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Palliative radiotherapy in recurrent head-and-neck tumors by a percutaneous superfractionated treatment schedule
Int. J. Radiation Oncology Biol. Phys., Vol. 50, No. 1, pp. 65– 68, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/01/$–see front matter
PII S0360-3016(00)01567-4
CLINICAL INVESTIGATION
Head and Neck
PALLIATIVE RADIOTHERAPY IN RECURRENT HEAD-AND-NECK TUMORS BY A PERCUTANEOUS SUPERFRACTIONATED TREATMENT SCHEDULE URSULA MARIA SCHLEICHER, M.D.,* DEMETRIOS ANDREOPOULOS, M.D.,*† JUERGEN AMMON, M.D., DR.PHIL.*
AND
*Department of Radiotherapy of the RWTH, Technical University, Aachen, Germany; †Radiotherapy Department, BOC Oncology Centre, Nicosia, Cyprus Purpose: A frequent problem in treatment of patients with head-and-neck tumors is recurrence in pre-irradiated areas, thus limiting dose for another full-course radiotherapy. We present our experience with a percutaneous superfractionated short-term radiotherapy regimen that may be useful for palliative irradiation. Methods and Materials: Twenty-three patients with head-and-neck tumor recurrence after radiotherapy or extensive tumor growth have been treated by a superfractionated regimen. At each of two subsequent days, eight fractions of 1 Gy were applied with an interfraction interval of 1 h, resulting in a total dose of 16 Gy. Time between the last fraction of the first day and the first fraction of the second day was 17 h. Results: In 16 of 23 patients (70%), our irradiation schedule could achieve a palliative effect such as tumor necrosis or reduction of swelling or pain. Seven patients showed erythema (WHO I) at the end of the second day. Neither mucositis nor late effects of treatment were observed. Conclusions: Our superfractionated schedule is feasible without severe acute side reactions and can achieve a palliative effect in advanced or recurrent head-and-neck cancer. © 2001 Elsevier Science Inc. Head-and-neck cancer, Recurrence, Altered fractionation, Palliative treatment.
are recommended to achieve a long-term remission of tumor. Nevertheless, late complications occur more frequently than in primary therapy, with necrosis of soft tissue, bone, or mucosa, trismus, or even myelitis being reported (3, 4). Unfortunately, these favorable prognostic factors are rarely given. Thus, in most cases of clinical routine, treatment is performed with only palliative intent. A combination of surgery and radiotherapy, as in intraoperative irradiation (IORT) for recurrent head-and-neck disease, can be performed with curative intent in only a limited number of patients in whom an almost complete surgical removal of tumor seems feasible (5). In more advanced or larger tumors, IORT can only be performed with palliative intent (6). Brachytherapy has the advantage of sparing a large amount of normal tissue. As only a limited area can be treated, however, some tumors are too large or too difficult to be reached by interstitial brachytherapy with tumoricide doses. The percutaneous radiotherapy regimen we describe was derived from a schedule developed by Busch and Alberti (7) for brachytherapy treatment of recurrent epipharynx carcinoma. Originally performed at a high dose rate unit, it simulates a pulsed dose rate therapy. To our knowledge, no such fractionation has been described so far for percutaneous therapy.
INTRODUCTION Patients with head-and-neck cancer sometimes present with far advanced large tumors or massive lymphonodular bulk that is too extended to be treated with curative intent by surgery or radiotherapy. Similar situations may occur in recurrent tumors where therapeutic options are often limited by previous radiotherapy or surgical procedures. Surgical retreatment is often limited by fibrosis generating from previous surgery or radiotherapy or cannot be performed with curative intent due to tumor invasion into cervical nerves or vessels (1). Response to radiotherapy in badly vasculated and oxygenated tumors, often presenting with central necrosis, is known to be poor (2). Treatment of tumors recurring locally after radiotherapy, obviously originating from radioresistant cell lines, as they have survived primary treatment, faces numerous problems due to tolerance of surrounding normal tissue. Another course of therapy will be limited in dose but will control a less sensitive tumor than in primary therapy. Percutaneous treatment in such a situation may lead to long-term control and 5-year survival rates in the range of 20 – 40%, especially in patients with good prognostic factors, such as a long interval between primary and retreatment, good differentiation, and small tumors suitable for additional brachytherapy. Doses of 50 Gy or even up to 65 Gy Reprint requests to: Dr. Ursula Maria Schleicher, Department of Radiotherapy of the RWTH, University Hospital, Pauwelsstr. 30, D-52057 Aachen, Germany. Tel: ⫹49.241.8088777; Fax: ⫹49.241.8888425; E-mail: [email protected]
Accepted for publication 28 November 2000.
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Table 1. Site of recurrence treated by superfractionated therapy Topography
Patients
Cervical lymph nodes Paranasal sinus Hypopharynx/larynx Floor of mouth Parotid gland Orbit (after exenteration in primary treatment) Skin of face
10 7 2 1 1 1 1
METHODS AND MATERIALS From 1989 to 1999, we treated 23 patients (7 female, 16 male) with advanced or recurrent tumors in the head-andneck region by a palliative treatment regimen. They were aged from 49 to 90 years (median: 68). Primary tumors were located at the oropharynx (4), hypopharynx (3), larynx (2), floor of the mouth (2), nose and paranasal sinuses (7), parotid gland (1), thyroid (1), and orbit (1), and two patients showed cervical lymph node involvement of an unknown primary tumor. Histology was squamous cell carcinoma in 18 patients, adenocarcinoma in three patients, and sarcoma in two. The site of recurrence treated by superfractionated therapy is shown in Table 1. Previous irradiation of the same site had been performed in all but one patient. Median time between the end of primary therapy and superfractionated treatment was 8.7 months (5 days to 5.5 years). Eleven patients had already received re-irradiation for tumor recurrence before starting the superfractionated schedule. Median time from the end of the last previous radiotherapy to the same site was 3.5 months. The radiotherapy courses and doses preceding superfractionation is shown in Table 2. Median cumulative dose of pre-irradiation was 59.4 Gy (ranging from 20 Gy IORT dose to 110.8 Gy from three percutaneous series). The symptoms to be palliated were swelling in 15 patients, pain in 12 patients, and ulcerating or exophytic tumor growth in seven patients, two of them preTable 2. Previous radiotherapy. IORT was used in one patient as solitary treatment for bad general condition not allowing percutaneous therapy, for the others in treatment of previous tumor recurrence. Number of patients None 1 percutaneous series 1 (IORT) 1 percutaneous series ⫹ 1 IORT 2 percutaneous series 2 percutaneous series ⫹ 1 IORT 2 percutaneous series ⫹ 3 IORT 3 percutaneous series Cumulative dose ⬍45 Gy Cumulative dose 45–60 Gy Cumulative dose 60–80 Gy Cumulative dose ⬎80 Gy IORT ⫽ intraoperative radiotherapy.
1 10 1 2 6 1 1 1 3 9 7 4
Volume 50, Number 1, 2001
senting with tumor bleeding. Eleven patients suffered from only one of the symptoms, the same number from two, and one patient from all of them. Quality of life was thus severely impaired in all of them. Patients selected for the described treatment schedule were regarded as having a very bad prognosis due to general condition and tumor extension. Other therapeutic options, such as surgery, IORT, or conventionally fractionated radiotherapy, did not seem feasible. Informed consent to treatment was obtained from all patients. Our treatment schedule consisted of 1-Gy single fractions, eight of which were applied on each of two consecutive treatment days with an interval of 1 h. The time between the last fraction on Day 1 and the first fraction on Day 2 was 17 h. Treatment volume, energy, and field arrangement were chosen individually according to tumor extension under palliative aspects. Treatment was performed at the telecobalt unit in the majority of patients (n ⫽ 17), with electrons in two cases and with linac photons (10, 12, or 18 MV) in four cases. The spinal cord was not part of the treated volume in any patient. Mucositis prophylaxis was supplied as usual in our department in treatment of the head-and-neck region. For the 2 days of treatment, patients were hospitalized for practical reasons. During and in the first days after treatment, they were seen by a doctor with regard to acute reactions. Actuarial survival has been calculated as a Kaplan-Meier estimate. RESULTS As all patients were treated with the intent only to palliate symptoms in rather advanced tumor recurrence, the results of therapy can hardly be described in terms of tumor remission. Results were assessed by clinical anamnesis referring to pain (reduction/stable/increase), with any increase of pain medication counted as “no response,” and by clinical examination regarding tumor swelling and ulceration. Palliation was ascribed to superfractionation when it occurred within one week after treatment without any other palliative measures. Overall palliation of symptoms, however, was achieved in 70% of our patients. It was best in 10/12 (83%) patients with pain, followed by 10/15 (67%) patients with tumor swelling, and 4/7 (57%) patients with ulcerating or exophytic tumor. Duration of response was 7.7 weeks in median, without a significant difference between the symptoms. Acute side effects of treatment have been seen in five patients, consisting of erythema (WHO Grade 1) in four patients and edema in one patient. We did not observe late effects of treatment in our patients. This may be due to the very limited prognosis, with a median survival time after treatment of four months (Fig. 1), which is too early to make definite statements about late effects. In the two patients surviving for longer than one year, we did not observe late effects, either, but these patients may not be representative. DISCUSSION The superfractionated treatment schedule we used for percutaneous radiotherapy was modified from the scheme
Palliative superfractionation for head-and-neck tumors
Fig. 1. Actuarial survival after superfractionated treatment.
first described by Busch and Alberti (7) in 1984 for intracavitary brachytherapy of recurrent tumors of the epipharynx performed with an Ir-192-HDR unit. They treated patients with 18 fractions to a total dose of 20 Gy or 24 Gy on two consecutive days. An advantage they claim for their therapy schedule is the reduction of side effects to normal tissue, due to protraction of dose compared to single-dose HDR therapy. More recently, de Pree et al. published their experience with pulsed dose rate (PDR) interstitial brachytherapy (8). Among their patients, 17 were treated for headand-neck disease and nine of them for recurrent tumor. Pulse doses of 0.4 to 1 Gy were given at 1-h intervals up to a total dose of 41.1 Gy. Side effects consisted of oral mucositis WHO Grade 3 in 23.5% of patients, half of them being treated for recurrent disease after previous radiotherapy, as well as erythema, xerostomia, and local necrosis in one patient. As our total dose of 16 Gy is considerably lower, and treatment was not applied in a 24-h schedule but in two blocks of seven treatment hours with a 17-h interval, the side effects we observed were lower, even though we treated a larger volume in pre-irradiated areas by percutaneous application. A radiobiologic basis for the use of a low-dose shortinterval regimen may be seen from the data of Woloschak et al., who describe a drop of total transcription within 15–30 min after in vitro exposure of Syrian Hamster Embryo (SHE) cells to low-dose irradiation (75 cGy X-rays or 90 cGy ␥-rays), with an increase beginning at 1 h post irradiation. In contrast to this, IL-1–specific mRNA was induced within 3 h after radiation exposure, which the authors concluded played a part in radioprotection on a cellular basis (9). As stated by Saunders (10), the linear quadratic formalism might fail to predict the effect of single doses in the range of 1 Gy and below. Especially so-called “radioresistant” cell lines might show a hypersensitivity to such schedules. Therefore we did not apply the radiobiologic formulas to our treatment schedule but just want to add our clinical data to this
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discussion. Nevertheless, we agree with Saunders (10) on the possible low-dose hypersensitivity of radioresistant tumors. The advantage of hyperfractionated therapy for squamous cell carcinoma of the head-and-neck has been evaluated by numerous clinical and radiobiologic studies and is reviewed in several meta-analyses (11, 12). It is based on different kinetics of sublethal damage repair in tumor cells and normal tissue. Half time of DNA strand repair is reported to be between 2 and 60 min, and a large part of lesions leading to chromosomal aberrations is eliminated within 1 h (13). As several radiobiologic studies have shown, hyperfractionation may reduce late toxicity without impairment of tumor control, due to smaller single doses (14). Repair half time of mouse lip mucosa at a twice daily hyperfractionation scheme was found to be 1 h by Ang et al. (2). From the CHART data, however, Bentzen et al. have recently calculated repair half times for laryngeal edema, skin telangiectasia, and s.c. fibrosis of 4 –5 h, which is much longer than was assumed so far (15) and may explain the sparing of late effects by CHART being lower and the incidence of myelitis higher than expected (16).With the single dose of 1 Gy used in our scheme, we might gain a greater effect in tumor than in acute or late reacting normal tissue according to the formalism developed by Joiner et al. for low dose in radiotherapy (17). Bumann et al. irradiated human fibroblasts with 1 Gy single dose and did not find a difference in response (colony formation reduced, BrdU incorporation unchanged) after multiple fractions in comparison to one single fraction (18). This might explain in part the lack of late effects in our long-surviving patients, but the experimental data cannot simply be transferred to our scheme, as the interfraction interval used was not one hour as in our series but one week. The uncertainty about late effects was the reason we offered this palliative radiotherapy scheme only to patients with very limited prognosis and in whom no other treatment option appeared promising. On this point, we agree with Denham et al.’s warning concerning consideration of late effects in new fractionation schedules (19). A different approach to altered fractionation was chosen by Percarpio and Fischer (20) and Henk and James (21), who examined the usefulness of higher single dose (4 Gy) vs. conventional fractionation for advanced head-and-neck cancer. Whereas Percarpio and Fischer (20) described a small benefit in disease-free survival for the large daily fraction group, Henk and James (21) did not find an advantage, neither in local control, nor in survival for high single doses applied one over the other day, but an increase in acute toxicity. Weppelmann et al. have treated patients with recurrent head-and-neck tumors with 5-fluorouracil, hydroxyurea, and re-irradiation every two weeks for four courses and report a response rate of 60% with a 1-year survival rate of 56% (22). In his series of full-dose reirradiation plus chemotherapy for recurrent head-and-neck tumors, De Crevoisier et al. (3) found an overall survival rate of 21% after 2 years and 9% after 5 years. Chemotherapy alone may also offer a palliative option for recurrent
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head-and-neck tumor patients. A good overview was given recently by Ganly and Kaye (23). Response rates of 30 – 40% and a median survival of 6 months are reported for the combination of cisplatin and 5-fluorouracil. New substances, such as the taxanes docetaxel and paclitaxel, can achieve response rates in the same range of 32% and 40%, respectively. A combination therapy with gemcitabine, producing a response in 41%, does not seem to increase results above the cisplatin/5-fluorouracil standard. Another approach, combining cisplatin and paclitaxel, seems more promising, with response rates of 67–77% being reported. Further treatment options for recurrent head-and-neck cancer may consist of IORT as reported by Calvo et al. (24). However, they observed local recurrence after resection and IORT in 7/9 pretreated patients. For mere palliative treatment of superficial recurrence, laser resection can also be used as a therapeutic option, as reported by Paiva et al. (25),
Volume 50, Number 1, 2001
with lasting tumor remission in 19/40 patients. Interstitial radiotherapy of recurrent head-and-neck tumors with or without hyperthermia may result in overall response rates (complete or partial remission) of 72– 89%, according to Emami et al. (26). Our results, however, are not quite comparable to these prospective studies, mostly performed on patients with good general condition and often treated after first recurrence. The patients reported here were treated merely under the aspect of palliation of tumor symptoms. For them, our treatment schedule of eight fractions with 1 Gy on two consecutive days is feasible without severe acute toxicity to skin or mucosa. It can successfully be used in palliative treatment of head-and-neck recurrences. Due to lack of experience with late toxicity, however, this treatment scheme should be reserved for patients without other treatment options.
REFERENCES 1. Watson JC, Ridge JA. Surgical management of local and regional recurrent head-and-neck squamous cell carcinoma. Curr Opin Oncol 1998;10:207–212. 2. Ang KK, Xu F-X, Landuyt W, van der Schueren E. The kinetics and capacity of repair of sublethal damage in mouse lip mucosa during fractionated irradiations. Int J Radiat Oncol Biol Phys 1985;11:1977–1983. 3. De Crevoisier R, Bourhis J, Domenge C, et al. Full-dose reirradiation for unresectable head-and-neck carcinoma. Experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 1998;16:3556 –3562. 4. Stewart FA. Re-treatment after full-course radiotherapy: Is it a viable option? Acta Oncol 1999;38:855– 862. 5. Toita T, Nakano M, Takizawa Y, et al. Intraoperative radiation therapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 1994;30:1219 –1224. 6. Spaeth J, Andreopoulos D, Unger T, et al. Intra-operative radiotherapy—5 years of experience in the palliative treatment of recurrent and advanced head-and-neck cancers. Oncology 1997;54:208 –213. 7. Busch M, Alberti W. Optimized afterloading application in case of tumors of the epipharynx. Strahlenther 1984;160:77– 80. 8. De Pree C, Popowski Y, Weber D, et al. Feasibility and tolerance of pulsed dose rate interstitial brachytherapy. Int J Radiat Oncol Biol Phys 1999;43:971–976. 9. Woloschak GE, Chang-Liu C, Jones PS, et al. Modulation of gene expression in syrian hamster embryo cells following ionizing irradiation. Cancer Res 1990;50:339 –344. 10. Saunders MI. Clinical superfractionation (Abstr.). Radiother Oncol 1998;48(Suppl. 1):S8. 11. Bentzen SM, Dische S. Altered fractionation in radiotherapy for head-and-neck cancer: Too early to close the race and announce the winner? Radiother Oncol 1999;51:105–107. 12. Stuschke M, Thames HD. Fractionation sensitivities and dosecontrol relations of head-and-neck carcinomas: Analysis of the randomized hyperfractionation trials. Radiother Oncol 1999;51: 113–121. 13. Hittelman WN, Pollard M. A comparison of the DNA and chromosome repair kinetics after ␥ irradiation. Radiat Res 1982;92:497–509. 14. Hagen U, Guttenberger R, Kummermehr J. Intracellular recovery— basis of hyperfractionation. Strahlenther Onkol 1988;164:653– 656.
15. Bentzen SM, Saunders MI, Dische S. Repair halftimes estimated from observations of treatment-related morbidity after CHART or conventional radiotherapy in head-and-neck cancer. Radiother Oncol 1999;53:219 –226. 16. Dische S, Saunders MI. The CHART regimen and morbidity. Acta Oncol 1999;38:147–152. 17. Joiner MC, Marples B, Johns B. The limitation of the linearquadratic model at low doses per fraction. In: Beck-Bornholdt H-P, editor. Current topics in clinical radiobiology of tumors. Berlin, Heidelberg: Springer-Verlag; 1993. p. 51– 66. 18. Bumann J, Sando-Ho¨ltje H, Lo¨ffler H, et al. Radiation-induced alterations the proliferation dynamics of human skin fibroblasts after repeated irradiation in the subtherapeutic dose range. Strahlenther Onkol 1995;171:35– 41. 19. Denham JW, Kron T, Hamilton CS. A timely reminder. Radiother Oncol 2000;56:129 –130. 20. Percarpio B, Fischer JJ. Irradiation of advanced head-andneck cancer with large daily fractions. Radiology 1976;121: 489 – 490. 21. Henk JM, James KW. Comparative trial of large and small fractions in the radiotherapy of head-and-neck cancer. Clin Radiol 1978;29:611– 616. 22. Weppelmann B, Wheeler RH, Peters GE, et al. Treatment of recurrent head-and-neck cancer with 5-fluorouracil, hydroxyurea and reirradiation. Int J Radiat Oncol Biol Phys 1992;22: 1051–1056. 23. Ganly I, Kaye SB. Recurrent squamous-cell carcinoma of the head-and-neck: Overview of current therapy and future prospects. Ann Oncol 2000;11:11–16. 24. Calvo FA, Abuchaibe O, Serra JM, et al. Head-and-neck cancer. In: Calvo FA, Santos M, Brady LW, editors. Medical radiology. Intraoperative Radiotherapy. Berlin, Heidelberg: Springer; 1992. p. 37– 41. 25. Paiva MB, Blackwell KE, Saxton RE, et al. Palliative laser therapy for recurrent head-and-neck cancer: A phase II clinical study. Laryngoscope 1998;108:1277–1283. 26. Emami B, Scott C, Perez CA, et al. Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1996;34:1097–1104.
PII S0360-3016(00)01567-4
CLINICAL INVESTIGATION
Head and Neck
PALLIATIVE RADIOTHERAPY IN RECURRENT HEAD-AND-NECK TUMORS BY A PERCUTANEOUS SUPERFRACTIONATED TREATMENT SCHEDULE URSULA MARIA SCHLEICHER, M.D.,* DEMETRIOS ANDREOPOULOS, M.D.,*† JUERGEN AMMON, M.D., DR.PHIL.*
AND
*Department of Radiotherapy of the RWTH, Technical University, Aachen, Germany; †Radiotherapy Department, BOC Oncology Centre, Nicosia, Cyprus Purpose: A frequent problem in treatment of patients with head-and-neck tumors is recurrence in pre-irradiated areas, thus limiting dose for another full-course radiotherapy. We present our experience with a percutaneous superfractionated short-term radiotherapy regimen that may be useful for palliative irradiation. Methods and Materials: Twenty-three patients with head-and-neck tumor recurrence after radiotherapy or extensive tumor growth have been treated by a superfractionated regimen. At each of two subsequent days, eight fractions of 1 Gy were applied with an interfraction interval of 1 h, resulting in a total dose of 16 Gy. Time between the last fraction of the first day and the first fraction of the second day was 17 h. Results: In 16 of 23 patients (70%), our irradiation schedule could achieve a palliative effect such as tumor necrosis or reduction of swelling or pain. Seven patients showed erythema (WHO I) at the end of the second day. Neither mucositis nor late effects of treatment were observed. Conclusions: Our superfractionated schedule is feasible without severe acute side reactions and can achieve a palliative effect in advanced or recurrent head-and-neck cancer. © 2001 Elsevier Science Inc. Head-and-neck cancer, Recurrence, Altered fractionation, Palliative treatment.
are recommended to achieve a long-term remission of tumor. Nevertheless, late complications occur more frequently than in primary therapy, with necrosis of soft tissue, bone, or mucosa, trismus, or even myelitis being reported (3, 4). Unfortunately, these favorable prognostic factors are rarely given. Thus, in most cases of clinical routine, treatment is performed with only palliative intent. A combination of surgery and radiotherapy, as in intraoperative irradiation (IORT) for recurrent head-and-neck disease, can be performed with curative intent in only a limited number of patients in whom an almost complete surgical removal of tumor seems feasible (5). In more advanced or larger tumors, IORT can only be performed with palliative intent (6). Brachytherapy has the advantage of sparing a large amount of normal tissue. As only a limited area can be treated, however, some tumors are too large or too difficult to be reached by interstitial brachytherapy with tumoricide doses. The percutaneous radiotherapy regimen we describe was derived from a schedule developed by Busch and Alberti (7) for brachytherapy treatment of recurrent epipharynx carcinoma. Originally performed at a high dose rate unit, it simulates a pulsed dose rate therapy. To our knowledge, no such fractionation has been described so far for percutaneous therapy.
INTRODUCTION Patients with head-and-neck cancer sometimes present with far advanced large tumors or massive lymphonodular bulk that is too extended to be treated with curative intent by surgery or radiotherapy. Similar situations may occur in recurrent tumors where therapeutic options are often limited by previous radiotherapy or surgical procedures. Surgical retreatment is often limited by fibrosis generating from previous surgery or radiotherapy or cannot be performed with curative intent due to tumor invasion into cervical nerves or vessels (1). Response to radiotherapy in badly vasculated and oxygenated tumors, often presenting with central necrosis, is known to be poor (2). Treatment of tumors recurring locally after radiotherapy, obviously originating from radioresistant cell lines, as they have survived primary treatment, faces numerous problems due to tolerance of surrounding normal tissue. Another course of therapy will be limited in dose but will control a less sensitive tumor than in primary therapy. Percutaneous treatment in such a situation may lead to long-term control and 5-year survival rates in the range of 20 – 40%, especially in patients with good prognostic factors, such as a long interval between primary and retreatment, good differentiation, and small tumors suitable for additional brachytherapy. Doses of 50 Gy or even up to 65 Gy Reprint requests to: Dr. Ursula Maria Schleicher, Department of Radiotherapy of the RWTH, University Hospital, Pauwelsstr. 30, D-52057 Aachen, Germany. Tel: ⫹49.241.8088777; Fax: ⫹49.241.8888425; E-mail: [email protected]
Accepted for publication 28 November 2000.
65
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Biology
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Physics
Table 1. Site of recurrence treated by superfractionated therapy Topography
Patients
Cervical lymph nodes Paranasal sinus Hypopharynx/larynx Floor of mouth Parotid gland Orbit (after exenteration in primary treatment) Skin of face
10 7 2 1 1 1 1
METHODS AND MATERIALS From 1989 to 1999, we treated 23 patients (7 female, 16 male) with advanced or recurrent tumors in the head-andneck region by a palliative treatment regimen. They were aged from 49 to 90 years (median: 68). Primary tumors were located at the oropharynx (4), hypopharynx (3), larynx (2), floor of the mouth (2), nose and paranasal sinuses (7), parotid gland (1), thyroid (1), and orbit (1), and two patients showed cervical lymph node involvement of an unknown primary tumor. Histology was squamous cell carcinoma in 18 patients, adenocarcinoma in three patients, and sarcoma in two. The site of recurrence treated by superfractionated therapy is shown in Table 1. Previous irradiation of the same site had been performed in all but one patient. Median time between the end of primary therapy and superfractionated treatment was 8.7 months (5 days to 5.5 years). Eleven patients had already received re-irradiation for tumor recurrence before starting the superfractionated schedule. Median time from the end of the last previous radiotherapy to the same site was 3.5 months. The radiotherapy courses and doses preceding superfractionation is shown in Table 2. Median cumulative dose of pre-irradiation was 59.4 Gy (ranging from 20 Gy IORT dose to 110.8 Gy from three percutaneous series). The symptoms to be palliated were swelling in 15 patients, pain in 12 patients, and ulcerating or exophytic tumor growth in seven patients, two of them preTable 2. Previous radiotherapy. IORT was used in one patient as solitary treatment for bad general condition not allowing percutaneous therapy, for the others in treatment of previous tumor recurrence. Number of patients None 1 percutaneous series 1 (IORT) 1 percutaneous series ⫹ 1 IORT 2 percutaneous series 2 percutaneous series ⫹ 1 IORT 2 percutaneous series ⫹ 3 IORT 3 percutaneous series Cumulative dose ⬍45 Gy Cumulative dose 45–60 Gy Cumulative dose 60–80 Gy Cumulative dose ⬎80 Gy IORT ⫽ intraoperative radiotherapy.
1 10 1 2 6 1 1 1 3 9 7 4
Volume 50, Number 1, 2001
senting with tumor bleeding. Eleven patients suffered from only one of the symptoms, the same number from two, and one patient from all of them. Quality of life was thus severely impaired in all of them. Patients selected for the described treatment schedule were regarded as having a very bad prognosis due to general condition and tumor extension. Other therapeutic options, such as surgery, IORT, or conventionally fractionated radiotherapy, did not seem feasible. Informed consent to treatment was obtained from all patients. Our treatment schedule consisted of 1-Gy single fractions, eight of which were applied on each of two consecutive treatment days with an interval of 1 h. The time between the last fraction on Day 1 and the first fraction on Day 2 was 17 h. Treatment volume, energy, and field arrangement were chosen individually according to tumor extension under palliative aspects. Treatment was performed at the telecobalt unit in the majority of patients (n ⫽ 17), with electrons in two cases and with linac photons (10, 12, or 18 MV) in four cases. The spinal cord was not part of the treated volume in any patient. Mucositis prophylaxis was supplied as usual in our department in treatment of the head-and-neck region. For the 2 days of treatment, patients were hospitalized for practical reasons. During and in the first days after treatment, they were seen by a doctor with regard to acute reactions. Actuarial survival has been calculated as a Kaplan-Meier estimate. RESULTS As all patients were treated with the intent only to palliate symptoms in rather advanced tumor recurrence, the results of therapy can hardly be described in terms of tumor remission. Results were assessed by clinical anamnesis referring to pain (reduction/stable/increase), with any increase of pain medication counted as “no response,” and by clinical examination regarding tumor swelling and ulceration. Palliation was ascribed to superfractionation when it occurred within one week after treatment without any other palliative measures. Overall palliation of symptoms, however, was achieved in 70% of our patients. It was best in 10/12 (83%) patients with pain, followed by 10/15 (67%) patients with tumor swelling, and 4/7 (57%) patients with ulcerating or exophytic tumor. Duration of response was 7.7 weeks in median, without a significant difference between the symptoms. Acute side effects of treatment have been seen in five patients, consisting of erythema (WHO Grade 1) in four patients and edema in one patient. We did not observe late effects of treatment in our patients. This may be due to the very limited prognosis, with a median survival time after treatment of four months (Fig. 1), which is too early to make definite statements about late effects. In the two patients surviving for longer than one year, we did not observe late effects, either, but these patients may not be representative. DISCUSSION The superfractionated treatment schedule we used for percutaneous radiotherapy was modified from the scheme
Palliative superfractionation for head-and-neck tumors
Fig. 1. Actuarial survival after superfractionated treatment.
first described by Busch and Alberti (7) in 1984 for intracavitary brachytherapy of recurrent tumors of the epipharynx performed with an Ir-192-HDR unit. They treated patients with 18 fractions to a total dose of 20 Gy or 24 Gy on two consecutive days. An advantage they claim for their therapy schedule is the reduction of side effects to normal tissue, due to protraction of dose compared to single-dose HDR therapy. More recently, de Pree et al. published their experience with pulsed dose rate (PDR) interstitial brachytherapy (8). Among their patients, 17 were treated for headand-neck disease and nine of them for recurrent tumor. Pulse doses of 0.4 to 1 Gy were given at 1-h intervals up to a total dose of 41.1 Gy. Side effects consisted of oral mucositis WHO Grade 3 in 23.5% of patients, half of them being treated for recurrent disease after previous radiotherapy, as well as erythema, xerostomia, and local necrosis in one patient. As our total dose of 16 Gy is considerably lower, and treatment was not applied in a 24-h schedule but in two blocks of seven treatment hours with a 17-h interval, the side effects we observed were lower, even though we treated a larger volume in pre-irradiated areas by percutaneous application. A radiobiologic basis for the use of a low-dose shortinterval regimen may be seen from the data of Woloschak et al., who describe a drop of total transcription within 15–30 min after in vitro exposure of Syrian Hamster Embryo (SHE) cells to low-dose irradiation (75 cGy X-rays or 90 cGy ␥-rays), with an increase beginning at 1 h post irradiation. In contrast to this, IL-1–specific mRNA was induced within 3 h after radiation exposure, which the authors concluded played a part in radioprotection on a cellular basis (9). As stated by Saunders (10), the linear quadratic formalism might fail to predict the effect of single doses in the range of 1 Gy and below. Especially so-called “radioresistant” cell lines might show a hypersensitivity to such schedules. Therefore we did not apply the radiobiologic formulas to our treatment schedule but just want to add our clinical data to this
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discussion. Nevertheless, we agree with Saunders (10) on the possible low-dose hypersensitivity of radioresistant tumors. The advantage of hyperfractionated therapy for squamous cell carcinoma of the head-and-neck has been evaluated by numerous clinical and radiobiologic studies and is reviewed in several meta-analyses (11, 12). It is based on different kinetics of sublethal damage repair in tumor cells and normal tissue. Half time of DNA strand repair is reported to be between 2 and 60 min, and a large part of lesions leading to chromosomal aberrations is eliminated within 1 h (13). As several radiobiologic studies have shown, hyperfractionation may reduce late toxicity without impairment of tumor control, due to smaller single doses (14). Repair half time of mouse lip mucosa at a twice daily hyperfractionation scheme was found to be 1 h by Ang et al. (2). From the CHART data, however, Bentzen et al. have recently calculated repair half times for laryngeal edema, skin telangiectasia, and s.c. fibrosis of 4 –5 h, which is much longer than was assumed so far (15) and may explain the sparing of late effects by CHART being lower and the incidence of myelitis higher than expected (16).With the single dose of 1 Gy used in our scheme, we might gain a greater effect in tumor than in acute or late reacting normal tissue according to the formalism developed by Joiner et al. for low dose in radiotherapy (17). Bumann et al. irradiated human fibroblasts with 1 Gy single dose and did not find a difference in response (colony formation reduced, BrdU incorporation unchanged) after multiple fractions in comparison to one single fraction (18). This might explain in part the lack of late effects in our long-surviving patients, but the experimental data cannot simply be transferred to our scheme, as the interfraction interval used was not one hour as in our series but one week. The uncertainty about late effects was the reason we offered this palliative radiotherapy scheme only to patients with very limited prognosis and in whom no other treatment option appeared promising. On this point, we agree with Denham et al.’s warning concerning consideration of late effects in new fractionation schedules (19). A different approach to altered fractionation was chosen by Percarpio and Fischer (20) and Henk and James (21), who examined the usefulness of higher single dose (4 Gy) vs. conventional fractionation for advanced head-and-neck cancer. Whereas Percarpio and Fischer (20) described a small benefit in disease-free survival for the large daily fraction group, Henk and James (21) did not find an advantage, neither in local control, nor in survival for high single doses applied one over the other day, but an increase in acute toxicity. Weppelmann et al. have treated patients with recurrent head-and-neck tumors with 5-fluorouracil, hydroxyurea, and re-irradiation every two weeks for four courses and report a response rate of 60% with a 1-year survival rate of 56% (22). In his series of full-dose reirradiation plus chemotherapy for recurrent head-and-neck tumors, De Crevoisier et al. (3) found an overall survival rate of 21% after 2 years and 9% after 5 years. Chemotherapy alone may also offer a palliative option for recurrent
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head-and-neck tumor patients. A good overview was given recently by Ganly and Kaye (23). Response rates of 30 – 40% and a median survival of 6 months are reported for the combination of cisplatin and 5-fluorouracil. New substances, such as the taxanes docetaxel and paclitaxel, can achieve response rates in the same range of 32% and 40%, respectively. A combination therapy with gemcitabine, producing a response in 41%, does not seem to increase results above the cisplatin/5-fluorouracil standard. Another approach, combining cisplatin and paclitaxel, seems more promising, with response rates of 67–77% being reported. Further treatment options for recurrent head-and-neck cancer may consist of IORT as reported by Calvo et al. (24). However, they observed local recurrence after resection and IORT in 7/9 pretreated patients. For mere palliative treatment of superficial recurrence, laser resection can also be used as a therapeutic option, as reported by Paiva et al. (25),
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with lasting tumor remission in 19/40 patients. Interstitial radiotherapy of recurrent head-and-neck tumors with or without hyperthermia may result in overall response rates (complete or partial remission) of 72– 89%, according to Emami et al. (26). Our results, however, are not quite comparable to these prospective studies, mostly performed on patients with good general condition and often treated after first recurrence. The patients reported here were treated merely under the aspect of palliation of tumor symptoms. For them, our treatment schedule of eight fractions with 1 Gy on two consecutive days is feasible without severe acute toxicity to skin or mucosa. It can successfully be used in palliative treatment of head-and-neck recurrences. Due to lack of experience with late toxicity, however, this treatment scheme should be reserved for patients without other treatment options.
REFERENCES 1. Watson JC, Ridge JA. Surgical management of local and regional recurrent head-and-neck squamous cell carcinoma. Curr Opin Oncol 1998;10:207–212. 2. Ang KK, Xu F-X, Landuyt W, van der Schueren E. The kinetics and capacity of repair of sublethal damage in mouse lip mucosa during fractionated irradiations. Int J Radiat Oncol Biol Phys 1985;11:1977–1983. 3. De Crevoisier R, Bourhis J, Domenge C, et al. Full-dose reirradiation for unresectable head-and-neck carcinoma. Experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 1998;16:3556 –3562. 4. Stewart FA. Re-treatment after full-course radiotherapy: Is it a viable option? Acta Oncol 1999;38:855– 862. 5. Toita T, Nakano M, Takizawa Y, et al. Intraoperative radiation therapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 1994;30:1219 –1224. 6. Spaeth J, Andreopoulos D, Unger T, et al. Intra-operative radiotherapy—5 years of experience in the palliative treatment of recurrent and advanced head-and-neck cancers. Oncology 1997;54:208 –213. 7. Busch M, Alberti W. Optimized afterloading application in case of tumors of the epipharynx. Strahlenther 1984;160:77– 80. 8. De Pree C, Popowski Y, Weber D, et al. Feasibility and tolerance of pulsed dose rate interstitial brachytherapy. Int J Radiat Oncol Biol Phys 1999;43:971–976. 9. Woloschak GE, Chang-Liu C, Jones PS, et al. Modulation of gene expression in syrian hamster embryo cells following ionizing irradiation. Cancer Res 1990;50:339 –344. 10. Saunders MI. Clinical superfractionation (Abstr.). Radiother Oncol 1998;48(Suppl. 1):S8. 11. Bentzen SM, Dische S. Altered fractionation in radiotherapy for head-and-neck cancer: Too early to close the race and announce the winner? Radiother Oncol 1999;51:105–107. 12. Stuschke M, Thames HD. Fractionation sensitivities and dosecontrol relations of head-and-neck carcinomas: Analysis of the randomized hyperfractionation trials. Radiother Oncol 1999;51: 113–121. 13. Hittelman WN, Pollard M. A comparison of the DNA and chromosome repair kinetics after ␥ irradiation. Radiat Res 1982;92:497–509. 14. Hagen U, Guttenberger R, Kummermehr J. Intracellular recovery— basis of hyperfractionation. Strahlenther Onkol 1988;164:653– 656.
15. Bentzen SM, Saunders MI, Dische S. Repair halftimes estimated from observations of treatment-related morbidity after CHART or conventional radiotherapy in head-and-neck cancer. Radiother Oncol 1999;53:219 –226. 16. Dische S, Saunders MI. The CHART regimen and morbidity. Acta Oncol 1999;38:147–152. 17. Joiner MC, Marples B, Johns B. The limitation of the linearquadratic model at low doses per fraction. In: Beck-Bornholdt H-P, editor. Current topics in clinical radiobiology of tumors. Berlin, Heidelberg: Springer-Verlag; 1993. p. 51– 66. 18. Bumann J, Sando-Ho¨ltje H, Lo¨ffler H, et al. Radiation-induced alterations the proliferation dynamics of human skin fibroblasts after repeated irradiation in the subtherapeutic dose range. Strahlenther Onkol 1995;171:35– 41. 19. Denham JW, Kron T, Hamilton CS. A timely reminder. Radiother Oncol 2000;56:129 –130. 20. Percarpio B, Fischer JJ. Irradiation of advanced head-andneck cancer with large daily fractions. Radiology 1976;121: 489 – 490. 21. Henk JM, James KW. Comparative trial of large and small fractions in the radiotherapy of head-and-neck cancer. Clin Radiol 1978;29:611– 616. 22. Weppelmann B, Wheeler RH, Peters GE, et al. Treatment of recurrent head-and-neck cancer with 5-fluorouracil, hydroxyurea and reirradiation. Int J Radiat Oncol Biol Phys 1992;22: 1051–1056. 23. Ganly I, Kaye SB. Recurrent squamous-cell carcinoma of the head-and-neck: Overview of current therapy and future prospects. Ann Oncol 2000;11:11–16. 24. Calvo FA, Abuchaibe O, Serra JM, et al. Head-and-neck cancer. In: Calvo FA, Santos M, Brady LW, editors. Medical radiology. Intraoperative Radiotherapy. Berlin, Heidelberg: Springer; 1992. p. 37– 41. 25. Paiva MB, Blackwell KE, Saxton RE, et al. Palliative laser therapy for recurrent head-and-neck cancer: A phase II clinical study. Laryngoscope 1998;108:1277–1283. 26. Emami B, Scott C, Perez CA, et al. Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1996;34:1097–1104.