PII S0360-3016(99)00218-7

CLINICAL INVESTIGATION Head and Neck

ACCELERATED RADIOTHERAPY WITH DELAYED CONCOMITANT BOOSTIN LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD

AND NECK

ROBERT MACKENZIE, M.D.,* JUDITH BALOGH, M.D.,* RICHARD CHOO, M.D.,* AND

EDMEE FRANSSEN, M.SC.†

Departments of *Radiation Oncology and†Clinical Trials and Epidemiology, Toronto-Sunnybrook Regional Cancer Centre, SunnybrookHealth Science Centre, University of Toronto, Toronto, Ontario, Canada

Purpose: To determine the toxicity, maximum tolerated dose (MTD), and clinical effectiveness of a 5-week courseof accelerated radiotherapy with delayed concomitant boost in locally advanced squamous cell carcinoma of thehead and neck (SCCHN).Methods and Materials: Thirty-five patients with untreated T3T4NM0 or TN2 ( > 3 cm) N3M0 SCC of the oralcavity, oropharynx, hypopharynx, or larynx were entered in the study between January 1994 and October 1997.The initial target volume was treated with conventional daily fractions. A small field boost covering gross diseasewas added as a second daily fraction during the last 2 weeks of the 5-week schedule, using a minimuminterfraction interval of 6 h. The study was initiated using 180-cGy fractions to deliver a total dose of 63 Gy over33–35 days. A classical dose escalation strategy was planned to increase the delivered dose in steps usingminimum cohorts of three patients, up to a maximum of 70 Gy in 200-cGy fractions.Results: In the dose escalation study, 4 patients were entered at level 1 (63 Gy), 9 at level 2 (65 Gy), and 8 at level3 (67 Gy). One patient was withdrawn at level 2 because of unstable angina, and 1 at level 3 because ofuncontrolled diabetes. One patient at level 3 failed to complete treatment because of radiation toxicity. RTOGGrade 3 mucositis, dermatitis, or pharyngitis was documented in 1 (25%), 5 (63%), and 7 (100%) evaluablepatients at levels 1, 2, and 3, respectively. Grade 4 reactions were documented in 1 patient at each level. Onepatient at level 3 died 5 weeks post-treatment of unknown causes. Two additional patients at level 3 died ofprogressive disease and RT toxicity. Sixty-five Gy (level 2) was chosen as the MTD. In the MTD study, 14additional patients were entered at level 2, providing a total of 22 evaluable patients with a median follow-up of21 months (range 12–41 months). Grade 3 mucositis, dermatitis, or pharyngitis were documented in 11 (50%),8 (36%), and 6 (27%) patients, respectively. One patient developed Grade 4 mucositis. A complete response wasrecorded in 16 (77%). Three of 5 patients with uncontrolled disease and 3 of 3 patients with recurrent diseaseunderwent salvage surgery with no postoperative complications. Radiotherapy controlled disease above theclavicles in 14 (68%). Ultimate locoregional control was achieved in 17 (77%). The disease-free, overall, andcause-specific survival of all patients entered at level 2 was 56%, 76%, and 80%, respectively, at 2 years. Latecomplications have been limited to 3 patients (trismus, chronic mucosal ulcer, and soft tissue necrosis).Conclusion: A 5-week course of accelerated radiotherapy with delayed concomitant boost can deliver 65 Gy withacceptable toxicity, encouraging rates of complete response, and locoregional control, and no compromise ofsalvage surgery in patients with locally advanced SCCHN. The regimen is worthy of further study in a Phase IIItrial. © 1999 Elsevier Science Inc.

Radiotherapy, Accelerated fractionation, Concomitant boost, Squamous cell carcinoma, Head and neck.

INTRODUCTION

Conventional fractionation (CF) yields suboptimal results inlocally advanced squamous cell carcinoma of the head andneck (SCCHN). Published rates of local control range be-tween 5% and 64%, with a median of 42% (1–13). Only asmall number of patients are eligible for surgical salvage.As a result, the reported overall 5-year survival seldom

exceeds 40%. There is increasing evidence from random-ized trials that altered fractionation can improve treatmentoutcomes in this group of patients (14–18). However, apractical and effective regimen within the resources of mostcenters has yet to be defined.

A careful review of clinical data suggests that localcontrol of SCCHN decreases as the overall treatment time

Presented at the 40th Annual Meeting of the American Societyfor Therapeutic Radiology and Oncology, Phoenix, AZ, October25–29, 1998.

Reprint requests to: Robert MacKenzie, M.D., Department ofRadiation Oncology, Toronto-Sunnybrook Regional Cancer Cen-

tre, 2075 Bayview Avenue, Toronto, Ontario, Canada, M4N 3M5.Tel: (416)480-6128;Fax: (416)480-6002;E-mail:bob.mackenzie@tsrcc.on.ca

Accepted for publication 26 May 1999.

Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 3, pp. 589–595, 1999Copyright © 1999 Elsevier Science Inc.Printed in the USA. All rights reserved

0360-3016/99/$–see front matter

589

increases if there is no adjustment in delivered dose (19,20). These observations provide compelling evidence fortumor proliferation during fractionated radiotherapy. Accel-erated fractionation (AF) regimens aim to counteract theproliferation of tumor clonogens by delivering the samedose in less time using multiple fractions per day. Theconcomitant boost is an example of an accelerated regimendelivering conventional treatment to a large volume encom-passing the primary tumor and regional nodes, and a smallvolume boost to sites of gross disease as the second dailytreatment in a shortened twice-daily schedule. The overalltreatment time can be reduced by modifying the fractionsize and number of boost fractions.

The optimal timing of the boost has been explored in aseries of sequential studies at the MD Anderson Hospital.Superior local control was documented among those treatedwith the concomitant boost during the last 12 treatment dayscompared to those treated during the first 12 treatment days,or twice weekly over the 6-week schedule (21). This findingis consistent with evidence supporting the onset of acceler-ated tumor proliferation around the third or fourth week ofconventionally fractionated treatment (19). A regimenbased on a delayed concomitant boost offers dose intensi-fication during the most critical period of tumor repopula-tion.

The aim of this study was to assess the feasibility, tox-icity, and clinical effectiveness of of a 5-week course ofaccelerated radiotherapy based on a delayed concomitantboost in untreated locally advanced SCCHN.

METHODS AND MATERIALS

PatientsBetween January 1994 and October 1997, 155 patients

were referred to the Toronto-Sunnybrook Regional CancerCenter with locally advanced cancer of the head and neck.Thirty-eight patients with untreated T3T4NM0 or TN2 (. 3cm) N3M0 squamous cell carcinoma of the oral cavity,oropharynx, hypopharynx, or larynx between the ages of 18and 75 years were eligible for study. No patients wereexcluded because of concurrent malignancy, documentedconnective tissue disorder, or poor performance status. Thir-ty-five patients provided informed consent and were en-rolled in the study.

The study cohort was characterized by a median age of 62years (range 39–72) and male:female ratio of 22:13. Theprimary originated in the oral cavity in 4 cases and orophar-ynx in 21 cases; the hypopharynx and larynx each ac-counted for 5 cases. The diagnostic work-up included ex-amination under anesthesia with biopsy (if not alreadyperformed by the referring otolaryngologist), completephysical examination including fiberoptic endoscopy withvideotape record, CBC, renal function tests, liver functiontests, chest X-ray, and CT scan of the head and neck. Anultrasound of the liver was performed in patients withabnormal liver function tests and bone scan in patients withunexplained skeletal pain. A pathology review was not

required. Patients were staged according to the 1992 UICCTNM classification (22). Distribution by TNM stage issummarized in Table 1.

RADIOTHERAPY

All patients were immobilized in a plastic mask andtreated on60Co or 6-MV linear accelerator. The primarytumor and bilateral neck nodes were irradiated throughlateral opposed photon beams. The supraclavicular nodeswere treated with a matched anterior photon field. Theinitial treatment volume, including the primary tumor, in-volved nodes, and potential sites of microscopic spread wastreated daily Monday through Friday over 5 weeks. Grossdisease was boosted with reduced lateral or oblique opposedportals with a margin of 1 cm, combined when necessary,with matched appositional electron beams to nodal areasoverlying the spinal cord. The central nervous system wasexcluded from the boosted volume. The boost was deliveredas a second daily fraction over the last 2 weeks of the5-week schedule, using a minimum interfraction interval of6 h. The total treatment time was 33–35 days.

All treatment setups were simulated. Isodose distribu-tions in three planes, wedges, and attenuators were usedroutinely to optimize dose homogeneity. Bolus was re-served for electron boosts to gross nodal disease. Portalfilms were obtained on first setup and as necessary, withchanges in field size or shielding.

Dose escalationThe study was initiated using 180 cGy per fraction to

deliver a total dose of 63 Gy. A classical dose escalationstrategy was employed to increase the delivered dose insteps using minimum cohorts of three patients. The studycalled for a stepwise increase in fraction size, as illustratedin Fig. 1 to deliver total doses ranging between 63 and 70Gy. Progression from one level to the next was permitted,provided that no more than 1 in 2 patients required hospi-talization, no more than 1 in 3 patients developed Grade 3reactions protracted beyond 8 weeks, no more than 1 in 6patients required treatment interruptions greater than 2weeks, and no patient suffered a treatment-related death.

Maximum tolerated dose (MTD)The dose escalation strategy was used to determine the

maximum dose acceptable to both patients and investiga-tors. Additional patients were entered at this level during the

Table 1. TNM stage distribution of all patients entered on study

N0 N1 N2 N3 Total

T1 0 0 1 0 1T2 0 0 4 0 4T3 3 7 5 1 16T4 6 2 6 0 14Total 9 9 16 1 35

590 I. J. Radiation Oncology● Biology ● Physics Volume 45, Number 3, 1999

second part of the study. It was estimated that a minimum of20 evaluable patients would be required to generate statis-tically valid estimates of toxicity and tumor response rates.

Monitoring and follow-upAssessment of radiation reactions and tumor response

was performed weekly during treatment until the peak re-actions subsided. Analgesic requirements, nutritional in-take, and weight were recorded at each visit. Toxicity wasdocumented using radiation morbidity criteria of the Radi-ation Therapy Oncology Group (RTOG) (23). Subse-quently, patients were assessed at monthly intervals. A CTscan of the head and neck was obtained 8–12 weeks post-treatment. Complete responders were followed every 3months for the first 2 years, every 6 months for the next 3years, and annually thereafter. Chest X-rays were performedat 3 months, 12 months, and annually thereafter. Suspectedsites of locoregional recurrence were evaluated by CT scanand confirmed by aspiration cytology or biopsy. Diseaseidentified on metastatic survey was not routinely biopsied.

Surviving patients have been followed for a median of 30months, with a range of 12–48 months since study entry.All patients undergoing salvage surgery have been followedfor a minimum of 1 year beyond hospital discharge.

Statistical analysisOverall survival and cause-specific survival were deter-

mined for 33 patients completing the protocol. Thirty-twopatients were evaluable for local control, locoregional con-trol, and disease-free survival. Five patients were evaluablefor ultimate locoregional control with salvage surgery.Those with no evidence of locoregional disease at lastfollow-up are reported as controlled above the clavicles.

Survival curves and actuarial rates of locoregional recur-rence were calculated using the Kaplan-Meier method for atime period beginning with the diagnostic biopsy (24).

RESULTS

Dose escalation phaseThe results of dose escalation are summarized in Table 2.

Four patients were entered at level 1 (63 Gy), 9 at level 2(65 Gy), and 8 at level 3 (67 Gy). One patient was with-

drawn at level 2 because of unstable angina, and 1 at level3 because of uncontrolled diabetes. An additional patient atlevel 3 failed to complete treatment because of radiationtoxicity. Confluent fibrinous mucositis, confluent moist des-quamation, or severe dysphagia was documented in 1(25%), 5 (63%), and 7 (100%) evaluable patients at levels 1,2, and 3, respectively. One patient at each level developedacute Grade 4 toxicity (aphagia at level 1, chronic mucosalulceration at level 2, and soft tissue necrosis at level 3). Thepeak toxicities were recorded 2 weeks following completionof treatment. The median interval to resolution of Grade 3toxicities was 6 weeks, with a range of 4–21 weeks. Thetime to recovery did not correlate with total dose. A percu-taneous gastrostomy was required for odynophagia andweight loss exceeding 10% of initial body weight in 1patient at each level. Hospitalization for supportive care wasnecessary for 1 patient at level 2 and 1 patient at level 3.Complete healing of the skin was documented in all patientsand complete healing of the mucosa in all but 2 patients.One patient at level 3 died at home 5 weeks post-treatmentof unknown causes. Two additional patients at level 3 diedof a combination of progressive disease and radiation tox-icity manifested by confluent fibrinous mucositis, extensivemoist desquamation, and malnutrition. Sixty-five gray (level2) was chosen as the maximum tolerated dose.

Maximum tolerated doseFourteen additional patients were entered at level 2.

These patients have been combined with the 8 evaluablepatients treated at level 2 during the escalation phase in thefollowing analysis of treatment outcomes. The TNM stagedistribution of this cohort is summarized in Table 3. Themedian follow-up was 21 months (range 12–41). No patienthas been lost to follow-up.

Fig. 1. Dose escalation strategy.

Table 2. Results of dose escalation

ObservationLevel 163 Gy

Level 265 Gy

Level 367 Gy

Number entered 4 9 8Number withdrawn 0 1 2Number grade III reactions 1 (25%) 5 (63%) 7 (100%)Number grade IV reactions 1 1 1Time to resolution (weeks) 10 8 4Treatment-related deaths 0 0 2

Table 3. TNM stage distribution of 22 evaluable patients enteredat level 2 (65 Gy)

N0 N1 N2 N3 Total

T1 0 0 1 0 1T2 0 0 4 0 4T3 1 3 4 1 9T4 4 1 3 0 8Total 5 4 12 1 22

591Phase I-II study of accelerated radiotherapy● R. MACKENZIE et al.

Acute toxicityRTOG Grade 3 mucositis, dermatitis, or pharyngitis was

documented in 11/22 (50%), 8/22 (36%), and 6/22 (27%)patients, respectively. Grade 4 reactions were limited to asingle patient. Two patients required hospitalization forG-tube insertion and 2 for supportive care. The medianduration of Grade 3 reactions was 5 weeks (range 3–9) fordermatitis, 7 weeks (range 6–10) for pharyngitis, and 10weeks (range 7–13) for mucositis. Complete healing wasdocumented in all but 1 patient with chronic mucosal ulcer.

Locoregional control and survivalSeventeen of 22 (77%) patients achieved a complete

clinical and radiological response. Three patients underwentneck dissection for apparent residual disease. Persistentsquamous cell carcinoma was confirmed in 2 cases. Threepatients experienced a local recurrence at 4, 5, and 7months, respectively. All 3 patients underwent salvage sur-gery (laryngectomy and neck dissection, pharyngectomyand neck dissection, partial glossectomy) without postoper-ative complications. Radiotherapy controlled disease abovethe clavicles in 15/22 (68%). All cases of confirmed failurecorresponded to lesions greater than 5 cm in diameter.Ultimate locoregional control was achieved in 17/22 (77%)patients. The disease-free, overall, and cause-specific sur-vival of all patients entered at level 2 was 64%, 82%, and86%, respectively, at 1 year, and 56%, 76%, and 80%,respectively, at 2 years (Fig. 2.). Local relapse-free survivalwas 72% at 2 years (Fig. 3).

Late complicationsOne patient presenting with T4N1 carcinoma of the tonsil

extending to the pterygoid fossa developed progressive tris-mus during radiotherapy. G-tube support was required up tothe time of salvage surgery for local recurrence 7 monthslater. An additional patient developed chronic mucosal ul-ceration of the oral cavity but was able to maintain weightwithout nutritional supplements. Pharyngolaryngeal edemawas documented with flexible endoscopy in 9 patients butdid not require surgical intervention.

DISCUSSION

On average, less than 50% of patients with locally ad-vanced SCCHN are cured with conventionally fractionatedradiotherapy. Prognosis appears to depend on a variety ofpatient, tumor, and treatment characteristics. The relevantpatient factors include gender, pretreatment hemoglobin,performance status, and history of continued smoking. Tra-ditional tumor factors include TNM stage, anatomic site,some measure of disease bulk such as maximal tumordiameter, and histology. Cure also appears related to totalradiation dose, fraction size, irradiated volume, and overalltreatment time.

Accelerated fractionation reduces the opportunity for tu-mor cell repopulation by decreasing overall treatment time.There are two strategies to accelerate radiation treatment.Pure accelerated fractionation reduces the overall treatmenttime without concurrent changes in fraction size or totaldose. Hybrid accelerated fractionation reduces the overalltreatment time in conjunction with changes in other param-eters, such as fraction size and total dose, with and withoutplanned breaks in treatment. Four variations of hybrid pro-tocols have emerged in clinical practice. Continuous hyper-fractionated accelerated radiotherapy (CHART) is the pro-totype of intensive short-course treatment in which theoverall duration of treatment is markedly reduced with acorresponding decrease in total dose. Split-course twice-daily protocols and concomitant boost regimens are exam-ples of schedules in which the duration of treatment is moremodestly reduced while the total dose is kept in the samerange as conventional therapy. There is more limited expe-rience with hybrid schedules in which the total dose deliv-ered per week is progressively increased during the courseof therapy.

Three prospective trials have tested pure accelerated frac-tionation against conventional regimens. The Vancouvertrial compared a twice-daily regimen delivering 66 Gy in 2Gy fractions over 22–28 days to a conventional arm deliv-ering 66 Gy in daily 2 Gy fractions over 43–55 days inpatients with CS III-IV SCCHN (25). The study was closedprematurely when an interim analysis revealed significantlyhigher Grade 3/4 acute toxicity in the accelerated fraction-ation arm. With entry limited to 41 patients per arm, the

Fig. 2. Survival of 22 patients treated at level 2 (65 Gy). Fig. 3. Control of the primary at level 2 (65 Gy).

592 I. J. Radiation Oncology● Biology ● Physics Volume 45, Number 3, 1999

study lacked sufficient power to detect a 15% difference intumor control between the arms.

In the CAIR trial conducted in Gliwice, Poland, 75 pa-tients with T2T3T4NM0 SCC of the oral cavity, orophar-ynx, supraglottic larynx, and hypopharynx were randomizedto a conventional arm of 64–72 Gy delivered as 1.8–2.0 Gyfractions 5 fractions per week, and an experimental armdelivering the same dose and fraction size 7 days per weekover 5 weeks (26). Boost fields were treated on the weekendon the accelerated arm. A significant increase in severeprotracted mucosal reactions and consequentional late ef-fects in the accelerated arm led to premature closure of thestudy.

In the Danish trials DAHANCA 6 and 7, patients withSCC of the larynx, pharynx, and oral cavity eligible forprimary radiotherapy alone were randomized between 5 and6 weekly fractions delivering 66–68 Gy in 33–34 fractions(T1 tumors were limited to 62 Gy in 33 fractions). Centersunable to treat on Saturday were permitted to deliver thesixth fraction Monday to Friday. All patients except thosewith glottic cancers were also treated with the radiosensi-tizer Nimorazole. A preliminary analysis of 977 patientsrevealed that 96% of patients received the planned totaldose (16). The incidence of acute severe mucositis anddysphagia was significantly higher in patients receiving 6fractions per week. There was no difference in the incidenceof late edema or fibrosis between arms. A reduction inmedian overall treatment time, from 46 to 39 days, yieldedsignificantly higher tumor control in the accelerated arm(odds ratio 1.3, 95% confidence interval 1.1–1.7). Thus far,this benefit has not translated into a significant increase inoverall survival (odds ratio 1.3, 95% confidence interval0.9–1.8).

Hybrid accelerated fractionation has been tested in tworandomized studies of primary management. In the multi-centre CHART trial patients with SCCHN (excluding T1N0lesions of the oral cavity, oropharynx, hypopharynx, andlarynx) were randomized between a conventional dose of 66Gy in 33 fractions delivered over 6.5 weeks, and theCHART protocol of 1.5 Gy t.i.d. on each of 12 consecutivedays using a minimum interfraction interval of 6 h. Apreliminary analysis of 918 patients (27) revealed a 3%increase in disease-free survival for patients treated on theaccelerated arm (p 5 0.33). There was some evidence thatCHART was more effective than CF with increasing tumorstage (x2 for trend 5 3.40, p 5 0.065). Acute mucositispeaked and resolved more quickly with CHART. No dif-ference in long-term morbidity has emerged during ongoingfollow-up.

In EORTC 22851, 325 patients with T2T3T4NM0 SC-CHN (excluding hypopharynx) were randomized to 70–72Gy delivered in 35–40 fractions over 7–8 weeks, or anexperimental arm delivering 28.8 Gy in 18 fractions over 7days, followed by a 2-week break and an additional 43.2 Gyin 27 fractions over 5 weeks (17). Accelerated fractionationproduced better locoregional control (59% vs. 46% at 5years,p 5 0.02) but was associated with higher rates of

Grade 3/4 mucositis, iatrogenic mortality, and late Grade 3fibrosis compared to CF. Seven cases of permanent periph-eral neuropathy and one case of radiation myelopathy weredocumented in the AF arm, prompting investigators toabandon the regimen.

Two randomized trials of hybrid accelerated fractionationhave been reported in the postoperative setting. Awwadreported a modest increase in 3-year disease-free survival(54% vs. 39%,p 5 0.37) at the cost of increased latemorbidity (87% vs. 64%) for 26 patients treated with AFcompared to 30 patients treated with CF (28). Preliminaryanalysis (29) of a joint trial of the M.D. Anderson Hospital,Moffitt Cancer Centre, and Mayo Clinic of 134 patientsdeemed at high risk of postoperative recurrence has re-vealed a nonsignificant increase in locoregional controlamong those treated with a concomitant boost schedule(60% vs. 38%,p 5 0.11). Late complications were less than10% in both arms. This study continues to accrue patients.

To date, there have been no published studies of random-ized trials based on the concomitant boost technique in theprimary management of SCCHN. RTOG has accrued 1,200patients to a four-arm trial comparing three altered fraction-ation schemes to conventional fractionation. Patients withCS III–IV SCCHN were randomized to standard therapy(70 Gy in 35 fractions over 7 weeks), hyperfractionation(81.6 Gy in 68 fractions over 7 weeks), split-course accel-erated fractionation (67.2 Gy in 42 fractions over 6 weeks),or accelerated fractionation with concomitant boost (72 Gyin 42 fractions over 6 weeks). Publication of the results ofthis important trial is eagerly awaited.

A number of Phase I–II studies of accelerated fraction-ation with concomitant boost have been published withencouraging results (21, 30–33). Two recent studies are ofparticular interest. Trottiet al. used a concomitant boosttechnique to deliver 63 Gy in 35 fractions over 37 days in 32patients deemed at high risk of postoperative failure (34).Patients were given 6 fractions per week (twice-a-day largefields on Fridays) for 4 weeks, followed by twice-a-daytreatments for the last 4 treatment days. The dose intensityof the regimen was similar to level 1 of the current study.Acute mucosal and skin reactions were increased but toler-able. A minor increase in consequential late effects wasnoted. Kaanderset al. combined an AF protocol delivering64 Gy in 2 Gy fractions to the primary over 35–37 days(while treating metastatic nodes to 68 Gy over 36–38 days)with carbogen and nicotinamide in 62 untreated patientswith CS III–IV carcinoma of the larynx (35). Carbogenbreathing was tested in the first 11 patients and the combi-nation of carbogen and nicotinamide in the subsequent 51patients. With a median follow-up of 24 months, the 2-yearactuarial local control was 92%. Five patients with localrecurrence and 1 patient with nodal relapse were salvagedwith surgery for an ultimate locoregional control of 100%.Acute toxicity was increased compared to CF. Laryngec-tomy was required for cartilage necrosis in 1 patient.

The current study was designed to evaluate the toxicityand clinical effectiveness of a novel schedule of accelerated

593Phase I-II study of accelerated radiotherapy● R. MACKENZIE et al.

fractionation based on the concomitant boost. The schedulewas limited to 35 fractions delivered Monday through Fri-day of each week. As such, it was felt to be practical and,unlike the CHART regimen or schedules of pure hyperfrac-tionation, well within the resources of most centers. Thedecision to limit overall treatment time to 5 weeks wasbased on emerging evidence regarding the onset of accel-erated tumor proliferation by week 4 (19) and preliminarydata suggesting that the toxicity accompanying a 1-weekreduction in radical treatment was acceptable with the con-comitant boost approach (21, 31). A minimum interfractioninterval of 6 h was used to facilitate repair of sublethaldamage in late responding tissues, as suggested by RTOGprotocol 8313 (36). A starting dose of 63 Gy in 5 weeks wasselected as a reasonable baseline on which to build a clas-sical dose escalation protocol. Incremental adjustments infraction size were planned to increase the total dose instepwise fashion up to 70 Gy. However, the documentationof 2 treatment-related deaths and Grade 3 reactions in all 7evaluable patients at 67 Gy represented an unacceptablelevel of toxicity. As a result, 65 Gy was regarded as themaximum tolerated dose. The entry of 14 additional patientsat this level provided an evaluable cohort of 22 patientscharacterized by a complete response rate of 77% andradiotherapy control above the clavicles of 68%. AlthoughGrade 3 reactions were documented in 82% of patients, thereactions were manageable and did not result in an unduerate of hospitalization. The schedule did not preclude neckdissection in 3 patients with suspected residual nodal dis-ease or salvage surgery in 3 patients relapsing at the primarysite. All 5 recurrences corresponded to sites of bulky dis-ease, raising the possibility that tumor hypoxia was at least

partly responsible for radiotherapy failure. There were nopostoperative complications and few late complications.The disease-free, overall, and cause-specific survival of thisgroup was 64%, 82%, and 86%, respectively, at 2 years.These results are superior to comparably staged patients inthe literature and historical controls at our own center.

To date, attempts to improve the therapeutic index withaccelerated radiotherapy have met with only partial successbecause of the unavoidable increase in acute toxicity. Stud-ies of pure accelerated fractionation have demonstrated that70 Gy in 2-Gy fractions cannot be delivered in less than 6weeks. The current study suggests that reduction in overalltreatment time by 2 weeks cannot be achieved with theconcomitant boost technique without reducing the total doseto 65 Gy. Within these constraints, AF has been shown toyield modest increases in locoregional control, reflectingsome success in overcoming the threat of tumor prolifera-tion. Further increases in dose intensity will not be possiblewithout some degree of radioprotection to reduce the sever-ity of mucositis.

The rightful place of altered fractionation in the manage-ment of locally advanced SCCHN remains to be deter-mined. In view of the accumulating evidence that radiother-apy and concurrent chemotherapy can improve locoregionalcontrol and survival when compared to standard fraction-ation (37, 38), many centers have adopted chemoradiationprotocols as standard therapy (39). In light of this progress,the clinical relevance of altered fractionation, including theaccelerated regimen reported in this paper, is probably bestdetermined in randomized trials using conventional frac-tionation and concurrent chemotherapy as the control arm.

REFERENCES

1. Wang CC. Radiation therapy for head and neck neoplasms:Indications, techniques and results. Littleton, MA: Wright-PSG Inc.; 1983.

2. Fletcher GH. Textbook of radiotherapy. Philadelphia; 1980.3. Garrett PG, Beale FA, Cummings BJ,et al. Carcinoma of the

tonsil: The effect of dose-time-volume factors on local con-trol. Int J Radiat Oncol Biol Phys1985;11:703–706.

4. Perez CA, Purdy JA, Breaux SR,et al. Carcinoma of thetonsillar fossa: A nonrandomized comparison of preoperativeradiation and surgery or irradiation alone: Long term results.Cancer1982;50:2314–2322.

5. Weller SA, Goffinet DR, Goode RL,et al. Carcinoma of theoropharynx: Results of megavoltage radiation therapy in 305patients.Am J Roentgenol1976;126:236–247.

6. Thames HD, Peters LJ, Spanos W. Dose response of squa-mous cell carcinomas of the upper respiratory and digestivetracts.Br J Cancer1980;41(Suppl. 4):35.

7. Marcial VA, Hanley JA, Hendrickson F,et al. Spit-courseradiation therapy of carcinoma of the base of the tongue:Results of a prospective national collaborative clinical trialconducted by the Radiation Therapy Oncology Group.Int JRadiat Oncol Biol Phys1983;9:437–443.

8. Keane TJ, Hawkins NV, Beale FA,et al. Carcinoma of thehypopharynx: Results of primary radical radiation therapy.IntJ Radiat Oncol Biol Phys1983;9:659–664.

9. Stewart JG, Jackson AW. The steepness of the dose response

curve both for tumor cure and normal tissue injury.Laryngo-scope1975;7:1107.

10. Harwood AR. Cancer of the larynx - the Toronto experience.J Otolaryngol1982;11(Suppl.):1–21.

11. Ghossein NA, Bataini JP, Ennuyer A,et al.Local control andsite of failure in radically irradiated supraglottic laryngealcancer.Radiology1974;112:187–192.

12. Fu KK, Eisenberg L, Dedo HH,et al. Results of integratedmanagement of supraglottic carcinoma.Cancer 1977;40:2874–2881.

13. Harwood AR, Hawkins NV, Beale FA,et al. Management ofadvanced glottic cancer: A 10 year review of the Torontoexperience.Int J Radiat Oncol Biol Phys1979;5:899–904.

14. Horiot JC, Le Fur R, N’Guyen T,et al.Hyperfractionation versusconventional fractionation in oropharyngeal carcinoma: Finalanalysis of a randomized trial of the EORTC cooperative groupof radiotherapy.Radiother Oncol1992;25:231–241.

15. Datta NR, Choudhry AD, Gupta S. Twice a day versus once aday radiation therapy in head and neck cancer. (Abstr.)Int JRadiat Oncol Biol Phys1989;17:132.

16. Overgaard J, Sand Hansen H, Sapru W,et al. Conventionalradiotherapy as the primary treatment of squamous cell carci-noma (SCC) of the head and neck: A randomized multicentrestudy of 5 versus 6 fractions per week—preliminary reportfrom DAHANCA 6 and 7 trial. (Abstr)Radiother Oncol1996;40(Suppl. 1):S31.

594 I. J. Radiation Oncology● Biology ● Physics Volume 45, Number 3, 1999

17. Horiot JC, Bontemps P, van den Bogaert W,et al.Acceleratedfractionation (AF) compared to conventional fractionation(CF) improved head and neck cancers: Results of the EORTC22851 randomized trial.Radiother Oncol1997;44:111–121.

18. Pinto L, Canary P, Araujo C,et al. Prospective randomizedtrial comparing hyperfractionated versus conventional radio-therapy in stages II and IV oropharyngeal carcinoma.Int JRadiat Oncol Biol Phys1991;21:557–562.

19. Withers HR, Taylor JM, Maciejewski B. The hazard of accel-erated tumor clonogen repopulation during radiotherapy.ActaOncologica1988;27:131–146.

20. Fowler JF, Lindstrom MJ. Loss of local control with prolon-gation in radiotherapy.Int J Radiat Oncol Biol Phys1992;23:457–467.

21. Ang KK, Peters LJ, Weber RS,et al. Concomitant boostradiotherapy schedules in the treatment of carcinoma of theoropharynx and nasopharynx.Int J Radiat Oncol Biol Phys1990;19:1339–1345.

22. International Union Against Cancer. TNM classification ofmalignant tumours. Berlin: Springer-Verlag; 1992.

23. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the RadiationTherapy Oncology Group (RTOG) and the European Organi-zation for Research and Treatment of Cancer (EORTC).Int JRadiat Oncol Biol Phys1995;31:1341–1346.

24. SAS/STAT User’s Guide. Cary, NC: SAS Institute Inc.; 1989.25. Jackson SM, Weir LM, Hay JH,et al. A randomized trial of

accelerated versus conventional radiotherapy in head and neckcancer.Radiother Oncol1997;43:39–46.

26. Maciejewski B, Skladowski K, Pilecki B,et al. Randomizedclinical trial of accelerated 7 days per week fractionation inradiotherapy for head and neck cancer: Preliminary report onacute toxicity.Radiother Oncol1996;40:137–145.

27. Dische S, Saunders MAB. A randomized multicentre trial ofCHART versus conventional radiotherapy in head and neckcancer.Radiother Oncol1997;44:123–136.

28. Awwad HK, Khafaagy Y, Barsoum M. Accelerated versusconventional fractionation in the postoperative irradiation oflocally advanced head and neck cancer: Influence of tumourproliferation.Radiother Oncol1992;25:261–266.

29. Ang KK, Trotti A, Garden AS,et al. Importance of overall

time factor in postoperative radiotherapy. Proceedings of the4th International Conference on Head and Neck Cancer, To-ronto, Ontario, Canada, 1996;1:231–235.

30. Knee R, Fields RS, Peters LJ. Concomitant boost radiotherapyfor advanced squamous cell carcinoma of the head and neck.Radiother Oncol1985;4:1–7.

31. Harrison LB, Pfister DG, Fass DE,et al.Concomitant chemo-therapy-radiation therapy followed by hyperfractioned radia-tion therapy for advanced unresectable head and neck cancer.Int J Radiat Oncol Biol Phys1991;21:703–708.

32. Kaanders JH, van Daal WA, Hoogenraad WJ,et al. Acceler-ated fractionaton radiotherapy for laryngeal cancer, acute andlate toxicity. Int J Radiat Oncol Biol Phys1992;24:497–503.

33. Schmidt-Ullrich RK, Johnson CR, Wazer DE,et al. Acceler-ated superfractionated irradiation for advanced carcinoma ofthe head and neck: Concomittant boost technique.Int J RadiatOncol Biol Phys1991;21:563–568.

34. Trotti A, Klotch D, Endicott J,et al.Postoperative acceleratedradiotherapy in high-risk squamous cell carcinoma of the headand neck: Long-term results of a prospective trial.Head Neck1998;20:119–123.

35. Kaanders JH, Pop LAM, Marres HAM,et al. Acceleratedradiotherapy with carbogen and nicotinamide (ARCON) forlaryngeal cancer.Radiother Oncol1998;48:115–122.

36. Cox JD, Pajak TF, Marcial VA,et al. Astro plenary: Inter-fraction interval is a major determinant of late effects, withhyperfractionated radiation therapy of carcinomas of upperrespiratory and digestive tracts: Results from Radiation Ther-apy Oncology Group protocol 8313.Int J Radiat Oncol BiolPhys1991;20:1191–1195.

37. Munro AJ. An overview of randomized controlled trials ofadjuvant chemotherapy in head and neck cancer.Br J Cancer1995;71:83–91.

38. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapyin the management of squamous cell carcinoma of the headand neck region: A meta-analysis of prospective and random-ized trials.J Clin Oncol1996;14:838–847.

39. Harari PM. Why has induction chemotherapy for advancedhead and neck cancer become a United States communitystandard of practice?J Clin Oncol1997;15:2050–2055.

595Phase I-II study of accelerated radiotherapy● R. MACKENZIE et al.