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Adding dose escalation to accelerated hyperfractionation for head and neck cancer: 76 Gy in 5 weeks
Adding D o s e E s c a l a t i o n to A c c e l e r a t e d H y p e r f r a c t i o n a t i o n For Head and N e c k Cancer: 76 Gy in 5 Weeks Paul M. Harari
O
ngoing proliferation of surviving tumor clonogens during a course of head and neck radiotherapy may compromise tumor control, particularly if accelerated repopulation is stimulated during treatment. This pilot study ~was designed with the following primary objective. Deliver the highest acutely tolerable radiation dose to the head and neck in the shortest overall time consistent with several constraints: 1. Maximum of two treatments per day spaced by 6 hours or more. 2. Single treatments on Saturdays; none on Sundays. 3. Achieve cumulative doses above 70 Gy. 4. Intensify or escalate dose in the latter segments of treatment. 5. Devise schedule for which the predicted late tissue effects would be well within the range of more conventional schedules with known late effects.
Materials and M e t h o d s The 22 patients included in this report have been treated by the author between January and July 1991, so that only acute tumor responses and tissue reactions can be assessed. A 4-MeV linear accelerator was used for all treatments. Most commonly, a threefield design was used to include the primary tumor volume within lateral portals, and the low neck and supraclavicular lymphatics through an anterior field. Early glottic tumors received lateral larynx fields alone. Computed tomographic (CT)-based treatment plans with computer dosimetrywere generated for the selection of isodose prescriptions in all cases. Wedges and asymmetric field weightings were often used to improve dose homogeneity and tailor isodose
From the Department of Human Oncology, University of Wisconsin Medical School, Madison, WL Address reprint requeststo Paul M. Harari, MD, Department of Human Oncology (K4/BIO0), University of Wisconsin Clinical Cancer Center, 600 Highland Ave, Madison, W153792. Copyright 9 1992 by W..B. Saunders Company 1053-4296/92/0201-0015505.00/0
58
curves to tumor volumes. A shrinking field technique was used such that the spinal cord dose was limited to 45 Gy, and a second field reduction was often performed at 60 Gy. Electrons were used to boost posterior cervical chains. Port (check) films were taken and reviewed twice per week, and all twice daily (BID) treatments were spaced by intervals of 6 hours or more. The detailed schedules for both primary and postoperative radiotherapy are outlined in Table 1. Precise adherence to the schedule would allow a patient commencing treatment on Monday of week 1 to complete treatment on Friday of week 5 (32 elapsed days).
Results For the 12 definitive radiotherapy patients thus treated, the mean dose and duration actually achieved were 75.8 Gy over 36.8 elapsed days. The causes of deviation from the prescribed elapsed days include: not initiating treatment on a Monday, department closure for holiday, and two cases of patient insistence for treatment break (4 and 6 days, respectively). For general comparison, a random selection of 12 charts from definitive head and neck treatments in our department during 1990 showed a mean dose of 64.4 Gy delivered over 53 mean elapsed days. The American Joint Committee on Cancer (AJCC) staging classification and site of tumor primary is summarized in Table 2 for the 12 primary radiotherapy cases. Eight of 12 patients (75%) presented with advanced stage disease (HI or IV), and all 4 early stage patients had tumors of the glottic larynx. An example of shrinking field design is shown in Fig 1 for a patient with a T3N1M0 tumor of the right tonsil with extension to both tonsillar pillars and the hard palate mucosa. Figure 2 depicts a patient (T4N3M0 base of tongue) 1 week following completion of 76 Gy in 33 elapsed days. Confluent mucositis is well outlined from the mid-body of the oral tongue posteriorly into the oropharynx. All palpable primary tumor (origi-
Seminars in Radiation Oncology, Vol 2, No 1 (Janua~), 1992:pp 58-61
Escalating Scheduleto 76 Gy in 5 Weeks
59
Table 1. Dose-Escalating Radiotherapy Schedules for Definitive (76 Gy in 5 Weeks) and Postoperative (65 Gy in 5 Weeks) Head and Neck Cancer Patients Week
Schedule
Dose
Definitive RadiotherapySchedule 1 and 2 1.2 Gy BID 3 and 4 1.4 Gy BID 5 1.6 Gy BID Saturday doses 2 Gy Q Saturday x 4
24 Gy 28 Gy 16 Gy 8 Gy
Total 76 Gy in 5 weeks PostoperativeRadiotherapySchedule First 289weeks 1.2 GyBID x 26 Last 289weeks 1.4 GyBID x 24
31.2 Gy 33.6 Gy
Total 64.8 Gyin 5 weeks
nally 4 X 6 cm) was resolved at 3 weeks following radiotherapy, and radical neck dissection at 6 weeks showed no residual tumor in the remaining 2 x 2 cm jugulodigastric mass (originally 5 x 7 cm and fixed). However, this patient had a residual focus of persistent mucosal pain and a visible ulceration (2 x 3 cm) along the lateral tongue base at 8 weeks following completion of radiotherapy. The pain and ulceration resolved completely by 14 weeks. Initial attempts to "score" the severity of acute mucosal reactions proved to be of limited usefulness, as all definitive patients developed confluent mucositis (the uppermost score in acute scales), during the latter portion of week 3 or early in week 4. Such scoring may prove to be of greater significance during the ongoing evaluation of the timetable for resolution of acute effects. Detailed evaluation of late tissue effects awaits longer follow-up.
Table 2. AJCC Stage and Tumor Primary Site for Definitive Radiotherapy Patients TNM 1 2 3 4 5 6 7 8 9 10 lI 12
T..,Nt~M~ T:~N~M~, T4N3M0 T2N3M0 T~N~Mo T:~N~M(~ T~N3M0 T~N~M~ T3NIM0 T~N~M0 T~N,~IVI~, T&N~M~
Stage
Site
II III IV IV II III IV I (Recurrent) III III II IV
Glottis Supraglottis Base of tongue Tonsil Glottis Tonsil Post pharyngeal wall Glottis Tonsil Soft palate Glottis Soft palate
Figure 1. Lateral field design for a T3NIM0 tumor of the right tonsillar fossa involving both tonsillar pillars and extending onto the hard palate mucosa.
Discussion It has become increasingly clear that adherence to a "standard" fractionation schedule for head and neck cancer such as 33 fractions for 2 Gy equals 66 Gy may not optimize either primary tumor control nor late normal tissue effects. The radiobiological prediction and clinical confirmation that hyperfractionated regimens can allow the safe delivery of higher radiation doses with greater rates of tumor control without corresponding increases in late tissue toxicity has prompted a complete re-analysis of what "standard" fractionation should be. 2~ The devotion of this entire journal issue to "altered fractionation" is testimony to the growing enthusiasm and activity in this field. This pilot radiotherapy protocol was devised to test the feasibility of delivering 76 Gy over 5 weeks to head and neck cancer patients using accelerated hyperfractionation and ongoing dose escalation during treatment. The accelerated hyperfractionation was chosen in attempt to maximize tumor cell kill without increasing late normal tissue toxicity. The dose escalation was selected in an attempt to maximize delivered dose and treatment compliance by"completing therapy within a rapid 5-week time frame with consideration of the phenomenon of accelerated tumor repopulation that may occur during a course of radiotherapy. ~ Institutional considerations typical
60
Paul M. Harari
Figure ~. Appearance of confluent oropharyngeal mucositis 7 claysfollowing completion of 76 Gy in 33 elapsed days. Primary tumor: T4N3M0 base of tongue with a 5 by 7 cm jugulodigastric mass. Direct laryngoscopy and radical neck dissection 6 weeks following radiotherapy showed no evidence of residual cancer. of many cancer treatment centers led to the choice of no more than two fractions per weekday, and a single fraction on Saturdays. With these provisos, plus an evaluation of predicted and reported early and late tissue effects for a variety of current head and neck regimens currently active worldwide, the present schedule was designed to deliver the highest radiation dose in the shortest reasonable overall time. Radiobiological predictions regarding the early and late tissue effects of this regimen in Comparison with others are presented elsewhere in this issue.
This author's clinical observations regarding this pilot can be summarized as follows:
1. The postoperative regimen of 65 Gy escalated over 5 weeks is very well tolerated with 0 of 10 patients requiring any form of treatment break. 2. Theprima?y radiotherapy regimen of 76 Gy escalated over 5 weeks induces dramatic tumor volume reductions, including complete resolution and sterilization of N3 neck disease in three of four patients. These regressions are most rapid between weeks 4 to 8 from initiation of treatment.
Escalating Scheduleto 76 Gy in 5 Weeks
3. The primary radiotherapy regimen of 76 Gy escalated over 5 weeks shows extremely brisk acute mucosal reactions, although it can be successfully accomplished without break in the majority of patients ( I0 of 12; 83%). However, 2 of 12 patients (17%) manifested prolonged rnucosal pain (12 and 14 weeks, respectively, following completion of treatment), which was then completely resolved. Both patients had complete tumor resolution. 4. Meticulous attention must be paid to the writing and carrying out of radiation dose prescriptions by both physician and technologist. The incorporation of ongoing dose escalation involves a changing dose from weekday to Saturday" (BID to QD), and from week to week, on top of an already complex treatment scheme including three-field design, two or more field reductions, and electron boosting. In light of the observation that 2 of 12 patients are experiencing marked prolongation of acute mucosal toxicity, a second phase of this pilot is now being initiated whereby the first and/or first two Saturday fractions of 2 Gy will be deleted. A cumulative dose of 76 Gy will still be achieved by adding one or two BID days at the end of the regimen. Evaluation of an additional 10 to 15 patients over several months will allow initial assessment of the recovery time for acute toxicities. Increasing numbers of our head and neck cancer patients are undergoing flow cytometry evaluation of individual tumor proliferation kinetics via in vivo labeling with BUdR or IUdR before treatment. As discussed elsewhere in this issue, this methodology may soon aid in the more judicious selection of patients who might benefit most from such aggressive, accelerated radiotherapy regimens. However, until such time as individual tumor kinetics and individual tumor radiosensitivites can be reliably and rapidly assayed, the optimal head and neck radiotherapy regimens are likely to be those that rigorously test the capacity for acute tissue tolerance, while
61
providing maximal log cell kill across a range of tumor proliferation rates and radiosensitivities.
Summary Twenty-two patients with head and neck cancer have been treated on a pilot protocol that incorporates dose escalation with accelerated hyperfractionation during a 5-week radiotherapy schedule. Twelve patients were treated with definitive radiotherapy alone and the remaining 10 patients were treated postoperatively. The definitive radiotherapy schedule delivers a cumulative dose of 76 Gy in 5 weeks, and the postoperative schedule delivers 65 Gy in 5 weeks. The acute tolerance of the postoperative regimen has been superb, whereas the acute treatment reactions in the definitive group are more potent. This is largely due to the fact that larger mucosal volumes were treated in the primary radiotherapy patients, in whom confluent mucositis manifests late in week 3. Complete tumor regression has been observed in 10 of 12 (83%) definitive patients, including 3 patients with N3 neck disease. Two o f 12 patients (17%) experienced prolonged painful mucositis (12 and 14 weeks), suggesting that 76 Gy over 32 elapsed days tests the capacity of the acute reacting tissues to recover fully. The radiobiological rationale for this schedule is discussed.
References 1. Harad PM, Ritter MA, FowlerJF, et al: Adding dose escalation to accelerated hyperfractionation for head and neck cancer. Ninth International Congress of Radiation Research,Toronto, Canada, in ChapmanJD, DeweyWC, Whitmore GF (eds). San Diego,CA, AcademicPress, 199I, pp 15-17,p 234 2. FowlerJF: Non-standard fractionation in radiotherapy. Int J Radiat Oncol BiolPhys 10:755-759, 1984 3. Peters LJ, Ang KK, Thames HD: Accelerated fractionation in the radiation treatment of head and neck cancer. Acta Oncol 27:185-194, 1988 4. Withers HR, Taylor JMG, Maciejewski B: The hazard of accelerated tumor clonogen repopulationduring radiotherapy. Acta Onco127:131-146, 1988
O
ngoing proliferation of surviving tumor clonogens during a course of head and neck radiotherapy may compromise tumor control, particularly if accelerated repopulation is stimulated during treatment. This pilot study ~was designed with the following primary objective. Deliver the highest acutely tolerable radiation dose to the head and neck in the shortest overall time consistent with several constraints: 1. Maximum of two treatments per day spaced by 6 hours or more. 2. Single treatments on Saturdays; none on Sundays. 3. Achieve cumulative doses above 70 Gy. 4. Intensify or escalate dose in the latter segments of treatment. 5. Devise schedule for which the predicted late tissue effects would be well within the range of more conventional schedules with known late effects.
Materials and M e t h o d s The 22 patients included in this report have been treated by the author between January and July 1991, so that only acute tumor responses and tissue reactions can be assessed. A 4-MeV linear accelerator was used for all treatments. Most commonly, a threefield design was used to include the primary tumor volume within lateral portals, and the low neck and supraclavicular lymphatics through an anterior field. Early glottic tumors received lateral larynx fields alone. Computed tomographic (CT)-based treatment plans with computer dosimetrywere generated for the selection of isodose prescriptions in all cases. Wedges and asymmetric field weightings were often used to improve dose homogeneity and tailor isodose
From the Department of Human Oncology, University of Wisconsin Medical School, Madison, WL Address reprint requeststo Paul M. Harari, MD, Department of Human Oncology (K4/BIO0), University of Wisconsin Clinical Cancer Center, 600 Highland Ave, Madison, W153792. Copyright 9 1992 by W..B. Saunders Company 1053-4296/92/0201-0015505.00/0
58
curves to tumor volumes. A shrinking field technique was used such that the spinal cord dose was limited to 45 Gy, and a second field reduction was often performed at 60 Gy. Electrons were used to boost posterior cervical chains. Port (check) films were taken and reviewed twice per week, and all twice daily (BID) treatments were spaced by intervals of 6 hours or more. The detailed schedules for both primary and postoperative radiotherapy are outlined in Table 1. Precise adherence to the schedule would allow a patient commencing treatment on Monday of week 1 to complete treatment on Friday of week 5 (32 elapsed days).
Results For the 12 definitive radiotherapy patients thus treated, the mean dose and duration actually achieved were 75.8 Gy over 36.8 elapsed days. The causes of deviation from the prescribed elapsed days include: not initiating treatment on a Monday, department closure for holiday, and two cases of patient insistence for treatment break (4 and 6 days, respectively). For general comparison, a random selection of 12 charts from definitive head and neck treatments in our department during 1990 showed a mean dose of 64.4 Gy delivered over 53 mean elapsed days. The American Joint Committee on Cancer (AJCC) staging classification and site of tumor primary is summarized in Table 2 for the 12 primary radiotherapy cases. Eight of 12 patients (75%) presented with advanced stage disease (HI or IV), and all 4 early stage patients had tumors of the glottic larynx. An example of shrinking field design is shown in Fig 1 for a patient with a T3N1M0 tumor of the right tonsil with extension to both tonsillar pillars and the hard palate mucosa. Figure 2 depicts a patient (T4N3M0 base of tongue) 1 week following completion of 76 Gy in 33 elapsed days. Confluent mucositis is well outlined from the mid-body of the oral tongue posteriorly into the oropharynx. All palpable primary tumor (origi-
Seminars in Radiation Oncology, Vol 2, No 1 (Janua~), 1992:pp 58-61
Escalating Scheduleto 76 Gy in 5 Weeks
59
Table 1. Dose-Escalating Radiotherapy Schedules for Definitive (76 Gy in 5 Weeks) and Postoperative (65 Gy in 5 Weeks) Head and Neck Cancer Patients Week
Schedule
Dose
Definitive RadiotherapySchedule 1 and 2 1.2 Gy BID 3 and 4 1.4 Gy BID 5 1.6 Gy BID Saturday doses 2 Gy Q Saturday x 4
24 Gy 28 Gy 16 Gy 8 Gy
Total 76 Gy in 5 weeks PostoperativeRadiotherapySchedule First 289weeks 1.2 GyBID x 26 Last 289weeks 1.4 GyBID x 24
31.2 Gy 33.6 Gy
Total 64.8 Gyin 5 weeks
nally 4 X 6 cm) was resolved at 3 weeks following radiotherapy, and radical neck dissection at 6 weeks showed no residual tumor in the remaining 2 x 2 cm jugulodigastric mass (originally 5 x 7 cm and fixed). However, this patient had a residual focus of persistent mucosal pain and a visible ulceration (2 x 3 cm) along the lateral tongue base at 8 weeks following completion of radiotherapy. The pain and ulceration resolved completely by 14 weeks. Initial attempts to "score" the severity of acute mucosal reactions proved to be of limited usefulness, as all definitive patients developed confluent mucositis (the uppermost score in acute scales), during the latter portion of week 3 or early in week 4. Such scoring may prove to be of greater significance during the ongoing evaluation of the timetable for resolution of acute effects. Detailed evaluation of late tissue effects awaits longer follow-up.
Table 2. AJCC Stage and Tumor Primary Site for Definitive Radiotherapy Patients TNM 1 2 3 4 5 6 7 8 9 10 lI 12
T..,Nt~M~ T:~N~M~, T4N3M0 T2N3M0 T~N~Mo T:~N~M(~ T~N3M0 T~N~M~ T3NIM0 T~N~M0 T~N,~IVI~, T&N~M~
Stage
Site
II III IV IV II III IV I (Recurrent) III III II IV
Glottis Supraglottis Base of tongue Tonsil Glottis Tonsil Post pharyngeal wall Glottis Tonsil Soft palate Glottis Soft palate
Figure 1. Lateral field design for a T3NIM0 tumor of the right tonsillar fossa involving both tonsillar pillars and extending onto the hard palate mucosa.
Discussion It has become increasingly clear that adherence to a "standard" fractionation schedule for head and neck cancer such as 33 fractions for 2 Gy equals 66 Gy may not optimize either primary tumor control nor late normal tissue effects. The radiobiological prediction and clinical confirmation that hyperfractionated regimens can allow the safe delivery of higher radiation doses with greater rates of tumor control without corresponding increases in late tissue toxicity has prompted a complete re-analysis of what "standard" fractionation should be. 2~ The devotion of this entire journal issue to "altered fractionation" is testimony to the growing enthusiasm and activity in this field. This pilot radiotherapy protocol was devised to test the feasibility of delivering 76 Gy over 5 weeks to head and neck cancer patients using accelerated hyperfractionation and ongoing dose escalation during treatment. The accelerated hyperfractionation was chosen in attempt to maximize tumor cell kill without increasing late normal tissue toxicity. The dose escalation was selected in an attempt to maximize delivered dose and treatment compliance by"completing therapy within a rapid 5-week time frame with consideration of the phenomenon of accelerated tumor repopulation that may occur during a course of radiotherapy. ~ Institutional considerations typical
60
Paul M. Harari
Figure ~. Appearance of confluent oropharyngeal mucositis 7 claysfollowing completion of 76 Gy in 33 elapsed days. Primary tumor: T4N3M0 base of tongue with a 5 by 7 cm jugulodigastric mass. Direct laryngoscopy and radical neck dissection 6 weeks following radiotherapy showed no evidence of residual cancer. of many cancer treatment centers led to the choice of no more than two fractions per weekday, and a single fraction on Saturdays. With these provisos, plus an evaluation of predicted and reported early and late tissue effects for a variety of current head and neck regimens currently active worldwide, the present schedule was designed to deliver the highest radiation dose in the shortest reasonable overall time. Radiobiological predictions regarding the early and late tissue effects of this regimen in Comparison with others are presented elsewhere in this issue.
This author's clinical observations regarding this pilot can be summarized as follows:
1. The postoperative regimen of 65 Gy escalated over 5 weeks is very well tolerated with 0 of 10 patients requiring any form of treatment break. 2. Theprima?y radiotherapy regimen of 76 Gy escalated over 5 weeks induces dramatic tumor volume reductions, including complete resolution and sterilization of N3 neck disease in three of four patients. These regressions are most rapid between weeks 4 to 8 from initiation of treatment.
Escalating Scheduleto 76 Gy in 5 Weeks
3. The primary radiotherapy regimen of 76 Gy escalated over 5 weeks shows extremely brisk acute mucosal reactions, although it can be successfully accomplished without break in the majority of patients ( I0 of 12; 83%). However, 2 of 12 patients (17%) manifested prolonged rnucosal pain (12 and 14 weeks, respectively, following completion of treatment), which was then completely resolved. Both patients had complete tumor resolution. 4. Meticulous attention must be paid to the writing and carrying out of radiation dose prescriptions by both physician and technologist. The incorporation of ongoing dose escalation involves a changing dose from weekday to Saturday" (BID to QD), and from week to week, on top of an already complex treatment scheme including three-field design, two or more field reductions, and electron boosting. In light of the observation that 2 of 12 patients are experiencing marked prolongation of acute mucosal toxicity, a second phase of this pilot is now being initiated whereby the first and/or first two Saturday fractions of 2 Gy will be deleted. A cumulative dose of 76 Gy will still be achieved by adding one or two BID days at the end of the regimen. Evaluation of an additional 10 to 15 patients over several months will allow initial assessment of the recovery time for acute toxicities. Increasing numbers of our head and neck cancer patients are undergoing flow cytometry evaluation of individual tumor proliferation kinetics via in vivo labeling with BUdR or IUdR before treatment. As discussed elsewhere in this issue, this methodology may soon aid in the more judicious selection of patients who might benefit most from such aggressive, accelerated radiotherapy regimens. However, until such time as individual tumor kinetics and individual tumor radiosensitivites can be reliably and rapidly assayed, the optimal head and neck radiotherapy regimens are likely to be those that rigorously test the capacity for acute tissue tolerance, while
61
providing maximal log cell kill across a range of tumor proliferation rates and radiosensitivities.
Summary Twenty-two patients with head and neck cancer have been treated on a pilot protocol that incorporates dose escalation with accelerated hyperfractionation during a 5-week radiotherapy schedule. Twelve patients were treated with definitive radiotherapy alone and the remaining 10 patients were treated postoperatively. The definitive radiotherapy schedule delivers a cumulative dose of 76 Gy in 5 weeks, and the postoperative schedule delivers 65 Gy in 5 weeks. The acute tolerance of the postoperative regimen has been superb, whereas the acute treatment reactions in the definitive group are more potent. This is largely due to the fact that larger mucosal volumes were treated in the primary radiotherapy patients, in whom confluent mucositis manifests late in week 3. Complete tumor regression has been observed in 10 of 12 (83%) definitive patients, including 3 patients with N3 neck disease. Two o f 12 patients (17%) experienced prolonged painful mucositis (12 and 14 weeks), suggesting that 76 Gy over 32 elapsed days tests the capacity of the acute reacting tissues to recover fully. The radiobiological rationale for this schedule is discussed.
References 1. Harad PM, Ritter MA, FowlerJF, et al: Adding dose escalation to accelerated hyperfractionation for head and neck cancer. Ninth International Congress of Radiation Research,Toronto, Canada, in ChapmanJD, DeweyWC, Whitmore GF (eds). San Diego,CA, AcademicPress, 199I, pp 15-17,p 234 2. FowlerJF: Non-standard fractionation in radiotherapy. Int J Radiat Oncol BiolPhys 10:755-759, 1984 3. Peters LJ, Ang KK, Thames HD: Accelerated fractionation in the radiation treatment of head and neck cancer. Acta Oncol 27:185-194, 1988 4. Withers HR, Taylor JMG, Maciejewski B: The hazard of accelerated tumor clonogen repopulationduring radiotherapy. Acta Onco127:131-146, 1988