Brachytherapy for Oral Cavity Cancers in the Era of Intensity-Modulated Radiotherapy: Save it or Shelve it

Abstract

Head and neck cancer treatment includes a multidisciplinary approach involving all specialties. Surgery and radiotherapy are equally effective in controlling small tumors. Intensity-modulated radiotherapy (IMRT) and interstitial brachytherapy (ISBT) play an important role in the treatment of head and neck cancers. Both are proved to be highly conformal techniques of radiotherapy. Our aim is to compare dosimetric aspects of ISBT alone, IMRT alone, and IMRT combined with ISBT in early stage node negative oral cavity cancer. Ten cases of histopathologically proven early stage node negative oral cavity cancer were treated with external beam therapy followed by interstitial brachytherapy boost or ISBT alone. All these patients had undergone computerized tomography (CT) planning for brachytherapy. Retrospectively, these images were utilized, and three sets of plans were done for each patient’s CT image set. Group A was IMRT alone plans, groups B had combined IMRT with ISBT boost, and group C was ISBT alone plans. Dosimetric details such as target coverage, dose to critical organs, and conformity index were compared between the three sets of plans. The mean values of the doses to the critical organs with IMRT alone and IMRT with ISBT boost were brainstem 10.40 Gy and 9.20 Gy, spinal cord 19.20 Gy and 16.10 Gy, mandible 62.99 Gy and 66.50 Gy, and I/L and C/L parotids were 6.03 Gy and 5.50 Gy and 5.70 Gy and 5.10 Gy where as in ISBT alone plans mean values were brainstem 1.30 Gy, spinal cord 1.40 Gy, mandible 36.50 Gy, I/L, and C/L parotids were 1.60 Gy and 1.00 Gy. Conformity index (CI) between IMRT and ISBT plans were 0.8580 and 0.7140 respectively. With comparable CI values, doses to critical organs appear to be in favor of ISBT plans as opposed to IMRT, and this was found to be statistically significant. Brachytherapy shows a dosimetric advantage over IMRT in this setting and could be translated to a benefit in terms of toxicities, organ preservation, and cosmesis in the actual clinical scenario. However, whether this would translate to significant benefit in terms of clinical outcome needs to be still verified.

Introduction

Head and neck cancer is a broad terminology used to group malignancies affecting sites from base of skull to thoracic inlet. Treatment of head and neck cancers includes a multidisciplinary approach involving all specialties. Radiotherapeutic management of head and neck cancers involves external beam radiation therapy (EBRT) and interstitial implant brachytherapy (ISBT). The sequencing of either modality is a point of contention as both are equally effective with its inherent advantages and disadvantages.

Brachytherapy involves placement of radioactive sources within or in close proximity to the target volumes. Recent advancements in technology like 3D visualization, dose optimization, and dwell points modifications with the help of CT/MRI compatible systems have added to the utility of this treatment modality and helped realize the ultimate goal of radiotherapy which is “Maximum dose to tumor and minimum dose to surrounding normal structures”. Although there is substantial data to support the use of brachytherapy in the management of oral cavity cancers [1], its utilization has been dwindling in the era of IMRT. Data comparing IMRT and brachytherapy is insufficient and difficult to generate.

In the present study, we retrospectively compare the dosimetric results of IMRT plans in patients who have undergone brachytherapy for early stage node negative oral cavity cancer.

Materials and Methods

Ten patients with squamous cell carcinoma of oral cavity treated with high dose rate (HDR) ISBT between January 2014 and February 2015 were reviewed retrospectively. Patients with T4 tumor having bone involvement, node positivity, reconstructive surgery, and any distant metastasis were excluded from the study. Four of these patients had received ISBT alone as a part of their initial treatment, five patients received ISBT as a boost after external beam radiotherapy, and one patient received ISBT as salvage treatment for recurrence after the initial surgery. The patient characteristics are shown in Table 1.

Table 1.

Patient characteristics

Sl no.	Characteristic	Number of patients
1	Primary site	Tongue—9 cases Floor of mouth—1 case
2	T stage	T1–6 T2–2 T3–2
3	N stage	All were node negative
4	Recurrent	1
5	Treatment aim	Definitive 2 Postoperative 8
6	Treatment plan	Brachytherapy alone, 5 Brachytherapy boost, 5

Interstitial Brachytherapy Treatment Details

Following preprocedure evaluation for feasibility and applicability for brachytherapy, all patients underwent interstitial implant brachytherapy under general anesthesia using nasopharyngeal intubation. All patients underwent a minimum of a double plane implant to ensure adequate coverage of the disease/tumor bed. All patients underwent computed tomography (CT) simulation with 3-mm slice thickness. Images were transferred to brachytherapy treatment planning system, the HDRPLUS 3.0 BEBIG Multisource unit (Eckert & Ziegler). Digitization of all the plastic tubes was done to define the source positions and calculate the dwell times followed by 3D treatment planning and optimization. Once the plan was accepted, the treatment was executed by connecting the catheters to HDR afterloading device which uses the cobalt-60 (Co⁶⁰) stepping source.

Dose of radiation was tailored based on the setting in which the treatment was being offered. In five patients, EBRT was combined with ISBT. EBRT to a dose of 50 Gy/25 fractions to the primary lesion/tumor bed with margins to include elective nodal regions/lymphovascular spaces was planned. ISBT was administered 2–3 weeks after EBRT (median—18 days). The total dose of ISBT given was 15 Gy in 5 fractions, 3 Gy/fraction delivered twice a day at least 6 h apart. Alternatively, ISBT was administered as the sole modality of treatment to five patients to a total dose of 35 Gy in 10 fractions over 5 days, 3.5 Gy/fraction delivered twice a day at least 6 h apart.

Planning for Intensity-Modulated Radiotherapy

In order to bring about uniformity among the separate treatment parameters being compared, the same CT image set available from the brachytherapy procedure was utilized retrospectively to derive IMRT plans which were generated using the Monaco treatment planning software (Elekta). Contouring of target volumes based on clinical examination and imaging findings was done, and these contours were independently verified slice-by-slice by two consultants to ensure accuracy. Target volumes when matched were comparable with a variance of less than 2%. In addition, the organs-at-risk particularly the mandible, ipsilateral, and contralateral parotids, brainstem and spinal cord were delineated. Each patient’s image set was planned for three different scenarios

1. IMRT only plan with doses up to 60 Gy in 30 fractions (designated as group A)

2. The combined plan which included IMRT of up to 50 Gy in 25 fractions followed by brachytherapy boost of 15 Gy in 5 fractions of ISBT (designated as group B)

3. The brachytherapy only plan with doses of 35 Gy in 10 fractions of ISBT (designated as group C)

Target volume coverage, doses to organs at risk (OAR), and conformity index (CI) were deduced for each plan. To compare between external beam treatment data and brachytherapy data, correction factor was applied, and equivalent doses were derived.

Statistical Analysis

To compare and assess the various parameters in the three different groups, statistical methods used were descriptive analysis such as t test and analysis of variance (ANOVA) studies as well as the post hoc analysis.

Results

Dosimetric comparison between groups A, B, and C were done for maximum doses (d_max) of brainstem, spinal cord, mandible as well as for mean doses to ipsilateral (I/L), and contralateral (C/L) parotids. For all these parameters, mean values were calculated and compared, as shown in Table 2.

Table 2.

Patient characteristics

Critical organs	Group A IMRT (Gy)	Group B IMRT + ISBT (Gy)	Group C ISBT (Gy)
Brainstem	10.40	9.20	1.30
Spinal cord	19.20	16.10	1.40
Mandible	62.99	66.50	36.50
I/L parotid	6.03	5.50	1.60
C/L parotid	5.70	5.10	1.00

The mean values of the doses to critical organs with IMRT plans (group A) were 9.47 Gy to brainstem, 19.21G y to spinal cord, 63.48 Gy to mandible, 6.64 Gy, and 5.19 Gy to I/L and C/L parotids respectively. Where as in the combined IMRT and ISBT plans (group B), the mean values were 9.2 Gy to brainstem, 16.10 Gy to spinal cord, 66.50 Gy to mandible, 5.50 Gy and 5.10 Gy to I/L and C/L parotids. Lastly, in the ISBT alone plans (group C), mean values recorded were 1.3 Gy to brainstem, 1.4 Gy to spinal cord, 36.50 Gy to mandible, and 1.60 Gy and 1.00 Gy to I/L and C/L parotids respectively [ISBT fared better in terms of reducing the dose to critical organs which was statistically significant (P value < 0.05).]

With regard to doses received by ipsilateral and contralateral parotids, groups A & B had almost similar doses whereas brachytherapy alone cases (group C) had nearly 75% lesser doses as compared with the other two groups (Tables 3 and 4; Figs. 1 and 2).

Table 3.

Ipsilateral parotid doses

	IMRT_I/L parotid (group A)	IMRT +BT_I/L parotid (group B)	BT_I/L parotid (group C)
Mean	6.03	5.50	1.60
N	10	10	10
Std. deviation	1.6357	1.3540	.5164

Table 4.

Contralateral parotid doses

	IMRT_C/L parotid (group A)	IMRT +BT_C/L parotid (group B)	BT_C/L parotid (group C)
Mean	5.70	5.10	1.00
N	10	10	10
Std. deviation	1.2517	1.1005	.0000

Fig. 1.

Ipsilateral parotid doses

Fig. 2.

Contralateral parotid doses

With regard to serial structures such as spinal cord and brain stem, doses when compared within the three groups revealed nearly 90% reduced doses when brachytherapy was used alone (Tables 5 and 6; Figs. 3 and 4).

Table 5.

Spinal cord doses

	IMRT_spinal cord (1CC) [group A]	IMRT +BT_spinal cord (1CC) [group B]	BT_spinal cord (1CC) [group C]
Mean	19.20	16.10	1.40
N	10	10	10
Std. deviation	2.6162	2.1318	.5164

Table 6.

Brain stem doses

	IMRT_brain stem (1CC) [group A]	IMRT +BT_brain stem (1CC) [group B]	BT_brain stem (1CC) [group C]
Mean	10.400	9.200	1.300
N	10	10	10
Std. deviation	3.5024	3.0478	.4830

Fig. 3.

Spinal cord doses

Fig. 4.

Brain stem doses

Five out of 10 cases, received more than 20 Gy to spinal cord in IMRT plans, due to constraints being applied as per standard protocol and allowing for planning freedom. Overall maximum dose to spinal cord or brain stem did not exceed its tolerance limit in any case, as conformal sparing fields were used. Hence, the doses to the spinal cord and brain stem were clinically acceptable in all the ISBT and IMRT plans. However, in comparison, dose received by spinal cord and brain stem in ISBT plans was very less as opposed to that received in IMRT plans, which augers well with the principle of radiotherapy of achieving a dose as less as possible to critical structures.

Maximum equivalent dose received by mandible (1 cc) ranged from 62.6 to 63.1 Gy in group A, 62.7 to 71.6 Gy in group B whereas in group C the range was between 27.6 and 41.6 Gy. Though brachytherapy alone cases showed acceptable mandible doses, when combined as a boost to external beam radiotherapy plans, these doses seem to be close to the tolerance limits for the mandible. The close proximity of the implant to the mandible seems to offset this concern. The doses received by the mandible in different groups are represented in Table 7 (Fig. 5).

Table 7.

Mandible doses

	IMRT_mandible (ICC) [group A]	IMRT +BT_mandible [group B]	BT_mandible (ICC) [group C]
Mean	62.99	66.50	36.50
N	10	10	10
Std. deviation	.0316	2.7988	5.0607

Fig. 5.

Mandible doses

Target volume coverage and conformity indices are other parameters that were also assessed. However, here we only compared the two separate modalities head on, namely IMRT versus brachytherapy as it would be difficult to interpret the combined treatment results. When both these parameters are compared, IMRT seems to have an edge over brachytherapy in terms of treatment planning indices. As brachytherapy volumes were defined by the achievable implant for each patient separately, small reduction in coverage and conformity indices was expected.

ISBT plans took 30 min on average to plan, with a range between 20 and 45 min. IMRT plans took 60 min on average to plan, with a range between 40 and 100 min. Hence, planning time in IMRT is longer in most of the cases as compared with that in brachytherapy. Cost of treatment in IMRT was higher when compared with ISBT. These results are quite encouraging in the treatment planning point of view to continue the practice of implant brachytherapy (Tables 8 and 9).

Table 8.

Percentage of coverage of target volumes

	IMRT_coverage (%)	BT_coverage (%)
Mean	97.580	85.770
N	10	10
Std. deviation	2.4412	4.0656

Table 9.

Conformity indices

	IMRT_CI/COIN	BT_CI/COIN
Mean	0.8580	0.7140
N	10	10
Std. deviation	0.02860	0.04575

Discussion

Tumors of the lip, tongue, buccal mucosa, retromolar trigone, and floor of mouth are grouped as oral cavity tumors as they all have a link in terms of etiology, staging, natural history, and management. Oral cavity is essential in coordinating functions like deglutination, phonation, and airway protection.

Management of oral cavity tumors involves surgery, radiotherapy, and chemotherapy. Sequencing of each is dependent on the clinical situations as well as acumen and experience of the physicians. In early stage tumors, the prognosis is similar between surgery and radiation therapy especially when brachytherapy is a part of treatment schema [2]. The major advantage with radiotherapy is superior cosmetic and functional outcome.

Even with the advent of newer technologies like IMRT where dose painting is an option, brachytherapy scores with its natural advantage of being in close proximity or within the tumor. Though advancements in brachytherapy have been at a rather slow pace, there have been some recent developments such as three dimensional image–based planning as well as optimization of dose distribution.

Several studies showed local control in cancer of mobile tongue is achieved in 79–97% for stage I and 65–95% for stage II when treated with radical BT with or without EBRT [1]. Approximately 10–20% of patients may develop soft tissue necrosis within the implant volume. Osteoradionecrosis (ORN) may occur in up to 5% of cases. Most ORN patients respond well to medical treatment. Surgical intervention is necessary in only 1–2% of patients. Eisbruch et al. [3] reviewed the experiences at two institutions, Michigan (n = 36) and Rotterdam (n = 77), with respect to dysphagia, which is a major late complication of radiotherapy after treating head and neck cancer. They reported that brachytherapy was the only significant factor, in their multivariate analysis, that reduced dysphagia associated with chemoradiotherapy of head and neck cancer, compared with IMRT.

In our study, ten patients with biopsy proven tumors of oral cavity cancer were treated with brachytherapy, as a sole modality of treatment or as a boost following EBRT. For all these patients, a replanning was done by applying an IMRT plan utilizing the CT scan images used for brachytherapy. Overall, on comparison of dosimetric parameters of spinal cord, brainstem, mandible, I/L, and C/L parotids, it was seen that the doses received using ISBT was very less as opposed to that received by IMRT plans. Target volume coverage and conformity indices though slightly inferior in the ISBT plans were still comparable with IMRT plans. Planning time and cost was also less in ISBT in comparison to IMRT.

Sresty et al. [4] compared ISBT with IMRT with respect to treatment planning in 15 patients of tongue cancer. They also reported that ISBT causes equal or superior planning results with regard to the conformity index and dose to critical organs.

However, it is very important to be aware that the interstitial application procedure, and the treatment at each fraction are time consuming. Hence, ISBT procedure is not faster, but its planning is faster when compared with IMRT. The use of IMRT requires significant resources and extensive quality assurance. It can also be time consuming to verify and deliver compared with ISBT.

These results support our notion that brachytherapy still plays a potential role in oral cavity cancers even in this era of IMRT with concurrent chemotherapy.

Conclusion

Our results show that brachytherapy is one of the most conformal techniques available to treat oral cavity tumors though in selective cases. It gives excellent results in terms of toxicities, organ preservation and cosmesis but seldom seems to be a dying art and restricted to few centers around the country.