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Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence?

Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the... Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 The Oncologist Head and Neck Cancer Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence? a b JACQUES BERNIER, JAY S. COOPER Department of Radiation Oncology, Oncology Institute of Southern Switzerland, San Giovanni Hospital, Bellinzona, Switzerland; Department of Radiation Oncology, Maimonides Medical Center, Brooklyn, New York, USA Key Words. Squamous cell carcinoma · Head and neck · Surgery · Radiotherapy · Chemotherapy · Chemoradiation LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. List the clinical and histopathologic risk factors that motivate a more aggressive adjuvant treatment in patients with locally advanced head and neck cancer. 2. Evaluate the impact of post operative radiotherapy and chemoradiation on treatment outcome for a variety of efficacy and toxicity end points. 3. Identify the most efficient chemotherapy agents in chemoradiation protocols for head and neck cancer patients. CME CME Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Patients with locally advanced, operable head and neck cisplatin-based combinations have been administered squamous cell carcinoma (HNSCC) are known to be at before surgery, in the interval between surgery and high risk of treatment failure, ranging from local radiotherapy, or after radiotherapy. Until very recently regrowth to lymphatic spread to systemic dissemination. these combinations, at best, decreased systemic failures Attacking specifically each of these patterns of failure without having a real impact on local outcome or sur- implies the use of a multimodal approach. Throughout vival. Indeed, until the mid-1990s, most trials that had the past two decades the management of stages III/IV tested postoperative combinations of chemotherapy and HNSCC remained a matter of debate, especially with radiotherapy did not show any significant benefit. In regards to treatment intensity and sequencing. Surgery 2004 level I evidence was established with the publication and/or radiotherapy were the mainstay of local-regional of the results of two large-scale, independent but similar treatment in patients with locally advanced disease, but trials conducted in Europe and the U.S. Both studies treatment outcome often remained disappointing. In the demonstrated that, compared with postoperative irradia- hope of improving the prognosis after radical surgery, tion alone, adjuvant concurrent chemoradiation was Correspondence: J. Bernier, M.D., Department of Radiation Oncology, Oncology Institute of Southern Switzerland, San Giovanni Hospital, CH-6504 Bellinzona, Switzerland. Telephone: 41-91-811-9157; Fax: 41-91-811-8678; e-mail: [email protected] Received September 16, 2004; accepted for publication December 10, 2004. ©AlphaMed Press 1083-7159/2005/$12.00/0 The Oncologist 2005;10:215–224 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 216 more efficacious in terms of local-regional control and dis- tional studies and comparative analysis of the selection ease-free survival. With the publication of these two trials criteria and treatment outcomes across these two trials the evidence demonstrating the potential value of concur- will be needed to gain a more accurate assessment of ben- rent postoperative chemoradiotherapy in high-risk efit and risk levels in specific patients with operable, operable head and neck cancer is strong; however, addi- locally advanced disease. The Oncologist 2005;10:215–224 INTRODUCTION Radiation Therapy Oncology Group (RTOG) database who For many years, primary ablative surgery of locally advanced had HNSCC showed a statistically significant increase in head and neck squamous cell carcinoma (HNSCC) was tra- the risk of DM (21% versus 38%) for patients whose local- ditionally followed by postoperative radiotherapy. Most regional disease was not controlled, as compared with those multi-institutional trials including patients treated this way whose disease was controlled [7]. yielded local-regional recurrence, distant metastasis (DM), As the potential benefit of more locally aggressive com- and 5-year survival rates of 30%, 25%, and 40%, respec- binations of chemotherapy and radiotherapy in advanced tively [1]. In essence, the management of stages III/IV inoperable disease began to accumulate, thoughts turned to HNSCC has been relatively unsatisfactory, and optimal ther- applying this strategy to the postoperative setting. In the apy has remained a matter of debate, especially with regard 1990s a number of institutions and cooperative groups began to treatment intensity and sequencing. to publish investigations of the role of concurrent chemora- The first suggestions that chemotherapy could help diation in the adjuvant setting as well. Unfortunately, the improve outcome came from patients who had inoperable or overall results of the first wave of relatively small-scale trials metastatic tumors. In the late 1970s, investigations of a num- did little more than create controversies about the real impact ber of cytotoxic drugs enabled oncologists to obtain the first of more aggressive adjuvant treatment on treatment outcome, promising response rates for head and neck cancers. The especially in terms of local control and survival [8-12]. enhanced activity of radiotherapy when combined concur- However, the situation changed markedly in early 2004 rently with platinum derivatives and 5-fluorouracil—the most when the results of two independent, large-scale prospec- widely investigated drugs in head and neck cancer tive randomized trials, conducted in parallel in Europe and patients—is thought to occur because the drugs are: A) the U.S., were published in the New England Journal of inhibiting repair of lethal and sublethal damage induced by Medicine [13, 14]. Both studies demonstrated that, for poor radiotherapy; B) radiosensitizing hypoxic cells; C) reducing prognosis carcinomas, adjuvant postoperative high-dose cis- tumor burden, leading to an improved blood supply; D) syn- platin and irradiation given concomitantly were more likely chronizing and redistributing tumor cells into the more sensi- to control local-regional disease and yield disease-free survival tive G -M cell-cycle phase, and E) inducing apoptosis. It was than postoperative radiotherapy alone. on these biological bases that various chemotherapy settings One of the objectives of this article is to show how, were tested: chemotherapy alone, induction chemotherapy, despite some differences in treatment outcome between the concurrent combination with radiotherapy, and adjuvant treat- two trials, these recent contributions give definitive answers ment following surgery and/or radiotherapy. Their respective to a number of long-lasting dilemmas fed by previous efficacy in combination with radiation therapy has been clinical studies on adjuvant treatment. assessed in various meta-analyses [2-6], and a small, but We will not address the issue of alternative approaches in unquestionable, benefit has been observed in some settings. It the management of locally advanced head and neck carcino- is worth noting, as preamble, that these studies also confirmed mas (first-line chemoradiation, induction chemotherapy), the disappointing prognosis of patients with locally advanced which are out of the scope of this review article. disease. For example, Pignon and colleagues [5] showed that in a meta-analysis of more than 10,000 high-risk patients hav- RADIOTHERAPY AND CHEMOTHERAPY IN THE ing advanced inoperable disease, the 5-year overall survival POSTOPERATIVE SETTING: WHERE DID WE rate did not exceed 32% after radiotherapy alone. COME FROM? The poor prognosis of patients with locally advanced In the 1950s the advent of megavoltage units in radiother- HNSCC actually results from two factors. First, local and apy paved the way for a more aggressive role of external regional recurrence remains the major obstacle to cure of radiotherapy in deeply seated tumors. After the radiosurgi- locally advanced HNSCC. Second, the impact of local- cal combination was pioneered in the 1960s by Fletcher and regional failure (LRF) on the treatment outcome is not Evers [15], postoperative irradiation became the standard restricted to progression or recurrence above the clavicles approach in most institutions, especially for stage III/IV only. Indeed, an analysis of more than 2,500 patients in the tumors. Both in Europe and in the U.S., retrospective studies Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 217 Adjuvant Chemoradiation in Head and Neck Cancer Patients of large cohorts of patients demonstrated a significant which this observation was also independently linked to a reduction in failures above the clavicles [16-18]. higher risk of local failure. Although close or microscopi- Notwithstanding the fact that surgery and postoperative cally involved mucosal margins were not shown to predict radiotherapy were the mainstay of therapeutic management local-regional recurrence independently in the MDAnderson in patients with locally advanced resectable HNSCC, the study [27], involved margins did correlate with recurrence range of local-regional control rates reported in the litera- when associated with other factors. ture for the radiosurgical combination was astonishingly broad, ranging from 35%-75% [19-21]. Adjuvant Radiotherapy: The Impact of Dose A variety of confounding factors linked to tumor or An important contribution to our understanding of postoper- host, such as variations in patient selection and tumor stage, ative therapy came from Fletcher et al. [15] who showed that as well as heterogeneities in both anatomic location and in combination with surgery, a dose of approximately 50 Gy histopathologic pattern, certainly contributed to the uncer- is sufficient to eradicate malignant microfoci in 95% of the tainty regarding the precise value of adjuvant treatment. cases with uninvolved surgical margins. Moreover, the prognosis of these patients is likely to have Whether there is any clinically important relationship been influenced by variations in surgeon and radiotherapist (which could be exploited for therapy) between clinically rel- expertise, equipment, support, etc. evant radiotherapy doses and control in adjuvant setting remains somewhat unclear. For example, the study by Peters Prognosticators of Postoperative Failures et al. [27] revealed no significant dose-response relationship Over the past 3 decades more attention has been paid to the for total doses ranging from 57.6-68.4 Gy. To explain this identification of factors that might help the surgeon assess apparent lack of a dose response, it was postulated that the the precise risk of failure in individual patients. By the late beneficial effect on tumor control of doses >57.6 Gy (given at 1970s, it was generally appreciated that the risk of LRF and 1.8 Gy/d) was offset by tumor cell repopulation occurring DM was highest in patients who presented with locally during the additional time taken to deliver the higher doses. advanced disease [16, 17, 19, 21]. For survival the main Thus, for adjuvant radiotherapy, the dose-effect relation- prognosticators included tumor location and stage, quality ship appears complex and is probably influenced by con- of surgical resection, and, in some studies, age and gender founding factors, the nature of which remains unknown. [19, 22-26]. Suffice it to say that while alterations in the way postopera- The concept of risk assessment by clusters was devel- tive radiation is delivered may influence outcome to some oped by Peters et al. [27] in the 1990s. Their analysis was degree, practical factors limit the intensification of treatment designed to clarify which patients needed postoperative solely by altering radiation therapy to a degree that other radiotherapy, and three main principles emerged. First, the ways of improving treatment likely are needed [32-34]. presence in the surgical specimen of two or more lymph nodes that contained cancer and/or extracapsular extension Adjuvant Chemotherapy in Locally Advanced HNSCC (ECE) of tumor beyond the capsule of a node were inde- The rationale that justified testing adjuvant chemotherapy in pendent variables linked to a significantly increased risk of patients with locally advanced resected high-risk HNSCC is recurrence. Second, increasing combinations of two or based on three observations [35]: A) even if 70%-75% of more risk factors (namely, oral cavity primary, close or pos- these patients remain free of disease at 2 years, the long-term itive mucosal margins, nerve invasion, two or more positive prognosis of high-risk patients is poor. Only one-third of lymph nodes, largest node >3 centimeters in diameter, them are alive at 5 years. This outcome results from both treatment delay >6 weeks, and Zubrod performance status treatment failures and other events not related to cancer, as ≥2) were associated with a progressively higher risk of usually observed in patients with head and neck cancer. B) local failure. Third, patients who had no adverse surgical- Recent phase II and III studies suggest the efficacy of a num- pathologic features were shown not to need postoperative ber of novel cytotoxic drugs against epithelial cell cancers, but radiotherapy; the 5-year actuarial local-regional control and often a relative lack of differential impact on tumor and nor- survival rates achieved with surgery alone were 90% and mal tissues. Improvements in local-regional recurrence and 83%, respectively [27]. disease-free survival rates are often obtained only at the price In data derived from the RTOG database, microscopi- of increased acute and late toxicity. C) While local-regional cally involved surgical margins of resection were also asso- control is improved by concurrent chemoradiotherapy-con- ciated with a significantly increased risk of recurrence taining strategies, the incidence of metastases becomes a more above the clavicles [28]. This finding was corroborated by significant problem, since they now develop in 15%-20% of the Intergroup #0034 and RTOG #85-03 trials [29-31] in cases. In essence, the role of concurrent chemotherapy in Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 218 enhancing the efficacy of the local-regional effects of radio- as suggested by laboratory and preclinical data? Does the therapy is not necessarily accompanied by an effect on dis- concurrent delivery of cytotoxic agents and radiotherapy seminated micrometastases, and chemotherapy needs not act translate in better treatment efficacy and more favorable clin- on metastatic disease to be beneficial. ical outcome than can be achieved by clinically tolerable Before the seminal paper by Dewit in 1987 [36], the doses of radiation therapy alone? Is the effect of concurrent addition of chemotherapy to radiotherapy-based treatments chemoradiation on tumor and normal tissue cells different essentially was based on sequential administration, both in enough to provide an improved therapeutic index? patients treated with primary ablative surgery and those A number of phase III trials in patients treated without treated with the hope of organ conservation. Dewit’s review ablative surgery were the first to attempt to answer these suggested that concurrent delivery of chemotherapy and questions [46-55]. Taken separately, all but one study [52] radiotherapy was a more promising strategy at a time when suggested a clear trend in favor of the chemoradiation reg- the clinical relevance of adjuvant chemotherapy in head and imen over radiotherapy alone, in regard to local control and neck oncology was far from obvious [37, 38]. As a matter of survival [48, 51, 53]. With respect to side effects, acute tox- fact, the few randomized trials completed in the 1990s were icity uniformly was significantly increased in the experimen- unable to validate encouraging results obtained in nonran- tal concurrent therapy arms, but the impact of chemoradiation domized studies [39-41], at least in terms of a significant on late effects in normal tissues was less clear. Some reports gain in survival [21, 42, 43]. Nevertheless, some of these indicated a higher incidence of severe late toxicity following randomized trials, such as the Intergroup study #0034 [29], concurrent therapy [48, 50, 51, 53, 54], while others did not a phase III trial of postoperative adjuvant, sequential radio- report differences in side effects between the two patient therapy and chemotherapy, provided important clues about groups [49, 52]. the relevance of stratification by risk. First, in the whole It was not until a number of meta-analyses clearly group, the sequential addition of chemotherapy to postoper- demonstrated a small but significant therapeutic benefit in ative radiotherapy did not significantly affect the prognosis favor of platinum-based concurrent chemoradiation regi- in terms of LRF and survival. Second, the subgroup of mens that the coadministration of cytotoxic drugs and irra- patients at higher risk appeared to be more likely to benefit diation was considered a mainstay of locally advanced head more from adjuvant chemotherapy than the low-risk group, and neck cancers [2-6]. both in terms of tumor control and survival (subgroup analy- sis of Intergroup #0034 suggested a possible value of PLATINUM-BASED CHEMORADIATION SCHEDULES: sequential chemotherapy and radiotherapy in decreasing the RATIONALE AND FIRST CLINICAL RESULTS likelihood of local-regional recurrence in the high-risk sub- Interactions of cisplatin with ionizing radiation are believed group, and comparison of similarly selected high-risk to include enhanced formation of toxic platinum intermedi- patients treated by concurrent chemotherapy and radiother- ates in the presence of radiation-induced free radicals, apy in RTOG #88-24 [28, 29] demonstrates the effect even while radiosensitizing mechanisms may be linked to a radi- more clearly). Third, the pattern of failure was shown to be ation-induced increase in cellular platinum uptake [37, 45]. modified by the addition of chemotherapy; the rate of tumor Various platinum-based schedules have been tested in the recurrence in regional lymph nodes and distant sites was adjuvant setting. In trials investigating postoperative chemo- decreased in the chemotherapy-containing arm. radiation, the dose/delivery schedules of cisplatin have In summary, these studies suggest that concurrent ranged from intermittent higher-dose (100 mg/m ) every 3 chemoradiotherapy may have a beneficial effect on local- weeks to low-dose (6 mg/m ) daily administration [35]. One regional tumor control in patients whose tumors have the of the first prospective studies of the combination of postop- following prognostic factors: presence of malignant cells in erative radiotherapy with cisplatin as single-agent therapy two or more lymph nodes and/or rupture of tumor through was completed by Bachaud and colleagues in 1996 [9, 12]. the lymph node capsule and/or microscopic involvement of In this relatively small-scale study of 83 patients, the group the margins of resection. treated with adjuvant radiotherapy alone displayed a higher These laboratory [36, 44] and clinical [37, 38, 45] data led LRF rate than the group receiving adjuvant chemoradiation clinicians to test this new paradigm based on the concomitant consisting of cisplatin 50 mg given weekly up to 7-9 cycles delivery of chemotherapy and radiotherapy in hopes of during radiation therapy (41% versus 23%; p = .08). answering three basic questions still unresolved in the late In the early 1990s the encouraging results of the study 1980s: In the clinical setting, is the combined effect of con- conducted by Al-Sarraf et al. [29] of cisplatin in single high current chemoradiation [24, 25] really greater than the sum doses (100 mg/m ) repeated every 3 weeks (days 1, 22, and of the individual effects of radiotherapy and chemotherapy, 43), led the European Organization for Research and Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 219 Adjuvant Chemoradiation in Head and Neck Cancer Patients Treatment of Cancer (EORTC) and the RTOG cooperative [59]. This situation may improve when more prolonged groups to consider this regimen as the reference chemoradi- follow-up becomes available. ation approach for adjuvant treatment of HNSCC and to acti- vate two large-scale randomized trials measuring treatment Towards and Reaching Level I Evidence outcome for this regimen after potentially curative surgery in In the early 1990s and in the recent past, two studies reported patients with high-risk operable, locally advanced tumors. on the results of concomitant delivery of chemo- and radio- therapy in the postoperative setting. As mentioned above, the Single-Agent or Multidrug Regimens? Intermittent High Dose Bachaud study [9, 12] emphasized a decrease in LRF rates in or More Frequent Low Dose? favor of the experimental arm, but early termination of the What is the ideal objective of chemoradiation? In addition to trial, because of decreasing accrual rates, prevented the inves- better control of local-regional disease, chemotherapy should tigators from including the planned number of patients in the prevent the subsequent appearance of metastases by eradi- trial (83 instead of 200). In another recent prospective trial cating occult metastatic deposits. Since distant metastases are recruiting 114 patients, Smid et al. [60] found that the addition now the cause of failure in 1 of 5 patients with stage III/IV of mitomycin C and bleomycin to adjuvant radiotherapy sig- HNSCC, high-dose bolus chemotherapy, at least in theory, is nificantly increased the local-regional control and overall sur- more likely to achieve this objective, since the gain from a vival rates in the subgroup having high-risk features compared pure radiosensitizing effect of a low-dose cytotoxic agent is with similar patients observed after adjuvant radiotherapy limited by the competing risk of distant failure. Obviously, alone. Together, these two studies provided suggestive, but not compliance to aggressive adjuvant therapy may be low in conclusive, evidence that adjuvant chemoradiation was more this category of patients whose general condition is often efficacious than postoperative radiation therapy. influenced by the surgery as well as comorbid conditions. This is reflected in dose-intensity reductions in some The Level 1 Evidence 25%-33% of cases receiving postoperative chemo- In the late 1990s, two similar, large-scale, prospective ran- radiation [35]. This reality may negate the theoretical domized independent trials designed by the EORTC and the advantage of intermittent high-dose chemotherapy. RTOG were conducted to evaluate the role of concomitant In this perspective, should we use mono- or multidrug high-dose chemoradiation (chemotherapy given every 3 regimens? In the adjuvant setting, single-agent chemo- weeks) in the postoperative treatment of high-risk head and therapy, based on platinum derivatives, is probably the neck tumors. The EORTC study [13] compared concomitant treatment of choice; indeed, in cohorts of patients treated cisplatin and radiotherapy versus radiotherapy alone in high- without ablative surgery, the addition of 5-fluorouracil to risk head and neck cancers of the oral cavity, oropharynx, cisplatin was not shown to improve treatment efficacy [56]. larynx, or hypopharynx. The primary end point was disease- Therefore, 5-fluorouracil is likely to account for an undue free survival, with overall survival, local control rates, and increase in acute mucosal reactions in this fragile category treatment toxicity as secondary end points. Following surgery of patients, and might be responsible for dose-intensity patients were randomly assigned to either radiotherapy alone reduction [57]. However, other combinations of drugs are (66 Gy in 33 fractions over 6.5 weeks) or chemoradiation, potentially possible and need to be tested in the future. using the same radiation therapy schedule combined with three courses of cisplatin 100 mg/m on days 1, 22, and 43. Toxicity of Adjuvant Chemoradiation Regimens and In this trial, as in the RTOG study, late toxicity was measured Supportive Treatment by objective criteria only using the RTOG/EORTC Late As mentioned earlier, acute reactions from adjuvant treat- Radiation Morbidity Scoring Scheme. ment are markedly increased with chemoradiation, espe- At a median follow-up of 60 months, there was a signif- cially in the mucosa and skin [13, 14, 58]. Intravenous icant (p = .044) difference in progression-free survival, the rehydration, gastric feeding tubes during treatment, primary end point of this trial, in favor of the chemoradia- and narcotics for severe pain must be implemented in a high tion group; the estimated median progression-free survival percentage of the patients undergoing chemoradiation. This was 23 months in the radiotherapy and 55 months in the implies the need for a significant intensification of support- chemoradiation group. In terms of overall survival, there ive care, which is not always manageable in all inpatient was a significant (p = .02) difference in overall survival in and outpatient units. Cautious implementation of this type favor of the chemoradiation group. Finally, in regard to the of therapeutic management is therefore needed. As men- local-regional outcome, the 5-year cumulative incidence tioned above, late side effects related to chemoradiation estimates of local-regional relapse were 31% for the radio- have been too often inadequately reported in the literature therapy group and 18% for the chemoradiation group Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 220 (p = .007). Objective acute mucositis and late toxicity were observed in 34% of patients treated by radiotherapy alone, not significantly increased in patients who received concurrent but more than doubled to 77% in the patients treated with therapy. concurrent therapy. Severe late toxicity was not significantly The RTOG study [14] similarly compared concomitant different between the treatments. cisplatin and radiotherapy versus radiotherapy alone in Why did these two similar studies not reach precisely high-risk head and neck cancers of the oral cavity, orophar- the same conclusions? Notwithstanding a relatively similar ynx, larynx, or hypopharynx. The end points were local- design, the definition of high-risk and therefore the inclu- regional control, as the primary end point, and overall sion criteria differed between the two studies. The eligibil- survival, disease-free survival, and treatment toxicity as ity criteria common to both trials were the presence of ECE secondary end points. Following surgery patients were ran- and/or microscopic-sized tumor involvement of the surgical domly assigned to either radiotherapy alone (60 Gy in 30 margins of resection. In addition, the RTOG included in its fractions over 6.0 weeks with or without a 0.6 Gy boost selection of risk factors the presence of tumor in two or over 3 days) or chemoradiation, using the same radiation more lymph nodes, as was suggested by the analysis of the therapy schedule combined with three courses of cisplatin, RTOG database discussed previously. In contrast, the other 100 mg/m , on days 1, 22, and 43. At a 36-month median EORTC eligibility criteria were stage III/IV disease, the follow-up in the RTOG study, concurrent therapy was asso- presence of enlarged lymph node(s) at level IV or V in ciated with a significant benefit in terms of local-regional patients with oral cavity or oropharynx carcinomas, patho- control (p = .011) and disease-free survival (p = .038). The logical demonstration of vascular embolisms, and/or per- benefit observed in the RTOG 95-01 study for overall sur- ineural disease. Table 2 presents a comparative analysis of vival did not reach statistical significance (p = .18). The the criteria of selection that, in each trial, were related to comparative analysis of treatment outcome in both trials is risk factors. summarized in Table 1. A number of differences were found regarding the dis- With regards to toxicity, the addition of chemotherapy tribution of some of these eligibility criteria in the two stud- resulted in a substantially greater incidence of severe acute ies. First of all, 94% of the cases in the RTOG trial had side effects in this trial. Grade 3 or higher toxicity was N2-3 disease as compared with only 57% in the EORTC Table 1. Comparative analysis of treatment outcome in EORTC trial 22931 and RTOG trial 9501 Outcome end points EORTC Trial 2931 5-year estimates RTOG Trial 9501 2-year estimates a a Disease-free survival 47% versus 36% (p = .04) 54% versus 45% (p = .04) a a Overall survival 53% versus 40% (p = .02) 64% versus 57% (p = .19) a a Local-regional failure rates 17% versus 31% (p = .007) 18% versus 28% (p = .01) a, b a Grade 3+ acute toxicity p = .008/p = .28 77% versus 34% (p <.0001) b a Late toxicity 38% versus 41% (p = .25) 21% versus 17% (p = .29) Impact on distant metastases p = .61 p = .46 Second primary tumors p = .83 NA Chemoradiation versus radiotherapy arm values Functional/objective acute reactions Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; NA = Data not available; RTOG = Radiation Therapy Oncology Group Table 2. Comparative analysis of criteria of selection related to risk factors in EORTC trial 22931 and RTOG trial 9501 EORTC 22931 only EORTC 22931 and RTOG 9501 RTOG 9501 only Stage III/IV disease Surgical margins microscopically involved Two or more positive lymph nodes Positive lymph nodes at levels IV or V in patients Extracapsular extension in positive lymph nodes with tumors arising from oropharynx or oral cavity Vascular embolisms Perineural infiltration Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; RTOG = Radiation Therapy Oncology Group Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 221 Adjuvant Chemoradiation in Head and Neck Cancer Patients trial. A second difference related to the presence of micro- Despite the improvement seen with concomitant scopic positive surgical margins for which the ratio chemoradiation, local-regional control levels remain between the EORTC and the RTOG studies was 2.9. unsatisfactory and distant metastases have become a more In contrast, the dose levels delivered in each trial were relevant problem in terms of survival. As a consequence, rather similar, and analyses of compliance indicate that most other drugs such as taxanes or combinations of drugs that cases received at least 60 Gy in either trial. The radiotherapy demonstrate a relatively high level of activity against dose factor is therefore unlikely to explain a difference in metastatic head and neck carcinomas need to be investigated treatment outcome across the two studies. Thus differences more extensively in the adjuvant setting. in outcome may reflect differences in the patient popula- In regard to local-regional control, a first complementary tions included in the two trials. Also, it must be remem- approach might be the addition of drugs that may further bered that the failure to detect a statistically significant improve the efficiency of chemoradiotherapy. Overexpres- improvement in the secondary end point of overall survival sion of the epidermal growth factor receptor has been corre- in the RTOG trial does not mean that one does not exist. In lated with more aggressive behavior and poor clinical addition, further analyses of selection criteria and treat- outcome [35]. The blockade of the epidermal growth factor ment-related parameters are still under way to explain the by a monoclonal antibody cetuximab (Erbitux ; ImClone differences in outcome between the two trials. Systems Inc., New York, NY, http://www.imclone.com) The recent EORTC and RTOG chemoradiation trials [13, was shown to increase significantly the median survival in 14] with high-dose cisplatin (100 mg/m on days 1, 23, and patients with locally advanced, unresectable disease and 43 of radiotherapy) and radiation doses of 60-66 Gy have this approach could also be tested in the postoperative shown that this combination more effectively controls dis- setting [61]. ease than radiotherapy alone in high-risk locally advanced Finally, more attention should be paid to the latency HNSCC and that the impact of adjuvant concomitant between the surgical procedure and the onset of radiother- chemoradiation is influenced by the precise type of high-risk apy or chemoradiation. Indeed, too often, either organiza- factors included. Addition of chemotherapy resulted in a sig- tional constraints or delayed wound healing postpone the nificant increase in local control and disease-specific survival start of adjuvant treatment beyond 6-7 weeks. Increased in both trials. Further study will be required to precisely concentrations of growth factors during the healing period explain the effect on overall survival rates and acute toxicity. might account for acceleration of tumor cell repopulation Even if longer follow-up is needed to accurately assess the during a long postoperative latency period. Very few stud- late morbidity after chemoradiation, this therapeutic ies, however, have taken this parameter into consideration approach can be considered an acceptable standard adjuvant [18]. The administration of postoperative chemotherapy treatment for this population of patients. within the first 2 weeks following surgery followed by con- current chemoradiation recently has been tested by the WHAT’S NEXT? RTOG, but no results are yet available. The advent of noncytotoxic drugs, the delivery of more efficacious cytotoxic agents, the optimization of mul- CONCLUSION tidrug regimens, and the application of modern techniques The role of concurrent chemoradiation in the adjuvant of radiation therapy are the tools we have now to test in setting of high-risk disease has now been established and our quest to control disease locally and eradicate occult validated. The best concomitant chemoradiotherapy regi- micrometastases. mens still need to be determined, although cisplatin- Indeed, the benefit of chemotherapy in the EORTC and based chemotherapy is the current standard. All the RTOG trials apparently does not accrue from the typical efforts expended throughout the past decade undoubtedly action of neoadjuvant or adjuvant systemic chemotherapy, have been justified and warrant continued efforts in the namely in reducing the risks of distant metastases; while lab and clinic to optimize the therapeutic index and fur- local-regional control improved in both trials, the sys- ther reduce the risk of both local-regional and distant fail- temic outcome was not affected by adjuvant chemoradia- ure. Moreover, the development of customized surgical tion. In the EORTC trial the estimated 5-year cumulative and reconstruction techniques combined with state-of- incidence of distant metastases was 25% following post- the-art radiation techniques such as three-dimensional operative radiotherapy and 21% following concurrent conformal radiation therapy and intensity-modulated chemoradiotherapy (p = .61 Gray’s test). In the RTOG radiotherapy logically are bound to boost the benefit trial the corresponding figures were 23% and 20%, accrued by high-risk patients from adjuvant concurrent respectively (p = .46). chemoradiation. Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 222 REFERENCES 1 Laramore GE, Scott CB, al-Sarraf M et al. Adjuvant squamous-cell carcinoma of the head and neck. N Engl J Med chemotherapy for resectable squamous cell carcinomas of the 350;19:1937–1944. head and neck: report on Intergroup Study 0034. Int J Radiat 15 Fletcher GH, Evers W. Radiotherapeutic management of sur- Oncol Biol Phys 1992;23:705–713. gical recurrences and postoperative residuals in tumors of the 2 Stell PM, Rawson NS. Adjuvant chemotherapy in head and head and neck. Radiology 1970;95:185–188. neck cancer. Br J Cancer 1990;61:779–787. 16 Kramer S, Gelber RD, Snow JB et al. Combined radiation 3 Munro AJ. 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Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence?

Bernier, Jacques; Cooper, Jay S.
The Oncologist , Volume 10 (3) – Mar 1, 2005
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Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 The Oncologist Head and Neck Cancer Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence? a b JACQUES BERNIER, JAY S. COOPER Department of Radiation Oncology, Oncology Institute of Southern Switzerland, San Giovanni Hospital, Bellinzona, Switzerland; Department of Radiation Oncology, Maimonides Medical Center, Brooklyn, New York, USA Key Words. Squamous cell carcinoma · Head and neck · Surgery · Radiotherapy · Chemotherapy · Chemoradiation LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. List the clinical and histopathologic risk factors that motivate a more aggressive adjuvant treatment in patients with locally advanced head and neck cancer. 2. Evaluate the impact of post operative radiotherapy and chemoradiation on treatment outcome for a variety of efficacy and toxicity end points. 3. Identify the most efficient chemotherapy agents in chemoradiation protocols for head and neck cancer patients. CME CME Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Patients with locally advanced, operable head and neck cisplatin-based combinations have been administered squamous cell carcinoma (HNSCC) are known to be at before surgery, in the interval between surgery and high risk of treatment failure, ranging from local radiotherapy, or after radiotherapy. Until very recently regrowth to lymphatic spread to systemic dissemination. these combinations, at best, decreased systemic failures Attacking specifically each of these patterns of failure without having a real impact on local outcome or sur- implies the use of a multimodal approach. Throughout vival. Indeed, until the mid-1990s, most trials that had the past two decades the management of stages III/IV tested postoperative combinations of chemotherapy and HNSCC remained a matter of debate, especially with radiotherapy did not show any significant benefit. In regards to treatment intensity and sequencing. Surgery 2004 level I evidence was established with the publication and/or radiotherapy were the mainstay of local-regional of the results of two large-scale, independent but similar treatment in patients with locally advanced disease, but trials conducted in Europe and the U.S. Both studies treatment outcome often remained disappointing. In the demonstrated that, compared with postoperative irradia- hope of improving the prognosis after radical surgery, tion alone, adjuvant concurrent chemoradiation was Correspondence: J. Bernier, M.D., Department of Radiation Oncology, Oncology Institute of Southern Switzerland, San Giovanni Hospital, CH-6504 Bellinzona, Switzerland. Telephone: 41-91-811-9157; Fax: 41-91-811-8678; e-mail: [email protected] Received September 16, 2004; accepted for publication December 10, 2004. ©AlphaMed Press 1083-7159/2005/$12.00/0 The Oncologist 2005;10:215–224 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 216 more efficacious in terms of local-regional control and dis- tional studies and comparative analysis of the selection ease-free survival. With the publication of these two trials criteria and treatment outcomes across these two trials the evidence demonstrating the potential value of concur- will be needed to gain a more accurate assessment of ben- rent postoperative chemoradiotherapy in high-risk efit and risk levels in specific patients with operable, operable head and neck cancer is strong; however, addi- locally advanced disease. The Oncologist 2005;10:215–224 INTRODUCTION Radiation Therapy Oncology Group (RTOG) database who For many years, primary ablative surgery of locally advanced had HNSCC showed a statistically significant increase in head and neck squamous cell carcinoma (HNSCC) was tra- the risk of DM (21% versus 38%) for patients whose local- ditionally followed by postoperative radiotherapy. Most regional disease was not controlled, as compared with those multi-institutional trials including patients treated this way whose disease was controlled [7]. yielded local-regional recurrence, distant metastasis (DM), As the potential benefit of more locally aggressive com- and 5-year survival rates of 30%, 25%, and 40%, respec- binations of chemotherapy and radiotherapy in advanced tively [1]. In essence, the management of stages III/IV inoperable disease began to accumulate, thoughts turned to HNSCC has been relatively unsatisfactory, and optimal ther- applying this strategy to the postoperative setting. In the apy has remained a matter of debate, especially with regard 1990s a number of institutions and cooperative groups began to treatment intensity and sequencing. to publish investigations of the role of concurrent chemora- The first suggestions that chemotherapy could help diation in the adjuvant setting as well. Unfortunately, the improve outcome came from patients who had inoperable or overall results of the first wave of relatively small-scale trials metastatic tumors. In the late 1970s, investigations of a num- did little more than create controversies about the real impact ber of cytotoxic drugs enabled oncologists to obtain the first of more aggressive adjuvant treatment on treatment outcome, promising response rates for head and neck cancers. The especially in terms of local control and survival [8-12]. enhanced activity of radiotherapy when combined concur- However, the situation changed markedly in early 2004 rently with platinum derivatives and 5-fluorouracil—the most when the results of two independent, large-scale prospec- widely investigated drugs in head and neck cancer tive randomized trials, conducted in parallel in Europe and patients—is thought to occur because the drugs are: A) the U.S., were published in the New England Journal of inhibiting repair of lethal and sublethal damage induced by Medicine [13, 14]. Both studies demonstrated that, for poor radiotherapy; B) radiosensitizing hypoxic cells; C) reducing prognosis carcinomas, adjuvant postoperative high-dose cis- tumor burden, leading to an improved blood supply; D) syn- platin and irradiation given concomitantly were more likely chronizing and redistributing tumor cells into the more sensi- to control local-regional disease and yield disease-free survival tive G -M cell-cycle phase, and E) inducing apoptosis. It was than postoperative radiotherapy alone. on these biological bases that various chemotherapy settings One of the objectives of this article is to show how, were tested: chemotherapy alone, induction chemotherapy, despite some differences in treatment outcome between the concurrent combination with radiotherapy, and adjuvant treat- two trials, these recent contributions give definitive answers ment following surgery and/or radiotherapy. Their respective to a number of long-lasting dilemmas fed by previous efficacy in combination with radiation therapy has been clinical studies on adjuvant treatment. assessed in various meta-analyses [2-6], and a small, but We will not address the issue of alternative approaches in unquestionable, benefit has been observed in some settings. It the management of locally advanced head and neck carcino- is worth noting, as preamble, that these studies also confirmed mas (first-line chemoradiation, induction chemotherapy), the disappointing prognosis of patients with locally advanced which are out of the scope of this review article. disease. For example, Pignon and colleagues [5] showed that in a meta-analysis of more than 10,000 high-risk patients hav- RADIOTHERAPY AND CHEMOTHERAPY IN THE ing advanced inoperable disease, the 5-year overall survival POSTOPERATIVE SETTING: WHERE DID WE rate did not exceed 32% after radiotherapy alone. COME FROM? The poor prognosis of patients with locally advanced In the 1950s the advent of megavoltage units in radiother- HNSCC actually results from two factors. First, local and apy paved the way for a more aggressive role of external regional recurrence remains the major obstacle to cure of radiotherapy in deeply seated tumors. After the radiosurgi- locally advanced HNSCC. Second, the impact of local- cal combination was pioneered in the 1960s by Fletcher and regional failure (LRF) on the treatment outcome is not Evers [15], postoperative irradiation became the standard restricted to progression or recurrence above the clavicles approach in most institutions, especially for stage III/IV only. Indeed, an analysis of more than 2,500 patients in the tumors. Both in Europe and in the U.S., retrospective studies Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 217 Adjuvant Chemoradiation in Head and Neck Cancer Patients of large cohorts of patients demonstrated a significant which this observation was also independently linked to a reduction in failures above the clavicles [16-18]. higher risk of local failure. Although close or microscopi- Notwithstanding the fact that surgery and postoperative cally involved mucosal margins were not shown to predict radiotherapy were the mainstay of therapeutic management local-regional recurrence independently in the MDAnderson in patients with locally advanced resectable HNSCC, the study [27], involved margins did correlate with recurrence range of local-regional control rates reported in the litera- when associated with other factors. ture for the radiosurgical combination was astonishingly broad, ranging from 35%-75% [19-21]. Adjuvant Radiotherapy: The Impact of Dose A variety of confounding factors linked to tumor or An important contribution to our understanding of postoper- host, such as variations in patient selection and tumor stage, ative therapy came from Fletcher et al. [15] who showed that as well as heterogeneities in both anatomic location and in combination with surgery, a dose of approximately 50 Gy histopathologic pattern, certainly contributed to the uncer- is sufficient to eradicate malignant microfoci in 95% of the tainty regarding the precise value of adjuvant treatment. cases with uninvolved surgical margins. Moreover, the prognosis of these patients is likely to have Whether there is any clinically important relationship been influenced by variations in surgeon and radiotherapist (which could be exploited for therapy) between clinically rel- expertise, equipment, support, etc. evant radiotherapy doses and control in adjuvant setting remains somewhat unclear. For example, the study by Peters Prognosticators of Postoperative Failures et al. [27] revealed no significant dose-response relationship Over the past 3 decades more attention has been paid to the for total doses ranging from 57.6-68.4 Gy. To explain this identification of factors that might help the surgeon assess apparent lack of a dose response, it was postulated that the the precise risk of failure in individual patients. By the late beneficial effect on tumor control of doses >57.6 Gy (given at 1970s, it was generally appreciated that the risk of LRF and 1.8 Gy/d) was offset by tumor cell repopulation occurring DM was highest in patients who presented with locally during the additional time taken to deliver the higher doses. advanced disease [16, 17, 19, 21]. For survival the main Thus, for adjuvant radiotherapy, the dose-effect relation- prognosticators included tumor location and stage, quality ship appears complex and is probably influenced by con- of surgical resection, and, in some studies, age and gender founding factors, the nature of which remains unknown. [19, 22-26]. Suffice it to say that while alterations in the way postopera- The concept of risk assessment by clusters was devel- tive radiation is delivered may influence outcome to some oped by Peters et al. [27] in the 1990s. Their analysis was degree, practical factors limit the intensification of treatment designed to clarify which patients needed postoperative solely by altering radiation therapy to a degree that other radiotherapy, and three main principles emerged. First, the ways of improving treatment likely are needed [32-34]. presence in the surgical specimen of two or more lymph nodes that contained cancer and/or extracapsular extension Adjuvant Chemotherapy in Locally Advanced HNSCC (ECE) of tumor beyond the capsule of a node were inde- The rationale that justified testing adjuvant chemotherapy in pendent variables linked to a significantly increased risk of patients with locally advanced resected high-risk HNSCC is recurrence. Second, increasing combinations of two or based on three observations [35]: A) even if 70%-75% of more risk factors (namely, oral cavity primary, close or pos- these patients remain free of disease at 2 years, the long-term itive mucosal margins, nerve invasion, two or more positive prognosis of high-risk patients is poor. Only one-third of lymph nodes, largest node >3 centimeters in diameter, them are alive at 5 years. This outcome results from both treatment delay >6 weeks, and Zubrod performance status treatment failures and other events not related to cancer, as ≥2) were associated with a progressively higher risk of usually observed in patients with head and neck cancer. B) local failure. Third, patients who had no adverse surgical- Recent phase II and III studies suggest the efficacy of a num- pathologic features were shown not to need postoperative ber of novel cytotoxic drugs against epithelial cell cancers, but radiotherapy; the 5-year actuarial local-regional control and often a relative lack of differential impact on tumor and nor- survival rates achieved with surgery alone were 90% and mal tissues. Improvements in local-regional recurrence and 83%, respectively [27]. disease-free survival rates are often obtained only at the price In data derived from the RTOG database, microscopi- of increased acute and late toxicity. C) While local-regional cally involved surgical margins of resection were also asso- control is improved by concurrent chemoradiotherapy-con- ciated with a significantly increased risk of recurrence taining strategies, the incidence of metastases becomes a more above the clavicles [28]. This finding was corroborated by significant problem, since they now develop in 15%-20% of the Intergroup #0034 and RTOG #85-03 trials [29-31] in cases. In essence, the role of concurrent chemotherapy in Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 218 enhancing the efficacy of the local-regional effects of radio- as suggested by laboratory and preclinical data? Does the therapy is not necessarily accompanied by an effect on dis- concurrent delivery of cytotoxic agents and radiotherapy seminated micrometastases, and chemotherapy needs not act translate in better treatment efficacy and more favorable clin- on metastatic disease to be beneficial. ical outcome than can be achieved by clinically tolerable Before the seminal paper by Dewit in 1987 [36], the doses of radiation therapy alone? Is the effect of concurrent addition of chemotherapy to radiotherapy-based treatments chemoradiation on tumor and normal tissue cells different essentially was based on sequential administration, both in enough to provide an improved therapeutic index? patients treated with primary ablative surgery and those A number of phase III trials in patients treated without treated with the hope of organ conservation. Dewit’s review ablative surgery were the first to attempt to answer these suggested that concurrent delivery of chemotherapy and questions [46-55]. Taken separately, all but one study [52] radiotherapy was a more promising strategy at a time when suggested a clear trend in favor of the chemoradiation reg- the clinical relevance of adjuvant chemotherapy in head and imen over radiotherapy alone, in regard to local control and neck oncology was far from obvious [37, 38]. As a matter of survival [48, 51, 53]. With respect to side effects, acute tox- fact, the few randomized trials completed in the 1990s were icity uniformly was significantly increased in the experimen- unable to validate encouraging results obtained in nonran- tal concurrent therapy arms, but the impact of chemoradiation domized studies [39-41], at least in terms of a significant on late effects in normal tissues was less clear. Some reports gain in survival [21, 42, 43]. Nevertheless, some of these indicated a higher incidence of severe late toxicity following randomized trials, such as the Intergroup study #0034 [29], concurrent therapy [48, 50, 51, 53, 54], while others did not a phase III trial of postoperative adjuvant, sequential radio- report differences in side effects between the two patient therapy and chemotherapy, provided important clues about groups [49, 52]. the relevance of stratification by risk. First, in the whole It was not until a number of meta-analyses clearly group, the sequential addition of chemotherapy to postoper- demonstrated a small but significant therapeutic benefit in ative radiotherapy did not significantly affect the prognosis favor of platinum-based concurrent chemoradiation regi- in terms of LRF and survival. Second, the subgroup of mens that the coadministration of cytotoxic drugs and irra- patients at higher risk appeared to be more likely to benefit diation was considered a mainstay of locally advanced head more from adjuvant chemotherapy than the low-risk group, and neck cancers [2-6]. both in terms of tumor control and survival (subgroup analy- sis of Intergroup #0034 suggested a possible value of PLATINUM-BASED CHEMORADIATION SCHEDULES: sequential chemotherapy and radiotherapy in decreasing the RATIONALE AND FIRST CLINICAL RESULTS likelihood of local-regional recurrence in the high-risk sub- Interactions of cisplatin with ionizing radiation are believed group, and comparison of similarly selected high-risk to include enhanced formation of toxic platinum intermedi- patients treated by concurrent chemotherapy and radiother- ates in the presence of radiation-induced free radicals, apy in RTOG #88-24 [28, 29] demonstrates the effect even while radiosensitizing mechanisms may be linked to a radi- more clearly). Third, the pattern of failure was shown to be ation-induced increase in cellular platinum uptake [37, 45]. modified by the addition of chemotherapy; the rate of tumor Various platinum-based schedules have been tested in the recurrence in regional lymph nodes and distant sites was adjuvant setting. In trials investigating postoperative chemo- decreased in the chemotherapy-containing arm. radiation, the dose/delivery schedules of cisplatin have In summary, these studies suggest that concurrent ranged from intermittent higher-dose (100 mg/m ) every 3 chemoradiotherapy may have a beneficial effect on local- weeks to low-dose (6 mg/m ) daily administration [35]. One regional tumor control in patients whose tumors have the of the first prospective studies of the combination of postop- following prognostic factors: presence of malignant cells in erative radiotherapy with cisplatin as single-agent therapy two or more lymph nodes and/or rupture of tumor through was completed by Bachaud and colleagues in 1996 [9, 12]. the lymph node capsule and/or microscopic involvement of In this relatively small-scale study of 83 patients, the group the margins of resection. treated with adjuvant radiotherapy alone displayed a higher These laboratory [36, 44] and clinical [37, 38, 45] data led LRF rate than the group receiving adjuvant chemoradiation clinicians to test this new paradigm based on the concomitant consisting of cisplatin 50 mg given weekly up to 7-9 cycles delivery of chemotherapy and radiotherapy in hopes of during radiation therapy (41% versus 23%; p = .08). answering three basic questions still unresolved in the late In the early 1990s the encouraging results of the study 1980s: In the clinical setting, is the combined effect of con- conducted by Al-Sarraf et al. [29] of cisplatin in single high current chemoradiation [24, 25] really greater than the sum doses (100 mg/m ) repeated every 3 weeks (days 1, 22, and of the individual effects of radiotherapy and chemotherapy, 43), led the European Organization for Research and Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 219 Adjuvant Chemoradiation in Head and Neck Cancer Patients Treatment of Cancer (EORTC) and the RTOG cooperative [59]. This situation may improve when more prolonged groups to consider this regimen as the reference chemoradi- follow-up becomes available. ation approach for adjuvant treatment of HNSCC and to acti- vate two large-scale randomized trials measuring treatment Towards and Reaching Level I Evidence outcome for this regimen after potentially curative surgery in In the early 1990s and in the recent past, two studies reported patients with high-risk operable, locally advanced tumors. on the results of concomitant delivery of chemo- and radio- therapy in the postoperative setting. As mentioned above, the Single-Agent or Multidrug Regimens? Intermittent High Dose Bachaud study [9, 12] emphasized a decrease in LRF rates in or More Frequent Low Dose? favor of the experimental arm, but early termination of the What is the ideal objective of chemoradiation? In addition to trial, because of decreasing accrual rates, prevented the inves- better control of local-regional disease, chemotherapy should tigators from including the planned number of patients in the prevent the subsequent appearance of metastases by eradi- trial (83 instead of 200). In another recent prospective trial cating occult metastatic deposits. Since distant metastases are recruiting 114 patients, Smid et al. [60] found that the addition now the cause of failure in 1 of 5 patients with stage III/IV of mitomycin C and bleomycin to adjuvant radiotherapy sig- HNSCC, high-dose bolus chemotherapy, at least in theory, is nificantly increased the local-regional control and overall sur- more likely to achieve this objective, since the gain from a vival rates in the subgroup having high-risk features compared pure radiosensitizing effect of a low-dose cytotoxic agent is with similar patients observed after adjuvant radiotherapy limited by the competing risk of distant failure. Obviously, alone. Together, these two studies provided suggestive, but not compliance to aggressive adjuvant therapy may be low in conclusive, evidence that adjuvant chemoradiation was more this category of patients whose general condition is often efficacious than postoperative radiation therapy. influenced by the surgery as well as comorbid conditions. This is reflected in dose-intensity reductions in some The Level 1 Evidence 25%-33% of cases receiving postoperative chemo- In the late 1990s, two similar, large-scale, prospective ran- radiation [35]. This reality may negate the theoretical domized independent trials designed by the EORTC and the advantage of intermittent high-dose chemotherapy. RTOG were conducted to evaluate the role of concomitant In this perspective, should we use mono- or multidrug high-dose chemoradiation (chemotherapy given every 3 regimens? In the adjuvant setting, single-agent chemo- weeks) in the postoperative treatment of high-risk head and therapy, based on platinum derivatives, is probably the neck tumors. The EORTC study [13] compared concomitant treatment of choice; indeed, in cohorts of patients treated cisplatin and radiotherapy versus radiotherapy alone in high- without ablative surgery, the addition of 5-fluorouracil to risk head and neck cancers of the oral cavity, oropharynx, cisplatin was not shown to improve treatment efficacy [56]. larynx, or hypopharynx. The primary end point was disease- Therefore, 5-fluorouracil is likely to account for an undue free survival, with overall survival, local control rates, and increase in acute mucosal reactions in this fragile category treatment toxicity as secondary end points. Following surgery of patients, and might be responsible for dose-intensity patients were randomly assigned to either radiotherapy alone reduction [57]. However, other combinations of drugs are (66 Gy in 33 fractions over 6.5 weeks) or chemoradiation, potentially possible and need to be tested in the future. using the same radiation therapy schedule combined with three courses of cisplatin 100 mg/m on days 1, 22, and 43. Toxicity of Adjuvant Chemoradiation Regimens and In this trial, as in the RTOG study, late toxicity was measured Supportive Treatment by objective criteria only using the RTOG/EORTC Late As mentioned earlier, acute reactions from adjuvant treat- Radiation Morbidity Scoring Scheme. ment are markedly increased with chemoradiation, espe- At a median follow-up of 60 months, there was a signif- cially in the mucosa and skin [13, 14, 58]. Intravenous icant (p = .044) difference in progression-free survival, the rehydration, gastric feeding tubes during treatment, primary end point of this trial, in favor of the chemoradia- and narcotics for severe pain must be implemented in a high tion group; the estimated median progression-free survival percentage of the patients undergoing chemoradiation. This was 23 months in the radiotherapy and 55 months in the implies the need for a significant intensification of support- chemoradiation group. In terms of overall survival, there ive care, which is not always manageable in all inpatient was a significant (p = .02) difference in overall survival in and outpatient units. Cautious implementation of this type favor of the chemoradiation group. Finally, in regard to the of therapeutic management is therefore needed. As men- local-regional outcome, the 5-year cumulative incidence tioned above, late side effects related to chemoradiation estimates of local-regional relapse were 31% for the radio- have been too often inadequately reported in the literature therapy group and 18% for the chemoradiation group Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 Bernier, Cooper 220 (p = .007). Objective acute mucositis and late toxicity were observed in 34% of patients treated by radiotherapy alone, not significantly increased in patients who received concurrent but more than doubled to 77% in the patients treated with therapy. concurrent therapy. Severe late toxicity was not significantly The RTOG study [14] similarly compared concomitant different between the treatments. cisplatin and radiotherapy versus radiotherapy alone in Why did these two similar studies not reach precisely high-risk head and neck cancers of the oral cavity, orophar- the same conclusions? Notwithstanding a relatively similar ynx, larynx, or hypopharynx. The end points were local- design, the definition of high-risk and therefore the inclu- regional control, as the primary end point, and overall sion criteria differed between the two studies. The eligibil- survival, disease-free survival, and treatment toxicity as ity criteria common to both trials were the presence of ECE secondary end points. Following surgery patients were ran- and/or microscopic-sized tumor involvement of the surgical domly assigned to either radiotherapy alone (60 Gy in 30 margins of resection. In addition, the RTOG included in its fractions over 6.0 weeks with or without a 0.6 Gy boost selection of risk factors the presence of tumor in two or over 3 days) or chemoradiation, using the same radiation more lymph nodes, as was suggested by the analysis of the therapy schedule combined with three courses of cisplatin, RTOG database discussed previously. In contrast, the other 100 mg/m , on days 1, 22, and 43. At a 36-month median EORTC eligibility criteria were stage III/IV disease, the follow-up in the RTOG study, concurrent therapy was asso- presence of enlarged lymph node(s) at level IV or V in ciated with a significant benefit in terms of local-regional patients with oral cavity or oropharynx carcinomas, patho- control (p = .011) and disease-free survival (p = .038). The logical demonstration of vascular embolisms, and/or per- benefit observed in the RTOG 95-01 study for overall sur- ineural disease. Table 2 presents a comparative analysis of vival did not reach statistical significance (p = .18). The the criteria of selection that, in each trial, were related to comparative analysis of treatment outcome in both trials is risk factors. summarized in Table 1. A number of differences were found regarding the dis- With regards to toxicity, the addition of chemotherapy tribution of some of these eligibility criteria in the two stud- resulted in a substantially greater incidence of severe acute ies. First of all, 94% of the cases in the RTOG trial had side effects in this trial. Grade 3 or higher toxicity was N2-3 disease as compared with only 57% in the EORTC Table 1. Comparative analysis of treatment outcome in EORTC trial 22931 and RTOG trial 9501 Outcome end points EORTC Trial 2931 5-year estimates RTOG Trial 9501 2-year estimates a a Disease-free survival 47% versus 36% (p = .04) 54% versus 45% (p = .04) a a Overall survival 53% versus 40% (p = .02) 64% versus 57% (p = .19) a a Local-regional failure rates 17% versus 31% (p = .007) 18% versus 28% (p = .01) a, b a Grade 3+ acute toxicity p = .008/p = .28 77% versus 34% (p <.0001) b a Late toxicity 38% versus 41% (p = .25) 21% versus 17% (p = .29) Impact on distant metastases p = .61 p = .46 Second primary tumors p = .83 NA Chemoradiation versus radiotherapy arm values Functional/objective acute reactions Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; NA = Data not available; RTOG = Radiation Therapy Oncology Group Table 2. Comparative analysis of criteria of selection related to risk factors in EORTC trial 22931 and RTOG trial 9501 EORTC 22931 only EORTC 22931 and RTOG 9501 RTOG 9501 only Stage III/IV disease Surgical margins microscopically involved Two or more positive lymph nodes Positive lymph nodes at levels IV or V in patients Extracapsular extension in positive lymph nodes with tumors arising from oropharynx or oral cavity Vascular embolisms Perineural infiltration Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; RTOG = Radiation Therapy Oncology Group Downloaded from https://academic.oup.com/oncolo/article/10/3/215/6386692 by DeepDyve user on 31 January 2022 221 Adjuvant Chemoradiation in Head and Neck Cancer Patients trial. A second difference related to the presence of micro- Despite the improvement seen with concomitant scopic positive surgical margins for which the ratio chemoradiation, local-regional control levels remain between the EORTC and the RTOG studies was 2.9. unsatisfactory and distant metastases have become a more In contrast, the dose levels delivered in each trial were relevant problem in terms of survival. As a consequence, rather similar, and analyses of compliance indicate that most other drugs such as taxanes or combinations of drugs that cases received at least 60 Gy in either trial. The radiotherapy demonstrate a relatively high level of activity against dose factor is therefore unlikely to explain a difference in metastatic head and neck carcinomas need to be investigated treatment outcome across the two studies. Thus differences more extensively in the adjuvant setting. in outcome may reflect differences in the patient popula- In regard to local-regional control, a first complementary tions included in the two trials. Also, it must be remem- approach might be the addition of drugs that may further bered that the failure to detect a statistically significant improve the efficiency of chemoradiotherapy. Overexpres- improvement in the secondary end point of overall survival sion of the epidermal growth factor receptor has been corre- in the RTOG trial does not mean that one does not exist. In lated with more aggressive behavior and poor clinical addition, further analyses of selection criteria and treat- outcome [35]. The blockade of the epidermal growth factor ment-related parameters are still under way to explain the by a monoclonal antibody cetuximab (Erbitux ; ImClone differences in outcome between the two trials. Systems Inc., New York, NY, http://www.imclone.com) The recent EORTC and RTOG chemoradiation trials [13, was shown to increase significantly the median survival in 14] with high-dose cisplatin (100 mg/m on days 1, 23, and patients with locally advanced, unresectable disease and 43 of radiotherapy) and radiation doses of 60-66 Gy have this approach could also be tested in the postoperative shown that this combination more effectively controls dis- setting [61]. ease than radiotherapy alone in high-risk locally advanced Finally, more attention should be paid to the latency HNSCC and that the impact of adjuvant concomitant between the surgical procedure and the onset of radiother- chemoradiation is influenced by the precise type of high-risk apy or chemoradiation. Indeed, too often, either organiza- factors included. Addition of chemotherapy resulted in a sig- tional constraints or delayed wound healing postpone the nificant increase in local control and disease-specific survival start of adjuvant treatment beyond 6-7 weeks. Increased in both trials. Further study will be required to precisely concentrations of growth factors during the healing period explain the effect on overall survival rates and acute toxicity. might account for acceleration of tumor cell repopulation Even if longer follow-up is needed to accurately assess the during a long postoperative latency period. Very few stud- late morbidity after chemoradiation, this therapeutic ies, however, have taken this parameter into consideration approach can be considered an acceptable standard adjuvant [18]. The administration of postoperative chemotherapy treatment for this population of patients. within the first 2 weeks following surgery followed by con- current chemoradiation recently has been tested by the WHAT’S NEXT? RTOG, but no results are yet available. The advent of noncytotoxic drugs, the delivery of more efficacious cytotoxic agents, the optimization of mul- CONCLUSION tidrug regimens, and the application of modern techniques The role of concurrent chemoradiation in the adjuvant of radiation therapy are the tools we have now to test in setting of high-risk disease has now been established and our quest to control disease locally and eradicate occult validated. The best concomitant chemoradiotherapy regi- micrometastases. mens still need to be determined, although cisplatin- Indeed, the benefit of chemotherapy in the EORTC and based chemotherapy is the current standard. All the RTOG trials apparently does not accrue from the typical efforts expended throughout the past decade undoubtedly action of neoadjuvant or adjuvant systemic chemotherapy, have been justified and warrant continued efforts in the namely in reducing the risks of distant metastases; while lab and clinic to optimize the therapeutic index and fur- local-regional control improved in both trials, the sys- ther reduce the risk of both local-regional and distant fail- temic outcome was not affected by adjuvant chemoradia- ure. Moreover, the development of customized surgical tion. In the EORTC trial the estimated 5-year cumulative and reconstruction techniques combined with state-of- incidence of distant metastases was 25% following post- the-art radiation techniques such as three-dimensional operative radiotherapy and 21% following concurrent conformal radiation therapy and intensity-modulated chemoradiotherapy (p = .61 Gray’s test). 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The Oncologist – Oxford University Press

Published: Mar 1, 2005

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