of patterns of practice (Smith et al. 1998). In this phase-III study, patients were randomized to treatments consisting of 5-FU (1000 mg/m

per day for 96 h), cisplatin (75 mg/m

, day 1) and 50 Gy in 25 fractions of daily irradiation starting on the first day of chemotherapy or 64 Gy of daily radiation in 2- Gy fractions. This chemotherapy was administered every 4 weeks during radiation and every 3 weeks after its completion. Concurrent therapy was asso- ciated with significant benefits in terms of 5-year overall survival (26% versus 0%, P<0.0001) as well as decreased local failure (45% versus 68%, P=0.0123).

Concurrent therapy as delivered in this trial is asso- ciated with significant toxicity, i.e., 20% grade-4 tox- icity and one treatment-related death. Based on these studies, concurrent chemotherapy and radiation has become the standard of care for the non-surgical management of esophageal cancer, with radiation alone being reserved for those patients unable to tolerate the addition of chemotherapy. Intensify- ing the radiation to deliver a dose of 64.8 Gy was more recently tested in a phase-III intergroup study (INT 0123/RTOG 94-05) with the intent of further improving local control and, potentially, survival.

Preliminary results revealed no significant differ- ence with the intensified radiation in the median survival (12.9 months versus 17.6 months), the 2- year survival (29% versus 38%) or the locoregional failure rates (59% versus 52%). After the first interim analysis, the trial was ended (Minsky et al. 2000).

Efforts to improve primary chemoradiation through the incorporation of novel radiosensitizing chemo- therapies continue.

The realm of treating resectable esophageal cancer is far less clear. While several randomized studies have been completed comparing neoadju- vant chemoradiation followed by esophagectomy to surgery alone, they either are underpowered, have used unconventional fractionation schemes, have used split course radiation, or may have had unbal- anced treatment arms (Walsh et al. 1996; Bosset et al. 1997; Urba et al. 2001). What may have been the more definitive trial (the CALGB 9781) was closed due to poor accrual. Given that the evidence from these randomized trials is plagued by design-related issues and conflicting results, the literature does not clearly support the use of pre-operative chemoradia- tion outside of a clinical trial. Efforts to incorporate new agents including the taxanes, UFT, and irinote- can are ongoing.

3.8 Rectum

The location of the rectum within the confines of the bony pelvis and its intimate relationships with adjacent organs make resection of these tumors with wide radial margins difficult unless a total meso- rectal excision is undertaken. Tumors originating in the rectum are often associated with a higher risk of local failure than extrapelvic colon cancers on a stage-by-stage basis. Neoadjuvant therapies are often given in an effort to improve the respectability of tumors and to hopefully increase sphincter pres- ervation rates. The value of adjuvant therapy with chemoradiation to improve local control as well as overall survival is well recognized.

The GITSG has performed a four-arm ran- domized trial looking at the benefit of adjuvant therapies with patients allocated to surgery alone, post-operative pelvic radiation, post-operative chemotherapy, or both post-operative chemother- apy and radiation in patients with B2 or C disease (Gastrointestinal Tumor Study Group 1985).

Local recurrence was reduced in the chemoradia- tion arm from 25% to 11%, and overall survival was improved from 14% to 56%. Confirmation of these results was found with the NSABP-R01 (Fisher et al. 1988) and, as such, the National Institutes of Health issued a clinical announcement recom- mending adjuvant 5-FU-based chemotherapy and concurrent radiation therapy for patients with stage B2, B3, or C rectal cancer (NIH Consensus Conference 1990). Although these initial trials included semustine, several randomized studies examined the value of adding this drug to therapy and their results have led to the dropping of semus- tine from adjuvant treatment, as it was not associ- ated with a significant benefit (Gastrointestinal Tumor Study Group 1992; O’Connell et al. 1994;

Wolmark et al. 2000).

An Intergroup trial (INT-0114) randomized

patients to pelvic irradiation plus 6 months of bolus

5-FU versus bolus 5-FU and levamisole, leucovorin,

or both (Tepper et al. 1997). A preliminary analy-

sis revealed no significant difference in disease-free

survival or overall survival (78–80%) among the

four treatment arms and, as expected, toxicity was

greatest with the three-drug regimen. Efforts to fur-

ther refine the delivery of 5-FU-based therapy are

ongoing and include the use of a prolonged venous

infusion, which is associated with less myelosup-

pression but more diarrhea (Mehta et al. 2003). The

current intergroup trial examines the benefit of this

regimen relative to bolus infusion of the drug with leucovorin and levamisole.

The value of pre-operative therapy is well recog- nized, and includes sphincter preservation and less bowel-related toxicity, at the possible expense of over treatment and increased wound-healing diffi- culties. A German trial randomized patients staged by means of endoscopic ultrasound to pre-opera- tive or post-operative radiation with concurrent 5-FU by prolonged venous infusion for two cycles followed by maintenance 5-FU (Sauer et al. 2000).

An interim analysis of toxicity reported fewer cases of grade-3+ diarrhea with pre-operative chemora- diation, and no difference in post-surgical compli- cations. In a subsequent report, Sauer et al. (2004) updated results of the trial, in which 421 patients were randomly assigned to receive pre-operative and 402 post-operative chemoradiotherapy. The 5- year local relapse rate was 6% and 13%, respectively (P=0.006), and overall survival was 76% and 74%

(P=0.8). Grade-3 to grade-4 acute toxicity occurred in 27% of the patients in the pre-operative group compared with 40% with post-operative chemora- diotherapy (P=0.001). The incidence of long-term sequelae was 14% and 24%, respectively (P=0.01).

This trial documented improved local tumor con- trol and a reduction in treatment morbidity with pre-operative chemoradiotherapy, although there was no impact on overall survival. Willett et al.

(2004) have shown that the concurrent administra- tion of the VEGF-specific antibody bevacizumab with 5-FU and radiation to the pelvis showed anti- vascular effects in human rectal cancer.

There have been several reported publications regarding pre-operative chemoirradiation in rectal cancer. Bosset et al. (2004) reported on the toxic- ity of the EORTC 22921 protocol, a four-arm study that compared pre-operative chemoirradiation with pre-operative irradiation alone or post-operative chemotherapy with no further therapy in T3-T4 M0 resectable rectal cancer. In the various groups, 6 patients died pre-operatively and 8 within 30 days after surgery. The addition of 5-FU and Leucovorin to pre-operative irradiation slightly increased acute toxicity, without affecting compliance to the radia- tion protocol.

At MD Anderson Cancer Center, Crane et al.

(2003) reported on 403 patients with clinical stage T3-T4 rectal cancer treated with pre-operative radi- ation therapy alone or combined with concurrent chemotherapy (continuous infusion of 5-FU). The use of concurrent chemotherapy and irradiation improved tumor response and down staging (62%

versus 42%) with radiation alone (P=0.001). Bonnen et al. (2004), from the same institution, published the results of a study of 431 patients with clinical stage-T3 rectal cancer treated with pre-operative chemoradiation followed by surgical resection. Sim- ilar pre-operative treatment was followed by total surgical excision in 405 patients. With 46 months mean follow-up, two intrapelvic recurrences were observed in 26 patients treated with local excision (6% at 5 years), compared with 8% pelvic recurrence in patients treated with mesorectal-excision and 6% in a subgroup of patients with complete clinical response to pre-operative chemoradiation treated with mesorectal excision. Actuarial overall 5-year survival was 86% in the local excision group com- pared with 81% in the mesorectal-excision patients, and 85% in the patients with complete clinical response to chemoradiation followed by mesorectal excision by abdominal perineal resection or lower anterior resection.

Similar results were reported by Bujko et al.

(2004) in a randomized trial comparing short-term radiation therapy with conventional fractionation chemoradiation. In the study in which 316 patients were randomized, the sphincter preservation rate was 61% in the short-term pre-operative irradia- tion group and 58% in the radiochemotherapy arm (P=0.57).

Some studies have addressed the efficacy of post- operative radiation therapy alone or combined with chemotherapy. Cafiero et al. (2003) reported on a study of 218 patients randomized to be treated with 50 Gy/2-Gy fractions administered post-operatively or a treatment consisting of 5-FU plus levamisole and radiation therapy to the same dose schedule as above. There was no significant difference with regard to disease-free survival or overall survival in the two arms. The local-regional recurrence rate was about 9%. The chemoirradiation regimen was asso- ciated with higher toxicity, which impaired patient compliance to chemotherapy.

A number of new chemotherapeutic agents are being used in the treatment of patients with colorec- tal cancer, usually in combination with pelvic radia- tion therapy. Among the newer drugs, oxaliplatin- based drugs or irinotecan and capecitabine have been used, frequently combined with 5-FU (Minsky 2004a, b).

Zhu and Willett (2005) recently reviewed the

gains that have been achieved with the integration

with radiation therapy, chemotherapy, and surgery

in the management of patients with localized rectal

cancer.

3.8.1

Central Nervous System

High-grade gliomas such as glioblastoma multi- forme are aggressive malignancies, with very poor control and survival rates. Therapy has traditionally been based on surgical extirpation to the maximal extent feasible, followed by limited field radiother- apy. A variety of chemotherapeutic regimens, mostly based around a nitrosourea, have been employed either concomitantly with radiation or sequentially, but the role of chemotherapy has remained contro- versial (Lonardi et al. 2005). However, a recent, phase-III randomized EORTC study compared a regimen of irradiation with concurrent and adju- vant temozolomide to radiotherapy alone (Stupp et al. 2005). This study showed a clinically mean- ingful and statistically significant survival benefit for the chemoirradiation arm, with the median survival being 14.6 months with radiotherapy plus temozolomide versus 12.1 months for radiotherapy alone. The 2-year survival in the combined modality arm was 26.5%, compared with only 10.4% for the radiotherapy alone arm. Toxicity with the combined regimen was modest.

3.9

Conclusion

The preceding discussion has been a brief overview of the varied ways in which chemotherapy and radio- therapy can be combined in treating patients with cancer. The practice of chemoirradiation is truly mul- tidisciplinary and, as knowledge in the field expands, should play an increasing role in the control of neo- plasms. As molecular biology brings us new targeted therapies, it is hoped that existing treatment regi- mens can be improved, in terms of both survival and ameliorating acute and late toxicity of therapy.

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