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A Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer
Clinical Oncology
Clinical Oncology (2000)12:392±396 # The Royal College of Radiologists
Original Article A Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer N. Shah, M. I. Saunders and S. Dische Mount Vernon Hospital, Northwood, UK Abstract. A Phase II pilot study of continuous hyperfractionated accelerated radiotherapy (CHART)/CHART weekend less (CHARTWEL) was carried out in the postoperative treatment of patients with squamous cell carcinoma of the head and neck. Twenty-four patients (17 male, seven female) with a median age of 64 years (range 34±80) were treated with postoperative radiotherapy between 1991 and 1999. All patients presented with primary squamous cell carcinoma, which, at surgery, had shown adverse pathological factors for recurrence. Intermediate risk was determined by the presence of two of the following factors: margins 5 mm, Stage T3/T4, perineural or vascular invasion, poor differentiation, oral primary, multicentric primary, and more than four positive lymph nodes. High-risk factors included the presence of extracapsular spread and/or incomplete resection margins, or the presence of four of the factors de®ning intermediate risk. The patients were treated using a CHART (n = 11) or a CHARTWEL (n = 13) schedule, administering a dose between 49.5 Gy and 54 Gy. High-risk factors were present in 18/24 patients. Treatment was commenced from a median time of 6.9 weeks (range 4.4±16.6) after radical surgery. All patients completed treatment. A con¯uent radiation mucositis occurred in 20/23 evaluable patients, which settled in 4±10 weeks after commencing radiotherapy. Moderate dysphagia was observed in 13 patients. Mild subcutaneus oedema was noted in 11 patients from 12 weeks after treatment. No signi®cant late toxicity has been observed. Over a median follow up-period of 17 months, local control has been maintained in 17 patients (71%). Seven patients have relapsed and died of disease. A mean survival of 24 months (range 1±84) has been observed. This pilot study demonstrates acceptable morbidity for CHART/CHARTWEL in the postoperative setting. A prospective multicentre randomized trial using an accelerated schedule of radiotherapy versus conventional fractionation for the radical postoperative treatment of primary head and neck cancer is currently in preparation. Keywords: CHART; CHARTWEL; Head and neck cancer; Postoperative
Introduction Head and neck cancer accounts for approximately 5% of all adult cancers [1] and is mainly seen in the sixth to eighth decades of life. Both radiotherapy and surgery are currently used as single modalities with curative intent. In recent years, there has been an increasing use of major surgery in the management of the more advanced patients with head and neck cancer. Unfortunately, after surgery, many of these patients are at a high risk of local recurrence. Where there is tumour at the margins of the surgical specimen and/or when there is spread outside an invaded lymph node, recurrence of disease is practically inevitable [2]. Other adverse prognostic Correspondence and offprint requests to: N. Shah, Marie Curie Research Wing, Mount Vernon Hospital, Northwood HA6 2RN, UK. Fax: 01923 844167.
factors can be identi®ed with recurrence rates of the order of 50% if further treatment is withheld [3±5]. Postoperative radiotherapy has become established in clinical practice. There has never been a randomized controlled trial of surgery plus postoperative radiotherapy or no further treatment. Retrospective series have, however, given con®rmation to the strong clinical impression that such treatment greatly reduces local recurrence [6±8]. Tumour cell kinetic studies have shown that squamous cell carcinoma has the capacity to proliferate rapidly. Most tumours in the head and neck region have been shown to have the capacity to double their cell numbers in 5 or fewer days [9]. In the more active areas of tumour, cell doubling times of less than 48 hours have been observed. Growth factors active upon tumour cells can be demonstrated in high concentrations in the postoperative ®eld [10]. Thus, it may be expected that residual or implanted
tumour cells in the vascular ®eld, which exist postoperatively, are likely to show the most rapid proliferation. When microscopic disease is irradiated, a linear relationship between dose and the probability of tumour cell eradication is postulated [11]. This begins after a very low threshold dose, so a modest reduction in total dose may have less effect on tumour control when a comparison is made with the situation in de®nitive radiotherapy, where a sigmoid curve relates dose and effect. Continuous hyperfractionated accelerated radiotherapy (CHART) was designed to deliver a radical tumour dose in a short time to squamous cell carcinoma of the head and neck, to counteract the effect of proliferation with a low dose per fraction and lower than usual total dose, to reduce late tissue effects. A randomized controlled trial using CHART (54 Gy over 12 days) against conventional fractionation (66 Gy over 42 days) demonstrated equivalent locoregional control with reduced late tissue morbidity and suggested the importance of the control of tumour proliferation over a shorter overall treatment time [12]. CHART used in the postoperative setting would be advantageous in counteracting proliferation and reducing late tissue moribidity.
The delivery of radiotherapy over the weekend is dif®cult practically. CHART without weekend treatment (CHARTWEL: CHART weekend loss) has been piloted and implemented at this centre. This study assesses the feasibility of postoperative CHART/ CHARTWEL in head and neck cancer with respect to acute morbidity and local control.
Methods Local ethics permission from the Mount Vernon and Watford Hospitals NHS Trust has been granted for the study of accelerated radiotherapy in the postoperative treatment of patients with head and neck malignancy. Between July 1991 and February 1999, 24 patients (17 male, seven female; median age 64 years) with squamous cell carcinoma were treated with postoperative radiotherapy (Table 1). Adjuvant radiotherapy was given to 17 patients after radical surgery as initial management. In seven patients there was recurrence after surgery, which was treated by further surgery and postoperative radiotherapy (one primary tumour recurrence, four nodal recurrences, and two recurrent primary and nodal disease).
Table 1. Patient characteristics Patient Tumour site no.
Risk status
TNM stage [23]
Treatment
Dose (Gy)
Status
Follow-up period (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Oral cavity Oral cavity Oral cavity Oral cavity Oral cavity Oral cavity Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Pinna Larynx
High High High High High Intermediate High High High High Intermediate Intermediate Intermediate High High High
T4/N1 T2/N1 T4/N1 T4/N2 T3/N2 T4/N2 T1/N2 T1/N1 T1/N1 Tx/N2 T4/N2 T3/N1 T4/N1 T1/N2 T4/N2 T3/N0
CHARTWEL CHARTWEL CHARTWEL CHARTWEL CHARTWEL CHART CHARTWEL CHART CHART CHARTWEL CHARTWEL CHARTWEL CHARTWEL CHART CHART CHART
49.5 49.5 51 49.5 51 54 49.5 54 54 54 54 49.5 49.5 54 54 54
30 14 26 15 26 7 27 84 35 36 10 3 25 63 43 29
17 18
Unknown Oral cavity
High High
primary and
CHARTWEL CHARTWEL
54 54
10 15
19 20
Oral cavity Oral cavity
High Intermediate
node primary and
CHART CHART
54 54
Dead, local recurrence Alive, no recurrence
5 37
21 22 23 24
Pinna Pinna Larynx Columnella
High High High Intermediate
Tx/N2 Recurrent node Recurrent Recurrent node Recurrent Recurrent Recurrent Recurrent
Alive, no recurrence Dead, local recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Dead, local recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Dead, local recurrence and metastases Alive, no recurrence Alive, local recurrence
node node node node
CHARTWEL CHART CHART CHART
49.5 54 54 54
Dead, local recurrence Alive, no recurrence Dead, local recurrence Dead, metastases
6 44 10 1
Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer
393
The indications for adjuvant radiotherapy were based on adverse factors de®ned from a review of the literature [2,4]. Extracapsular spread, incomplete resection margins or four other prognostic factors detailed below were considered to give a high risk of local recurrence. An intermediate risk for recurrence was determined by the presence of two prognostic factors, including excision margins >5 mm, Stage T3/ T4 disease, perineural or vascular invasion, poor differentiation, oral primary, multicentric primary, more than four positive nodes, invasion of soft tissues, and the presence of carcinoma in situ or dysplasia at the edge of the resection margin. Other patients were regarded as at low risk for local recurrence and were excluded from the trial. Percutaneous gastrostomy tubes were inserted as departmental policy prior to radiotherapy. The planning process for radiotherapy was similar for all patients. In the ®rst phase of treatment the volume encompassed the surgical bed and lymphatic drainage with a margin of 1±2 cm to include all sites of microscopic disease. The second phase of treatment included known sites of high-risk microscopic disease. Radiation doses were prescribed to the intersection point as de®ned by international recommendations (ICRU 50 [13]) and administered using a linear accelerator (6 MV photons). A dose of 1.5 Gy per fraction was given three times a day, with a minimum interfraction interval of 6 hours. The Phase I dose was 37.5 Gy in 25 fractions; in Phase II a maximum of 16.5 Gy was given in 11 fractions, to reach 54 Gy in 36 fractions. The spinal cord dose was normally restricted to 40 Gy and was never allowed to exceed 44 Gy. Between July 1991 and August 1999 patients were treated with postoperative CHART to a total dose of 54 Gy in 36 fractions over 12 days. Following the introduction of CHARTWEL, a dose escalation study from 49.5 Gy in 33 fractions over 15 days to 54 Gy in 36 fractions over 16 days was instituted. All patients were seen weekly for the ®rst 6 weeks from the start of treatment, at 8 weeks, 12 weeks and then 3-monthly intervals to 2 years, and 6-monthly intervals to 5 years. Local control, the appearance of distant metastases, morbidity and survival were recorded.
Results CHART to a total dose of 54 Gy was administered to 11 patients; CHARTWEL to 49.5 Gy, 51 Gy and 54 Gy was given to seven, two and four patients respectively. Treatment was commenced at a median time of 6.9 weeks (range 4.4±16.6) after radical surgery. All patients except one completed treatment within the 12±16-day speci®ed treatment period with no interruptions. One patient had treatment extended by a day owing to gastrostomy tube complications resulting in missed radiotherapy fractions. One patient, who died 4 weeks after the start of radiotherapy, due to pulmonary metastases (diagnosed postmortem), has not been assessed in scoring acute morbidity. A con¯uent radiation mucositis occurred in 20/23 patients, with all patients recording maximal mucositis from days 14 to 21 of treatment (Fig. 1). The acute mucositis settled in 4±10 weeks after the beginning of radiotherapy. Moderate to severe dysphagia was conformed in 15/23 patients. Narcotic analgesics were prescribed for 14/23 patients during the period of mucositis (Fig. 2). Skin erythema
a
Statistical Methods All end-points were measured from the date of initiation of postoperative radiotherapy. The diseasefree interval was de®ned as the time from the initiation of radiotherapy to the appearance of locoregional disease or of distant metastatic disease. For this end-point, patients dying without progression of local disease or the appearance of metastatic disease were censored at the time of death. All other patients were censored at the time of their last followup. Overall survival was de®ned as the time from initiation of radiotherapy to the time of death. 394
N. Shah et al.
b Fig. 1. (a) Grade of maximal mucositis recorded; and (b) time course of mucositis for all patients. The mean mucositis score is an average score for all patients for the selected week.
a
a
b Fig. 3. Comparison of (a) maximum mucositis and (b) maximum dysphagia scores over 12 weeks for patients receiving postoperative CHARTWEL (&) and published data from the CHART randomized trial (&).
Discussion b Fig. 2. (a) Grade of maximal dysphagia recorded; and (b) time course of dysphagia for all patients. The mean dysphagia score is an average score for all patients for the selected week.
was noted in all patients, with dry and moist desquamation appearing from 2 weeks in the region of the high-dose ®eld. Resolution of the desquamation occurred in all patients from 4 weeks. There were no trends noted for the treatment groups as de®ned. All mucosal reactions have healed, with no consequential late necrosis. No occurrences of transient or permanent radiation myelitis have been observed. Two patients described mild to moderate dysphagia with no persistent mucositis at 19 and 45 weeks after radiotherapy. Mild subcutaneous oedema was observed in eight patients from 12 weeks after treatment. Over a median follow-up period of 17 months (range 1±84) there were seven disease-related deaths (®ve due to local tumour at 5, 6, 7, 9 and 14 months; one due to distant disease at 1 month; one due to local and distant disease at 26 months). Eighteen patients continue on follow-up; one has developed a local recurrence 6 months after radiotherapy. Local control is maintained in 17 patients (71%) and a mean survival of 24 months (95% con®dence interval 22± 26) has been observed.
The results of this pilot trial demonstrate acceptable early morbidity and local control for CHARTWEL postoperative radiotherapy in head and neck squamous cell carcinoma. There is accumulating evidence that the duration of radiotherapy in¯uences treatment outcome [12,14±16]. In the postoperative setting, further advantages from a short overall treatment time may arise from improved local control and encourage the earlier rehabilitation of patients. The time delay between surgery and the initiation of radiotherapy may play an important part in tumour clonogen repopulation [17[. Improved outcome has been demonstrated when irradiation is commenced within 6 weeks of surgery [15,18,19]. In our patients, the median time to commencement of radiotherapy after surgery was 6.9 weeks. This may be improved by the identi®cation of suitable patients preoperatively, and the rapid referral of postoperative patients for initiation of treatment. A comparison of the rates of maximal mucositis and dysphagia (Fig. 3) for this pilot study and the CHART randomized trial [12] suggests a higher level of con¯uent mucositis with increased dysphagia in patients receiving postoperative CHARTWEL. However, the small numbers analysed in the pilot study do not allow further conclusions to be drawn. Clinically, the tolerance of patients to radiotherapy after surgery was acceptable and not signi®cantly worse than that observed in patients who were treated de®nitively with CHART.
Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer
395
After radical surgery for a head and neck malignancy, some patients report long-term feeding dif®culties, [20] which may be made worse by the diminishing of salivary ¯ow after radiotherapy. It can be expected that in the long term the late changes may be signi®cantly less after CHARTWEL, as observed in the randomized trial for CHART. Of 24 patients, there were 18 who were at a high risk for local recurrence; of these, 13 (72%) remain free of recurrence. Patients treated for recurrent tumours and primary oral cavity tumours appear to have higher recurrence rates and mortality. Local control rates at 2 years of 70%±80% have been noted in retrospective studies [4,21,22] that used conventionial once-daily fractionated radiotherapy to doses of 52±68 Gy. Salvage treatment has previously been reported to have inferior survival rates [3]. This pilot study demonstrates acceptable acute morbidity for CHART/CHARTWEL in the postoperative setting. A prospective multicentre randomized trial using an accelerated schedule of radiotherapy (51 Gy and 54 Gy for intermediate and high-risk populations respectively), versus conventional fractionation for the radical postoperative tretament of primary head and neck cancer is currently in preparation. Acknowledgement. The authors are grateful to the Marie Curie Research Wing staff for their support and participation in this study.
References 1. Munro A. Head and neck. In: Price P, Sikora K, editors. Treatment of Cancers. 3rd ed. London: Chapman and Hall, 1995:271. 2. Huang DT, Johnson CR, Schmidt-Ullrich R, et al. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys 1992;23:737±42. 3. Huang D, Johnson CR, Schmidt-Ullrich RK, et al. Incompletely resected advanced squamous cell carcinoma of the head and neck: the effectiveness of adjuvant vs. salvage radiotherapy. Radiother Oncol 1992;24:87±93. 4. Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: ®rst report of a prospective randomized trial. Int J Radiat Oncol Biol Phys 1993;26:3±11. 5. Ravasz LA, Hordijk GJ, Slootweg PJ, et al. Uni- and multivariate anlaysis of eight indications for postoperative radiotherapy and their signi®cance forlocalreginal cure in advanced head and neck cancer. J Laryngol Otol 1993;107:437±40. 6. Vikram B. Importance of the time interval between surgery and postoperative radiation therapy in the combined management of head and neck cancer. Int J Radiat Oncol Biol Phys 1979;5:1837±40.
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7. Tupchong L, Scott CB, Blitzer PH, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73±03. Int J Radiat Oncol Biol Phys 1991;20:21±8. 8. Lundahl RE, Foote RL, Bonner JA, et al. Combined neck dissection and postoperative radiation therapy in the management of the high-risk neck: a matched-pair analysis. Int J Radiat Oncol Biol Phys 1998;40:529±34. 9. Wilson GD, Dische S, Saunders MI. Studies with bromodeoxyuridine in head and neck cancer and accelerated radiotherapy. Radiother Oncol 1995;36:189± 97. 10. Hofer SO, Shrayer D, Reichner JS, et al. Wound-induced tumor progression: a probable role in recurrence after tumor resection. Arch Surg 1998;133:383±9. 11. Withers HR, Suwinski R. Radiation dose response for subclinical metastases. Semin Radiat Oncol 1998;8:224±8. 12. Dische S, Saunders M, Barrett A, et al. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;44:123±36. 13. International Commission on Radiation Units and Measurements. Prescribing, recording and reporting photon beam therapy (Report no. 50). Washington, DC: ICRU, 1993. 14. Awwad HK, Khafagy Y, Barsoum M, et al. Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: in¯uence of tumour proliferation. Radiother Oncol 1992;25:261±6. 15. Ang K, Trotti A, Garden A, et al. Overall time factor in postoperative radiation: results of a prospective randomised trial. In: Proceedings of 15th Annual ESTRO meeting; 1996; Vienna; S30 (108). 16. 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±23. 17. Peters LJ, Withers HR. Applying radiobiological principles to combined modality treatment of head and neck cancer ± the time factor. Int J Radiat Oncol Biol Phys 1997;39:831±6. 18. Vikram B, Strong EW, Shah JP, et al. Failure in the neck following multimodality treatment for advanced head and neck cancer. Head Neck Surg 1984;6:724±9. 19. Trotti A, Klotch D, Endicott J, et al. A prospective trial of accelerated radiotherapy in the postoperative treatment of high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1993;26:13±21. 20. Coleman JJD. Complications in head and neck surgery. Surg Clin North Am 1986;66:149±67. 21. Vikram B, Strong EW, Shah J, et al. Elective postoperative radiation therapy in Stages III and IV epidermoid carcinoma of the head and neck. Am J Surg 1980;140:580±4. 22. Ampil FL. Surgery and postoperative external irradiation for head and neck cancer recurrent after surgery alone. Laryngoscope 1988;98:888±90. 23. Heremanek P, Hutter R, Sobin L, et al., editors. TNM atlas. 4th ed. Berlin: Springer-Verlag, 1997. Received for publication December 1999 Accepted June 2000
Clinical Oncology (2000)12:392±396 # The Royal College of Radiologists
Original Article A Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer N. Shah, M. I. Saunders and S. Dische Mount Vernon Hospital, Northwood, UK Abstract. A Phase II pilot study of continuous hyperfractionated accelerated radiotherapy (CHART)/CHART weekend less (CHARTWEL) was carried out in the postoperative treatment of patients with squamous cell carcinoma of the head and neck. Twenty-four patients (17 male, seven female) with a median age of 64 years (range 34±80) were treated with postoperative radiotherapy between 1991 and 1999. All patients presented with primary squamous cell carcinoma, which, at surgery, had shown adverse pathological factors for recurrence. Intermediate risk was determined by the presence of two of the following factors: margins 5 mm, Stage T3/T4, perineural or vascular invasion, poor differentiation, oral primary, multicentric primary, and more than four positive lymph nodes. High-risk factors included the presence of extracapsular spread and/or incomplete resection margins, or the presence of four of the factors de®ning intermediate risk. The patients were treated using a CHART (n = 11) or a CHARTWEL (n = 13) schedule, administering a dose between 49.5 Gy and 54 Gy. High-risk factors were present in 18/24 patients. Treatment was commenced from a median time of 6.9 weeks (range 4.4±16.6) after radical surgery. All patients completed treatment. A con¯uent radiation mucositis occurred in 20/23 evaluable patients, which settled in 4±10 weeks after commencing radiotherapy. Moderate dysphagia was observed in 13 patients. Mild subcutaneus oedema was noted in 11 patients from 12 weeks after treatment. No signi®cant late toxicity has been observed. Over a median follow up-period of 17 months, local control has been maintained in 17 patients (71%). Seven patients have relapsed and died of disease. A mean survival of 24 months (range 1±84) has been observed. This pilot study demonstrates acceptable morbidity for CHART/CHARTWEL in the postoperative setting. A prospective multicentre randomized trial using an accelerated schedule of radiotherapy versus conventional fractionation for the radical postoperative treatment of primary head and neck cancer is currently in preparation. Keywords: CHART; CHARTWEL; Head and neck cancer; Postoperative
Introduction Head and neck cancer accounts for approximately 5% of all adult cancers [1] and is mainly seen in the sixth to eighth decades of life. Both radiotherapy and surgery are currently used as single modalities with curative intent. In recent years, there has been an increasing use of major surgery in the management of the more advanced patients with head and neck cancer. Unfortunately, after surgery, many of these patients are at a high risk of local recurrence. Where there is tumour at the margins of the surgical specimen and/or when there is spread outside an invaded lymph node, recurrence of disease is practically inevitable [2]. Other adverse prognostic Correspondence and offprint requests to: N. Shah, Marie Curie Research Wing, Mount Vernon Hospital, Northwood HA6 2RN, UK. Fax: 01923 844167.
factors can be identi®ed with recurrence rates of the order of 50% if further treatment is withheld [3±5]. Postoperative radiotherapy has become established in clinical practice. There has never been a randomized controlled trial of surgery plus postoperative radiotherapy or no further treatment. Retrospective series have, however, given con®rmation to the strong clinical impression that such treatment greatly reduces local recurrence [6±8]. Tumour cell kinetic studies have shown that squamous cell carcinoma has the capacity to proliferate rapidly. Most tumours in the head and neck region have been shown to have the capacity to double their cell numbers in 5 or fewer days [9]. In the more active areas of tumour, cell doubling times of less than 48 hours have been observed. Growth factors active upon tumour cells can be demonstrated in high concentrations in the postoperative ®eld [10]. Thus, it may be expected that residual or implanted
tumour cells in the vascular ®eld, which exist postoperatively, are likely to show the most rapid proliferation. When microscopic disease is irradiated, a linear relationship between dose and the probability of tumour cell eradication is postulated [11]. This begins after a very low threshold dose, so a modest reduction in total dose may have less effect on tumour control when a comparison is made with the situation in de®nitive radiotherapy, where a sigmoid curve relates dose and effect. Continuous hyperfractionated accelerated radiotherapy (CHART) was designed to deliver a radical tumour dose in a short time to squamous cell carcinoma of the head and neck, to counteract the effect of proliferation with a low dose per fraction and lower than usual total dose, to reduce late tissue effects. A randomized controlled trial using CHART (54 Gy over 12 days) against conventional fractionation (66 Gy over 42 days) demonstrated equivalent locoregional control with reduced late tissue morbidity and suggested the importance of the control of tumour proliferation over a shorter overall treatment time [12]. CHART used in the postoperative setting would be advantageous in counteracting proliferation and reducing late tissue moribidity.
The delivery of radiotherapy over the weekend is dif®cult practically. CHART without weekend treatment (CHARTWEL: CHART weekend loss) has been piloted and implemented at this centre. This study assesses the feasibility of postoperative CHART/ CHARTWEL in head and neck cancer with respect to acute morbidity and local control.
Methods Local ethics permission from the Mount Vernon and Watford Hospitals NHS Trust has been granted for the study of accelerated radiotherapy in the postoperative treatment of patients with head and neck malignancy. Between July 1991 and February 1999, 24 patients (17 male, seven female; median age 64 years) with squamous cell carcinoma were treated with postoperative radiotherapy (Table 1). Adjuvant radiotherapy was given to 17 patients after radical surgery as initial management. In seven patients there was recurrence after surgery, which was treated by further surgery and postoperative radiotherapy (one primary tumour recurrence, four nodal recurrences, and two recurrent primary and nodal disease).
Table 1. Patient characteristics Patient Tumour site no.
Risk status
TNM stage [23]
Treatment
Dose (Gy)
Status
Follow-up period (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Oral cavity Oral cavity Oral cavity Oral cavity Oral cavity Oral cavity Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Oropharynx Pinna Larynx
High High High High High Intermediate High High High High Intermediate Intermediate Intermediate High High High
T4/N1 T2/N1 T4/N1 T4/N2 T3/N2 T4/N2 T1/N2 T1/N1 T1/N1 Tx/N2 T4/N2 T3/N1 T4/N1 T1/N2 T4/N2 T3/N0
CHARTWEL CHARTWEL CHARTWEL CHARTWEL CHARTWEL CHART CHARTWEL CHART CHART CHARTWEL CHARTWEL CHARTWEL CHARTWEL CHART CHART CHART
49.5 49.5 51 49.5 51 54 49.5 54 54 54 54 49.5 49.5 54 54 54
30 14 26 15 26 7 27 84 35 36 10 3 25 63 43 29
17 18
Unknown Oral cavity
High High
primary and
CHARTWEL CHARTWEL
54 54
10 15
19 20
Oral cavity Oral cavity
High Intermediate
node primary and
CHART CHART
54 54
Dead, local recurrence Alive, no recurrence
5 37
21 22 23 24
Pinna Pinna Larynx Columnella
High High High Intermediate
Tx/N2 Recurrent node Recurrent Recurrent node Recurrent Recurrent Recurrent Recurrent
Alive, no recurrence Dead, local recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Dead, local recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Alive, no recurrence Dead, local recurrence and metastases Alive, no recurrence Alive, local recurrence
node node node node
CHARTWEL CHART CHART CHART
49.5 54 54 54
Dead, local recurrence Alive, no recurrence Dead, local recurrence Dead, metastases
6 44 10 1
Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer
393
The indications for adjuvant radiotherapy were based on adverse factors de®ned from a review of the literature [2,4]. Extracapsular spread, incomplete resection margins or four other prognostic factors detailed below were considered to give a high risk of local recurrence. An intermediate risk for recurrence was determined by the presence of two prognostic factors, including excision margins >5 mm, Stage T3/ T4 disease, perineural or vascular invasion, poor differentiation, oral primary, multicentric primary, more than four positive nodes, invasion of soft tissues, and the presence of carcinoma in situ or dysplasia at the edge of the resection margin. Other patients were regarded as at low risk for local recurrence and were excluded from the trial. Percutaneous gastrostomy tubes were inserted as departmental policy prior to radiotherapy. The planning process for radiotherapy was similar for all patients. In the ®rst phase of treatment the volume encompassed the surgical bed and lymphatic drainage with a margin of 1±2 cm to include all sites of microscopic disease. The second phase of treatment included known sites of high-risk microscopic disease. Radiation doses were prescribed to the intersection point as de®ned by international recommendations (ICRU 50 [13]) and administered using a linear accelerator (6 MV photons). A dose of 1.5 Gy per fraction was given three times a day, with a minimum interfraction interval of 6 hours. The Phase I dose was 37.5 Gy in 25 fractions; in Phase II a maximum of 16.5 Gy was given in 11 fractions, to reach 54 Gy in 36 fractions. The spinal cord dose was normally restricted to 40 Gy and was never allowed to exceed 44 Gy. Between July 1991 and August 1999 patients were treated with postoperative CHART to a total dose of 54 Gy in 36 fractions over 12 days. Following the introduction of CHARTWEL, a dose escalation study from 49.5 Gy in 33 fractions over 15 days to 54 Gy in 36 fractions over 16 days was instituted. All patients were seen weekly for the ®rst 6 weeks from the start of treatment, at 8 weeks, 12 weeks and then 3-monthly intervals to 2 years, and 6-monthly intervals to 5 years. Local control, the appearance of distant metastases, morbidity and survival were recorded.
Results CHART to a total dose of 54 Gy was administered to 11 patients; CHARTWEL to 49.5 Gy, 51 Gy and 54 Gy was given to seven, two and four patients respectively. Treatment was commenced at a median time of 6.9 weeks (range 4.4±16.6) after radical surgery. All patients except one completed treatment within the 12±16-day speci®ed treatment period with no interruptions. One patient had treatment extended by a day owing to gastrostomy tube complications resulting in missed radiotherapy fractions. One patient, who died 4 weeks after the start of radiotherapy, due to pulmonary metastases (diagnosed postmortem), has not been assessed in scoring acute morbidity. A con¯uent radiation mucositis occurred in 20/23 patients, with all patients recording maximal mucositis from days 14 to 21 of treatment (Fig. 1). The acute mucositis settled in 4±10 weeks after the beginning of radiotherapy. Moderate to severe dysphagia was conformed in 15/23 patients. Narcotic analgesics were prescribed for 14/23 patients during the period of mucositis (Fig. 2). Skin erythema
a
Statistical Methods All end-points were measured from the date of initiation of postoperative radiotherapy. The diseasefree interval was de®ned as the time from the initiation of radiotherapy to the appearance of locoregional disease or of distant metastatic disease. For this end-point, patients dying without progression of local disease or the appearance of metastatic disease were censored at the time of death. All other patients were censored at the time of their last followup. Overall survival was de®ned as the time from initiation of radiotherapy to the time of death. 394
N. Shah et al.
b Fig. 1. (a) Grade of maximal mucositis recorded; and (b) time course of mucositis for all patients. The mean mucositis score is an average score for all patients for the selected week.
a
a
b Fig. 3. Comparison of (a) maximum mucositis and (b) maximum dysphagia scores over 12 weeks for patients receiving postoperative CHARTWEL (&) and published data from the CHART randomized trial (&).
Discussion b Fig. 2. (a) Grade of maximal dysphagia recorded; and (b) time course of dysphagia for all patients. The mean dysphagia score is an average score for all patients for the selected week.
was noted in all patients, with dry and moist desquamation appearing from 2 weeks in the region of the high-dose ®eld. Resolution of the desquamation occurred in all patients from 4 weeks. There were no trends noted for the treatment groups as de®ned. All mucosal reactions have healed, with no consequential late necrosis. No occurrences of transient or permanent radiation myelitis have been observed. Two patients described mild to moderate dysphagia with no persistent mucositis at 19 and 45 weeks after radiotherapy. Mild subcutaneous oedema was observed in eight patients from 12 weeks after treatment. Over a median follow-up period of 17 months (range 1±84) there were seven disease-related deaths (®ve due to local tumour at 5, 6, 7, 9 and 14 months; one due to distant disease at 1 month; one due to local and distant disease at 26 months). Eighteen patients continue on follow-up; one has developed a local recurrence 6 months after radiotherapy. Local control is maintained in 17 patients (71%) and a mean survival of 24 months (95% con®dence interval 22± 26) has been observed.
The results of this pilot trial demonstrate acceptable early morbidity and local control for CHARTWEL postoperative radiotherapy in head and neck squamous cell carcinoma. There is accumulating evidence that the duration of radiotherapy in¯uences treatment outcome [12,14±16]. In the postoperative setting, further advantages from a short overall treatment time may arise from improved local control and encourage the earlier rehabilitation of patients. The time delay between surgery and the initiation of radiotherapy may play an important part in tumour clonogen repopulation [17[. Improved outcome has been demonstrated when irradiation is commenced within 6 weeks of surgery [15,18,19]. In our patients, the median time to commencement of radiotherapy after surgery was 6.9 weeks. This may be improved by the identi®cation of suitable patients preoperatively, and the rapid referral of postoperative patients for initiation of treatment. A comparison of the rates of maximal mucositis and dysphagia (Fig. 3) for this pilot study and the CHART randomized trial [12] suggests a higher level of con¯uent mucositis with increased dysphagia in patients receiving postoperative CHARTWEL. However, the small numbers analysed in the pilot study do not allow further conclusions to be drawn. Clinically, the tolerance of patients to radiotherapy after surgery was acceptable and not signi®cantly worse than that observed in patients who were treated de®nitively with CHART.
Pilot Study of Postoperative CHART and CHARTWEL in Head and Neck Cancer
395
After radical surgery for a head and neck malignancy, some patients report long-term feeding dif®culties, [20] which may be made worse by the diminishing of salivary ¯ow after radiotherapy. It can be expected that in the long term the late changes may be signi®cantly less after CHARTWEL, as observed in the randomized trial for CHART. Of 24 patients, there were 18 who were at a high risk for local recurrence; of these, 13 (72%) remain free of recurrence. Patients treated for recurrent tumours and primary oral cavity tumours appear to have higher recurrence rates and mortality. Local control rates at 2 years of 70%±80% have been noted in retrospective studies [4,21,22] that used conventionial once-daily fractionated radiotherapy to doses of 52±68 Gy. Salvage treatment has previously been reported to have inferior survival rates [3]. This pilot study demonstrates acceptable acute morbidity for CHART/CHARTWEL in the postoperative setting. A prospective multicentre randomized trial using an accelerated schedule of radiotherapy (51 Gy and 54 Gy for intermediate and high-risk populations respectively), versus conventional fractionation for the radical postoperative tretament of primary head and neck cancer is currently in preparation. Acknowledgement. The authors are grateful to the Marie Curie Research Wing staff for their support and participation in this study.
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