Adjuvant chemo- and radiotherapy for poor prognosis head and neck squamous cell carcinomas

Critical Reviews in Oncology/Hematology 56 (2005) 353 364 Adjuvant chemo- and radiotherapy for poor prognosis head and neck squamous cell carcinomas Jacques Bernier a,, David G. Pfister b, Jay S. Cooper c a Department of Radiation Oncology, Oncology Institute of Southern Switzerland, San Giovanni Hospital, CH-6504 Bellinzona, Switzerland b Department of Medical Oncology Memorial Sloan-Kettering Cancer Center, New York, NY, USA c Department of Radiation Oncology, Maimonides Medical Center, Brooklyn, NY, USA Accepted 26 April 2005 Contents 1. Introduction... 354 2. Methods... 355 2.1. Post-operative radiotherapy... 355 2.2. Chemotherapy... 355 2.3. Concomitant chemo- and radiotherapy... 355 2.3.1. Messages from translational research: the choice of the drug and the impact of the treatment time... 356 2.3.2. Platinum-derived compounds as reference drugs in chemo-radiation... 356 2.3.3. Clinical implementation of chemo-radiation schemes... 356 3. Adjuvant treatment in locally advanced HNSCC: how to exploit the lessons from the past... 357 3.1. Biological bases of cell response to radio- and chemotherapy in the post-operative setting... 357 3.2. A critical step: to identify the right prognostic factors... 357 3.3. Does the time effect matter in post-operative setting?... 358 3.4. High-dose versus low-dose chemo-radiation: a question of objectives... 358 3.5. Toxicity of chemo-radiation schedules in adjuvant setting... 359 4. Chemo-radiation: what regimens for which patients?... 359 4.1. Objectives and outcome of recent prospective studies using chemo-radiation... 359 4.2. EORTC 22931 and the RTOG 9501 trials: what are their differences and what they have in common... 360 4.2.1. Dose intensity of chemo- and radiotherapy regimes... 360 4.2.2. Patient selection and eligibility criteria... 360 4.2.3. Endpoints and evaluation times... 360 4.2.4. Distribution of primary tumor sites... 360 4.2.5. Distribution of T and N stages... 360 4.2.6. Surgical margin status... 361 4.2.7. Compliance with planned treatment... 361 4.2.8. Acute and late toxicities... 361 4.2.9. Treatment efficacy... 361 5. Future options for HNSCC adjuvant treatment... 361 6. Conclusions... 362 Reviewers... 362 References... 362 Biography... 364 Abstract The treatment of squamous cell carcinomas of the head and neck is multidisciplinary, especially when the disease is diagnosed at an intermediate or advanced stage. Very often the clinician chooses between surgery, chemo- and radiotherapy options on the basis of Corresponding author. Tel.: +41 91 811 9157; fax: +41 91 811 8678. E-mail address: jbernier@siak.ch (J. Bernier). 1040-8428/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2005.04.010

354 J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 the most recent data from the literature, prior experience in head and neck oncology and patient preferences. Nevertheless, for operable tumors, primary surgery, combined in poor-risk patients with radiation, is traditionally considered as the approach offering the best opportunity of cure. Randomized controlled trials and meta-analyses conducted in the 1990s have demonstrated major improvements not only in loco-regional tumor control, but also in terms of survival when chemotherapy is added to radiotherapy in the post-operative setting. The therapeutic index yielded by the co-administration of cytotoxic agents and ionizing radiation following primary surgery as compared with radiotherapy alone has nevertheless been at the center of many debates recently. Notwithstanding the fact that two randomized trials have recently provided new evidence that adjuvant chemo-radiation in poor-risk patients improves loco-regional control and disease-free survival, a number of questions regarding the optimization of the post-operative approaches remain unanswered. There is remaining need for further research efforts that would enable scientists and clinicians to improve, in the next decade, the management of this complex entity of diseases. 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Radiotherapy; Chemotherapy; Chemo-radiation; Head and neck; Randomized trials 1. Introduction Head and neck cancers account for nearly 4% of all newly diagnosed cancers every year [1]. In 2000, the estimated number of new cases worldwide was 550,000. At least 40% of patients presenting with oral cavity or pharynx carcinoma have locally advanced disease, and the associated prognosis remains disappointing: in U.S.A. the 5-year-relative survival rates for the period 1989 1995 did not exceed 45% for this group. Primarily, this reflects the loco-regionally advanced nature of disease often found at the time of diagnosis, since distant metastases are then found in less than 10% of the cases. Traditionally, patients with tumors considered unresectable were treated, until the early 1990s, with primary radiation therapy alone. Both conventional and altered fractionation regimens achieved 5-year overall survival (OS) rates of less than 30% [2]. In a meta-analysis of chemotherapy in locally advanced head and neck cancer (HNSCC) [3], the overall survival at 5 years was 32% with radiotherapy alone. After primary surgery the prognosis of HNSCC is predicted by the disease s clinical stage and presence of unfavorable histopathological features. Indeed, it has been repeatedly substantiated that, while most T1 2 tumors, with no evidence of neck node involvement, can be treated adequately by surgery or radiation therapy alone, the incidence of locoregional failure (LRF) and distant metastases (DM) is high in patients with locally advanced disease [4 9]. In these cases, radiotherapy is traditionally delivered as an adjuvant therapy to surgery, and the benefit in disease control for patients with poor prognosis factors from such an approach is now well documented [4 8]. Obviously, a significant number of patients experience after surgery, a notable impairment resulting from treatment sequelae, especially with regards to swallowing, speech and cosmetic outcomes, but in chosing one of the treatment sequences (primary versus salvage versus elective planned surgery), we should never lose sight of the fact that cure represents the primary goal of management and that the concept of radio-surgical association remains one of the cardinal points in the achievement of that objective. Throughout the 1960s and 1970s, surgery and/or radiotherapy were the mainstay of loco-regional treatment in patients with locally advanced tumors. In the 1980s, the disappointing prognosis of locally advanced HNSCC, even with the sequential integration of chemotherapy as induction or as an adjuvant treatment [10] led a number of investigators to assess the value of regimens combining concomitantly chemoand radiotherapy. A series of potential interactions between chemo- and radiotherapy in co-administration justified this approach. Among them: (a) changes in the cell survival curve; (b) a cooperation to prevent the emergence of resistant clones; (c) a decrease in tumor mass and re-oxygenation; (d) a selective toxicity for hypoxic cells; (e) a selective toxicity depending on cell-cycle phase; (f) a cytokinetic interaction; (g) an action on DNA repair and (h) an increased apoptosis [11]. Investigators were also aiming at drawing a significant benefit from the so-called supra-additive (or synergistic or radiosensitizing) effect [12,13] that is observed when the cytotoxic effect of the combination is greater than the sum of the effects of radiotherapy and chemotherapy considered separately. Thus, a number of institutions embarked on a concurrent application of both modalities. The fact that, in patients treated conservatively, early meta-analyses had shown that this co-administration was able to increase significantly both loco-regional control and survival rates [3,14 17] led, throughout the last decade, some institutions and cooperative groups to activate prospective trials investigating the role of cytotoxic drugs as adjuvant treatment to primary surgery as well. Various issues can now be addressed by the datasets from these studies, especially from those that addressed prospectively the following questions: 1. What are the clinical and pathologic features that are the most accurate prognostic factors for prognosis after primary surgery? 2. What is the impact of various post-operative combinations of radio- and chemotherapy on the pattern of failure and survival? 3. Is there any influence of dose intensity for various radiotherapy and/or chemotherapy schedules on treatment feasibility and outcome?

J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 355 4. Is there any difference in sensitivity to post-operative chemo- and radiotherapy between intermediate and poor prognosis tumors? 5. What is the sensitivity of tumor response to variations in overall combined treatment time? To answer these questions, this review will deal with adjuvant treatment delivered to patients with loco-regionally advanced tumors, who have been operated with curative intent. Patients with gross residual disease after surgery require salvage, not adjuvant therapy and will not be considered in this analysis. 2. Methods 2.1. Post-operative radiotherapy After Fletcher and Evers [4] had, in the early 70s, pioneered the implementation of radio-surgical approaches, a number of institutions provided prompt confirmation that post-operative radiotherapy significantly reduced the risk of failure above the clavicles [5,6]. Until 1980s, operable patients, particularly those with worrisome histological features, were usually managed with surgery followed by post-operative radiotherapy. A broad range of loco-regional control rates is found in the literature for the radio-surgical association, ranging from 35 to 75%, according to the tumor stage and histopathological pattern [11,18 20]. Whilst a dose of 50 Gy was found to eradicate malignant microfoci in 95% of the cases with light-microscopy assessed negative surgical margins [4], high doses, up to 70 Gy, were recommended for oropharyngeal or oral cavity squamous cell carcinomas in case of positive surgical margins [4,5]. Outcome following post-operative radiotherapy also compared favorably with that observed when somewhat lower dose radiotherapy was delivered before curative surgery, as shown by Tupchong et al., in a Phase III study of pre-operative radiation therapy (50.0 Gy) versus post-operative radiation therapy (60.0 Gy) for supra-glottic larynx and hypopharynx tumors [20]. In patients treated with post-operative radiotherapy, prognostic factors for survival are tumor location and stage, quality of surgical resection, and in some studies, age and gender [4 11,21]. 2.2. Chemotherapy In the early 1980s, the rationale for the inclusion of chemotherapy in the therapeutic management of locally advanced tumors related to two main observations. First their long-term prognosis is poor: although 70 75% of these cases remain free of disease at 2 years [5], the 5-year survival rates are usually poor and don t usually exceed 30 35% [5]. Second, although deaths are linked frequently to intercurrent diseases, most reports from the late 1980s indicated that as treatment of loco-regional disease improved the incidence of distant metastases in patients with locally advanced and resectable HNSCC reached 15 20% [22 25]. From the 1980s on, various schemes of adjunctive chemotherapy were tested, first in a sequential (induction and/ or adjuvant) manner thereafter concurrently with radiation therapy. Interestingly enough, the actual role of sequential chemotherapy still remained to be defined when investigators decided, in the 1990s, to move more consistently to modalities combining concurrent chemo- and radiotherapy [26,27]; indeed, the encouraging results obtained in non-randomized studies [26] had not been fully consolidated in randomized trials, at least in terms of a significant gain in survival indices [10,27 29]. Despite encouraging results from selected nonrandomized trials that suggested good tolerance and survival benefit [26], available randomized trials evaluating the use of chemotherapy in this manner are more disappointing. Compliance with chemotherapy, particularly after radiation can be suboptimal. For example, in the Head and Neck Contracts program, only 9% of patients received all six planned cycles of single-agent cisplatin [9]. Efficacy data suggest that adjuvant chemotherapy may alter the pattern of failure (decrease distant metastases), [HN Contract, Intergroup 0034], but demonstrating an improvement in overall survival has been elusive. The recent update of the MACH-NC revealed a 2% impact on absolute survival at 5 years among randomized studies evaluating the impact of adjuvant chemotherapy added to loco-regional treatment [70]. Among the randomized studies [10,27 29], the probability of finding a direct relationship between the addition of chemotherapy and a beneficial effect on survival was highest for resectable tumors with unfavorable histopathological factors. For instance, the Intergroup study 0034 [10] showed that, while adjuvant chemotherapy given sequentially to radiotherapy after surgery did not affect the prognosis in terms of loco-regional failures and survival rates, the high-risk group benefited more from adjuvant chemotherapy than the lowrisk group, both for tumor control and survival indices. As noted above, the pattern of failure was modified by the addition of chemotherapy: a reduction of recurrences in the nodes and of distant metastases was observed in the chemotherapycontaining arm, compared to those found after radiotherapy alone. Observations like this suggested that, rather than focusing on sensitizing processes between chemotherapy at a low dose and radiotherapy, higher dose regimens of chemotherapy with anticipated systemic activity would be preferred in post-operative setting if the targets were both an effect on loco-regional control and a significant impact on microscopic cell deposits at the systemic level. 2.3. Concomitant chemo- and radiotherapy At the turn of the 1990s, the rather disappointing results yielded by adjuvant chemotherapy led some groups to inves-

356 J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 tigate the potential benefit that might be drawn from concomitant radio- and chemotherapy (called chemo-radiation in this article) [31 34]. It was assumed that both additive and supra-additive effects of this co-administration were likely to be more effective than the sequential administration of these cytotoxic agents and that the higher progression-free survival observed in patients with gross disease treated with concurrent chemotherapy and radiotherapy might also apply to the post-operative model. 2.3.1. Messages from translational research: the choice of the drug and the impact of the treatment time Whilst, in the past, cytotoxic agents were selected on the basis of their observed effects in vitro or in animal models, the choice of the drug to administer in a concomitant way with radiotherapy was, in the more recent past, based on the mechanism of action of the compound and its capacity to influence pathways leading to cell death after irradiation. Platinum-derivative compounds, often in conjunction with 5-Fluoruracil, combined concurrently with radiotherapy have been most studied in prospective trials [31 37]. The activity of both drugs against head and neck cancer is related to the following properties: (a) inhibiting repair of lethal and sublethal damage induced by radiotherapy; (b) capacity of radiosensitizing hypoxic cells; (c) reducing tumor burden leading to an improved blood supply; (d) synchronizing and redistributing tumor cells into the more sensitive G2-M cell-cycle phase and (e) induction of apoptosis [38]. Encouraging preclinical results were also found for combinations of irradiation with taxanes, nucleoside analogues (fludarabine, gemcitabine), etc. [39] (see Section 5), although those agents have received much less scrutiny in randomized trials. Another important issue refers to the link between treatment duration and outcome. In patients with rapidly proliferating tumors, the therapeutic efficacy is greater with shorter overall treatment time. The time effect is actually based on the fact that, after a few weeks of treatment, the acceleration of cell repopulation reduces disease control probabilities. This is the reason why in head and neck oncology, the use of accelerated radiotherapy has been frequently advocated since a significant proportion of these neoplasms have a short potential doubling time [40]. The use of concurrent combined modality regimens actually is an extension of this concept, representing an acceleration of treatment that can theoretically overcome the deleterious time effect by increasing dose intensity [41 45]. 2.3.2. Platinum-derived compounds as reference drugs in chemo-radiation Throughout the past three decades, various agents have been shown to be active in patients with HNSCC. The first consistent clinical investigations of platinum-derived compounds can be traced to the 1970s. In one randomized study, patients receiving cisplatin had a significantly prolonged survival compared with patients receiving symptomatic care or Bleomycin. The addition of Bleomycin to cisplatin conferred no additional survival benefit [46]. A few years later, the same institution reported a significant benefit, in terms of survival, for patients randomized to receive cisplatin compared to methotrexate. As in the previous study, the addition of 5-FU to cisplatin conferred no additional survival benefit [47]. Other randomized trials, however, have not confirmed the superiority of cisplatin to Methotrexate in terms of survival in this setting [48,49]. Platinum-derived analogs, and specifically cisdiamminoplatinum [II] (cisplatin), cis-diammine-l, 1- cyclobutane dicarboxyplatinum [II] (carboplatin) are the agents most often delivered concomitantly with radiation in the treatment of locally advanced head and neck squamous cell carcinomas. Their mechanisms of interaction with ionizing agents are not still fully understood and a number of recent laboratory studies have focused on their administration before or after cell irradiation. Among the potential mechanisms mentioned in Section 2.3.1 and associated with cisplatin- and carboplatin-mediated radiation sensitization under both oxic and hypoxic conditions, are enhanced formation of toxic platinum intermediates in the presence of radiation-induced free radicals [31,41 45] and a radiation-induced increase in cellular platinum uptake. 2.3.3. Clinical implementation of chemo-radiation schemes Platinum-derived compounds thus represent reference agents to combine with radiotherapy in head and neck cancer patients since they are both potentially strong radiosensitizers and active chemotherapeutic compounds to treat squamous cell carcinomas. Also, mucositis is generally not a dose-limiting toxicity for platin drugs, facilitating their combination with radiation. These factors explain why schemes based on concomitant administration of this chemotherapy agent and radiation therapy have been widely investigated. In trials, the dose/delivery schedules of platinum vary dramatically, ranging from every 3 weeks (100 mg/m 2 ) to low-dose daily (6 mg/m 2 ) [39]. One of the first prospective studies using the combination of RT with cisplatin, as single-agent therapy in the adjuvant setting, was completed by Bachaud et al. [50]. They randomized 83 patients with Stage III or IV HNSCC with histological evidence of extra-capsular spread of tumor in lymph node metastases to receive radiotherapy alone, using a daily dose of 1.7 Gy for the first 54 and 1.8 2 Gy until the completion of the treatment. In the combined modality arm, cisplatin 50 mg i.v. with forced hydration was given every week (i.e., seven to nine cycles) concurrently with radiotherapy. The radiotherapy group displayed a higher LRF rate as compared with the chemo- and radiotherapy group (41% versus 23%; p = 0.08). Survival without LRF was better in the CM group, the difference being close to the level of significance (p = 0.05). Meanwhile various groups of investigators [48 52] have investigated the feasibility and efficacy of regimens combining concomitantly radiotherapy with cisplatin or Mitomycin C at various dose levels and intensities. Table 1 lists the results

J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 357 Table 1 First generation of trials on adjuvant treatments comparing chemo-radiation to radiotherapy alone after primary line surgery Author Patients (n) Sites Type of CT LRC Survival [50b] 120 a Mitomycin C p < 0.01 NS [51a] 88 b Cisplatin p < 0.01 NS [51b] 26 b Cisplatin, 5-FU NS NS [52] c 120 b Mitomycin C p < 0.01 NS a Oral cavity, naso-, oro- and hypoparynx, larynx. b Oral cavity, oro- and hypoparynx, larynx. c Update of Weissberg s study. from publications on randomized studies conducted in the late 1980 1990s and comparing post-operative radiotherapy to chemotherapy added to radiation in the attempt to achieve radio-sensitization and spatial cooperation. The agents most frequently administered were cisplatin and Mitomycin C. In the two studies, which accrued the largest number of patients, disease-free survival rates were increased in the arm combining radio- and chemotherapy concomitantly [51,52]. In the early 1990s, the encouraging results of the study conducted by Al-Sarraf et al. [2,53], giving cisplatin in high doses (100 mg/sqm) repeated every 3 weeks (days 1, 22 and 43), led various European and U.S. cooperative groups to consider this regimen as the reference chemo-radiation approach for adjuvant treatment of HNSCC and to activate randomized trials measuring treatment outcome for this regimen after curative surgery in patients with locally advanced tumors. Over the last decade, substantial improvements have occurred in the way concurrent chemotherapy and radiotherapy regimens are delivered, especially with regards to treatment safety and supportive care. 3. Adjuvant treatment in locally advanced HNSCC: how to exploit the lessons from the past The reasons why the prognosis for patients with stage III-IV squamous cell carcinoma remains globally disappointing are at least two-fold. First, these patients with locally advanced HNSCC may also die from distant metastatic disease, intercurrent disease or second primary tumors. Second, the fact that, until a few years ago, loco-regional control rates remained unsatisfactory was related to sub-optimal applications of a number of biological and methodological concepts. 3.1. Biological bases of cell response to radio- and chemotherapy in the post-operative setting Theoretically radiotherapy induces differential sublethal damage repair in tumor cells versus normal tissue. Antagonists of radiosensitivity include: hypoxia due to defective oxygen perfusion or diffusion; large proportions of quiescent cells, which are usually resistant to radiotherapy; rapid proliferation, with a high amount of radioresistant S-phase cells; over-expression of growth factors receptors; defective apoptosis pathways; tumor cells mutated or deleted for genes involved in genome maintenance or cell-cycle control. The concomitant delivery of chemo- and radiotherapy, which was born in the 1960s, aims at overcoming the deleterious effects of a number of these biological factors. Later on, efforts were put forth to develop new regimens, with the additional goal of eradicating micrometastatic disease. The concept of chemo-radiation is based on the theoretical hypothesis that the additivity and synergy of chemoand radiotherapy are optimized by the co-administration of both cytostatic agents. As far as additivity is concerned, it is assumed that chemotherapy should increase cell killing in radioresistant tumor-cell subtypes such as cells with low ph and hypoxic cells (e.g., Mitomycin), or as cells in the radioresistant S phase (e.g., Hydroxyurea). Regarding synergy, it is postulated that cytostatic agents may hinder regrowth between fractions through inhibition repair of radiation-induced DNA damage (e.g., cisplatin), and synchronize or arrest cells during radiosensitive phases (e.g., Hydroxyurea, Paclitaxel, Cetuximab). Although only microfoci of residual cells are likely to be found after curative surgery, antagonist factors of radiosensitivity such as hypoxia due to post-operative vascular impairment and rapid cell proliferation caused by the release of growth factors during the wound healing period, presumably account for a significant proportion of failures following radiotherapy. Concomitant addition of cytotoxic agents is therefore likely to play a significant role in counterbalancing these biological factors. 3.2. A critical step: to identify the right prognostic factors Defining the prognosticators of treatment outcome represents the first step in the search for treatment optimization after curative surgery, as more advanced and aggressive disease will likely warrant greater treatment intensity and/or the investigation of new approaches in hopes of improving outcome. Although a study conducted in the 1990s [54] failed to demonstrate, in the post-operative setting, any significant benefit for either higher doses of radiotherapy or the addition of chemotherapy to radiotherapy, it provided clear indications regarding the need to stratify the patient population according to their level of risk. This study indeed demonstrated the critical importance of various disease patterns such as primary tumor site and disease extension, surgical margin status, peri-neural invasion, vascular embolisms, number and location of positive lymph nodes and presence of extra-capsular extension (ECE) of nodal disease.

358 J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 Nevertheless the dose effect relationship can be rather complex. For instance, the study by Peters et al. [54], revealed no significant dose response relationship for total doses ranging from 57.6 to 68.4 Gy. To explain this apparent lack of a dose response, it was postulated that the beneficial effect on tumor control of doses >57.6 Gy was offset by tumor cell regeneration occurring during the additional time taken to deliver the higher doses (given at 1.8 Gy/day). Four main messages emerged thereafter from the Anderson study that showed that risk assessment by clusters of surgical-pathologic features differentiated the relative need for post-operative radiotherapy. Firstly, ECE was the only significant independent variable, and that combinations of two risk factors were associated with a progressively higher risk of recurrence. Secondly, patients with no adverse surgicalpathologic features were shown not to need post-operative radiotherapy, because the 5-year actuarial LRC and survival rates achieved with surgery alone were 90 and 83%, respectively. Thirdly, patients with one adverse feature other than ECE who received 57.6 Gy post-operatively had a 5-year actuarial LRC rate of 94%. This moderate dose induced a lower incidence of acute and late morbidity than did 63 Gy, in their patient cohort, and appears to be sufficient to cure a significant number of patients with an intermediate risk of recurrence. Finally, high-risk patients (i.e., those with ECE or 2+ other adverse features) had a 5-year actuarial LRC rate of 68%, despite having received a higher radiation dose (63 Gy). 3.3. Does the time effect matter in post-operative setting? Traditionally, patients have started their radiotherapy 4 6 weeks after their surgical procedure, when wound healing is essentially complete. When the time interval between surgery and the onset of radiotherapy exceeds 6 7 weeks, cell repopulation may occur and the proliferation of residual malignant microfoci may be responsible for the deleterious impact of radiotherapy delays on loco-regional control and survival [7]. Of note, in a subsequent analysis [55] of one of the studies [4], the direct relationship between the latency to onset of radiotherapy and failure risks disappeared for longer follow-up times, indicating that doses higher than 60 Gy may compensate for the potential negative impact of radiotherapy delay on LRC. The temporal concept of treatment package should be considered at the time of the planning, as demonstrated by Ang et al. [56]: in the high-risk group, the dose delivered by random assignment was 63 Gy during 5 weeks (n = 76) or 7 weeks (n = 75). The first message of this study was there was a trend toward higher LRC and survival rates in favor of the 5- week regimen. Secondly, in the 7-week schedule, a prolonged interval between surgery and post-operative radiotherapy was associated with significantly lower LRC (p = 0.03) and survival (p = 0.01) rates. Thirdly, with regards to the impact of the overall treatment time on the therapeutic outcome, the 5-year actuarial LRC rate for <11 weeks was 76% compared with 62% for 11 13 weeks and 38% for >13 weeks (p = 0.002). Likewise, Rosenthal et al. [57] recommended that every effort should be made to keep the time from surgery to the completion of post-operative RT below 100 days. These two studies, together with those by Sanguineti et al. [58], Trotti et al. [59], Shah et al. [60] and Awwad et al. [61] support the concept that microscopic tumor cell aggregates escaping surgical excision repopulate before completion of a traditional course of radiation therapy. The overall treatment time (not only of radiotherapy, but also of the whole treatment starting from the time of the surgical procedure until the completion of the radiotherapy treatment) should therefore be carefully planned to optimize the biological efficacy of the multidisciplinary approach. Most studies support the recommendation that this treatment package needs to be delivered in a short overall time, and Ang et al. strive to complete the combined treatment in <11 weeks [56]. One way to implement this rule is to accelerate the radiotherapy fractionation. In unresectable HNSCC, it is now well documented that a number of accelerated fractionation (AF) regimens improve LRC rates [40]. As an alternative, an acceleration based on the concomitant delivery of cytotoxic drugs and ionizing radiation could reach equivalent or better results both at the local and systemic levels. 3.4. High-dose versus low-dose chemo-radiation: a question of objectives High-dose chemo-radiation effect is based at least on five mechanisms: independent cell killing by chemotherapy (without any interaction with radiotherapy); independent cell killing by radiotherapy (without any interaction with chemotherapy); interactive effects between chemo- and radiotherapy (supra-additive effects); enhancement of dose-intensity through reduction of overall treatment time; spatial cooperation between chemo- and radiotherapy at the primary tumor site and systemic level. Therefore, while chemo-radiation based on low doses of cytostatic agents focuses only on a chemo- and/or radiosensitizing effect, the goal of high-dose chemo-radiation is to achieve a better control of the loco-regional disease as well as a prevention of metastasis and efficient treatment of occult metastatic deposits. This distinction between what we can expect from low-dose (sensitization) and high-dose (sensitization and systemic effect) chemo-radiation regimens is important for it implies that meta-analyses of concomitant radiochemotherapy are likely to study not only heterogeneous groups of patients, but also combination treatments with quite different goals. Their results should therefore interpreted with caution, especially with regards to the efficacy of the various chemotherapy regimens tested in the adjuvant setting, while

J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 359 cisplatin-based schedules turn out to be the first choice, there is no convincing data so far that multidrug regimens are superior to cisplatin or carboplatin alone. 3.5. Toxicity of chemo-radiation schedules in adjuvant setting Undoubtedly acute reactions from adjuvant treatments are increased with chemo-radiation [62]. This toxicity enhancement has prevented so far an easy transfer of aggressive chemo-radiation regimens from academic institutions to community practice. Indeed, the performance status of patients accrued in clinical trials is generally moderate to good and may differ from that of patients treated in community hospitals. Moreover, the need for intravenous rehydration, gastric feeding tubes during treatment and narcotics for severe pain implies an intensive supportive care that not all in- and out-patient units are able to manage and not all patients are willing to endure and/or capable of tolerating. If not carefully controlled, these management situations might account both for more protocol violations (in terms of dose intensity) and higher risks of grade IV complications during and after the chemo-radiation. Caution is therefore needed before implementing this type of therapeutic management in unprepared community hospitals. Most reports show only a limited increase of severe late side-effects, but we should realize that, in many studies, follow-up is not long enough to document accurately the incidence of delayed complications [63 65]. Moreover, we cannot exclude the possibility that these complications are to date under-reported, especially in a significant number of retrospective studies. 4. Chemo-radiation: what regimens for which patients? 4.1. Objectives and outcome of recent prospective studies using chemo-radiation The objectives of the recent multicenter studies conducted in Europe and the U.S.A. [66,67] were to determine if, in the post-operative setting, the addition of concurrent high doses of cisplatin to radiotherapy significantly alters the disease outcome in high-risk HNSCC of the oral cavity, oropharynx, larynx or hypopharynx as compared to that observed after post-operative radiotherapy alone, especially with respect to (a) progression-free survival, overall survival, time to progression and loco-regional control rates and (b) to compare acute and late toxicity. Thus, the European and U.S. trials were designed to validate, in the post-operative setting, the results observed among patients treated with the combination of radiotherapy and concomitant chemotherapy as primary treatment. Three recently published meta-analyses [14 18] showed that cisplatin-based concomitant chemo-radiation is superior to conventional radiotherapy alone (70 Gy in 7 weeks) in improving not only loco-regional control, but also survival in locally advanced HNSCC. In the EORTC 22931 study [66] conducted from 1994 until 2000, 334 patients from 23 institutions were randomly assigned to either RT (66 Gy in 33 fractions over 6.5 weeks, arm 1), or RCT, using the same RT schedule combined with three courses of cisplatin 100 mg/sqm, on D1, D22 and D43 (arm 2). Radiotherapy was completed on schedule in 73.9% of the cases (73.1% in arm 1; 74.7% in arm 2). In arm 2, 29.5% of the cases did not receive the third course of chemotherapy. In arm 2, grades 3 4 functional mucosal reactions were significantly more frequent (44.5% versus 21.3%; p = 0.0004), but there was no difference in objective mucosal reactions between the two arms (p = 0.211). Grades 3 4 chemotherapy-related acute toxicity was mainly hematological with 10.9% granulocytopenia and 1.9% thrombocytopenia. Longer follow-up is needed for an accurate evaluation of late toxicity in normal tissues, but so far the analysis does not elicit any significant differences in late toxicity between the two arms. In the EORTC trial (Fig. 1), progression-free survival was the primary end-point. At a median follow-up of 60 months, there was a significant (p = 0.044) difference in progressionfree survival in favor of the chemo-radiation group: the estimates of median progression-free survival were 23 months (95% confidence interval: [18 30]) in the radiotherapy arm and 55 months [33 75] in the chemo-radiation group, while the 5-year Kaplan Meier estimates were 36 and 47%, respectively. In terms of overall survival, there was a significant (p = 0.02) difference in overall survival in favor of the chemoradiation group: the 5-year estimates were 40% for the control arm and 53% in the experimental one. Finally, with regards to loco-regional outcome, the 5-year cumulative incidence estimates of loco-regional relapses were 31% for the radiotherapy and 18% for the chemo-radiation group (p = 0.007). Adding chemotherapy to post-operative irradiation did not affect significantly the incidence of distant metastases. Fig. 1. Comparative analysis of endpoints in radiotherapy and chemoradiation arm.

360 J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 Finally, the cumulative incidences of late complications were not significantly different across the two groups. A higher incidence of grade 3+ muscular fibrosis was found after chemo-radiation (10% versus 5%), severe xerostomia was observed less often in the standard arm (22% versus 14%). The benefit observed in the RTOG 95-01 study [67] was also significant in terms of disease-free survival, but overall survival was not significantly improved. With regards to toxicity, the addition of chemotherapy resulted in a greater incidence of severe side-effects in this trial. Grade 3 or greater was observed in 34% of patients treated by radiotherapy, but more than doubled to 77% in the experimental arm. Severe late toxicity was not significantly different between the treatments. A comparison of these two trials features shows that notwithstanding an apparent similar design, criteria of selection were different in the two studies (Table 2). 4.2. EORTC 22931 and the RTOG 9501 trials: what are their differences and what they have in common 4.2.1. Dose intensity of chemo- and radiotherapy regimes Both trials delivered the same dose intensity, both with regards to the radiation schedule and chemotherapy regime. The only difference concerned the planned radiation boost doses: 12 and 6 Gy in the EORTC and RTOG studies, respectively. 4.2.2. Patient selection and eligibility criteria The RTOG based its selection of risk factors on the experience gained from Intergroup 0034 (also called RTOG 8503) [22], namely the presence of tumor in two or more lymph nodes and/or extra-capsular spread of nodal disease and/or microscopic-size tumor involvement of the surgical margins of resection, as the factors most significantly associated with a high risk of loco-regional relapse. In contrast, the EORTC selected the risk factors based on literature data, especially from the study conducted in the early 1990s by Peters et al. [54]: vascular embolisms, perineural disease, oral cavity and oropharynx carcinomas with positive lymph nodes at levels IV or V. This means that, in addition to the presence of Stages III or IV disease, the common high-risk criteria in the EORTC and RTOG trials were extra-capsular spread, and positive surgical margins. 4.2.3. Endpoints and evaluation times The main endpoints were disease-free survival in the EORTC trial and loco-regional failure in the RTOG study. The number of analyzable cases were 334 in the former study and 415 in the latter, and the interim analyses reported estimates at 3 years in the EORTC study versus 2 years in the RTOG trial (the median follow-up was 34 and 26.6 months in the EORTC and the RTOG trials, respectively). 4.2.4. Distribution of primary tumor sites In the RTOG trial, the most common site was oropharynx cancer, particularly in the chemo-radiation arm (48% versus 37%), while patients presenting with hypopharynx lesions were more often treated with post-operative radiotherapy than with chemo-radiation (12% versus 7%) The primary site distribution was different in the EORTC trial: hypopharynx lesions accounted for 21% of the cases (22% in arm 1 and 20% in arm 2), while only 29% of the patients presented with oropharynx cancers in this study (27% versus 30%, respectively). 4.2.5. Distribution of T and N stages As regards T stages, T3 4 were found in 60 and 62% of the cases treated in the control and experimental arms of Table 2 Comparative analyses between EORTC 22931 and RTOG 95-01 trials: disease pattern, treatment-related factors and treatment outcome EORTC 22931 (n = 334) RTOG 9501 (n = 459) Disease pattern Primary site distribution Oropharynx > oral cavity > larynx > hypopharynx a Oropharynx > oral cavity > larynx > hypopharynx a N2 3 (%) 56 93 Treatment-related factors Positive margins (%) 29 18 Radiotherapy dose (Gy) 54 + 12 60 ± 6 Patient compliance to RT (%) 74 80 Full compliance to CT (%) 50 61 Outcome endpoints 5-year estimates 2-year estimates Disease-free survival 48% vs. 36% (p = 0.04) b 54% vs. 45% (p = 0.04) b Overall survival 53% vs. 40% (p = 0.02) b 64% vs. 57% (p = 0.19) b Loco-regional failure rates 17% vs. 31% (p = 0.007) b 18% vs. 28% (p = 0.01) b Grade 3+ acute toxicity (p = 0.008)/(p = 0.28) b,c 77% vs. 34% (p < 0.0001) b Late toxicity 38% vs. 41% (p = 0.25) b 21% vs. 17% (p = 0.29) b Impact on distant metastases p = 0.61 p = 0.46 Second primary tumors p = 0.83 NA a But higher proportion of hypopharynx SCC in EORTC (20%) than in RTOG (10%) trial. b Chemo-radiation vs. RT values. c Functional/objective acute reactions.

J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 361 the RTOG trial, respectively, while the corresponding figures were 62 and 60% in the EORTC arms. There was a marked difference in N stage distribution between the two trials: in the RTOG trial, more than 93% of the cases presented with N2 3 stage as compared with only 56% in the EORTC trial. 4.2.6. Surgical margin status Positive margins were found in 29% of the cases treated in the EORTC study (arm 1: 32%; arm 2: 27%). In the RTOG trial, the corresponding figures were lower 19 and 17% in the control and experimental arms, respectively. 4.2.7. Compliance with planned treatment In the RTOG trial, the compliance with the radiotherapy schedule was reduced with chemo-radiotherapy compared to that of the control arm (77% versus 83%), while slightly less than 75% of the patients enrolled in the EORTC trials completed their radiotherapy on schedule, irrespective of treatment arm. Likewise, in the RTOG trial, dose deviations were found more frequently when chemotherapy was added to radiation, with 90 and 94% of the patients receiving 60 Gy. As regards compliance to chemotherapy, 61% of the cases registered in the experimental arm of the RTOG completed three full courses of radiotherapy, while 84% of them received two cycles. The corresponding figures in the EORTC trial were 49 and 66%. 4.2.8. Acute and late toxicities In the RTOG trial, severe acute and late toxicities (Grade 3+) were significantly more often observed after chemoradiation and this is in contrast with the absence of significant difference in objective mucosal reactions observed in the EORTC study. 4.2.9. Treatment efficacy On the basis of the dataset contained in the most recent abstracts, both the EORTC (at 5 years) and RTOG (at 2 years) studies elicited a significant gain in terms of disease-free survival (p = 0.04) and loco-regional control (p = 0.011), which were the main endpoints of the trials. To summarize, this comparison shows that, while the outlines of both protocols are very similar with regards to the treatment prescription, marked variations in patient selection and distribution can be observed between the two studies, including tumor sites, neck disease stage, and risk factor selection. As for treatment, the proportion of positive surgical margins was higher in the EORTC trial. Finally, there is no indication that one of the treatment arms was given in a sub-optimal way in these two prospective trials, since the compliance to treatment fell in line with that usually reported in the literature, both for radio- and chemotherapy dose intensity. Of note, the most recent reports on post-operative chemoradiation have indicated a reversal of the pattern of failure with an increase in distant metastases as cause of death in up to 25% of cases with locally advanced disease. This reversal has paralleled the application of more intensive loco-regional treatments. 5. Future options for HNSCC adjuvant treatment The loco-regional control levels reached so far highlight the limitations not only of single-modality approaches, such as definitive radiotherapy, but also of high-intensity multimodality treatments. A first strategy to increase the efficacy of combined treatments is the addition of more active drugs that may further improve the efficiency of the combination, such as hypoxic cell killing agents (e.g., tirapazamine) [39]. Another strategy involves blockade of the epidermal growth factor receptor [EGFR], a member of the ErbB receptor tyrosine kinase family. Over-expression of the EGFR has been correlated with more aggressive behaviour and poor clinical outcome. The blockade of the EGFR by the monoclonal antibody C225 [Cetuximab] was shown to increase the cell radiosensitivity in vitro [39]. The suggested mechanisms of action for C225 include inhibition of cell proliferation, radiation-induced DNA damage repair and angiogenesis, induction of cell-cycle arrest and enhancement of radiationinduced apoptosis. In radiotherapy, the arena of altered fractionation remains ripe for further prospective trials since few mature data are available regarding the concomitant delivery of more intensive radiation regimens and chemotherapy, particularly in the adjuvant setting. The main concern is that toxicity of frontline chemotherapy, given concurrently with hyperfractionated or accelerated radiation therapy, is significant, especially in a population of patients who, after surgery, already experience potentially severe impairments. The enhanced severe mucosal and skin toxicity require, in a significant number of cases, long hospitalization for medical care and supportive measures. With respect to radiotherapy side-effects, attention was paid recently to compounds that could possible reduce treatment toxicity. Agents such as amifostine [68] and pilocarpine [69] are currently under investigation and it is too early to draw definitive conclusions about the impact of these agents on salivary gland function when combined with chemotherapy and radiation. Molecular targets are also to be taken into account at the time of the treatment planning: for example, there may be a direct relationship between p53 mutations and cellular chemo-resistance, possibly through mechanisms linked to increased DNA repair and apoptosis inhibition. As mentioned above, not infrequently, both for organ preservation programs and in patients treated with primary surgery followed by chemo-radiation, distant metastases have emerged as a real impediment to cure in patients with locally advanced tumors. This new pattern, demonstrating an increased risk of distant failure, suggests that chemotherapy should be reinforced either through the use of more active

362 J. Bernier et al. / Critical Reviews in Oncology/Hematology 56 (2005) 353 364 agents, the application of more aggressive protocols in terms of dose intensity and an urgent need for new experimental approaches. Therefore, more efforts must now be focused on both the prevention and efficient treatment of distant metastases. Taxanes and other agents, which demonstrate a high level of activity in HNSCC patients, should be investigated more extensively in adjuvant or neoadjuvant setting. After the surgical procedure, we should finally keep in mind that one of the main concerns is time delay before the onset of radiotherapy [7,51]. Although it seems logical to begin radiation therapy as soon as possible to avoid any tumor cell repopulation, wound healing can unavoidably postpone, in a number of cases, the onset of the adjuvant treatment beyond 6 7 weeks. The link between the time interval between surgery and post-operative radiotherapy and loco-regional failures is conditioned by the tumor potential doubling times, which in head and neck, can be very short [7]. Therefore, it seems logical to consider that, after surgery, residual cancer cells could rapidly proliferate. Very few studies, however, have taken this parameter into consideration. The critical issues in these trials are that after surgical procedures, blood flow to residual cancer cells could be low and could make them partially resistant to radiation. The delivery of a peri-operative chemotherapy initiated no later than 10 days after surgery and protracted, on a weekly basis, until the onset of the chemo-radiation should be investigated prospectively. 6. Conclusions To define and optimize the adjuvant treatment in patients presenting with locally advanced disease primarily treated with curative surgery, the first step is to analyze, at the time of diagnosis, the tumor pattern as well as the distribution of pathological prognostic factors, which are known to determine accurately the risk level not only for loco-regional recurrence, but also for distant metastases. Microscopically involved margins, involvement of two or more nodes, extracapsular spread, presence of peri-neural involvement or vascular embolisms are associated with an approximately 25 30% probability of developing loco-regional failures. The presence of a number of unfavourable prognostic factors clearly indicates the need for combining, in the post-operative setting, chemo- and radiotherapy. Platinumderived compounds appear to be the reference chemotherapy agents to administer concurrently with radiotherapy. Both the EORTC and RTOG trials indicate that after curative surgery, patients with locally advanced tumors significantly benefit from high-dose regimes of cisplatin in co-administration with radiotherapy doses of at least 60 Gy resulting in a significant increase in loco-regional control and survival. These conclusions are being borne out by the final analyses of these two randomized trials and now constitute level I evidence. These recent prospective trials addressing the issue of chemo-radiation in the post-operative setting represent a long-awaited advance, and the results of these trials should allow a broader application of high-dose chemo-radiation regimens outside the strict context of controlled clinical trials. The reasons why recent randomized trials of postoperative chemo-radiation yield variations in effect magnitude for both disease control and morbidity might be linked to differences in patient selection. Variations in sensitivity to chemo-radiation could also be a function of both the types and clustering of prognostic factors. Obviously, the usually high-dose intensity of multidisciplinary regimens significantly affects patients compliance: in most studies, only one-half to two-thirds of the patients treated with chemo-radiation based on high-dose cisplatin regimens successfully complete the three planned courses of chemotherapy, while two of the three courses can be delivered in about 50 60% of the cases. Thus, compliance to chemoradiation schedules remains a significant concern, especially for multidrug regimes that would enhance significantly acute mucosal reactions. Finally, it is found that a 25% distant recurrence risk at 5 years has to be considered when high-dose cisplatin is added concomitantly to radiotherapy, indicating the need for further research on novel agents and optimized regimens with higher efficacy at the systemic level and putting more effort forth in the framework of multimodality management. Reviewers Prof. P.H.M. De Mulder, MD, PhD, Department of Medical Oncology, University Medical Center Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands. Prof. Jean Bourhis, Department of Radiotherapy, Institut Gustave Roussy, 39 rue C. Desmoulins, F-94805 Villejuif, France. References [1] Parkin DM, Muir CS, Whelan SL, Gao YT, Ferlay J, Powell J. Cancer incidence in five continents, vol. 6. Lyon: IARC; 1992. [2] Al-Sarraf M, Hussein M. Head and neck cancer: present status and future prospects of adjuvant chemotherapy. Cancer Invest 1995;13:41 53. [3] Pignon JP, Bourhis J, Domenge C, Designe L, MACH-NC Collaborative Group. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355(9208):949 55. [4] Fletcher GH, Evers W. Radiotherapeutic management of surgical recurrences and post-operative residuals in tumors of the head and neck. Radiology 1970;95:185 8. [5] Kramer S, Gelber RD, Snow JB, et al. Combined radiation therapy and surgery in the management of Head and cancer: final report of study 73 03 of the radiation therapy Oncology group. Head Neck Surg 1987;10:19 30. [6] Snow GB, Annyas AA, van Slotten EA, Bartelink H, Hart AA. Prognostic factors of neck node metastases. Clin Otolaryngol 1982:185 92.