MARGINAL RECURRENCES AFTER SELECTIVE TARGETING WITH INTENSITY-MODULATED RADIOTHERAPY FOR ORAL TONGUE CANCER

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1 CASE REPORT Eben L. Rosenthal, MD, Section Editor MARGINAL RECURRENCES AFTER SELECTIVE TARGETING WITH INTENSITY-MODULATED RADIOTHERAPY FOR ORAL TONGUE CANCER Shari Damast, MD, Suzanne Wolden, MD, Nancy Lee, MD Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York. Accepted 5 October 2010 Published online 31 January 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. No universal consensus of optimal radiation target coverage for oral tongue cancer exists, and there is wide variability in practice. Some centers use intensitymodulated radiotherapy (IMRT) to selectively target only certain regions at risk while sparing others; however, patterns of failure after such selective targeting are rarely reported. Methods and Results. We critically examined the location of failure in 4 patients with stage III to IV oral tongue cancer who presented to our department with locoregional recurrence after receiving IMRT with selective radiation targeting at outside institutions. All 4 patients cancer recurred marginally in regions that were not initially targeted, whereas the regions would have been targeted if comprehensive IMRT targeting had been used. The median time to recurrence was short (3.9 months; range, months). Conclusion. This case series highlights the occurrence of marginal failures after selective targeting with IMRT for oral tongue cancer and cautions against this practice unless further supporting evidence becomes available. VC 2011 Wiley Periodicals, Inc. Head Neck 34: , 2012 Keywords: intensity-modulated radiation therapy; head and neck cancer; target volume delineation; oral cavity cancer; quality assurance Oral tongue cancer has a worse prognosis compared to other subsites of the oral cavity, 1 with a high incidence of occult cervical metastases, 2 locoregional recurrence, 1 and poor salvage rates. 3 Radiation plays an important role in locoregional control 4 and traditional radiation fields with conventional external beam radiotherapy (RT), include the submaxillary and subdigastric lymph nodes if the neck is clinically negative, and the contralateral neck and lower neck lymph nodes on both sides if the neck is clinically positive. 5 With the emergence of intensity-modulated radiotherapy (IMRT), radiation oncologists now have the potential ability to selectively target only certain neck levels while sparing others, thereby reducing radiation-associated toxicity. However, many experts have cautioned against an overly selective targeting approach with Correspondence to: S. Damast VC 2011 Wiley Periodicals, Inc. IMRT for fear of an increase in marginal recurrence rates due to inadequate radiation coverage. 6,7 At Memorial Sloan Kettering Cancer Center, we have practiced comprehensive nodal irradiation with IMRT for any patient with node-positive oral tongue cancer. 8 Comprehensive fields include at least levels I to IV in both the node-positive and the contralateral, node-negative necks. 9 Gomez et al 8 described the outcomes of 35 patients with oral cavity cancer treated with IMRT. The 2-year local control rate was 84% and there were no cases of marginal recurrence. Thirty-one percent of patients in this series had oral tongue cancer. 8 These outcomes are comparable to those of other published series on IMRT for oral cavity cancer, whose authors have similarly advocated comprehensive nodal target coverage. 10,11 These results are encouraging, even with the relatively small numbers of patients, and demonstrate that IMRT is feasible and effective in controlling local recurrence in oral cavity cancer when target volume selection is comprehensive. Our recent observation of the patient mix referred to our department for re-irradiation of locoregionally recurrent oral tongue cancer, however, suggests that the use of more selective targeting may be common practice at other institutions. An audit of the radiation records of all patients with locoregionally recurrent oral tongue cancer referred to our department over a 2-year period after treatment elsewhere found that selective targeting was used in 5 of 10 patients (50%; Table 1). Examples included selective targeting of the ipsilateral-only neck in node-positive disease, or selectively targeting certain upper echelon nodes while excluding lower ones. In this case series, we describe 4 patients (patients 1 4; Table 1) who had presented to our department with marginal recurrence after receiving postoperative IMRT for oral tongue cancer at a variety of outside institutions, both foreign and domestic. All 4 patients had received selective, rather than comprehensive, radiation targeting, and their cases illustrate important concepts concerning the use of postoperative 900 Marginal Recurrences after Selective IMRT HEAD & NECK DOI /hed June 2012

2 Table 1. Cases of locoregionally recurrent oral tongue cancer presenting for reirradiation to Memorial Sloan Kettering Cancer Center (August 2007 August 2009) after initial course of postoperative conformal radiotherapy elsewhere. Time to local failure, mo Location of failure Selective or comprehensive RT targeting IMRT or 3D conformal RT (3DCRT) Initial neck surgical management Initial TNM classification (pathologic) Patient no. Age, y Sex 1 60 M T4aN3 Ipsilateral IMRT Selective (excluded level IA) Marginal F T1N1 (recurrent) Ipsilateral IMRT Selective (excluded level V) Marginal F T2N1 Ipsilateral IMRT þ 3DCRT Selective (ipsilateral only) Marginal M T4aN1 Ipsilateral IMRT Selective (ipsilateral only) Marginal M TXN2b (recurrent) Ipsilateral IMRT Selective (ipsilateral only) In-field M T1N2b (recurrent) Ipsilateral IMRT Comprehensive In-field M T4aN2c Bilateral IMRT Comprehensive In-field M T4aN2c (recurrent) Ipsilateral IMRT þ 3DCRT Comprehensive In-field F T1NX Ipsilateral 3DCRT Comprehensive In-field M T4aN2b Bilateral IMRT Comprehensive In-field 16.8 Abbreviations: IMRT, intensity-modulated radiotherapy; 3D, 3-dimensional; RT, radiotherapy; 3DCRT, 3D-conformal radiotherapy. IMRT for oral tongue cancer. Institutional board review approval was obtained to retrospectively review their records. Radiographic images obtained at the time of locoregional recurrence were presented and compared with the initial radiation target volumes to determine the relationship between the location of recurrence and the initial radiation treatment volume. CASE SERIES Characteristics of initial treatment are summarized in Table 2. Patient 1. Patient 1 was a 60-year-old man who initially presented with a small tumor located in the left anterior portion of the tongue, with floor of mouth invasion (Figure 1A and 1B). He underwent left hemiglossectomy and ipsilateral selective neck dissection. Pathology revealed a 2.2-cm squamous cell carcinoma (SCC) invading the floor of mouth, which measured 0.75 cm in thickness. One level Ib lymph node was positive, 3 of 7 level II lymph nodes were positive, including 1 measuring >6 cm with extracapsular extension. An additional 57 lymph nodes in levels III to V were negative. His pathologic classification was pt4an3. Postoperatively, the patient received IMRT to the primary site and bilateral neck with concurrent cisplatin, with the technique and dose outlined in Table 2. Despite an anterior location of the tongue lesion, involvement of floor of mouth, a pathologically positive level Ib node, and proximity of the submental region to the surgical bed, level Ia was not targeted in the initial IMRT plan (Figure 1C). The patient presented to our department 4.8 months after IMRT, with a positron emission tomography (PET) scan demonstrating pathologic uptake in a submental mass, corresponding to a cold spot in the initial IMRT plan (Figure 1D). Patient 2. Patient 2 was a 41-year-old woman with a distant history of localized T1N0 oral tongue cancer treated with primary resection and left modified radical neck dissection. She remained without evidence of disease for 7 years until she presented with a small lesion suspicious for tumor recurrence in the left lateral tongue. She underwent a left partial glossectomy and a left sublingual neck dissection. Pathology demonstrated a 1.9-cm SCC measuring 0.72 cm in thickness with superficial muscle invasion. The single lymph node that was removed from the sublingual region was positive for cancer. Her pathologic classification was T1N1 (recurrent). She received postoperative IMRT for locally recurrent disease, as detailed in Table 2, without any concurrent chemotherapy. Despite the presence of recurrent disease in the dissected left neck, only levels I to IV were included in the IMRT plan with exclusion of level V (Figure 2A). The patient presented to our department 10.1 months after IMRT, with a PET/CT scan demonstrating recurrence in ipsilateral level V, just outside of the initial IMRT fields (Figure 2B and 2C). Marginal Recurrences after Selective IMRT HEAD & NECK DOI /hed June

3 Table 2. Initial treatment characteristics of patients 1 to 4 with marginal recurrences. Patient no. Surgery Chemo RT technique and dose, Gy Site of recurrence 1 Left hemiglossectomy and left radical neck dissection 2 Left partial glossectomy and left sublingual neck dissection 3 Right hemiglossectomy and right selective neck dissection 4 Left hemiglossectomy and left modified neck dissection Cisplatin IMRT alone Ia 63.0: primary site, left level Ib II 60.0: right level II, bilateral levels III V None IMRT alone Ipsilateral level V 66.6: primary site, bilateral levels I IV C225 IMRT/3DCRT Ipsilateral level III, 53.2: primary site contralateral level II 46.0: right level I II, and partial coverage of right level III None IMRT alone Contralateral level II and IV 39.6: primary site and left level IB V* Abbreviations: RT, radiotherapy; IMRT, intensity-modulated radiotherapy; 3DCRT, 3D-conformal radiotherapy. *Treatment held due to recurrence in right neck; IMRT plan then modified to incorporate bilateral neck and the new gross disease. Patient 3. Patient 3 was a 22-year-old woman who presented with a small tumor in the right lateral oral tongue. She underwent right hemiglossectomy and right selective neck dissection. Pathology demonstrated a 2.1-cm SCC with a thickness of 0.70 cm. There was superficial muscle invasion as well as perineural and lymph-vascular infiltration. One of 6 level II lymph nodes were positive, and the remaining 24 lymph nodes in levels I and III were negative. Her pathologic classification was T2N1. Postoperatively, FIGURE 1. (A) and (B) Axial pretreatment positron emission tomography (PET)/CT images demonstrating the anterior location of the first patient s enhancing left oral tongue tumor. (C) A sagittal view of the original intensity-modulated radiotherapy (IMRT) plan illustrating the dose distribution in the primary site and the upper neck. The contoured region is outlined in light blue. The hotspot in the red shaded region was 107.6%. The green shaded area received 74.3% of the prescribed dose. Note that the submental region was not adequately targeted (white arrow). (D) A sagittal PET image demonstrates pathologic uptake in a submental mass, corresponding to a cold spot in the initial IMRT plan [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 902 Marginal Recurrences after Selective IMRT HEAD & NECK DOI /hed June 2012

4 FIGURE 2. (A) Axial view of the second patient s original intensity-modulated radiotherapy (IMRT) plan at the level of the supraclavicular nodes. The planned target volume (PTV) is shaded in red. Note that level V was completely excluded. (B) Axial positron emission tomography (PET) image (B) and CT scan (C) demonstrate level V recurrence, marginal to the initial PTV [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] she underwent concurrent cetuximab with radiotherapy (combined IMRT and 3-dimensional (3D)-conformal technique) to the primary site and upper portion of the right neck, as detailed in Table 2. Her initial radiation plan selectively targeted only ipsilateral levels I and II and only the superior part of level III. The low neck and the contralateral neck were not targeted at all (Figure 3A and 3B). Three months after IMRT, a CT scan of the neck demonstrated recurrent disease in the left level II that had been avoided FIGURE 3. Selected axial images from the third patient s intensity-modulated radiotherapy (IMRT) plan (A and C) with juxtaposition of the patient s CT scan at 3 months demonstrating recurrence in regions which were excluded (B and D). The red contour in (A) is the tumor bed and the light blue contour is the high risk planning target volume (PTV). Note that the left neck was not targeted (black arrows). (B) Recurrence in a left level II lymph node was initially excluded. (C) The exiting edges of the beams are seen at the level of the cricoid marking the inferior border of the radiation field. Neither ipsilateral nor contralateral lymph node regions beneath this level were targeted. (D) Recurrence in a right necrotic-appearing level III lymph node just at the inferior boundary of the radiation portal [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Marginal Recurrences after Selective IMRT HEAD & NECK DOI /hed June

5 FIGURE 4. Coronal (A) and axial (B) slices from the original intensity-modulated radiotherapy (IMRT) plan of the fourth patient illustrate an ipsilateral-only dose distribution. (C) The patient developed palpable disease in the contralateral neck during treatment, demonstrated in the positron emission tomography (PET)-CT image [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] completely and right levels III and IV immediately below the inferior boundary of her radiation field (Figure 3C and 3D). Patient 4. Patient 4 was a 37-year-old man who initially presented with a suspicious, small left lateral oral tongue lesion. He underwent left hemiglossectomy and ipsilateral modified radical neck dissection. Pathology demonstrated a 2.2-cm SCC with a thickness of 1.6 cm. There was invasion to the floor of mouth and superficial muscle invasion. There was also perineural and lymph-vascular infiltration in the specimen. One of 4 level IIa lymph nodes demonstrated disease with extracapsular extension. Thirtyfour lymph nodes in levels I, IIb, and III to V were all negative. His pathologic classification was T4aN1. Postoperatively, the patient received IMRT selectively targeting only ipsilateral neck levels I to V, without concurrent chemotherapy (Table 2). The plan did not target the contralateral neck at all (Figure 4A and 4B). The patient presented to our department 1.2 months after initiating postoperative IMRT, with palpable disease in the contralateral neck and a PET scan that demonstrated failure at the right level II and IV (Figure 4C). DISCUSSION Multiple reports have demonstrated previously that the predominant location of locoregional recurrence after IMRT for head and neck cancer is within the high-risk tumor volume, which normally receives a high radiation dose Based on pooled published data from various academic institutions, it has been estimated that marginal recurrence accounts for <10% of cases of locoregional recurrence. 16 Therefore, 4 cases of marginal recurrence after IMRT for oral tongue cancer reported in this series demand attention, especially because these 4 cases represented 40% of the locoregionally recurrent oral tongue cancer cases treated at outside institutions referred to our department over a 2-year period (patients 1 4; Table 1). A major difference between the IMRT techniques used in these 4 cases as opposed to techniques previously reported in the literature was the use of selective, as opposed to comprehensive, nodal targeting. 9 Excluded from the radiation fields were either a single at-risk region (level IA, level V in patients 1 and 2, respectively) or the contralateral and/or low neck regions (patients 3 and 4). All sites of marginal recurrence occurred in regions that would have been targeted had comprehensive targeting been used. 9 An important point to consider is that lymphatics may become altered and unpredictable in a neck that has been previously treated with surgery. This may explain an unexpected recurrence in level V in patient 2. Other authors have recommended generous target-volume margins, especially in surgically manipulated sites, to decrease the risk of marginal recurrence. 9,17 Surely, in these cases, selective targeting was used because the treating physicians deemed the excluded neck regions to be at low risk for recurrence and aimed to reduce radiation-associated toxicity. 18 Although this rationale is understandable, we are unable to establish support for this selective approach from the currently existing radiation literature, especially in the setting of nodepositive disease. Before the era of IMRT, total neck irradiation was common practice when treating oral tongue cancer with node-positive disease, 5 and was even supported in cases of node-negative disease. 4 Spaulding et al 4 analyzed 84 patients treated at the University of Virginia Medical Center with oral tongue cancer and found a significant difference in the 3-year adjusted neck control rate for patients with node-negative disease treated with limited (no, partial bilateral, or ipsilateral-only) neck therapy versus those treated with bilateral, whole neck irradiation (38% vs 95%, respectively). In both patients with node-positive and nodenegative disease, the authors found that in all of the 904 Marginal Recurrences after Selective IMRT HEAD & NECK DOI /hed June 2012

6 patients who had treatment failure the after partial external beam therapy to the neck, the failure was outside of the irradiation portal. 4 The authors concluded that for patients with node-negative disease, whole neck elective radiation was beneficial, and for patients with node-positive disease, a combination of whole neck irradiation and neck dissection was optimal. 4 There have been 3 recent retrospective studies which focused exclusively on outcomes after IMRT for oral cavity cancer which together report 2-year local control rates between 82% to 92%. 8,10,11 Oral tongue cancer represented between 31% to 36% of all patients. The latter publication by Yao et al 11 specifically addressed the question of the necessity of contralateral neck coverage through analysis of patterns of failure. Of 9 locoregional failures reported, 6 patients had oral tongue cancer, including 1 patient with T1N1 left oral tongue tumor treated postoperatively to the primary, bilateral I to II and ipsilateral whole neck. The failure occurred in right level III, which was out of the field. The authors concluded that it is critical to include the contralateral neck in cases of ipsilateral nodal involvement and further supported this conclusion with available surgical literature For example, Chow et al 19 reported on 73 patients undergoing surgery for carcinoma of the oral cavity and oropharynx. Eight of these patients developed contralateral or bilateral neck recurrence, of whom 5 had oral tongue cancer (62.5%), and ipsilateral positive nodal status was the only significant prognostic factor. 19 A significant finding in a study by Kurita et al 20 of 129 patients with oral cavity cancer, in which 19 had contralateral lymph node metastasis, was that contralateral lymph node metastasis never occurred in patients without ipsilateral lymph node metastasis. A prospective study by Fakih et al 21 found a 40% neck recurrence, all within the contralateral neck, in a cohort of patients with histologically involved nodes that underwent hemiglossectomy and elective ipsilateral radical neck dissection with no adjuvant postoperative radiation. Based on these studies, Yao et al 11 postulate that elective neck dissection may predispose aberrant migration of in-transit cancer cells to the opposite side of the neck. Therefore, contralateral neck should be included in the radiation field in postoperative IMRT for oral tongue cancer. One might wonder whether such aggressive, comprehensive coverage is warranted in the setting of just a single involved lymph node (N1 disease), as was the case in 3 of the 4 patients in this case series (patients 2 4). A recent report by Chen et al 22 specifically looked at the question of the role of postoperative RT for primary oral tongue cancer with pathologic T1-2N1 neck in a retrospective review of 59 patients. Sixteen of 59 patients developed locoregional recurrences with a mean followup of 46 months. Postoperative RT was delivered to the tongue and bilateral neck in 28 patients, whereas the remaining 31 patients did not receive any RT. The regional recurrence rate was 14% versus 39% in those receiving RT versus no RT. The authors conclude that pathologic N1 disease may be indicative of the existence of more occult metastases in the neck. 22 Another retrospective study to assess the role of selective neck dissection and postoperative RT in patients with oral tongue cancer from The University of Texas M.D. Andersen Cancer Center drew similar conclusions concerning potential benefit of adjuvant RT in N1 disease. 23 Although a prospective trial to answer the question of the value of comprehensive neck RT in patients with node-positive disease, and specifically N1 neck disease, is not available, one might extrapolate from a recent prospective trial by Brennan et al 24 which attempted to answer the question of elective neck treatment with surgery versus RT in patients with node-negative (N0) oral tongue disease. This study, in fact, had to close early after accrual of only 25 patients because of the high locoregional recurrence rate (23% at 3.4 years). The investigators concluded that better prognostic factors are needed, and that in the absence of these, aggressive neck treatment for all patients may be warranted. 24 Therefore, if aggressive neck treatment is warranted in N0 disease, one might extrapolate from these conclusions all the more so in cases of N1 disease. Thus, based on the above data, it has been our tendency at this institution to be more aggressive with oral tongue cancer compared with other oral cavity subsites. In addition, this practice is supported by anatomic considerations, namely, the extensive lymphatic drainage of the oral tongue, a midline structure that drains bilaterally to levels I to III via anterior, lateral, or central pathways. Finally, it is known that salvage outcomes for patients who have recurrence after a first course of radiation is poor, 3,25 and 1 study reported a median survival of only 9 months. 25 Therefore, aggressive up-front treatment seems appropriate. We conclude that although ipsilateral radiation may be appropriate for certain head and neck subsites, such as buccal mucosa or tonsil, 26,27 the present series, together with previous outcomes after comprehensive IMRT for oral cavity cancer, 8,10,11 might caution against this practice for oral tongue cancer until more data become available. There are many limitations to the present case series. It cannot be determined definitively whether comprehensive targeting would have improved outcomes for these specific patients. In general, oral tongue cancer has a worse prognosis and survival than other oral cavity sites, 1 and in this series, there may have been a selection bias toward patients with the poorest prognosis. This study population consisted only of patients presenting for re-irradiation. Additionally, many of these patients had other negative prognostic features associated with regional recurrence including T4 stage, extracapsular extension, and perineural infiltration. 28 Although this case series looked only at existing cases of locoregional recurrence, an ideal cohort study design would have included all possible patients with selective Marginal Recurrences after Selective IMRT HEAD & NECK DOI /hed June

7 and comprehensive radiation plans (with or without recurrence), but that is obviously impossible given the multiple treatment centers in which initial radiation therapy was delivered both foreign and domestic, and the lack of accessibility of patient records. CONCLUSIONS IMRT to treat head and neck cancer has been adopted successfully not only by specialized centers, but also community practices worldwide This case series should, like previous reports of recurrence after IMRT, help remind clinicians that there are valuable lessons to be learned from analyzing patterns of failure. For example, Eisbruch et al 32 reported on marginal recurrences near the base of the skull and, based on their findings, changed their definition of the superior boundary of the retropharyngeal lymph nodes. Cannon et al 33 reported on periparotid recurrence after IMRT and recommended caution when using a parotid-sparing technique in the presence of periparotid nodules and multinodal metastases. These studies and others have supported the notion that careful and accurate target volume delineation is essential to the success of IMRT. We hope that this case series will help to inform practice patterns and encourage future publication of patterns of failure after IMRT in oral tongue cancer. REFERENCES 1. Rusthoven K, Ballonoff A, Raben D, Chen C. Poor prognosis in patients with stage I and II oral tongue squamous cell carcinoma. Cancer 2008;112: Huang SF, Kang CJ, Lin CY, et al. Neck treatment of patients with early stage oral tongue cancer: comparison between observation, supraomohyoid dissection, and extended dissection. Cancer 2008;112: Kowalski LP. Results of salvage treatment of the neck in patients with oral cancer. Arch Otolaryngol Head Neck Surg 2002;128: Spaulding CA, Korb LJ, Constable WC, Cantrell RW, Levine PA. The influence of extent of neck treatment upon control of cervical lymphadenopathy in cancers of the oral tongue. 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