- Email: [email protected]
Intraoperative single fraction high-dose-rate brachytherapy for head and neck cancers
Brachytherapy 4 (2005) 217–223
Intraoperative single fraction high-dose-rate brachytherapy for head and neck cancers Subir Nag1,*, Mehmet Koc1, David E. Schuller2, Douglas Tippin1, John C. Grecula1 1
Division of Radiation Oncology, The Arthur G. James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH 2 Department of Otolaryngology, Head and Neck Surgery, The Arthur G. James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH
ABSTRACT
PURPOSE: To report on the use of single fraction high-dose-rate brachytherapy in delivering localized intraoperative radiation therapy to sites in the head and neck region inaccessible to intraoperative electron beam radiotherapy (IOERT). METHODS AND MATERIALS: After maximal surgical resection, 7.5–20 Gy intraoperative high-dose-rate brachytherapy (IOHDR) was delivered to 65 patients using custom-made surface applicators. RESULTS: The 1-, 3-, and 5-year local control rates for the entire group were 77%, 69%, and 59%, respectively. The 1-, 3-, and 5-year overall survival rates were 83%, 63%, and 42%, respectively, with a median overall survival of 50 months. There were no major intraoperative or postoperative complications. CONCLUSIONS: IOHDR can be used to treat selected locally advanced head and neck tumors arising at sites inaccessible to IOERT or at institutions not using IOERT. A prospective multiinstitutional study with a larger number of patients treated with IOHDR is needed to firmly establish the efficacy of IOHDR in this population group. Ó 2005 American Brachytherapy Society. All rights reserved.
Keywords:
Head and neck neoplasms; Skull base; High-dose rate; Brachytherapy; Intraoperative radiotherapy
Introduction Head and neck cancers constitute about 5% of all newly diagnosed cases in the United States. Despite aggressive surgical and radiotherapeutic treatment, locally advanced tumors recur in 30–50% of patients (1, 2). Chemotherapy has produced encouraging results in nasopharyngeal, laryngeal, and pyriform sinus tumors (3–5). In an attempt to improve local control, a few centers have advocated the use of intraoperative electron beam radiotherapy (IOERT) as part of the overall management of
Received 8 June 2005; received in revised form 21 June 2005; accepted 21 June 2005. Financial disclosure: Supported in part by grant P30-CA 16058, National Cancer Institute, Bethesda, MD. * Corresponding author. Department of Radiation Medicine, Arthur G. James Cancer Hospital and Research Institute, The Ohio State University, 300 W. 10th Avenue, Columbus, OH 43210. Tel.: 11-614-293-3246; fax: 11-614-293-4044. E-mail address: [email protected] (S. Nag).
selected primary and recurrent head and neck tumors (6– 18). Some of the potential advantages include shielding and/or retraction of critical structures from the radiation beam and ability to visualize the tumor bed thereby minimizing treatment volume and avoiding geographic miss. Incorporating IOERT in primary management has led to local control rates on the order of 40–70% with acceptable complication rates (6, 7). However, IOERT has distinct limitations. It is not possible to use the IOERT applicator at certain sites in the base of the skull or in the periorbital and paranasal sinuses because of their narrow anatomy. Although not mandatory, it is preferable to perform IOERT with a dedicated intraoperative linear accelerator, which is available in only a few centers. Conventional brachytherapy, though possible, is difficult to deliver at the base of the skull and paranasal sinuses due to limited access. Further, it is not possible to shield critical tissues. Hence, in an effort to treat these relatively inaccessible sites optimally, an intraoperative high-dose rate (IOHDR) brachytherapy program was initiated at The Ohio State University in 1992. This report presents our
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entire experience with IOHDR in a variety of head and neck tumors to illustrate the scope of IOHDR in the head and neck area. Methods and materials The IOHDR procedure is performed as previously described (20, 21). In brief, the surgery is performed in a dedicated shielded surgery suite. After optimal resection of the primary site, the tumor bed is evaluated. The tumor bed may be grossly positive, grossly resected with microscopically positive or microscopically negative margins as determined by the surgeon, radiation oncologist, and the pathologist. Gold marker seeds are placed at the resection margins whenever possible to delineate the extent of the tumor to facilitate subsequent external beam radiation treatment (EBRT) planning. Gold marker seeds are preferred over surgical hemoclips that are used at some institutions because they are more radio-opaque and moreover cannot be confused with the hemoclips placed for hemostasis. At The Ohio State University, IOHDR is used only if IOERT cannot be performed, because the latter is faster, easier, and less personnel intensive. Sterile IOHDR applicators of various sizes and shapes with parallel in-built holes 1 cm apart are available in the operating room (Fig. 1). For flat or gently sloping surfaces, a silicone applicator with limited flexibility is used, whereas, for irregular or curved surfaces a foam applicator is more appropriate. Hollow plastic catheters are inserted into the holes of the selected applicator 1 cm apart and held in place using buttons and friction collars. The number of catheters varies depending on the target width and ranges from one to eight. The applicator with the embedded catheters is placed on the target volume and secured with sutures or gauze packing. In rare cases the catheters are sutured directly onto the tumor bed. In some instances, the overlying bone (usually the maxilla) may have to be resected to facilitate applicator positioning. The bone is subsequently regrafted after the IOHDR procedure. Critical structures adjoining the treatment volume are displaced with the aid of a retractor or gauze. Pliable and sterile lead sheets of various sizes are available, if needed, to shield the uninvolved critical normal tissues that cannot be displaced.
A radiograph is obtained with dummy sources placed in the catheters for verification/documentation and quality assurance. Whereas these radiographs are not used for brachytherapy treatment planning, they are useful in planning the postoperative EBRT field. While the clinician is preparing the IOHDR applicator, the brachytherapy technologist transports the remote highdose rate afterloading machine to the operating room and the physicist prepares the final treatment plan. The availability of preplanned dosimetry simplifies the treatment planning procedure and avoids delay. Treatment plans using parallel catheters 1 cm apart are available for the various applicators. As detailed in our previous report (19) equal dwell weights are used to permit dose intensification at the center of the target volume, which can be presumed to have the highest risk for residual tumor. In addition, quality assurance is simplified with fewer chances for error. This is very important in the intraoperative setting. The use of an optimized plan (with the dose optimized at a plane 1 cm from the catheter plane) will provide satisfactory dose homogeneity at 1 cm from the dwell positions. However, with an optimized plan, the dose distribution at the applicator surface (which is the presumed site of microscopic disease) has the undesirable effect of being higher at the periphery where there is low risk of disease, as opposed to the center that has the maximum risk for tumor but receives a lower dose (19). Under these circumstances, we prefer the treatment plan using equal dwell weights, which results in dose intensification at the tumor site but with lower doses to normal tissue sites (19). Occasionally, an applicator needs to be cut to custom fit the tumor bed. In these cases, the available treatment plan is modified. The final treatment plan is transferred over the network to the treatment console. The ends of the catheter are connected to the HDR machine after the required quality assurance checks. The dose delivered ranges from 7.5 to 20 Gy and is prescribed at 0.5 cm depth from the applicator surface (1 cm from the catheter plane) at the center of the implant. The treatment duration generally varies from 5 to 30 min depending on the treatment volume and source activity. During the entire treatment, the patient and the machine are monitored using video cameras and remote anesthesia monitors.
Fig. 1. Intraoperative HDR applicators made of foam (a) are used to treat irregular and sharply curved surfaces, whereas silicone-based applicators (b) are used to treat flat or gently sloping tumor beds.
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From January 1992 through March 2001, 65 patients (aged 9 to 80 years) with locally advanced tumors arising in the head and neck were treated with IOHDR of 7.5–20 Gy after maximal surgical excision. Fifty-three patients had new primaries, and supplementary local-field EBRT of 45– 50 Gy was planned postoperatively. However, only 46 patients actually received the EBRT, whereas 7 did not receive the planned EBRT for various reasons. Twelve patients with recurrent previously irradiated disease (45– 63 Gy) were treated with IOHDR of 15–20 Gy alone after gross excision. Of the 12 patients, 1 had an additional I-125 permanent brachytherapy for gross residual disease. Most patients had tumors arising in the paranasal sinuses. The predominant histopathology was squamous cell carcinoma. The treatment volume varied from 2 to 42 cm3 (median 8 cm3). See Table 1 for patient summary. The patients included in this report were treated with IOHDR on three different protocols: 1. Seven previously untreated patients with advanced squamous cell carcinomas of the oral cavity and oropharynx (Stages III and IV) and hypopharynx (Stages II–IV) who met the eligibility criteria were treated on our intensification protocol (12). They received concomitant, preoperative, continuous infusion of cis-platinum (80 mg/m2) chemotherapy and hyperfractionated EBRT (9.1 Gy in seven BID fractions), followed by surgical resection and IOHDR of 7.5 Gy at 0.5 cm depth. Four weeks postoperatively, EBRT was delivered to the primary site (40 Gy in 20 fractions) and neck (45 Gy in 20 fractions), together with cis-platinum (100 mg/m2) by rapid infusion on days 29 and 50. 2. In 46 previously nonirradiated patients with advanced head and neck tumors who did not meet the criteria for intensification protocol, the tumor was grossly resected with microscopically positive or negative margins. These patients were given an IOHDR of 10– 12.5 Gy. Supplementary EBRT of 45–50 Gy was planned 4 weeks postoperatively for all patients in this group. However, 7 patients did not receive the planned EBRT. Two patients died before EBRT could be delivered; 3 others refused further radiotherapy; 1 patient was unable to complete treatment because of deteriorating medical condition; and, in one case, EBRT was not delivered because of extensive postoperative reconstructive surgery. 3. Twelve patients had previously received 50–63 Gy EBRT and the tumor had recurred. After maximal resection, these patients were given a single IOHDR dose of 15–20 Gy at 0.5 cm depth for microscopically positive or negative margins. One patient had an additional I-125 permanent brachytherapy for the gross residual disease. The 1-, 3-, and 5-year local control rates, disease-free survival, and overall survival were analyzed using the
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Table 1 Patient summary Number of patients Mean age Range Disease status Primary disease Recurrent disease Metastatic
65 61 9–80 yr 53 11 1
Radiation therapy HDR alone HDR 1 EBRT HDR 1 I-125
18a 46 1
Mean radiation dose HDR (range 7.5–20 Gy) EBRT (range 20–60 Gy)
10 Gy 45.5 Gy
Margins Grossly positive Microscopically positive Microscopically negative
7 44 14
Sites irradiated Ethmoid Maxillary NP/sphenoid Pterygoid Orbit/cavernous sinus Tonsil Soft palate Nose
31 4 6 1 4 6 1 1
Nasal cavity Base of skull Tongue Parotid Retromolar region Base of skin Neck Histology Squamous Undifferentiated Esthesioneuroblastoma Melanoma Chondrosarcoma Adeno ca Adenoid cystic ca Otherb
3 1 3 1 1 1 1 33 6 6 3 2 5 2 8
a Includes 11 previously irradiated patients and 7 patients who did not receive their planned postoperative EBRT. b Other histologies include mucoepidermoid, basal cell, basoloid ca, Merkel’s cell ca, large cell, small cell, alveolar rhabdoid, and fibromatosis.
Kaplan–Meier method and compared using the log-rank test. Cox regression analysis was used to evaluate the effect of potentially prognostic variables.
Results The median followup was 65 months (range 3–133 months). Cox regression analysis was used to compare the following possible prognostic variables: primary vs. recurrent
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tumor, gross vs. close/micromargins, and IOHDR plus EBRT vs. IOHDR alone.
Local control Local control was defined as the absence of disease within the primary treated area. The 1-, 3-, and 5-year local control rates for the entire group were 77%, 69%, and 59%, respectively. Subgroup analysis showed that the presence of gross disease after surgical resection is the strongest prognosticator, with 5-year survival and local control rates of 17% and 33%, respectively, compared to 45% and 64% for microscopic disease ( p!0.01) (Table 2). Patients who received IOHDR plus EBRT and close/micromargins had significantly increased local control rates (p !0.05 and p !0.01) (Figs. 2 and 3).
Fig. 2. Effect of adding EBRT on local control rate (log rank, p !0.05).
Complications
Survival Overall survival was defined as the time from therapy to death from any cause. Disease-free survival was defined as survival without any evidence of disease. The 1-, 3-, and 5year overall survival rates were 83%, 63%, and 42%, respectively (Table 2 and Fig. 4). The median overall survival was 50 months (range 3–133). The 1-, 3-, and 5year disease-free survival results were 72%, 65%, and 52%, respectively. Subset analysis showed that patients with grossly negative (but microscopically positive or negative) margins had significantly increased disease-free survival compared to those with grossly positive margins ( p! 0.01) (Table 2 and Fig. 5). The addition of EBRT to IOHDR significantly increased overall survival (48% and 28%) (p !0.05) (Table 2 and Fig. 6).
Distant failure Distant failure was documented in 16 (25%) patients. In 2 patients the tumor recurred in the cervical lymph nodes.
There were no major intraoperative or acute postoperative complications. The rate of both acute and longterm morbidities was acceptable and comparable to those seen in patients historically treated with surgery and EBRT alone. Other than an incidence of perioperative bacteremia and delayed wound healing, there were no major postoperative complications. Xerostomia (most likely from the EBRT component) was the most common long-term complication identified. Others observed were mild unilateral facial paralysis, enophthalmos, tearing (2 patients) that resolved within 2 years, double vision (2 patients), ptosis, and trismus (2 patients). It was difficult to differentiate morbidity due to radiotherapy from that due to surgery. There were three deaths attributed to postoperative complications and another due to septicemia subsequent to chemotherapy. Six patients died from unrelated causes. No increased acute or late side effects were observed in patients treated with IOHDR for recurrent disease, despite previous external beam irradiation.
Table 2 Results of IOHDR Local control (%)
Disease free (%)
Overall survival (%)
1 year 3 years 5 years
77 69 59
72 65 52
83 63 42
HDR 1 XRT HDR alone
65a 46
63 53
48a 28
Primary Recurrent
73 50
60 59
45 30
Gross margin Micromargin
33b 64
17b 65
17 45
a
p!0.05. p!0.01.
b
Fig. 3. Effect of gross vs. microscopic margins on local control rate (log rank, p!0.01).
S. Nag et al. / Brachytherapy 4 (2005) 217–223
Fig. 4. Overall survival of all patients in months.
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Fig. 6. Effect of adding EBRT on the overall survival (log rank, p !0.05).
Discussion The control rates of advanced head and neck tumors, especially those arising from the paranasal and adjoining base of skull sites, remain dismal. The conventional treatment has been surgery and postoperative EBRT. The location of these tumors and their proximity to critical structures make complete surgical resection difficult. Higher doses of EBRT can lead to an improvement in local control, but they increase the long-term morbidity. IOERT is a novel treatment approach to improve the therapeutic ratio. Most experience gained from intraoperative radiotherapy to head and neck cancer has been with the use of IOERT, which has produced encouraging results in advanced and recurrent head and neck cancers (6–12, 14, 15, 17, 18, 23, 24). However, complications such as carotid blowout and radionecrosis due to the use of higher intraoperative radiation doses (20–30 Gy) emanated in the early experience with this modality (6–8). In a review of 92 patients with recurrent head and neck cancers treated
Fig. 5. Effect of gross vs. microscopic margins on disease-free survival (log rank, p ! 0.01).
intraoperatively by electron beam, Ir-192, or I-125, Verniers et al. (22) reported a mean local control rate of 63%, mean survival of 49%, and mortality of 8.5%. The local control rate for advanced and recurrent head and neck cancers with IOERT has been reported at 40–64% (6, 7, 10). Better local control has been achieved with close and microscopic surgical margins compared to those seen when gross residual disease remains. Freeman et al. observed that most failures in IOERT cases occurred outside the IOERT port. To minimize these failures, they suggested the use of multiple abutting IOERT ports. However, the use of the latter would require prolonged periods with the patient under general anesthesia, and it creates areas of overdosing or underdosing at the site of field overlap. Relatively inferior results are seen with inaccessible tumors located in the base of the skull treated with IOERT (46–52% control rate), compared to results seen with tumors of the parotid and base of tongue, which are easily accessible (57–69% local control) (23, 24). The addition of IOERT to conventional therapy has shown encouraging local control. However, the use of IOERT requires a rigid applicator whose placement is limited by the skull base anatomy because the electron beam must travel along a straight path, and the IOERT applicator cannot be placed into a narrow cavity. IOHDR was introduced as an alternative treatment modality to tumors at sites inaccessible to IOERT (20). Because IOHDR catheters are sufficiently flexible to accommodate the contours of the skull base, thus allowing the therapy to be delivered along a curved pathway and into narrow cavities, IOHDR can be used to treat areas in the skull base that are inaccessible to the IOERT applicator. Moreover, IOHDR irradiates from all surfaces of the applicator. When the applicator is positioned in the sinus cavity, one surface irradiates the cribriform plate, whereas the other surfaces irradiate the possible microscopic disease in the lateral sinus, deep in the sphenoid sinus and the inferior orbit. This is an important issue in sinuses that have irregular
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surfaces and those that cannot be easily encompassed by other techniques. The Ohio State University has a dedicated linear accelerator in a shielded operating suite. Our policy has been to treat tumors at accessible head and neck sites with IOERT and to reserve IOHDR for those tumor locations that cannot be treated with IOERT. The overall operating time is extended by about 30–60 min for IOERT and about 60–90 min for IOHDR. The actual treatment time is 2–3 min for the IOERT and about 5–20 min for IOHDR. Although we use IOHDR only at sites inaccessible to IOERT, institutions not possessing a dedicated intraoperative linear accelerator can perform IOHDR at all head and neck sites. The present study of 56 cases with primary disease showed an impressive 3-year local control and survival, which compared favorably with those seen in groups historically treated with conventional methods with or without IOERT (1, 5–7, 9–11, 15, 17, 18, 22, 23). Twelve patients with recurrent disease achieved poor local control. These patients were treated after surgery with an IOHDR dose ranging from 15 to 20 Gy. One patient received additional EBRT (20 Gy) and is free of disease and the other received 60 Gy of EBRT and is alive with disease in the neck node. A third patient had an I-125 seed implant in addition to a dose of 140 Gy, but died of postoperative complications. Although this is a small number of patients, it does suggest a potential role for supplementary EBRT in achieving reasonable tumor control in this unfavorable group. Enhanced tumor control with minimal long-term morbidity has been obtained using fractionated EBRT and low-dose rate brachytherapy (25, 26). IOHDR is potentially disadvantageous because it is given in a single fraction. The use of biological models including the linear quadratic formula (27) and animal experiments (28, 29), may predict isoeffect doses and toxicity, but their limitations must be borne in mind (30). In our current study, 10 Gy of IOHDR is equivalent to 16.7 Gy of conventionally fractionated radiotherapy for early reacting tissue effects (alpha–beta ratio 5 10). For late reacting tissue, the figure is 22–29 Gy, depending on the alpha–beta ratio used. The corresponding figures for 15 Gy of IOHDR are 31–35 Gy for tumor effects and 45–58 Gy for late effects; whereas the corresponding figures for 20 Gy of IOHDR are 50–56 Gy for tumor effects and 80–100 Gy for late effects. The doses obtained vary depending on the alpha–beta ratio and the repair kinetics chosen. This model has aided us in using a judicious combination of EBRT and IOHDR. Equally important has been its role in preventing excessive long-term morbidity by facilitating the choice of appropriate doses. Recently, Nag and Gupta (30) have developed an Excel (Microsoft Corp., Redmond, WA) spread sheet program to derive biologically equivalent doses for HDR brachytherapy. The linear quadratic formula is used to derive the BED, and then the BED is reconverted to express the doses as if they
were given at 2 Gy/fraction and thus be more meaningful to the clinicians. Because time is of essence in IOHDR, this program has been used in the operating room to calculate bioequivalent doses rapidly when required to modify the required dose. In IOHDR, the dose is prescribed at 0.5 cm depth in the tissue. However, due to the inverse square law, the actual dose at the surface (which is the site of microscopic residual tumor after resection) is about twice the prescribed dose, whereas radiosensitive structures (brain, optic nerve) located deeper receive much less radiation than the prescribed dose. Hence, IOHDR is more suited for the treatment of microscopic disease in tumor beds, rather than gross disease deep within tissues. Based on the gratifying results obtained, we now routinely incorporate IOHDR brachytherapy in conjunction with EBRT and optimum surgery in the management of tumors arising in the paranasal sinus and base of skull sites. IOHDR is also strongly considered in the treatment of selected recurrent cases. We now routinely add a limited dose of EBRT even in previously irradiated patients. However, the experience in using IOHDR for head and neck cancers has thus far been restricted only to Ohio State University (20, 31). Given the advantages of this treatment modality in the management of head and neck cancers and the availability of IOHDR in a handful of institutions, we would welcome multicenter studies that can help further define the role of IOHDR in this poor risk patient population. Conclusions IOHDR can be used to treat selected locally advanced head and neck tumors arising at sites inaccessible to IOERT or at institutions not performing IOERT. IOHDR enhances local control and overall survival in previously unirradiated patients if supplemented with EBRT. A prospective multiinstitutional study with a larger number of patients treated with IOHDR is needed to firmly establish the efficacy of IOHDR in this population group. The results of IOHDR are disappointing in recurrent and previously irradiated patients. Additional EBRT and higher IOHDR doses are considered for the latter group. References [1] Amdur RJ, Parson JT, Mendenhall WM, et al. Postoperative irradiation for squamous cell carcinoma of the head and neck: An analysis of treatment results and complications. Int J Radiat Oncol Biol Phys 1989;16:25–36. [2] Chen TY, Emrich LJ, Driscoll DL. The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys 1987;13:833–837. [3] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091–2098. [4] Lefebrre JL, Chevalier D, Luboinski B, et al. Larynx preservation in piriform sinus cancer: Preliminary results of a European Organization
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for Research and Treatment of Cancer Phase III Trial. J Natl Cancer Inst 1996;88:890–899. Al-Sarraf M, LeBlanc M, Giri PGS, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310– 1317. Freeman SB, Hamaker RC, Singer MI, et al. Intraoperative radiotherapy of head and neck cancer. Arch Otolaryngol Head Neck Surg 1990;116:165–168. Freeman SB, Hamaker RC, Singer MI, et al. Intraoperative radiotherapy of skull base cancer. Laryngoscope 1991;101:507–509. Haller J, Mountain RE, Schuller DE, et al. Mortality and morbidity with intraoperative radiotherapy for head and neck cancer. Am J Otolaryngol 1996;17:308–310. Katoshi D, Kuth G, Schmachtenberg A, et al. Intraoperative radiotherapy in recurrent head and neck cancer, data of 25 patients. Strahlenther Onkol 1992;168:470–472. Rate WR, Garrett P, Hamaker R, et al. Intraoperative radiation therapy for recurrent head and neck cancer. Cancer 1991;67:2738–2740. Toita T, Nakano M, Takizawa Y, et al. Intraoperative radiation therapy (IOERT) for head and neck cancer. Int J Radiat Oncol Biol Phys 1994;30:1219–1224. Schuller DE, Grecula JC, Gahbauer RA, et al. Intensification regimen for previously untreated resectable advanced stage squamous cell carcinoma of the oral cavity, oropharynx, and hypopharynx. Arch Otolaryngol Head Neck Surg 1997;123:139–144. Nag S, Martinez-Monge R, Gupta N. Intraoperative radiation therapy using electron-beam and high-dose-rate brachytherapy. Cancer J 1997;10:94–101. Nag S, Schuller DE, Martinez-Monge R, et al. Intraoperative electron beam radiotherapy for previously irradiated advanced head and neck malignancies. Int J Radiat Oncol Biol Phys 1998;42:1085–1089. Coleman C, Roach M 3rd, Ling S, et al. Adjuvant electron-beam IORT in high-risk head and neck cancer patients. Front Radiat Ther Oncol 1997;31:105–111. Nag S, Schuller D, Pak V, et al. Intraoperative radiation therapy using electron beam or HDR brachytherapy for previously unirradiated head and neck cancers. Front Radiat Ther Oncol 1997;31:112–116. Martı´nez-Monge R, Azinovic I, Alcalde J, et al. IORT in the management of locally advanced or recurrent head and neck cancer. Front Radiat Oncol 1997;31:122–125.
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[18] Spaeth J, Andropulus 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. [19] Nag S, Samsami N. Pitfalls of inappropriate optimization. J Brachytherapy Int 2000;16:187–198. [20] Nag S, Schuller D, Pak V, et al. Pilot study of intraoperative high dose rate brachytherapy for head and neck cancer. Radiother Oncol 1996;41:125–130. [21] Nag S, Orton C. Development of intraoperative high dose rate brachytherapy for treatment of resected tumor beds in anesthetized patients. Endocuriether Hypertherm Oncol 1993;9:187–193. [22] Verniers DAAG, Koper PCM, Visser AG, et al. IORT for primary or recurrent cancer with special reference to intraoperative brachytherapy. Activity International Selectron Brachytherapy J Special report 1993;No.1:1–16. [23] Pinheiro AD, Foote RL, McCaffrey TV, et al. Intraoperative radiotherapy for head and neck and skull base cancer. Head Neck 2003;25:217–226. [24] Schmitt T, Prades J, Pinto N, et al. Carcinoma of the oropharynx extended to the base of the tongue: Radiosurgical treatment with intraoperative radiotherapy. Bull Cancer Radiother 1996;83:79–85. [25] Vikram B, Hilaris BS, Anderson L, et al. Permanent iodine-125 implants in head and neck cancer. Cancer 1983;51:1310–1314. [26] Beitler JJ, Vikram B, Levendag P. Brachytherapy for cancer of head and neck. In: Nag S, editor. Principles and practice of brachytherapy. Armonk, NY: Futura Publ Co., Inc., 1997. P. 269–290. [27] Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–694. [28] Kinsella TJ, Deluca AM, Barnes M, et al. Threshold dose for peripheral neuropathy following intraoperative radiotherapy (IORT) in a large animal model. Int J Radiat Oncol Biol Phys 1991;20: 697. [29] Shaw E, Gunderson L, Martin K, et al. Peripheral nerve and ureteral tolerance to intraoperative radiation therapy: Clinical and dose– response analysis. Radiother Oncol 1990;18:247–255. [30] Nag S, Gupta N. A simple method of obtaining equivalent doses for use in HDR brachytherapy. Int J Radiat Oncol Biol Phys 2000;46: 507–513. [31] Nag S, Tippin D, Grecula J, et al. Intraoperative high dose rate brachytherapy for paranasal sinus tumors. Int J Radiat Oncol Biol Phys 2004;58:155–160.
Intraoperative single fraction high-dose-rate brachytherapy for head and neck cancers Subir Nag1,*, Mehmet Koc1, David E. Schuller2, Douglas Tippin1, John C. Grecula1 1
Division of Radiation Oncology, The Arthur G. James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH 2 Department of Otolaryngology, Head and Neck Surgery, The Arthur G. James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH
ABSTRACT
PURPOSE: To report on the use of single fraction high-dose-rate brachytherapy in delivering localized intraoperative radiation therapy to sites in the head and neck region inaccessible to intraoperative electron beam radiotherapy (IOERT). METHODS AND MATERIALS: After maximal surgical resection, 7.5–20 Gy intraoperative high-dose-rate brachytherapy (IOHDR) was delivered to 65 patients using custom-made surface applicators. RESULTS: The 1-, 3-, and 5-year local control rates for the entire group were 77%, 69%, and 59%, respectively. The 1-, 3-, and 5-year overall survival rates were 83%, 63%, and 42%, respectively, with a median overall survival of 50 months. There were no major intraoperative or postoperative complications. CONCLUSIONS: IOHDR can be used to treat selected locally advanced head and neck tumors arising at sites inaccessible to IOERT or at institutions not using IOERT. A prospective multiinstitutional study with a larger number of patients treated with IOHDR is needed to firmly establish the efficacy of IOHDR in this population group. Ó 2005 American Brachytherapy Society. All rights reserved.
Keywords:
Head and neck neoplasms; Skull base; High-dose rate; Brachytherapy; Intraoperative radiotherapy
Introduction Head and neck cancers constitute about 5% of all newly diagnosed cases in the United States. Despite aggressive surgical and radiotherapeutic treatment, locally advanced tumors recur in 30–50% of patients (1, 2). Chemotherapy has produced encouraging results in nasopharyngeal, laryngeal, and pyriform sinus tumors (3–5). In an attempt to improve local control, a few centers have advocated the use of intraoperative electron beam radiotherapy (IOERT) as part of the overall management of
Received 8 June 2005; received in revised form 21 June 2005; accepted 21 June 2005. Financial disclosure: Supported in part by grant P30-CA 16058, National Cancer Institute, Bethesda, MD. * Corresponding author. Department of Radiation Medicine, Arthur G. James Cancer Hospital and Research Institute, The Ohio State University, 300 W. 10th Avenue, Columbus, OH 43210. Tel.: 11-614-293-3246; fax: 11-614-293-4044. E-mail address: [email protected] (S. Nag).
selected primary and recurrent head and neck tumors (6– 18). Some of the potential advantages include shielding and/or retraction of critical structures from the radiation beam and ability to visualize the tumor bed thereby minimizing treatment volume and avoiding geographic miss. Incorporating IOERT in primary management has led to local control rates on the order of 40–70% with acceptable complication rates (6, 7). However, IOERT has distinct limitations. It is not possible to use the IOERT applicator at certain sites in the base of the skull or in the periorbital and paranasal sinuses because of their narrow anatomy. Although not mandatory, it is preferable to perform IOERT with a dedicated intraoperative linear accelerator, which is available in only a few centers. Conventional brachytherapy, though possible, is difficult to deliver at the base of the skull and paranasal sinuses due to limited access. Further, it is not possible to shield critical tissues. Hence, in an effort to treat these relatively inaccessible sites optimally, an intraoperative high-dose rate (IOHDR) brachytherapy program was initiated at The Ohio State University in 1992. This report presents our
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entire experience with IOHDR in a variety of head and neck tumors to illustrate the scope of IOHDR in the head and neck area. Methods and materials The IOHDR procedure is performed as previously described (20, 21). In brief, the surgery is performed in a dedicated shielded surgery suite. After optimal resection of the primary site, the tumor bed is evaluated. The tumor bed may be grossly positive, grossly resected with microscopically positive or microscopically negative margins as determined by the surgeon, radiation oncologist, and the pathologist. Gold marker seeds are placed at the resection margins whenever possible to delineate the extent of the tumor to facilitate subsequent external beam radiation treatment (EBRT) planning. Gold marker seeds are preferred over surgical hemoclips that are used at some institutions because they are more radio-opaque and moreover cannot be confused with the hemoclips placed for hemostasis. At The Ohio State University, IOHDR is used only if IOERT cannot be performed, because the latter is faster, easier, and less personnel intensive. Sterile IOHDR applicators of various sizes and shapes with parallel in-built holes 1 cm apart are available in the operating room (Fig. 1). For flat or gently sloping surfaces, a silicone applicator with limited flexibility is used, whereas, for irregular or curved surfaces a foam applicator is more appropriate. Hollow plastic catheters are inserted into the holes of the selected applicator 1 cm apart and held in place using buttons and friction collars. The number of catheters varies depending on the target width and ranges from one to eight. The applicator with the embedded catheters is placed on the target volume and secured with sutures or gauze packing. In rare cases the catheters are sutured directly onto the tumor bed. In some instances, the overlying bone (usually the maxilla) may have to be resected to facilitate applicator positioning. The bone is subsequently regrafted after the IOHDR procedure. Critical structures adjoining the treatment volume are displaced with the aid of a retractor or gauze. Pliable and sterile lead sheets of various sizes are available, if needed, to shield the uninvolved critical normal tissues that cannot be displaced.
A radiograph is obtained with dummy sources placed in the catheters for verification/documentation and quality assurance. Whereas these radiographs are not used for brachytherapy treatment planning, they are useful in planning the postoperative EBRT field. While the clinician is preparing the IOHDR applicator, the brachytherapy technologist transports the remote highdose rate afterloading machine to the operating room and the physicist prepares the final treatment plan. The availability of preplanned dosimetry simplifies the treatment planning procedure and avoids delay. Treatment plans using parallel catheters 1 cm apart are available for the various applicators. As detailed in our previous report (19) equal dwell weights are used to permit dose intensification at the center of the target volume, which can be presumed to have the highest risk for residual tumor. In addition, quality assurance is simplified with fewer chances for error. This is very important in the intraoperative setting. The use of an optimized plan (with the dose optimized at a plane 1 cm from the catheter plane) will provide satisfactory dose homogeneity at 1 cm from the dwell positions. However, with an optimized plan, the dose distribution at the applicator surface (which is the presumed site of microscopic disease) has the undesirable effect of being higher at the periphery where there is low risk of disease, as opposed to the center that has the maximum risk for tumor but receives a lower dose (19). Under these circumstances, we prefer the treatment plan using equal dwell weights, which results in dose intensification at the tumor site but with lower doses to normal tissue sites (19). Occasionally, an applicator needs to be cut to custom fit the tumor bed. In these cases, the available treatment plan is modified. The final treatment plan is transferred over the network to the treatment console. The ends of the catheter are connected to the HDR machine after the required quality assurance checks. The dose delivered ranges from 7.5 to 20 Gy and is prescribed at 0.5 cm depth from the applicator surface (1 cm from the catheter plane) at the center of the implant. The treatment duration generally varies from 5 to 30 min depending on the treatment volume and source activity. During the entire treatment, the patient and the machine are monitored using video cameras and remote anesthesia monitors.
Fig. 1. Intraoperative HDR applicators made of foam (a) are used to treat irregular and sharply curved surfaces, whereas silicone-based applicators (b) are used to treat flat or gently sloping tumor beds.
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From January 1992 through March 2001, 65 patients (aged 9 to 80 years) with locally advanced tumors arising in the head and neck were treated with IOHDR of 7.5–20 Gy after maximal surgical excision. Fifty-three patients had new primaries, and supplementary local-field EBRT of 45– 50 Gy was planned postoperatively. However, only 46 patients actually received the EBRT, whereas 7 did not receive the planned EBRT for various reasons. Twelve patients with recurrent previously irradiated disease (45– 63 Gy) were treated with IOHDR of 15–20 Gy alone after gross excision. Of the 12 patients, 1 had an additional I-125 permanent brachytherapy for gross residual disease. Most patients had tumors arising in the paranasal sinuses. The predominant histopathology was squamous cell carcinoma. The treatment volume varied from 2 to 42 cm3 (median 8 cm3). See Table 1 for patient summary. The patients included in this report were treated with IOHDR on three different protocols: 1. Seven previously untreated patients with advanced squamous cell carcinomas of the oral cavity and oropharynx (Stages III and IV) and hypopharynx (Stages II–IV) who met the eligibility criteria were treated on our intensification protocol (12). They received concomitant, preoperative, continuous infusion of cis-platinum (80 mg/m2) chemotherapy and hyperfractionated EBRT (9.1 Gy in seven BID fractions), followed by surgical resection and IOHDR of 7.5 Gy at 0.5 cm depth. Four weeks postoperatively, EBRT was delivered to the primary site (40 Gy in 20 fractions) and neck (45 Gy in 20 fractions), together with cis-platinum (100 mg/m2) by rapid infusion on days 29 and 50. 2. In 46 previously nonirradiated patients with advanced head and neck tumors who did not meet the criteria for intensification protocol, the tumor was grossly resected with microscopically positive or negative margins. These patients were given an IOHDR of 10– 12.5 Gy. Supplementary EBRT of 45–50 Gy was planned 4 weeks postoperatively for all patients in this group. However, 7 patients did not receive the planned EBRT. Two patients died before EBRT could be delivered; 3 others refused further radiotherapy; 1 patient was unable to complete treatment because of deteriorating medical condition; and, in one case, EBRT was not delivered because of extensive postoperative reconstructive surgery. 3. Twelve patients had previously received 50–63 Gy EBRT and the tumor had recurred. After maximal resection, these patients were given a single IOHDR dose of 15–20 Gy at 0.5 cm depth for microscopically positive or negative margins. One patient had an additional I-125 permanent brachytherapy for the gross residual disease. The 1-, 3-, and 5-year local control rates, disease-free survival, and overall survival were analyzed using the
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Table 1 Patient summary Number of patients Mean age Range Disease status Primary disease Recurrent disease Metastatic
65 61 9–80 yr 53 11 1
Radiation therapy HDR alone HDR 1 EBRT HDR 1 I-125
18a 46 1
Mean radiation dose HDR (range 7.5–20 Gy) EBRT (range 20–60 Gy)
10 Gy 45.5 Gy
Margins Grossly positive Microscopically positive Microscopically negative
7 44 14
Sites irradiated Ethmoid Maxillary NP/sphenoid Pterygoid Orbit/cavernous sinus Tonsil Soft palate Nose
31 4 6 1 4 6 1 1
Nasal cavity Base of skull Tongue Parotid Retromolar region Base of skin Neck Histology Squamous Undifferentiated Esthesioneuroblastoma Melanoma Chondrosarcoma Adeno ca Adenoid cystic ca Otherb
3 1 3 1 1 1 1 33 6 6 3 2 5 2 8
a Includes 11 previously irradiated patients and 7 patients who did not receive their planned postoperative EBRT. b Other histologies include mucoepidermoid, basal cell, basoloid ca, Merkel’s cell ca, large cell, small cell, alveolar rhabdoid, and fibromatosis.
Kaplan–Meier method and compared using the log-rank test. Cox regression analysis was used to evaluate the effect of potentially prognostic variables.
Results The median followup was 65 months (range 3–133 months). Cox regression analysis was used to compare the following possible prognostic variables: primary vs. recurrent
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tumor, gross vs. close/micromargins, and IOHDR plus EBRT vs. IOHDR alone.
Local control Local control was defined as the absence of disease within the primary treated area. The 1-, 3-, and 5-year local control rates for the entire group were 77%, 69%, and 59%, respectively. Subgroup analysis showed that the presence of gross disease after surgical resection is the strongest prognosticator, with 5-year survival and local control rates of 17% and 33%, respectively, compared to 45% and 64% for microscopic disease ( p!0.01) (Table 2). Patients who received IOHDR plus EBRT and close/micromargins had significantly increased local control rates (p !0.05 and p !0.01) (Figs. 2 and 3).
Fig. 2. Effect of adding EBRT on local control rate (log rank, p !0.05).
Complications
Survival Overall survival was defined as the time from therapy to death from any cause. Disease-free survival was defined as survival without any evidence of disease. The 1-, 3-, and 5year overall survival rates were 83%, 63%, and 42%, respectively (Table 2 and Fig. 4). The median overall survival was 50 months (range 3–133). The 1-, 3-, and 5year disease-free survival results were 72%, 65%, and 52%, respectively. Subset analysis showed that patients with grossly negative (but microscopically positive or negative) margins had significantly increased disease-free survival compared to those with grossly positive margins ( p! 0.01) (Table 2 and Fig. 5). The addition of EBRT to IOHDR significantly increased overall survival (48% and 28%) (p !0.05) (Table 2 and Fig. 6).
Distant failure Distant failure was documented in 16 (25%) patients. In 2 patients the tumor recurred in the cervical lymph nodes.
There were no major intraoperative or acute postoperative complications. The rate of both acute and longterm morbidities was acceptable and comparable to those seen in patients historically treated with surgery and EBRT alone. Other than an incidence of perioperative bacteremia and delayed wound healing, there were no major postoperative complications. Xerostomia (most likely from the EBRT component) was the most common long-term complication identified. Others observed were mild unilateral facial paralysis, enophthalmos, tearing (2 patients) that resolved within 2 years, double vision (2 patients), ptosis, and trismus (2 patients). It was difficult to differentiate morbidity due to radiotherapy from that due to surgery. There were three deaths attributed to postoperative complications and another due to septicemia subsequent to chemotherapy. Six patients died from unrelated causes. No increased acute or late side effects were observed in patients treated with IOHDR for recurrent disease, despite previous external beam irradiation.
Table 2 Results of IOHDR Local control (%)
Disease free (%)
Overall survival (%)
1 year 3 years 5 years
77 69 59
72 65 52
83 63 42
HDR 1 XRT HDR alone
65a 46
63 53
48a 28
Primary Recurrent
73 50
60 59
45 30
Gross margin Micromargin
33b 64
17b 65
17 45
a
p!0.05. p!0.01.
b
Fig. 3. Effect of gross vs. microscopic margins on local control rate (log rank, p!0.01).
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Fig. 4. Overall survival of all patients in months.
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Fig. 6. Effect of adding EBRT on the overall survival (log rank, p !0.05).
Discussion The control rates of advanced head and neck tumors, especially those arising from the paranasal and adjoining base of skull sites, remain dismal. The conventional treatment has been surgery and postoperative EBRT. The location of these tumors and their proximity to critical structures make complete surgical resection difficult. Higher doses of EBRT can lead to an improvement in local control, but they increase the long-term morbidity. IOERT is a novel treatment approach to improve the therapeutic ratio. Most experience gained from intraoperative radiotherapy to head and neck cancer has been with the use of IOERT, which has produced encouraging results in advanced and recurrent head and neck cancers (6–12, 14, 15, 17, 18, 23, 24). However, complications such as carotid blowout and radionecrosis due to the use of higher intraoperative radiation doses (20–30 Gy) emanated in the early experience with this modality (6–8). In a review of 92 patients with recurrent head and neck cancers treated
Fig. 5. Effect of gross vs. microscopic margins on disease-free survival (log rank, p ! 0.01).
intraoperatively by electron beam, Ir-192, or I-125, Verniers et al. (22) reported a mean local control rate of 63%, mean survival of 49%, and mortality of 8.5%. The local control rate for advanced and recurrent head and neck cancers with IOERT has been reported at 40–64% (6, 7, 10). Better local control has been achieved with close and microscopic surgical margins compared to those seen when gross residual disease remains. Freeman et al. observed that most failures in IOERT cases occurred outside the IOERT port. To minimize these failures, they suggested the use of multiple abutting IOERT ports. However, the use of the latter would require prolonged periods with the patient under general anesthesia, and it creates areas of overdosing or underdosing at the site of field overlap. Relatively inferior results are seen with inaccessible tumors located in the base of the skull treated with IOERT (46–52% control rate), compared to results seen with tumors of the parotid and base of tongue, which are easily accessible (57–69% local control) (23, 24). The addition of IOERT to conventional therapy has shown encouraging local control. However, the use of IOERT requires a rigid applicator whose placement is limited by the skull base anatomy because the electron beam must travel along a straight path, and the IOERT applicator cannot be placed into a narrow cavity. IOHDR was introduced as an alternative treatment modality to tumors at sites inaccessible to IOERT (20). Because IOHDR catheters are sufficiently flexible to accommodate the contours of the skull base, thus allowing the therapy to be delivered along a curved pathway and into narrow cavities, IOHDR can be used to treat areas in the skull base that are inaccessible to the IOERT applicator. Moreover, IOHDR irradiates from all surfaces of the applicator. When the applicator is positioned in the sinus cavity, one surface irradiates the cribriform plate, whereas the other surfaces irradiate the possible microscopic disease in the lateral sinus, deep in the sphenoid sinus and the inferior orbit. This is an important issue in sinuses that have irregular
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surfaces and those that cannot be easily encompassed by other techniques. The Ohio State University has a dedicated linear accelerator in a shielded operating suite. Our policy has been to treat tumors at accessible head and neck sites with IOERT and to reserve IOHDR for those tumor locations that cannot be treated with IOERT. The overall operating time is extended by about 30–60 min for IOERT and about 60–90 min for IOHDR. The actual treatment time is 2–3 min for the IOERT and about 5–20 min for IOHDR. Although we use IOHDR only at sites inaccessible to IOERT, institutions not possessing a dedicated intraoperative linear accelerator can perform IOHDR at all head and neck sites. The present study of 56 cases with primary disease showed an impressive 3-year local control and survival, which compared favorably with those seen in groups historically treated with conventional methods with or without IOERT (1, 5–7, 9–11, 15, 17, 18, 22, 23). Twelve patients with recurrent disease achieved poor local control. These patients were treated after surgery with an IOHDR dose ranging from 15 to 20 Gy. One patient received additional EBRT (20 Gy) and is free of disease and the other received 60 Gy of EBRT and is alive with disease in the neck node. A third patient had an I-125 seed implant in addition to a dose of 140 Gy, but died of postoperative complications. Although this is a small number of patients, it does suggest a potential role for supplementary EBRT in achieving reasonable tumor control in this unfavorable group. Enhanced tumor control with minimal long-term morbidity has been obtained using fractionated EBRT and low-dose rate brachytherapy (25, 26). IOHDR is potentially disadvantageous because it is given in a single fraction. The use of biological models including the linear quadratic formula (27) and animal experiments (28, 29), may predict isoeffect doses and toxicity, but their limitations must be borne in mind (30). In our current study, 10 Gy of IOHDR is equivalent to 16.7 Gy of conventionally fractionated radiotherapy for early reacting tissue effects (alpha–beta ratio 5 10). For late reacting tissue, the figure is 22–29 Gy, depending on the alpha–beta ratio used. The corresponding figures for 15 Gy of IOHDR are 31–35 Gy for tumor effects and 45–58 Gy for late effects; whereas the corresponding figures for 20 Gy of IOHDR are 50–56 Gy for tumor effects and 80–100 Gy for late effects. The doses obtained vary depending on the alpha–beta ratio and the repair kinetics chosen. This model has aided us in using a judicious combination of EBRT and IOHDR. Equally important has been its role in preventing excessive long-term morbidity by facilitating the choice of appropriate doses. Recently, Nag and Gupta (30) have developed an Excel (Microsoft Corp., Redmond, WA) spread sheet program to derive biologically equivalent doses for HDR brachytherapy. The linear quadratic formula is used to derive the BED, and then the BED is reconverted to express the doses as if they
were given at 2 Gy/fraction and thus be more meaningful to the clinicians. Because time is of essence in IOHDR, this program has been used in the operating room to calculate bioequivalent doses rapidly when required to modify the required dose. In IOHDR, the dose is prescribed at 0.5 cm depth in the tissue. However, due to the inverse square law, the actual dose at the surface (which is the site of microscopic residual tumor after resection) is about twice the prescribed dose, whereas radiosensitive structures (brain, optic nerve) located deeper receive much less radiation than the prescribed dose. Hence, IOHDR is more suited for the treatment of microscopic disease in tumor beds, rather than gross disease deep within tissues. Based on the gratifying results obtained, we now routinely incorporate IOHDR brachytherapy in conjunction with EBRT and optimum surgery in the management of tumors arising in the paranasal sinus and base of skull sites. IOHDR is also strongly considered in the treatment of selected recurrent cases. We now routinely add a limited dose of EBRT even in previously irradiated patients. However, the experience in using IOHDR for head and neck cancers has thus far been restricted only to Ohio State University (20, 31). Given the advantages of this treatment modality in the management of head and neck cancers and the availability of IOHDR in a handful of institutions, we would welcome multicenter studies that can help further define the role of IOHDR in this poor risk patient population. Conclusions IOHDR can be used to treat selected locally advanced head and neck tumors arising at sites inaccessible to IOERT or at institutions not performing IOERT. IOHDR enhances local control and overall survival in previously unirradiated patients if supplemented with EBRT. A prospective multiinstitutional study with a larger number of patients treated with IOHDR is needed to firmly establish the efficacy of IOHDR in this population group. The results of IOHDR are disappointing in recurrent and previously irradiated patients. Additional EBRT and higher IOHDR doses are considered for the latter group. References [1] Amdur RJ, Parson JT, Mendenhall WM, et al. Postoperative irradiation for squamous cell carcinoma of the head and neck: An analysis of treatment results and complications. Int J Radiat Oncol Biol Phys 1989;16:25–36. [2] Chen TY, Emrich LJ, Driscoll DL. The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys 1987;13:833–837. [3] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091–2098. [4] Lefebrre JL, Chevalier D, Luboinski B, et al. Larynx preservation in piriform sinus cancer: Preliminary results of a European Organization
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