Accelerated radiotherapy with delayed concomitant boost in locally advanced squamous cell carcinoma of the head and neck

Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 3, pp. 589 –595, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter

PII S0360-3016(99)00218-7

CLINICAL INVESTIGATION

Head and Neck

ACCELERATED RADIOTHERAPY WITH DELAYED CONCOMITANT BOOST IN LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK ROBERT MACKENZIE, M.D.,* JUDITH BALOGH, M.D.,* RICHARD CHOO, M.D.,* EDMEE FRANSSEN, M.SC.†

AND

Departments of *Radiation Oncology and †Clinical Trials and Epidemiology, Toronto-Sunnybrook Regional Cancer Centre, Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada Purpose: To determine the toxicity, maximum tolerated dose (MTD), and clinical effectiveness of a 5-week course of accelerated radiotherapy with delayed concomitant boost in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials: Thirty-five patients with untreated T3T4NM0 or TN2 (> 3 cm) N3M0 SCC of the oral cavity, 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 disease was added as a second daily fraction during the last 2 weeks of the 5-week schedule, using a minimum interfraction interval of 6 h. The study was initiated using 180-cGy fractions to deliver a total dose of 63 Gy over 33–35 days. A classical dose escalation strategy was planned to increase the delivered dose in steps using minimum 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 level 3 (67 Gy). One patient was withdrawn at level 2 because of unstable angina, and 1 at level 3 because of uncontrolled diabetes. One patient at level 3 failed to complete treatment because of radiation toxicity. RTOG Grade 3 mucositis, dermatitis, or pharyngitis was documented in 1 (25%), 5 (63%), and 7 (100%) evaluable patients at levels 1, 2, and 3, respectively. Grade 4 reactions were documented in 1 patient at each level. One patient at level 3 died 5 weeks post-treatment of unknown causes. Two additional patients at level 3 died of progressive disease and RT toxicity. Sixty-five Gy (level 2) was chosen as the MTD. In the MTD study, 14 additional patients were entered at level 2, providing a total of 22 evaluable patients with a median follow-up of 21 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 was recorded in 16 (77%). Three of 5 patients with uncontrolled disease and 3 of 3 patients with recurrent disease underwent salvage surgery with no postoperative complications. Radiotherapy controlled disease above the clavicles in 14 (68%). Ultimate locoregional control was achieved in 17 (77%). The disease-free, overall, and cause-specific survival of all patients entered at level 2 was 56%, 76%, and 80%, respectively, at 2 years. Late complications 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 with acceptable toxicity, encouraging rates of complete response, and locoregional control, and no compromise of salvage surgery in patients with locally advanced SCCHN. The regimen is worthy of further study in a Phase III trial. © 1999 Elsevier Science Inc. Radiotherapy, Accelerated fractionation, Concomitant boost, Squamous cell carcinoma, Head and neck.

INTRODUCTION

exceeds 40%. There is increasing evidence from randomized trials that altered fractionation can improve treatment outcomes in this group of patients (14 –18). However, a practical and effective regimen within the resources of most centers has yet to be defined. A careful review of clinical data suggests that local control of SCCHN decreases as the overall treatment time

Conventional fractionation (CF) yields suboptimal results in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Published rates of local control range between 5% and 64%, with a median of 42% (1–13). Only a small number of patients are eligible for surgical salvage. As a result, the reported overall 5-year survival seldom Presented at the 40th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Phoenix, AZ, October 25–29, 1998. Reprint requests to: Robert MacKenzie, M.D., Department of Radiation 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. 589

590

I. J. Radiation Oncology

●

Biology

●

Physics

increases if there is no adjustment in delivered dose (19, 20). These observations provide compelling evidence for tumor proliferation during fractionated radiotherapy. Accelerated fractionation (AF) regimens aim to counteract the proliferation of tumor clonogens by delivering the same dose in less time using multiple fractions per day. The concomitant boost is an example of an accelerated regimen delivering conventional treatment to a large volume encompassing the primary tumor and regional nodes, and a small volume boost to sites of gross disease as the second daily treatment in a shortened twice-daily schedule. The overall treatment time can be reduced by modifying the fraction size and number of boost fractions. The optimal timing of the boost has been explored in a series of sequential studies at the MD Anderson Hospital. Superior local control was documented among those treated with the concomitant boost during the last 12 treatment days compared to those treated during the first 12 treatment days, or twice weekly over the 6-week schedule (21). This finding is consistent with evidence supporting the onset of accelerated tumor proliferation around the third or fourth week of conventionally fractionated treatment (19). A regimen based on a delayed concomitant boost offers dose intensification during the most critical period of tumor repopulation. The aim of this study was to assess the feasibility, toxicity, and clinical effectiveness of of a 5-week course of accelerated radiotherapy based on a delayed concomitant boost in untreated locally advanced SCCHN. METHODS AND MATERIALS Patients Between January 1994 and October 1997, 155 patients were referred to the Toronto-Sunnybrook Regional Cancer Center with locally advanced cancer of the head and neck. Thirty-eight patients with untreated T3T4NM0 or TN2 (⬎ 3 cm) N3M0 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx between the ages of 18 and 75 years were eligible for study. No patients were excluded because of concurrent malignancy, documented connective tissue disorder, or poor performance status. Thirty-five patients provided informed consent and were enrolled in the study. The study cohort was characterized by a median age of 62 years (range 39 –72) and male:female ratio of 22:13. The primary originated in the oral cavity in 4 cases and oropharynx in 21 cases; the hypopharynx and larynx each accounted for 5 cases. The diagnostic work-up included examination under anesthesia with biopsy (if not already performed by the referring otolaryngologist), complete physical examination including fiberoptic endoscopy with videotape record, CBC, renal function tests, liver function tests, chest X-ray, and CT scan of the head and neck. An ultrasound of the liver was performed in patients with abnormal liver function tests and bone scan in patients with unexplained skeletal pain. A pathology review was not

Volume 45, Number 3, 1999

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

T1 T2 T3 T4 Total

N0

N1

N2

N3

Total

0 0 3 6 9

0 0 7 2 9

1 4 5 6 16

0 0 1 0 1

1 4 16 14 35

required. Patients were staged according to the 1992 UICC TNM classification (22). Distribution by TNM stage is summarized in Table 1. RADIOTHERAPY All patients were immobilized in a plastic mask and treated on 60Co or 6-MV linear accelerator. The primary tumor and bilateral neck nodes were irradiated through lateral opposed photon beams. The supraclavicular nodes were treated with a matched anterior photon field. The initial treatment volume, including the primary tumor, involved nodes, and potential sites of microscopic spread was treated daily Monday through Friday over 5 weeks. Gross disease was boosted with reduced lateral or oblique opposed portals with a margin of 1 cm, combined when necessary, with matched appositional electron beams to nodal areas overlying the spinal cord. The central nervous system was excluded from the boosted volume. The boost was delivered as a second daily fraction over the last 2 weeks of the 5-week schedule, using a minimum interfraction interval of 6 h. The total treatment time was 33–35 days. All treatment setups were simulated. Isodose distributions in three planes, wedges, and attenuators were used routinely to optimize dose homogeneity. Bolus was reserved for electron boosts to gross nodal disease. Portal films were obtained on first setup and as necessary, with changes in field size or shielding. Dose escalation The study was initiated using 180 cGy per fraction to deliver a total dose of 63 Gy. A classical dose escalation strategy was employed to increase the delivered dose in steps using minimum cohorts of three patients. The study called for a stepwise increase in fraction size, as illustrated in Fig. 1 to deliver total doses ranging between 63 and 70 Gy. Progression from one level to the next was permitted, provided that no more than 1 in 2 patients required hospitalization, no more than 1 in 3 patients developed Grade 3 reactions protracted beyond 8 weeks, no more than 1 in 6 patients required treatment interruptions greater than 2 weeks, 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 investigators. Additional patients were entered at this level during the

Phase I-II study of accelerated radiotherapy

● R. MACKENZIE et al.

591

Table 2. Results of dose escalation

Fig. 1. Dose escalation strategy.

second part of the study. It was estimated that a minimum of 20 evaluable patients would be required to generate statistically valid estimates of toxicity and tumor response rates. Monitoring and follow-up Assessment of radiation reactions and tumor response was performed weekly during treatment until the peak reactions subsided. Analgesic requirements, nutritional intake, and weight were recorded at each visit. Toxicity was documented using radiation morbidity criteria of the Radiation Therapy Oncology Group (RTOG) (23). Subsequently, patients were assessed at monthly intervals. A CT scan of the head and neck was obtained 8 –12 weeks posttreatment. Complete responders were followed every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. Chest X-rays were performed at 3 months, 12 months, and annually thereafter. Suspected sites of locoregional recurrence were evaluated by CT scan and confirmed by aspiration cytology or biopsy. Disease identified on metastatic survey was not routinely biopsied. Surviving patients have been followed for a median of 30 months, with a range of 12– 48 months since study entry. All patients undergoing salvage surgery have been followed for a minimum of 1 year beyond hospital discharge. Statistical analysis Overall survival and cause-specific survival were determined for 33 patients completing the protocol. Thirty-two patients were evaluable for local control, locoregional control, and disease-free survival. Five patients were evaluable for ultimate locoregional control with salvage surgery. Those with no evidence of locoregional disease at last follow-up are reported as controlled above the clavicles. Survival curves and actuarial rates of locoregional recurrence were calculated using the Kaplan-Meier method for a time period beginning with the diagnostic biopsy (24).

Observation

Level 1 63 Gy

Level 2 65 Gy

Level 3 67 Gy

Number entered Number withdrawn Number grade III reactions Number grade IV reactions Time to resolution (weeks) Treatment-related deaths

4 0 1 (25%) 1 10 0

9 1 5 (63%) 1 8 0

8 2 7 (100%) 1 4 2

drawn at level 2 because of unstable angina, and 1 at level 3 because of uncontrolled diabetes. An additional patient at level 3 failed to complete treatment because of radiation toxicity. Confluent fibrinous mucositis, confluent moist desquamation, 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 developed acute Grade 4 toxicity (aphagia at level 1, chronic mucosal ulceration at level 2, and soft tissue necrosis at level 3). The peak toxicities were recorded 2 weeks following completion of treatment. The median interval to resolution of Grade 3 toxicities was 6 weeks, with a range of 4 –21 weeks. The time to recovery did not correlate with total dose. A percutaneous gastrostomy was required for odynophagia and weight loss exceeding 10% of initial body weight in 1 patient at each level. Hospitalization for supportive care was necessary for 1 patient at level 2 and 1 patient at level 3. Complete healing of the skin was documented in all patients and complete healing of the mucosa in all but 2 patients. One patient at level 3 died at home 5 weeks post-treatment of unknown causes. Two additional patients at level 3 died of a combination of progressive disease and radiation toxicity manifested by confluent fibrinous mucositis, extensive moist desquamation, and malnutrition. Sixty-five gray (level 2) was chosen as the maximum tolerated dose. Maximum tolerated dose Fourteen additional patients were entered at level 2. These patients have been combined with the 8 evaluable patients treated at level 2 during the escalation phase in the following analysis of treatment outcomes. The TNM stage distribution of this cohort is summarized in Table 3. The median follow-up was 21 months (range 12– 41). No patient has been lost to follow-up.

Table 3. TNM stage distribution of 22 evaluable patients entered at level 2 (65 Gy) N0

N1

N2

N3

Total

0 0 1 4 5

0 0 3 1 4

1 4 4 3 12

0 0 1 0 1

1 4 9 8 22

RESULTS Dose escalation phase The 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-

T1 T2 T3 T4 Total

592

I. J. Radiation Oncology

●

Biology

●

Physics

Volume 45, Number 3, 1999

Fig. 2. Survival of 22 patients treated at level 2 (65 Gy).

Fig. 3. Control of the primary at level 2 (65 Gy).

Acute toxicity RTOG 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 a single patient. Two patients required hospitalization for G-tube insertion and 2 for supportive care. The median duration of Grade 3 reactions was 5 weeks (range 3–9) for dermatitis, 7 weeks (range 6 –10) for pharyngitis, and 10 weeks (range 7–13) for mucositis. Complete healing was documented in all but 1 patient with chronic mucosal ulcer.

DISCUSSION

Locoregional control and survival Seventeen of 22 (77%) patients achieved a complete clinical and radiological response. Three patients underwent neck dissection for apparent residual disease. Persistent squamous cell carcinoma was confirmed in 2 cases. Three patients experienced a local recurrence at 4, 5, and 7 months, respectively. All 3 patients underwent salvage surgery (laryngectomy and neck dissection, pharyngectomy and neck dissection, partial glossectomy) without postoperative complications. Radiotherapy controlled disease above the clavicles in 15/22 (68%). All cases of confirmed failure corresponded 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 survival of all patients entered at level 2 was 64%, 82%, and 86%, respectively, at 1 year, and 56%, 76%, and 80%, respectively, at 2 years (Fig. 2.). Local relapse-free survival was 72% at 2 years (Fig. 3).

Late complications One patient presenting with T4N1 carcinoma of the tonsil extending to the pterygoid fossa developed progressive trismus during radiotherapy. G-tube support was required up to the time of salvage surgery for local recurrence 7 months later. An additional patient developed chronic mucosal ulceration of the oral cavity but was able to maintain weight without nutritional supplements. Pharyngolaryngeal edema was documented with flexible endoscopy in 9 patients but did not require surgical intervention.

On average, less than 50% of patients with locally advanced SCCHN are cured with conventionally fractionated radiotherapy. Prognosis appears to depend on a variety of patient, tumor, and treatment characteristics. The relevant patient factors include gender, pretreatment hemoglobin, performance status, and history of continued smoking. Traditional tumor factors include TNM stage, anatomic site, some measure of disease bulk such as maximal tumor diameter, and histology. Cure also appears related to total radiation dose, fraction size, irradiated volume, and overall treatment time. Accelerated fractionation reduces the opportunity for tumor cell repopulation by decreasing overall treatment time. There are two strategies to accelerate radiation treatment. Pure accelerated fractionation reduces the overall treatment time without concurrent changes in fraction size or total dose. Hybrid accelerated fractionation reduces the overall treatment time in conjunction with changes in other parameters, such as fraction size and total dose, with and without planned breaks in treatment. Four variations of hybrid protocols have emerged in clinical practice. Continuous hyperfractionated accelerated radiotherapy (CHART) is the prototype of intensive short-course treatment in which the overall duration of treatment is markedly reduced with a corresponding decrease in total dose. Split-course twicedaily protocols and concomitant boost regimens are examples of schedules in which the duration of treatment is more modestly reduced while the total dose is kept in the same range as conventional therapy. There is more limited experience with hybrid schedules in which the total dose delivered per week is progressively increased during the course of therapy. Three prospective trials have tested pure accelerated fractionation against conventional regimens. The Vancouver trial compared a twice-daily regimen delivering 66 Gy in 2 Gy fractions over 22–28 days to a conventional arm delivering 66 Gy in daily 2 Gy fractions over 43–55 days in patients with CS III-IV SCCHN (25). The study was closed prematurely when an interim analysis revealed significantly higher Grade 3/4 acute toxicity in the accelerated fractionation arm. With entry limited to 41 patients per arm, the

Phase I-II study of accelerated radiotherapy

study lacked sufficient power to detect a 15% difference in tumor control between the arms. In the CAIR trial conducted in Gliwice, Poland, 75 patients with T2T3T4NM0 SCC of the oral cavity, oropharynx, supraglottic larynx, and hypopharynx were randomized to a conventional arm of 64 –72 Gy delivered as 1.8 –2.0 Gy fractions 5 fractions per week, and an experimental arm delivering the same dose and fraction size 7 days per week over 5 weeks (26). Boost fields were treated on the weekend on the accelerated arm. A significant increase in severe protracted mucosal reactions and consequentional late effects in the accelerated arm led to premature closure of the study. In the Danish trials DAHANCA 6 and 7, patients with SCC of the larynx, pharynx, and oral cavity eligible for primary radiotherapy alone were randomized between 5 and 6 weekly fractions delivering 66 – 68 Gy in 33–34 fractions (T1 tumors were limited to 62 Gy in 33 fractions). Centers unable to treat on Saturday were permitted to deliver the sixth fraction Monday to Friday. All patients except those with glottic cancers were also treated with the radiosensitizer Nimorazole. A preliminary analysis of 977 patients revealed that 96% of patients received the planned total dose (16). The incidence of acute severe mucositis and dysphagia was significantly higher in patients receiving 6 fractions per week. There was no difference in the incidence of late edema or fibrosis between arms. A reduction in median overall treatment time, from 46 to 39 days, yielded significantly 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 in overall survival (odds ratio 1.3, 95% confidence interval 0.9 –1.8). Hybrid accelerated fractionation has been tested in two randomized studies of primary management. In the multicentre CHART trial patients with SCCHN (excluding T1N0 lesions of the oral cavity, oropharynx, hypopharynx, and larynx) were randomized between a conventional dose of 66 Gy in 33 fractions delivered over 6.5 weeks, and the CHART protocol of 1.5 Gy t.i.d. on each of 12 consecutive days using a minimum interfraction interval of 6 h. A preliminary analysis of 918 patients (27) revealed a 3% increase in disease-free survival for patients treated on the accelerated arm (p ⫽ 0.33). There was some evidence that CHART was more effective than CF with increasing tumor stage (␹2 for trend ⫽ 3.40, p ⫽ 0.065). Acute mucositis peaked and resolved more quickly with CHART. No difference in long-term morbidity has emerged during ongoing follow-up. In EORTC 22851, 325 patients with T2T3T4NM0 SCCHN (excluding hypopharynx) were randomized to 70 –72 Gy delivered in 35– 40 fractions over 7– 8 weeks, or an experimental arm delivering 28.8 Gy in 18 fractions over 7 days, followed by a 2-week break and an additional 43.2 Gy in 27 fractions over 5 weeks (17). Accelerated fractionation produced better locoregional control (59% vs. 46% at 5 years, p ⫽ 0.02) but was associated with higher rates of

● R. MACKENZIE et al.

593

Grade 3/4 mucositis, iatrogenic mortality, and late Grade 3 fibrosis compared to CF. Seven cases of permanent peripheral neuropathy and one case of radiation myelopathy were documented in the AF arm, prompting investigators to abandon the regimen. Two randomized trials of hybrid accelerated fractionation have been reported in the postoperative setting. Awwad reported a modest increase in 3-year disease-free survival (54% vs. 39%, p ⫽ 0.37) at the cost of increased late morbidity (87% vs. 64%) for 26 patients treated with AF compared to 30 patients treated with CF (28). Preliminary analysis (29) of a joint trial of the M.D. Anderson Hospital, Moffitt Cancer Centre, and Mayo Clinic of 134 patients deemed at high risk of postoperative recurrence has revealed a nonsignificant increase in locoregional control among those treated with a concomitant boost schedule (60% vs. 38%, p ⫽ 0.11). Late complications were less than 10% in both arms. This study continues to accrue patients. To date, there have been no published studies of randomized trials based on the concomitant boost technique in the primary management of SCCHN. RTOG has accrued 1,200 patients to a four-arm trial comparing three altered fractionation schemes to conventional fractionation. Patients with CS 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 accelerated fractionation (67.2 Gy in 42 fractions over 6 weeks), or accelerated fractionation with concomitant boost (72 Gy in 42 fractions over 6 weeks). Publication of the results of this important trial is eagerly awaited. A number of Phase I–II studies of accelerated fractionation with concomitant boost have been published with encouraging results (21, 30 –33). Two recent studies are of particular interest. Trotti et al. used a concomitant boost technique to deliver 63 Gy in 35 fractions over 37 days in 32 patients deemed at high risk of postoperative failure (34). Patients were given 6 fractions per week (twice-a-day large fields on Fridays) for 4 weeks, followed by twice-a-day treatments for the last 4 treatment days. The dose intensity of the regimen was similar to level 1 of the current study. Acute mucosal and skin reactions were increased but tolerable. A minor increase in consequential late effects was noted. Kaanders et al. combined an AF protocol delivering 64 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 patients with CS III–IV carcinoma of the larynx (35). Carbogen breathing was tested in the first 11 patients and the combination of carbogen and nicotinamide in the subsequent 51 patients. With a median follow-up of 24 months, the 2-year actuarial local control was 92%. Five patients with local recurrence and 1 patient with nodal relapse were salvaged with surgery for an ultimate locoregional control of 100%. Acute toxicity was increased compared to CF. Laryngectomy was required for cartilage necrosis in 1 patient. The current study was designed to evaluate the toxicity and clinical effectiveness of a novel schedule of accelerated

594

I. J. Radiation Oncology

●

Biology

●

Physics

fractionation based on the concomitant boost. The schedule was limited to 35 fractions delivered Monday through Friday of each week. As such, it was felt to be practical and, unlike the CHART regimen or schedules of pure hyperfractionation, well within the resources of most centers. The decision to limit overall treatment time to 5 weeks was based on emerging evidence regarding the onset of accelerated tumor proliferation by week 4 (19) and preliminary data suggesting that the toxicity accompanying a 1-week reduction in radical treatment was acceptable with the concomitant boost approach (21, 31). A minimum interfraction interval of 6 h was used to facilitate repair of sublethal damage in late responding tissues, as suggested by RTOG protocol 8313 (36). A starting dose of 63 Gy in 5 weeks was selected as a reasonable baseline on which to build a classical dose escalation protocol. Incremental adjustments in fraction size were planned to increase the total dose in stepwise fashion up to 70 Gy. However, the documentation of 2 treatment-related deaths and Grade 3 reactions in all 7 evaluable patients at 67 Gy represented an unacceptable level of toxicity. As a result, 65 Gy was regarded as the maximum tolerated dose. The entry of 14 additional patients at this level provided an evaluable cohort of 22 patients characterized by a complete response rate of 77% and radiotherapy control above the clavicles of 68%. Although Grade 3 reactions were documented in 82% of patients, the reactions were manageable and did not result in an undue rate of hospitalization. The schedule did not preclude neck dissection in 3 patients with suspected residual nodal disease or salvage surgery in 3 patients relapsing at the primary site. All 5 recurrences corresponded to sites of bulky disease, raising the possibility that tumor hypoxia was at least

Volume 45, Number 3, 1999

partly responsible for radiotherapy failure. There were no postoperative complications and few late complications. The disease-free, overall, and cause-specific survival of this group was 64%, 82%, and 86%, respectively, at 2 years. These results are superior to comparably staged patients in the literature and historical controls at our own center. To date, attempts to improve the therapeutic index with accelerated radiotherapy have met with only partial success because of the unavoidable increase in acute toxicity. Studies of pure accelerated fractionation have demonstrated that 70 Gy in 2-Gy fractions cannot be delivered in less than 6 weeks. The current study suggests that reduction in overall treatment time by 2 weeks cannot be achieved with the concomitant boost technique without reducing the total dose to 65 Gy. Within these constraints, AF has been shown to yield modest increases in locoregional control, reflecting some success in overcoming the threat of tumor proliferation. Further increases in dose intensity will not be possible without some degree of radioprotection to reduce the severity of mucositis. The rightful place of altered fractionation in the management of locally advanced SCCHN remains to be determined. In view of the accumulating evidence that radiotherapy and concurrent chemotherapy can improve locoregional control and survival when compared to standard fractionation (37, 38), many centers have adopted chemoradiation protocols as standard therapy (39). In light of this progress, the clinical relevance of altered fractionation, including the accelerated regimen reported in this paper, is probably best determined in randomized trials using conventional fractionation and concurrent chemotherapy as the control arm.

REFERENCES 1. Wang CC. Radiation therapy for head and neck neoplasms: Indications, techniques and results. Littleton, MA: WrightPSG 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 control. Int J Radiat Oncol Biol Phys 1985;11:703–706. 4. Perez CA, Purdy JA, Breaux SR, et al. Carcinoma of the tonsillar fossa: A nonrandomized comparison of preoperative radiation and surgery or irradiation alone: Long term results. Cancer 1982;50:2314 –2322. 5. Weller SA, Goffinet DR, Goode RL, et al. Carcinoma of the oropharynx: Results of megavoltage radiation therapy in 305 patients. Am J Roentgenol 1976;126:236 –247. 6. Thames HD, Peters LJ, Spanos W. Dose response of squamous cell carcinomas of the upper respiratory and digestive tracts. Br J Cancer 1980;41(Suppl. 4):35. 7. Marcial VA, Hanley JA, Hendrickson F, et al. Spit-course radiation therapy of carcinoma of the base of the tongue: Results of a prospective national collaborative clinical trial conducted by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1983;9:437– 443. 8. Keane TJ, Hawkins NV, Beale FA, et al. Carcinoma of the hypopharynx: Results of primary radical radiation therapy. Int J Radiat Oncol Biol Phys 1983;9:659 – 664. 9. Stewart JG, Jackson AW. The steepness of the dose response

10. 11. 12. 13. 14.

15. 16.

curve both for tumor cure and normal tissue injury. Laryngoscope 1975;7:1107. Harwood AR. Cancer of the larynx - the Toronto experience. J Otolaryngol 1982;11(Suppl.):1–21. Ghossein NA, Bataini JP, Ennuyer A, et al. Local control and site of failure in radically irradiated supraglottic laryngeal cancer. Radiology 1974;112:187–192. Fu KK, Eisenberg L, Dedo HH, et al. Results of integrated management of supraglottic carcinoma. Cancer 1977;40: 2874 –2881. Harwood AR, Hawkins NV, Beale FA, et al. Management of advanced glottic cancer: A 10 year review of the Toronto experience. Int J Radiat Oncol Biol Phys 1979;5:899 –904. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992;25:231–241. Datta NR, Choudhry AD, Gupta S. Twice a day versus once a day radiation therapy in head and neck cancer. (Abstr.) Int J Radiat Oncol Biol Phys 1989;17:132. Overgaard J, Sand Hansen H, Sapru W, et al. Conventional radiotherapy as the primary treatment of squamous cell carcinoma (SCC) of the head and neck: A randomized multicentre study of 5 versus 6 fractions per week—preliminary report from DAHANCA 6 and 7 trial. (Abstr) Radiother Oncol 1996; 40(Suppl. 1):S31.

Phase I-II study of accelerated radiotherapy

17. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improved head and neck cancers: Results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111–121. 18. Pinto L, Canary P, Araujo C, et al. Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages II and IV oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1991;21:557–562. 19. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncologica 1988;27:131–146. 20. Fowler JF, Lindstrom MJ. Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 1992;23: 457– 467. 21. Ang KK, Peters LJ, Weber RS, et al. Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 1990;19:1339 –1345. 22. International Union Against Cancer. TNM classification of malignant tumours. Berlin: Springer-Verlag; 1992. 23. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;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 neck cancer. Radiother Oncol 1997;43:39 – 46. 26. Maciejewski B, Skladowski K, Pilecki B, et al. Randomized clinical trial of accelerated 7 days per week fractionation in radiotherapy for head and neck cancer: Preliminary report on acute toxicity. Radiother Oncol 1996;40:137–145. 27. Dische S, Saunders MAB. A randomized multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;44:123–136. 28. Awwad HK, Khafaagy Y, Barsoum M. Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: Influence of tumour proliferation. Radiother Oncol 1992;25:261–266. 29. Ang KK, Trotti A, Garden AS, et al. Importance of overall

30. 31.

32. 33.

34.

35. 36.

37. 38.

39.

● R. MACKENZIE et al.

595

time factor in postoperative radiotherapy. Proceedings of the 4th International Conference on Head and Neck Cancer, Toronto, Ontario, Canada, 1996;1:231–235. Knee R, Fields RS, Peters LJ. Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1985;4:1–7. Harrison LB, Pfister DG, Fass DE, et al. Concomitant chemotherapy-radiation therapy followed by hyperfractioned radiation therapy for advanced unresectable head and neck cancer. Int J Radiat Oncol Biol Phys 1991;21:703–708. Kaanders JH, van Daal WA, Hoogenraad WJ, et al. Accelerated fractionaton radiotherapy for laryngeal cancer, acute and late toxicity. Int J Radiat Oncol Biol Phys 1992;24:497–503. Schmidt-Ullrich RK, Johnson CR, Wazer DE, et al. Accelerated superfractionated irradiation for advanced carcinoma of the head and neck: Concomittant boost technique. Int J Radiat Oncol Biol Phys 1991;21:563–568. Trotti A, Klotch D, Endicott J, et al. Postoperative accelerated radiotherapy in high-risk squamous cell carcinoma of the head and neck: Long-term results of a prospective trial. Head Neck 1998;20:119 –123. Kaanders JH, Pop LAM, Marres HAM, et al. Accelerated radiotherapy with carbogen and nicotinamide (ARCON) for laryngeal cancer. Radiother Oncol 1998;48:115–122. Cox JD, Pajak TF, Marcial VA, et al. Astro plenary: Interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from Radiation Therapy Oncology Group protocol 8313. Int J Radiat Oncol Biol Phys 1991;20:1191–1195. Munro AJ. An overview of randomized controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995;71:83–91. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 1996;14:838 – 847. Harari PM. Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 1997;15:2050 –2055.