34 Brachytherapy for Oral Cavity Cancer
Summary
Interstitial brachytherapy has a longstanding history of success in treating oral cavity cancers. It can be employed in the definitive setting either alone or as a boost in conjunction with external beam radiation therapy (EBRT) as an alternative to surgical approaches to preserve organ and function. The incorporation of brachytherapy to EBRT is associated with improved local disease control and survival. Brachytherapy can also be utilized adjuvantly for close or positive margins following surgical resection, or in the salvage setting in recurrent or previously treated cancers of the oropharynx. In this chapter we will cover the role of interstitial brachytherapy in treating squamous cancers of the lip, oral tongue, floor of mouth, buccal mucosa, and recurrent oral cavity squamous cell carcinoma. Brachytherapy is well tolerated, with acute mucositis that can be managed conservatively, and potential long-term complications are soft-tissue necrosis and osteoradionecrosis, which may be reduced with appropriate spacer or shielding. The development of new radioisotopes, improvement in implant technique and treatment delivery, as well as emergence of CT-based modern planning algorithms have increased safety, conformality and efficacy of brachytherapy treatment. When appropriate, patients should be referred to tertiary centers or centers of excellence with experience and expertise in brachytherapy treatment. Critical to the successful application of interstitial brachytherapy in oral cavity cancer is an experienced multi- and interdisciplinary team.
34.1 Introduction
Brachytherapy plays an important role in the multidisciplinary treatment of cancers of the head and neck. It offers the unique advantage of directly delivering high doses of radiation locally to tumors while largely sparing surrounding tissues due to rapid dose fall-off. In appropriate setting, brachytherapy offers an organ and functional preservation alternative to surgical resection of oral cavity cancers. It is also a useful technique for local radiation delivery in the adjuvant or salvage settings.
34.2 Principles of Oral Cavity Brachytherapy
Marie and Pierre Curie first discovered radium and its radioactive properties, which they announced to the French Academy of Sciences in 1898. It was noted that a small amount of radium left on the skin resulted in ulceration at the site. In 1901, Danlos and Bloch treated nonmalignant skin lesions with local application of unsealed radium sources. Its oncologic application soon followed with the first reported radium treatment for cancer of the palate and pharynx in 1902 in Vienna. Alternative forms of radioactive sources such as Cs-137 and Ir-192 became available in the 1950s. These high-activity/lower energy sources require less shielding and deliver radiation at a high or low dose rate. High dose rate (HDR) brachytherapy with remotely controlled afterloading has gained popularity over the past two decades because of its primary advantage of minimal radiation exposure to hospital personnel and equivalent efficacy as low dose rate (LDR) brachytherapy. For permanent seed implants, I-125 is commonly used as it has a low energy that can safely be implanted without shielding requirements.
Brachytherapy allows dose escalation beyond the prescribed standard along with external beam radiation therapy (EBRT); yet because of the direct delivery into the implanted tumor volume, it allows for better sparing of adjacent normal tissue and higher dose conformality. It typically is utilized in a multidisciplinary setting along with external beam chemoradiation to optimize treatment of the primary site. However, for selected tumors with minimal risk of regional nodal involvement, it can be used as primary stand-alone definitive treatment such as in small tumors of the lip or tongue. It can also be utilized as an adjuvant treatment after surgical resection or as salvage therapy.
34.3 Diagnosis and Evaluation
Prior to receiving treatment, patients should undergo thorough medical evaluation and physical examination. Patients with bleeding disorders and multiple medical comorbidities are at higher risk for complications and are not ideal candidates for brachytherapy treatment. In addition, patients with altered mental status that can interfere with treatment compliance are also suboptimal candidates. The team needs to assess the patient’s understanding and ability to comply with the radiation procedures and precautions associated with brachytherapy implants. Patients should be capable of self-care for the duration of brachytherapy treatment, including management of tracheostomy, percutaneous endoscopic gastrostomy or nasogastric tube, and patient-controlled analgesia, as indicated. Patients should have a dental evaluation prior to receiving brachytherapy to fabricate custom dental shields and spacers to shield the mandible from the implant.
34.4 Treatment Planning and Delivery
Brachytherapy treatments for head and neck cancer are typically delivered via interstitial implants or surface mold applicators. Interstitial brachytherapy may be delivered with radioactive sources (typically Ir-192) threaded into catheters temporarily implanted into the tumor volume. Less commonly, it is delivered with permanently implanted radioactive seeds, usually with I-125. Surface mold applicators are commonly used to treat exposed tumors located superficially. Generally, no operative procedures are required for this technique.
Brachytherapy can be delivered at different dose rates, taking into account clinical and radiobiological considerations. LDR brachytherapy has been the historic “gold standard” in treating head and neck tumors. Given at a rate of 0.4-0.5 Gy/hr over several days, LDR provides continuous radiation to the cancer cells and allows for normal tissue repair, thereby lowering the risk of late toxicity. The long duration requires patient isolation with significant staff exposure. More data have emerged demonstrating equivalent efficacy and similar late toxicity with HDR technique. Often given as twice daily treatments spaced at least 6 hours apart, HDR treatment is delivered remotely in a shielded room at more than 12 Gy/hr and allows for much shorter delivery time (minutes compared to days), enhanced dosimetry, and considerably decreased radiation exposure to medical personnel. Pulsed dose rate (PDR) brachytherapy uses similar afterloading technique as HDR but spreads delivery to hourly treatments at 0.4-0.7 Gy/hr. PDR therefore reduces radiation exposure to healthcare personnel compared to LDR and theoretically may have a normal tissue repair advantage compared to HDR given its more spread out dosing.
The technique of brachytherapy delivery has also evolved from using rigid sources of finite length like in the “Paris System” to employing flexible catheters with the afterloading technique. Paterson and Parker introduced the concept of source loading rules to a single point with the Manchester system for cervical cancer in 1934. Current brachytherapy techniques utilize CT-based planning to delineate the tumor volume and normal structures for more conformal and homogeneous radiation delivery. Inverse planning allows the planner to generate an idealized plan based on the prescription and dose constraints for the target and organs at risk. The use of geometrical, volume, and inverse optimization forms the basis of optimal planning. Fine tuning to customize clinical target volume coverage versus organ at risk of exposure can be achieved using manual tools that allow manipulation of the dose cloud by the radiation oncologist.
34.5 Supportive Care
Brachytherapy treatment is usually a coordinated multidisciplinary effort by head and neck surgeons, anesthesiologist, palliative care specialists, nutritionists, dentists, radiation oncologists, physicists, and nurses. For interstitial brachytherapy, prophylactic antibiotics are given to decrease the risk of infection at catheter insertion and surgical sites as well as pneumonia. Patient-controlled analgesia is often needed for effective pain management. Nutrition during treatment is administered with a nasogastric or gastrostomy tube. A tracheostomy may be necessary to maintain a patent airway and prevent aspiration. Tracheostomy care and suctioning of excess secretions is imperative. Patients should be monitored closely for the duration of brachytherapy treatment to ensure minimal displacement of the catheters and encouraged to ambulate to minimize risk of deep vein thrombosis. During catheter removal, the patient may develop hemorrhage, which can be controlled with bi-digital?compression while the airway is protected with an inflated tracheostomy cuff. Upon removal, the insertion sites should be cleaned with iodine and saline. Patients should be discharged with adequate analgesics and appropriate education regarding oral hygiene, nutrition, and potential acute side effects, including mucositis and pain.
34.6 Site-Specific Radiotherapy Considerations
34.6.1 Squamous Cell Carcinoma of Lip
Cancer of the lip occurs most commonly as an isolated ulcer or blister on the lower lip. It can be treated by surgical excision or radiation. Radiation has the advantage of preserving lip function and cosmesis. Janeway published a series of 24 patients treated from 1915 to 1917 for lip cancer with superficial or deep tissue invasion. 1 Treatment with radium catheters embedded in dental mold in one to four sessions resulted in low failure rates. Since then, brachytherapy for lip cancer has evolved to include new techniques and technology. Brachytherapy has been employed alone or with external beam radiation as definitive treatment, adjuvantly for positive or close surgical margins, or as salvage treatment. See ▶ Table 34.1 for series of squamous cell carcinoma (SCC) of the lip treated with interstitial brachytherapy.
Low Dose Rate
LDR interstitial brachytherapy achieves excellent local control of lip cancer in single- and multi-institution studies. Jorgensen et al reported a large single-institution series of 869 cases of newly diagnosed carcinoma of the lip. 2 The majority of patients had T1-2N0 disease. Radium needles were inserted transversely and longitudinally into the lesion in the lip. Patients received a single treatment lasting for 4 hours. Five-year survival was 84% for the entire cohort. Tumors with deep invasion (T3) had a higher rate of recurrence of 24.6% at five years compared to 7.4% for T1 and 12.7% for T2 lesions, respectively. Recurrences were salvaged with surgery or further radiation treatment. The European Curietherapy Group reported the largest series of 2,363 patients treated for lip cancer from 23 centers. 3 The majority of patients had T1-2N0 disease, and 1,870 patients received brachytherapy with iridium, radium, or cesium treatments using rigid or flexible catheters delivering 60-85 Gy. Recurrence rates were 2.5, 5, and 11% for T1, T2, and T3 tumors, respectively. In this multi-institutional report, iridium was found to have improved local control of 96.6% compared to 89.1% for radium. It is thought that improved dosimetry and implant technique contributed to improved therapeutic efficacy of iridium. Beauvois et al reported outcomes of 237 patients treated with brachytherapy for SCC of the lower lip. 4 There were 158 T1, 61 T2, 17 T3, and 1 T4 lesions. Some patients were also treated with EBRT for advanced local disease. Using flexible parallel Ir-192 wires, a mean dose of 65 Gy was delivered for superficial tumors, and 68 Gy was delivered for tumors = 5 mm. Five-year local control was 95%, and 5-year regional control was 91%. Increased lesion thickness = 1 cm was found to be associated with a higher recurrence rate due to poorer regional control. Guibert et al reported treatment of 92 patients using iridium wires and the Paris system afterloading technique. 5 An average of 65 Gy was delivered with coplanar or multiplanar implanted wires. The authors reported 5-year local recurrence of 10.9%, and 8-year relapse-free survival of 75%. Patient-reported functional results were satisfactory for 99% of patients, and cosmetic results were satisfactory for 92%. Another modern single-institution series included 89 node-negative?lip cancer cases, 10 after wedge-excision (6 microscopic positive margin, 4 macroscopic residual disease). 6 Patients were treated with two to five iridium wires delivering 50-62 Gy. Five-year local control rate was 95%. Five-year disease-free survival was 82% for the entire cohort, 100% for T1 and 89% for T2-T3 disease, respectively. All 61 surveyed patients reported satisfactory lip mobility and function. Patient-reported cosmesis (deformity, telangiectasia, dyspigmentation, and change in skin texture) was good for 77% of patients, fair for 21%, and one patient reported poor outcome. It was found that large tumors of > 2 cm thickness or previous surgery was associated with worse cosmesis.
High Dose Rate
HDR brachytherapy gained popularity given the shorter treatment time, widely available source, optimal treatment planning, and minimal staff exposure. Mukherji et al reported treatment of seven patients with lip cancer using HDR catheters embedded in a mold. 7 Five patients had T1N0 lesions and two patients had T2N0 lesions. The mold prepared with thermoplastic sheet and dental wax held catheters in position to the tumor surface. Using CT-based planning, 12.5-48 Gy was delivered in 2.5-3.5 Gy fractions to 80-85% isodose line. There was only one case of relapse in an ipsilateral submandibular node at 18 months after therapy. Mut et al reported outcomes of 68 patients treated with HDR for T1-T2 lip cancer. 8 Three to eight rigid needles were inserted in parallel with an external template system used for fixation. Patients received twice daily treatments (minimum 6 hours apart) of 4.5-5.5 Gy per fraction for 8-10 fractions. Eleven patients (5 T1 and 6 T2, 3 with commissural involvement) received elective cervical node treatment (four with EBRT and seven with nodal dissection). Five-year local control was 96.9% for the entire cohort, and 100 and 93.2% for T1 and T2 disease, respectively. Five-year regional control rates were 93.8 and 80.8% for T1 and T2, respectively. There were no nodal relapses in the patients who received elective nodal treatment compared to seven nodal relapses in 57 patients who did not receive neck treatment.
Several published studies reported comparable rates of effectiveness and toxicity profile between HDR and LDR treatments. Guinot et al compared 104 patients treated with HDR brachytherapy for lip cancer with a former series of 99 patients treated with LDR brachytherapy. 9 Patients were treated with definitive brachytherapy, adjuvant brachytherapy following surgery for involved margins, or salvage brachytherapy. HDR treatments consisted of nine twice daily treatments of 4.5-5 Gy per fraction prescribed to the 90% isodose line. The authors aimed to reproduce equivalent of 60-70 Gy in their previous series of patients treated with LDR. At median follow-up of 63 months for LDR and 51 months for HDR, local control rates were 94.9% for LDR versus 95.2% for HDR, and by T-stage were 100 versus 100%, 86.6 versus 94.1%, and 89.3 versus 80% for T1, T2, and T4 tumors, respectively. Overall survival and cause-specific survival were 76.7 and 95.9% for LDR and 64.4 and 94.2% for HDR, respectively. In another study comparing 33 HDR and 70 LDR cases, the two techniques demonstrated similar rates of local recurrence-free survival and similar rates of regional control of 96% at 3 years and 87% at 5 years for both groups. 10 Lastly, there is one published study using PDR brachytherapy in 32 patients with T1-4N0 lip cancer. 11 Treatment was delivered by 1 Gy/pulse every hour to a total dose of 60-70 Gy. Local control rate was 94% at 5 years.
Toxicity
Acute toxicities associated with brachytherapy for lip cancer may include desquamation, mucositis, and pain in the area being treated. Mut et al reported that severe mucositis occurred in all 68 patients treated with HDR brachytherapy, including grade 3 confluent and grade 4 hemorrhagic mucositis, which resolved within 6 weeks of topical treatment. 8 Lip mucositis with confluent ulceration or bleeding ulcer was similarly observed by Guinot et al in all 104 patients treated with HDR brachytherapy with resolution within 6 weeks of catheter removal. 9 Overall toxicities from LDR and HDR brachytherapy seem comparable. In a study comparing 100 LDR and 21 HDR brachytherapy treatments, grade 3 mucosal toxicity was observed in 23% with LDR compared to 33% with HDR; grade 4 mucosal toxicity was observed in 9% with LDR versus 0% with HDR. 12 In another study comparing 70 LDR and 33 HDR treatments, there was no difference in low grade or grade 3 acute toxicity (pain, mucositis, dermatitis) between HDR and LDR treatments (p = 0.52). 10
Long-term toxicity rate is low and may include tissue atrophy, fibrosis, hypopigmentation, and pain. It was found that the rate of complications increased with treatment thickness > 1.4 cm, and treatment volume of 85% dose to = 8 cm3 in one report of LDR brachytherapy. 4 Chronic ulcer was observed in patients receiving more than one LDR brachytherapy treatment. 2 Similarly in HDR brachytherapy, toxicity may be related to the dose and volume of treated tissue, as reported by Ghadjar et al. 10 HDR brachytherapy was found to contribute to lower rates of late complications, with rates of soft tissue necrosis reported as 15.1% for LDR versus 0% for HDR, bone necrosis as 1% for LDR versus 0% for HDR, and patient-reported fair/bad cosmesis as 11.1% for LDR versus 0% for HDR. 9 However, other studies have reported similar rates of late toxicity (mucositis, pain, dermatitis, hyper/hypopigmentation, fibrosis, skin atrophy, telangiectasia) for HDR and LDR treatments. 10 , 12
In order to decrease toxicity to organs near the treated lesion including the opposing lip, mandible, and oral cavity, multiple institutions put a lead wedge or plate between the lip and gingival sulcus. 3 , 4 , 8 They have noted a decrease in the rate of severe complications. Feldman et al reported a technique using catheters embedded in a customized surface mold that distances the lip from adjacent mandible or maxilla, and no osteonecrosis was observed. 13
Lip: Case Study
For brachytherapy treatment in patient with SCC of lip refer to ▶ Fig. 33.4.
34.6.2 SCC of Oral Tongue
Oral tongue cancer is the most common cancer of the oral cavity. The standard treatment for early stage disease limited to the tongue is surgical resection. Alternatively, brachytherapy with interstitial implants can be used to achieve both organ and function preservation in combination with regional management either with neck dissection or external beam radiation. It can also be utilized after surgery if adverse pathologic risk factors indicate a need for adjuvant therapy. For locally advanced disease, brachytherapy may be added as a local boost with definitive external beam chemoradiation to achieve dose-escalation.
Definitive Brachytherapy
The two largest series reporting experience in LDR brachytherapy for oral tongue cancer were published in 1981 by Decroix et al and in 1990 by Mazeron et al. 14 , 15 One study included over 600 patients with T1-T3 disease treated with radium implants, and the other included 166 patients with T1-T2 disease treated with iridium implants. Local control rates were 70-80%, with higher rates of local control for smaller lesions at 85, 77, and 50% for T1, T2, and T3 tumors, respectively, comparable to historic outcomes from large surgical series such as that from the Memorial Sloan-Kettering Cancer Center. 16 Soft tissue necrosis and osteoradionecrosis are the two principal reported adverse effects that are dependent on dose rate and inter-source distance. Stannard et al reported a modern experience of LDR brachytherapy in the treatment of oral cavity and oropharyngeal cancer using I-125. 17 Brachytherapy was delivered to 72 out of 144 cases of mostly early stage tongue, soft palate, floor of mouth (FOM), and tonsil cancers. The majority of cases were treated with definitive radiation, and 47 cases were treated postoperatively. With a median number of 20 seeds and median activity of 51.6 mCi, 5-year and 10-year local control rates were 80.7 and 80%, respectively. The treatment was well tolerated, with 18.4% rate of development of mucosal ulcer. There was no observed mandibular necrosis.
More modern series have reported the experience of treating oral tongue cancers with HDR brachytherapy (see ▶ Table 34.2). In a phase III randomized trial comparing HDR and LDR treatments for early stage tongue cancer, locoregional control rates were found to be comparable between the two groups. 18 In this study including 51 patients with T1-2N0 cancers, 26 patients were treated with LDR brachytherapy (70 Gy over 4-9 days) and 25 patients were treated with HDR brachytherapy (60 Gy in 10 BID fractions). Five-year local control rates were 84 versus 87%, respectively. Similar rates of local control were reported in other nonrandomized studies. 19 Subsequently, single institutions reported their HDR experiences. Akiyama et al described the outcome of 18 patients with treated with HDR brachytherapy as monotherapy for T1-3N0 mobile tongue cancers. 20 Patients received twice a day treatments with 54 Gy in nine fractions prescribed to the 85% isodose line. Two-year local control and cause-specific survival rates were 82 and 83%, respectively. Patients with lower T stage had lower incidence of neck nodal failure after brachytherapy treatment with rates of 33, 55, and 50% for T1, T2, and T3 tumors, respectively. All patients with neck recurrence were treated with salvage neck dissection. Patients with T1-2N0 cancer also had improved cause-specific survival of 88% compared to 79% for T3N0 cancers. While there is no recommended optimal dose schedule for HDR treatment in oral tongue cancer, higher biologically equivalent doses seem to be related to local control. In a report of 92 patients with stages I and II oral tongue cancer treated with HDR brachytherapy alone (40-52 Gy) or in combination with EBRT (40 Gy EBRT and brachytherapy 18-24 Gy), Bansal et al found higher 5-year local control rate with brachytherapy alone (68.2%) compared to combined brachytherapy and EBRT (57.6%). 21 The authors attributed the higher local recurrence rates in the combined group to lower biologic equivalent dose (BED) achieved in this group. The authors concluded that dose escalation with brachytherapy alone and/or in combination with EBRT is needed to control primary tumors. For more advanced cases, Santos reported outcomes of 24 patients with locally advanced tongue carcinoma treated with HDR interstitial brachytherapy (18-24 Gy) as a boost to gross tumor volume following definitive chemotherapy and EBRT of 50-60 Gy to the oral cavity and cervical nodes. 22 The series included 11 patients with stage III and 13 patients with stage IV cancer, and all but one patient received chemotherapy. Brachytherapy was delivered using parallel catheters spaced 10-12 mm apart targeting residual palpable tumor and pretreatment gross tumor volume. Four-year local control, cause-specific survival, and regional control rates were 80, 68, and 76%, respectively. All patients experienced acute mucositis that resolved 4-6 weeks after treatment completion. Late complications including mucositis and dysphagia were observed in five patients, and one case of osteoradionecrosis was observed.
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