• 6/26/2005
  • Jacques Bernier
  • Nature Clinical Practice Oncology (2005) 2, 305-314

Summary
Despite recent advances in multimodality management of patients with stage III−IV head and neck squamous cell carcinoma, the prognosis in these patients remains disappointing. In an attempt to improve treatment outcome, several teams recently investigated the role of altered fractionation radiotherapy in conjunction with systemic chemotherapy. The controlled trials that investigated this combined approach indicate that, although the magnitude of its effect was less marked for survival indices than for local-regional control, the addition of chemotherapy to altered fractionation regimens results in a clear improvement for these endpoints compared with hyperfractionated or accelerated regimens alone. The key challenge now is to optimize the synergism of these regimens in order to increase their therapeutic ratio in terms of both local-regional and systemic outcomes. This review is a critical appraisal of the real opportunities offered by the application of treatments aimed at increasing the dose intensity of radiotherapy delivered concurrently with cytotoxic drugs.

Introduction
Head and neck squamous cell carcinomas (HNSCC) represent 4−5% of all solid malignancies, with almost half a million cases diagnosed annually worldwide.1 Until the late 1970s radiation therapy was the treatment of choice for locally advanced HNSCC but, despite significant technologic improvements in radiation therapy, the high incidence of local-regional recurrences continued to pose the greatest threat.2 Tumor hypoxia, repopulation of tumor cells during treatment, and intrinsic resistance to radiotherapy, have all been implicated as causes of treatment failure.3, 4 From the late 1970s, altered fractionation radiation therapy was extensively investigated in an attempt to target some of these factors.5, 6, 7

In parallel, systemic chemotherapy applied to advanced HNSCC had demonstrated good indices of antitumor activity.8 Throughout the last two decades, therefore, chemotherapy was often added to radiotherapy, with many clinicians opting for a concurrent delivery approach for these two modalities.9, 10, 11 The biological rationale for this was twofold. First, tumor-cell clonogens could be sensitized by the concurrent delivery of chemotherapy and ionizing radiation.12 Second, the irradiated tumor and micrometastases were exposed at the same time to the drugs’ cytotoxic effects. From the biological viewpoint, concurrent chemotherapy and radiotherapy is also likely to help clinicians implement more efficacious, multitargeted therapies directed towards—among others—cell killing, oxygen-factor manipulation, cell-cycle alteration and signaling pathways attack.

Many clinical trials showed that concurrent chemotherapy and radiation therapy—also referred to as chemotherapy-enhanced radiation therapy (CERT)13—could improve the prognosis of patients with locally advanced disease.14, 15 The fact that local-regional recurrences remained a major cause of failure, however, led a number of institutions to investigate the additional impact of radiotherapy dose intensification on disease control. While the first CERT trials were based on the use of conventional fractionation radiotherapy, also called CERT-conventional fractionation (CERT-CF) a variety of hyperfractionation and acceleration schedules, known collectively as CERT-altered fractionation (CERT-AF), were more recently tested in conjunction with chemotherapy.16 This review is a critical appraisal of the real opportunities offered by the application of treatments that aim to increase the dose intensity of radiotherapy delivered concurrently with cytotoxic drugs.

The road to modern CERT-AF regimens

Altered fractionation
A conventional course of radiation for HNSCC generally delivers 70−72 Gy in 7−7.5 weeks, with a once-daily dose of 1.8−2.0 Gy delivered over 36−40 fractions. In the late 1970s, to optimize treatment delivery various efforts were initiated to alter the conventional fractionation regimen and to test new schedules; this was termed altered fractionation.17 Altered fractionation regimens allow multiple fractions per day that are smaller than the standard once-daily 1.8−2 Gy dose. There are two types of altered fractionation: hyperfractionation and accelerated fractionation. Hyperfractionation relates to radiotherapy delivered for each fraction rather than the total treatment time, and in this regimen small doses per fraction are delivered—in most cases, 1.10−1.25 Gy/fraction for a total of 56 fractions, over a relatively standard period of time (usually 7 weeks). Accelerated fractionation relates to the intensity of total dose delivered over time; the fraction size is usually larger (e.g. 1.6−1.8 Gy/fraction) and delivered more than once daily, and to a dose of 10 Gy per week but treatment is delivered over a reduced total period of time (usually 6 weeks or less) compared with hyperfractionation.

Both hyperfractionation and accelerated fractionation cause increased acute morbidity relative to conventional fractionation. Hyperfractionation aims to improve efficacy by increasing the total dose while maintaining the total treatment time and risk of late morbidity relative to standard fractionation. It exploits the difference in fractionation sensitivity between tumors and normal tissues, which lead to late morbidity, and can enhance tumor-cell killing without significantly increasing late toxicity.18 In contrast, accelerated fractionation relates to the intensity of radiation therapy delivered over time; a schedule that exceeds 10 Gy per week is classified as accelerated. Total dose must be equivalent to or slightly reduced relative to standard radiotherapy regimens in order to prevent increased late morbidity. The aim of accelerated regimens is to target tumor proliferation, which is a major cause of radiotherapy failure. Treatment acceleration helps overcome this problem because it counterbalances tumor-cell repopulation, especially in fast-growing tumors such as head and neck carcinomas.18

In terms of local-regional control, small but significant gains were observed when hyperfractionation and accelerated fractionation were tested in randomized trials, which showed that altered fractionation significantly enhances local control rates with P values of less than 0.0001. Compared with conventional regimens of 2 Gy daily fractions, hyperfractionation and acceleration also yield a small but significant benefit in terms of overall survival.19, 20 In a recent meta-analysis conducted at Villejuif,20 an absolute benefit of 3% (from 36 to 39%, hazard ratio [HR] 0.92, 95% CI 0.87−0.97; P = 0.004) was observed at 5 years in favor of the altered fractionation regimens.

CERT-CF regimens
Platinum-derived compounds and 5-fluorouracil (5-FU) are the chemotherapeutic drugs that have been most widely used in prospective trials on CERT-CF.21, 22 These drugs have been shown to sensitize cells to radiation therapy. Radiation-induced free radicals, adduct formation, DNA-damage-repair inhibition and a radiation-induced increase in cellular platinum uptake were among the potential mechanisms associated with cisplatin-mediated radiation sensitization, induced by the enhanced formation of toxic platinum intermediates.12, 23 The selectivity of the platinum radiosensitization remains unclear, however.

The rationale for adding chemotherapy to radiation therapy is based on three main clinical observations. First, although 70−75% of patients with stage III−IV disease remain free of disease at 2 years, their long-term prognosis is poor: 5-year survival rates rarely exceed 30−35%. Second, despite the fairly high number of deaths linked to concomitant diseases, the incidence of metastases can reach 15−20%. Third, a variety of cytotoxic agents have demonstrated efficacy against epithelial-cell cancers. The CERT-CF approach thus represents a logical extension of the protocols based on radiotherapy alone, and was adopted as the standard of care when the results of several meta-analyses demonstrated the superiority of the combined treatments over irradiation alone.24, 25, 26, 27, 28 In a recent analysis by Bourhis et al.,29 the HR calculated for survival rates following CERT versus radiotherapy was 0.81 (P <0.0001). Nonetheless, treatment toxicity and, in particular, early reactions, are often a limiting factor when attempts are made to intensify local-regional therapy. Although cisplatin when used as single-agent chemotherapy in CERT-CF was shown to have little effect on mucous membranes,15 acute mucosal reactions are likely to reduce and delay chemotherapy delivery, and/or prolong overall treatment time.

CERT-AF regimens
Between 1998 and 2005, seven prospective trials30, 31, 32, 33, 34, 35, 36 and one influential retrospective study37 addressed the efficacy of CERT-AF. All studies compared altered fractionation with CERT-AF. Five trials compared accelerated fractionation alone versus accelerated fractionation with chemotherapy, and in two studies altered fractionation and CERT-AF were based on hyperfractionation regimens. Four of the seven trials combined a chemotherapeutic drug—cisplatin, carboplatin or mitomycin C—with 5-FU, and the other three used mono-chemotherapy (cisplatin or mitomycin C)

Treatment outcome after CERT-AF
In the controlled trials that investigated CERT-AF, the common theme was a significant enhancement of local-regional control rates.30, 31, 32, 33, 35, 36, 37 This trend was observed for the various radiotherapy and chemotherapy schedules tested. The trial by Staar and co-workers34 was the only study that did not observe any increase in local-regional control for the experimental arm, but it is not clear whether this trial had sufficient statistical power to resolve a clinically relevant difference between the altered fractionation and CERT-AF effects. Although the magnitude of the CERT-AF effect was less marked for survival indices than for local-regional control, the addition of chemotherapy to altered fractionation regimens results in a clear improvement for these endpoints.

In the absence of a direct and randomized study, any comparative analysis between fractionation schedules or chemotherapy regimens is likely to be biased by, for instance, variations in patient selection. This review nevertheless suggests that, while it is not possible to determine whether accelerated fractionation is superior to hyperfractionation or vice versa, mono-chemotherapy appears to be as affective as multi-agent chemotherapy, because patients treated with only one cytotoxic agent (cisplatin or mitomycin C) benefited to a similar extent as those receiving either cisplatin or carboplatin in combination with 5-FU.

Compliance to treatment and acute side effects
Patient compliance to different treatment protocols varied significantly across the randomized trials and data must be interpreted with caution. Compliance to radiotherapy was clearly affected by the addition of chemotherapy in only two studies.30, 31 For example, although Brizel and colleagues31 reported differences across the two arms of the study in terms of the mean radiotherapy dose (74.00 2.73 Gy in the altered fractionation arm versus 70.50 1.6 Gy in the CERT-AF arm, P <0.001) and overall treatment time (42 6 days versus 47 5 days, P <0.001), it should be noted that this trial was intentionally designed so the radiotherapy alone arm would deliver higher doses over a shorter time period compared with the CERT-AF arm. Thus, in this trial, the compliance was excellent and in concordance with the protocol design. The acute toxicity induced by CERT regimens was shown to vary considerably for different studies. For example, the incidence of grade 3 and 4 mucositis ranged from 16 to 90% in the altered fractionation group; in the CERT-AF arms, it ranged from 38 to 95%. CERT-AF significantly increased the mucosal reaction intensity compared with altered fractionation in only two of the seven trials.30, 34 Non-hematologic acute toxicity was significantly enhanced by CERT-AF for some endpoints only. As expected, hematologic toxicity was more severe in the chemotherapy-containing arm but remained acceptable in all trials.

The advantages of aggressive interventions are also offset by treatment-related toxicities, such as severe mucositis, dysphagia, and weight loss. The transient nature of these acute toxicities, however, is also dependent on the effectiveness of supportive care, such as aggressive monitoring, early hospitalization, antibiotic therapy for neutropenic fever, and prompt nutritional intervention, all of which are known to be of critical importance. Although the toxicity encountered in patients treated with CERT-AF regimens can sometimes be formidable, it appears to remain manageable if handled by teams with expertise in supportive care. The addition of 5-FU to cisplatin or carboplatin might reduce the THERAPEUTIC RATIO of CERT-AF, as demonstrated in two trials using multi-agent chemotherapy30, 34 where a significant increase in the incidence of severe mucositis was observed compared with patients treated with mono-chemotherapy.

Treatment Toxicity
In terms of acute toxicity, side effects were observed more often during CERT-AF for some endpoints only, such as confluent mucositis or severe emesis . Undoubtedly, this increase in side effects results from the significantly enhanced cytotoxicity yielded by the high dose-intensity levels of CERT-AF compared with those of altered fractionation alone, especially in normal tissues, such as mucosa, which are characterized by a fast cell repopulation.

Differences in late toxicity across the two arms are reported in three of the seven reviewed trials,30, 31, 34 in which investigators observed that, following CERT-AF, there were higher incidences of severe diffuse laryngopharyngeal edema—necessitating a feeding tube in a significant number of patients— as well as of mucosal necrosis and severe muscular fibrosis. In the remaining four trials32, 33, 35, 36 no difference in late toxicity was observed between the altered fractionation and CERT-AF groups.

Optimization of radiotherapy and concurrent chemotherapy
The management of patients with locally advanced HNSCC has undergone a major paradigm shift during the past decade. Local control is paramount in the treatment of these patients and since the 1970s intensive efforts have been made to test the efficacy of various CERT regimens, in an attempt to improve further the prognosis of stage III−IV disease.16 The literature indicates that CERT-AF significantly enhances local-regional control rates (Box 2) and, in most studies, has been shown to improve survival indices compared with those observed after altered fractionation alone.30, 31, 32, 33, 34, 35, 36 The improved survival rates seen with CERT-AF are also associated with a high toxicity, however. For most endpoints the toxicity is not significantly higher than that observed after altered fractionation. The severity of toxicity might be a function of the dose intensity of the selected CERT-AF regimen, especially if the chemotherapy combination contains 5-FU. To investigate whether radiotherapy dose intensity and 5-FU-containing chemotherapy regimens increase toxicity severity, future randomized trials would require a factorial 2 2 design to test this formally.

Key messages from trials comparing altered fractionation with chemotherapy-enhanced radiation therapy-altered fractionation
Chemotherapy-enhanced radiation therapy-altered fractionation (CERT-AF) has the most significant impact on local-regional disease control
There are improved survival indices with CERT-AF
There is increased acute toxicity with CERT-AF, but this is still manageable
There is no significant enhancement of late toxicity with CERT-AF
There is similar efficacy of hyperfractionation and accelerated fractionation schedules in CERT-AF
Mono-chemotherapy is as efficient as multidrug chemotherapy
Careful selection of regimens and patients is of critical importance

The data retrieved from these published trials clearly reveals two conclusions. First, in most studies, the enhancement in efficacy observed for altered fractionation doesn’t differ significantly between hyperfractionated and accelerated regimens. Second, in patients treated with CERT-AF, mono-chemotherapy is as effective as multidrug regimens. This finding correlates with the results of the meta-analysis conducted by Bourhis et al.,29 which did not demonstrate any significant difference in terms of efficacy between mono-chemotherapy (HR = 0.84) and multidrug chemotherapy (HR = 0.77). In this meta-analysis, the HR for overall survival gain was lower for CERT-AF (HR = 0.73) compared with CERT-CF (HR = 0.83), indicating that alteration of fractionation might even boost the effects of CERT strategies based so far on conventional radiotherapy regimens. This suggests that CERT-based policies should also be revisited by prospectively comparing the respective efficacy of CF and altered fractionation when combined with concurrent chemotherapy.

Interestingly, the incidence of severe acute and late toxicities varies considerably from one CERT-AF study to another, which might indicate that side effects have not been reported uniformly by the investigators. Also, several late endpoints are often reported for the study as a whole rather than according to treatment arm. This makes a comparison with other studies difficult. The comparative analysis of randomized trials on both altered fractionation and CERT-AF results in high levels of acute toxicity, requiring management by an experienced supportive care team. Caution is therefore needed when introducing this type of therapeutic intervention into community hospitals, because these levels of toxicity imply an intensive supportive care that not all inpatient and outpatient units are able to manage. Moreover, the use of opioids, hospitalization, feeding tube use, and in some cases topical applications, can yield higher costs associated with the treatment of complications caused by CERT-AF-related toxicity.

Two conclusions can therefore be drawn. Despite the fact that most studies document acute toxicity, which can be severe but manageable, more attention should be directed toward possible toxicity reduction, either by modifying the type of drugs combined with radiotherapy, or by adding agents that reduce the sensitivity of normal tissues to cytotoxic attack. For cisplatin-based regimens, further investigations should compare the toxicities of this high-dose “bolus” drug and fractionated (weekly) delivery. In addition, the therapeutic ratio of some CERT-AF regimens might turn out to be lower than that of most altered fractionation schedules. For instance, in the Staar’s study,34 the proportion of long-term survivors who remained dependent on a feeding tube was unacceptable (51%), and this toxicity level indicated that the investigated regimen was too toxic and should be discarded. The results of this study do not imply that CERT-AF should be abandoned, but confirm that combining chemotherapy with intensive radiotherapy warrants caution with respect to both the drug type and dose, and fractionation selection. An inadequate choice of chemotherapy and/or radiotherapy schedule might indeed lead to an undue enhancement in acute or late toxicities likely to jeopardize any increase in therapeutic ratio.

Although the exact magnitude of therapeutic gain afforded by CERT-AF is difficult to estimate from the literature, the late-morbidity results indicate that the clinician’s decision should be made by careful consideration of the benefits and harmful effects of the treatment. This implies that a careful selection of the patients able to sustain CERT-AF dose intensities should be made through an accurate assessment of their general conditions and expected compliance not only to cytotoxic drugs, but also to supra-additive treatments. Finally, although patient mortality associated with locally advanced disease can vary, systemic failures tend to become the overwhelming cause of death. Attention should, therefore, be focused on the control of micrometastases present at the time of diagnosis.

Future options
A complementary and logical approach to improving the prognosis of stage III−IV disease is the addition of more active drugs that might boost the efficiency of CERT-AF regimens; for example cytotoxic drugs such as taxanes,38 or hypoxic-cell-killing agents such as tirapazamine.39 While the concomitant use of docetaxel and irradiation is currently being investigated in phase I and II studies, a randomized phase III trial combining tirapazamine, cisplatin and a conventional regimen of radiotherapy will soon be closed and will give important indications as to the clinical relevance of novel strategies exploiting—rather than overcoming—the presence of hypoxic cells in large tumors. Overexpression of the epidermal growth factor receptor has been correlated with a more aggressive tumor behavior and poor clinical outcome. In terms of both local-regional control and overall survival, the use of epidermal growth factor receptor monoclonal antibodies was recently shown to be a superior strategy to radiotherapy alone, and can be applied, in phase I and II studies, to CERT-AF.40 With respect to radiotherapy side effects, there has been some interest in compounds that could possibly reduce treatment toxicity. One example is the drug amifostine,41 which is currently under investigation, but it is too early to draw definitive toxicity conclusions. This is partly owing to the uncertainty regarding the value of these agents in sparing the salivary gland function after treatments with high-dose intensity radiotherapy.

To intertwine more efficiently the ‘optimal’ radiation fractionation with the ‘best’ concurrent chemotherapy will actually require both the development of highly conformal irradiation techniques, and the use of novel agents to increase tumor-cell killing and ameliorate mucosal toxicity. Regarding chemotherapy, it will be important to continue to develop techniques such as MRI to allow the measurement of intracellular metabolites over time.42 Cisplatin and gemcitabine, which are active in the micromolar range, will require high-sensitivity imaging techniques such as positron-emission tomography.42 With respect to radiotherapy, the delivery of high conformality irradiation, based on techniques of intensity modulation, is bound to spare more normal tissues and therefore allow the use of more vigorous regimens of chemoradiation.

Conclusion
Based on published data, it is clear that the use of altered fractionation and CERT significantly improve efficacy. Although the advantages of improved efficacy can be jeopardized by the severity of acute reactions, long-term complications observed after altered fractionation and CERT-AF appear to be similar, except if the dose intensification of the selected regimen is too marked. Caution should be exercised in interpreting long-term results, however, because for CERT-AF the limits of acute and late toxicities in normal tissues have only been partly elucidated. The results yielded by CERT-AF are encouraging and undoubtedly help us reshape the therapeutic approaches in patients with locally advanced disease. Owing to the use of more efficacious and less toxic combinations, unprecedented opportunities are now available for clinicians in their search for improving tumor control and functional outcomes.

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