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Initial experience using intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma
Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 3, pp. 682– 687, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/S0360-3016(03)01508-6
CLINICAL INVESTIGATION
Head and Neck
INITIAL EXPERIENCE USING INTENSITY-MODULATED RADIOTHERAPY FOR RECURRENT NASOPHARYNGEAL CARCINOMA TAI-XIANG LU, M.D.,* WEI-YUAN MAI, M.D.,*† BIN S. TEH, M.D.,† CHONG ZHAO, M.D.,* FEI HAN, M.D.,* YIN HUANG, M.D.,* XIAO-WU DENG, PH.D.,* LI-XIA LU, M.D.,* SHAO-MIN HUANG, C.M.D.,* ZHI-FAN ZENG, M.D.,* CHENG-GUANG LIN, R.T.T.,* HSIN H. LU, M.D.,† J. KAM CHIU, M.D.,† L. STEVEN CARPENTER, M.D.,† WALTER H. GRANT III, PH.D.,† SHIAO Y. WOO, M.D.,† NAN-JI CUI, M.D.,* AND E. BRIAN BUTLER, M.D.† *Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China; † Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX Purpose: To report our initial experience on the feasibility, toxicity, and tumor control using intensity-modulated radiotherapy (IMRT) for retreatment of recurrent nasopharyngeal carcinoma (NPC). Methods and Materials: A total of 49 patients with locoregional recurrent carcinoma in the nasopharynx were treated with IMRT between January 2001 and February 2002 at the Sun Yat-Sen University Cancer Center, Guangzhou, China. The average time to the nasopharyngeal recurrence was 30.2 months after initial conventional RT. The median isocenter dose to the nasopharynx was 70 Gy (range 60.9 –78.0) for the initial conventional RT. All patients were restaged at the time of recurrence according to the 1992 Fuzhou, China staging system on NPC. The number of patients with Stage I, II, III and IV disease was 4, 9, 10, and 26, respectively. T1, T2, T3, and T4 disease was found in 4, 9, 11, and 25 patients, respectively. N0, N1, N2, and N3 disease was found in 46, 2, 0, and 1 patient, respectively. Invasion of the nasal cavity, maxillary sinus, ethmoid sinus, sphenoid sinus, and cavernous sinus and erosion of the base of the skull was found in 8, 1, 3, 8, 15, and 20 patients, respectively. The gross tumor volume (GTV) was contoured according to the International Commission on Radiation Units and Measurements (ICRU) Report 62 guidelines. The critical structures were contoured, and the doses to critical structures were constrained according to ICRU 50 guidelines. The GTV in the nasopharynx and positive lymph nodes in the neck received a prescription dose of 68 –70 Gy and 60 Gy, respectively. All patients received full-course IMRT. Three patients who had positive lymph nodes were treated with five to six courses of chemotherapy (cisplatin ⴙ 5-fluorouracil) after IMRT. Results: The treatment plans showed that the percentage of GTV receiving 95% of the prescribed dose (V95-GTV) was 98.5%, and the dose encompassing 95% of GTV (D95-GTV) was 68.1 Gy in the nasopharynx. The mean dose to the GTV was 71.4 Gy. The average doses of the surrounding critical structures were much lower than the tolerable thresholds. At a median follow-up of 9 months (range 3–13), the locoregional control rate was 100%. Three cases (6.1%) of locoregional residual disease were seen at the completion of IMRT, but had achieved a complete response at follow-up. Three patients developed metastases at a distant site: two in the bone and one in the liver and lung at 13 months follow-up. Acute toxicity (skin, mucosa, and xerostomia) was acceptable according to the Radiation Therapy Oncology Group criteria. Tumor necrosis was seen toward the end of IMRT in 14 patients (28.6%). Conclusion: The improvement in tumor target coverage and significant sparing of adjacent critical structures allow the feasibility of IMRT as a retreatment option for recurrent NPC after initial conventional RT. This is the first large series using IMRT to reirradiate local recurrent NPC after initial RT failed. The treatment-related toxicity profile was acceptable. The initial tumor response/local control was also very encouraging. In contrast to primary NPC, recurrent NPC reirradiated with high-dose IMRT led to the shedding of tumor necrotic tissue toward the end of RT. More patients and longer term follow-up are warranted to evaluate late toxicity and treatment outcome. © 2004 Elsevier Inc. IMRT, Reirradiation, Recurrent, Nasopharyngeal carcinoma.
LA, October 6 –10, 2002. Acknowledgments—The authors thank Shirley Clark for her assistance in the preparation of this manuscript. Received Mar 13, 2003, and in revised form Jul 3, 2003. Accepted for publication Jul 11, 2003.
Reprint requests to: Wei-Yuan Mai, M.D., Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, 6565 Fannin, MS 121-B, Houston, TX 77030. Tel: (713) 790-2637; Fax: (713) 793-1300; E-mail: [email protected] Presented at the 44th American Society for Therapeutic Radiology and Oncology (ASTRO) Annual Meeting, New Orleans, 682
IMRT for recurrent nasopharyngeal carcinoma
INTRODUCTION Local recurrent nasopharyngeal carcinoma (NPC) that has received previous full-dose radiotherapy (RT) poses a challenge to additional treatment options. Additional RT, especially with a conventional technique, could cause significant undesirable complications and side effects, because the normal tissue tolerance has previously been reached. In the past several decades, various treatment modalities, including external beam radiotherapy (EBRT), intracavitary brachytherapy, interstitial radioactive implantation, stereotactic radiosurgery, nasopharyngectomy, chemotherapy, and a combination of these methods, have been used (1–14). Despite the advances in surgery and chemotherapy, reirradiation remains the most effective modality for salvaging local recurrent NPC. High-dose reirradiation (ⱖ60 Gy) has been shown to be more effective than low-dose reirradiation (⬍60 Gy), with greater additional local control and survival rates (4, 15). However, the higher reirradiation dose is also associated with a greater risk of severe complications. Before the advent of conformal RT, the major modality used was conventional EBRT combined with brachytherapy to achieve the high-dose objective. Advancements in technology potentially offer improved precision in the delivery of RT. More than 30 years ago, the concept of conformal therapy using arc therapy and a continuously changing shape of the treatment port was first described by Takahashi (16). Through advances in computer software and hardware, a new concept of RT—intensity-modulated RT (IMRT)— has been developed. IMRT uses inverse treatment planning and computer controlled radiation deposition (17–19). The chief advantage of IMRT is its ability to precisely deliver radiation to the target tissue while relatively sparing the surrounding tissues. Recently, IMRT has gained popularity in the treatment of head-andneck cancer (20 –25). NPC, as a special type of head-andneck cancer, has gained attention in IMRT research. In the treatment of primary NPC, IMRT has been shown to provide an incremental improvement in both dose distribution (26 –29) and therapeutic result (30). In this study, we used a commercial IMRT system (NOMOS Peacock System, NOMOS Corp., Cranberry Township, PA) for planning and delivery in locoregional recurrent NPC. We found that IMRT is a feasible and safe option in this group of patients.
METHODS AND MATERIALS Patient characteristics Between January 2001 and February 2002, 49 patients (Karnofsky performance status ⱖ80) with locoregional recurrence in the nasopharynx were treated with IMRT at the Cancer Center, Sun Yat-Sen University, Guangzhou, China. Local failure was diagnosed by biopsy and/or CT/MRI evidence of progressive skull base erosion and clinical symptoms. Forty patients were diagnosed by biopsy. Nine patients had recurrence in the skull base only and were
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Table 1. Patient characteristics Gender (n) Male Female Age (y) Mean Range Median T stage (n) T1 T2 T3 T4 N stage (n) N0 N1 N2 N3 Previous RT dose (Gy) Mean Range Median Time to relapse (mo) Mean Range Median
37 (75.5) 12 (24.5) 46 28–70 45 4 (8.1) 9 (18.4) 11 (22.4) 25 (51.0) 46 (93.9) 2 (4.1) 0 (0.0) 1 (2.0) 71 66–78 70 30.2 6–184 19.5
Abbreviation: RT ⫽ radiotherapy. Numbers in parentheses are percentages.
diagnosed by CT/MRI and clinical symptoms. The average time for recurrent locoregional disease in the nasopharynx was 30.2 months after initial conventional RT. The median isocenter dose of the nasopharynx was 70 Gy (range 60.9 – 78.0) for initial conventional RT. All patients were restaged according to the 1992 Fuzhou, China staging system on NPC (31). This staging system is essentially similar to the recent TNM staging criteria for NPC (32). The number of patients with Stage I, II, III, and IV disease was 4, 9, 10, and 26 respectively. T1, T2, T3, and T4 disease was found in 4, 9, 11, and 25 patients, respectively. N0, N1, N2, and N3 disease was found in 46, 2, 0, and 1 patient, respectively (Table 1). Of these patients, invasion of the nasal cavity, maxillary sinus, ethmoid sinus, sphenoid sinus, and cavernous sinus and erosion of the skull base was found in 8, 1, 3, 8, 15, and 20 patients, respectively. RT details The gross tumor volume (GTV) was defined as the gross extent of the tumor shown by CT/MRI imaging studies and was contoured according to International Commission on Radiation Units and Measurements (ICRU) Report 62 (ICRU 62) guidelines (33). The clinical target volume was defined as the GTV plus a margin for potential microscopic spread. Two margins (margin 1 and margin 2) were set up for the subclinical disease in the nasopharynx. Margin 1 was defined as 0.5–1 cm away from the border of GTV. Margin 2 was defined as 1–1.5 cm away from the border of margin 1. The surrounding critical normal structures, namely the brainstem, spinal cord, optic nerves, chiasm, pituitary gland,
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Fig. 1. Axial and sagittal treatment plan with isodose lines. M1 ⫽ margin 1; M2 ⫽ margin 2; BS ⫽ brainstem; SC ⫽ spinal cord.
lens, temporal lobes, parotid gland, temporomandibular joints, and mandible bone were contoured, and the doses to these structures were constrained according to the ICRU 50 guidelines (34). All target volumes were outlined slice by slice on the treatment planning CT images. Inverse planning was created with the Corvus, version 3.0 (NOMOS Corp., Cranberry Township, PA) planning system, and the treatment was delivered with a dynamic multivane intensity modulating collimator called MIMiC using segmental tomotherapy techniques (NOMOS). The gantry rotation arc was 105–255°, and beamlet patterns changed every 5°. A treatment plan is shown in Fig. 1. The GTV in the nasopharynx and the positive lymph nodes in the neck received a prescription dose of 68 –70 Gy and 60 Gy, respectively. Our goal was to prescribe 1.8 –2.0 Gy/fraction/d, 5 d/wk to the clinical target volume. The GTV received a higher dose per fraction, typically 2.2–2.3 Gy/fraction/d. The dose–volume histogram parameters of the GTV and margins 1 and 2 are shown in Table 2. All patients received full-course IMRT. Three patients who had
positive lymph nodes were also treated with five to six courses of chemotherapy (cisplatin plus 5-fluorouracil) after IMRT. RESULTS Treatment planning dosimetry The plans showed that the percentage of the GTV receiving 95% of the prescribed dose (V95-GTV) was 98.5%, and the dose encompassing 95% of the GTV (D95-GTV) was 68.1 Gy in the nasopharynx. The mean dose of the GTV, margin 1, and margin 2 was 71.4, 68.2, and 63.1 Gy, respectively (Table 2). The average doses and volumes of critical structures in these 49 patients are shown in Table 3. At a median follow-up of 9 months (range 3–13), the locoregional control rate was 100%. Three cases (6.1%) of locoregional residual disease were seen in 49 patients by the end of IMRT, but they achieved a complete response at 3 months of follow-up. Tumor necrosis was seen in 14 patients (28.6%) toward the completion of IMRT. Three patients
Table 2. Dose–volume histogram summary for target volumes
Volume (cm3) Prescribed dose (Gy) Fractionation (Gy) Maximal dose (Gy) Mean dose (Gy) Minimal dose (Gy) D95 (Gy) V95 (%)
GTV
Margin 1
Margin 2
47.2 (7.0–158.9) 68.8 (66.0–70.0) 2.2 (2.0–2.8) 79.2 (72.5–89.1) 71.4 (68.7–75.4) 54.8 (33.1–66.8) 68.1 (64.0–72.2) 98.5 (88.6–100.0)
55.9 (23.0–132.3) 61.2 (60.0–66.0) 2.0 (1.8–2.2) 76.6 (72.3–83.9) 68.2 (65.4–71.3) 48.5 (27.6–59.1) 63.5 (60.3–67.1) 99.6 (98.5–100.0)
70.2 (16.1–120.7) 52.7 (50.0–58.0) 1.8 (1.4–2.0) 76.1 (70.2–83.4) 63.1 (57.5–69.2) 41.5 (25.3–51.0) 55.6 (50.3–64.9) 99.4 (96.2–100.0)
Abbreviations: GTV ⫽ gross target volume; D95 ⫽ dose encompassing 95% of volume of target; V95 ⫽ percentage of volume receiving 95% of prescribed dose. Numbers in parentheses are the range.
IMRT for recurrent nasopharyngeal carcinoma
Table 3. IMRT doses and volume of critical structures irradiated by IMRT in 49 patients with recurrent nasopharyngeal carcinoma Volume (cm3)
Mean dose (Gy)
23.0 (6.8–34.7) 5.4 (3.0–7.5) 0.9 (0.4–1.3)
28.5 (9.1–55.3) 20.2 (5.5–38.7) 21.6 (12.4–33.0)
0.6 (0.5–0.8) 0.6 (0.4–1.4)
19.6 (10.1–34.1) 19.2 (10.1–32.6)
0.2 (0.2–0.2) 0.2 (0.2–0.2)
3.9 (2.3–6.4) 4.1 (3.0–6.5)
40.5 (29.0–64.8) 39.2 (29.7–65.2)
21.0 (4.5–61.0) 22.1 (5.0–60.9)
11.0 (3.4–23.1) 14.2 (3.8–27.1)
21.0 (9.2–39.8) 18.4 (7.6–35.3)
1.8 (1.5–1.9) 1.8 (1.4–2.1)
27.9 (19.4–43.3) 28.8 (19.7–43.6)
36.3 (22.5–47.3) 35.8 (29.2–46.9) 0.2 (0.1–0.4)
20.2 (5.4–51.0) 19.7 (4.9–48.5) 32.6 (23.5–43.4)
Critical structure Brainstem Spinal cord Optical chiasm Optical nerves Left Right Lens Left Right Temporal lobes Left Right Parotids Left Right Temporomandibular joints Left Right Mandible bone Left Right Pituitary
Numbers in parentheses are the range.
developed metastases at a distant site at 13 months of follow-up: two in the bone and one in the liver and lung. Acute toxicity Acute toxicity in 49 patients was evaluated according to the RTOG radiation morbidity scoring criteria. Grade 0, 1, and 2 skin toxicity developed in 29, 19, and 1 patient, respectively. Grade 0, 1, 2, and 3 oral mucosa toxicity occurred in 16, 10, 21, and 2 patients, respectively, and 26 and 23 patients had Grade 1 and 2 xerostomia, respectively. Among the Grade 2 xerostomia patients, 18 had moderate dryness and 5 had complete dryness (Table 4). DISCUSSION Currently, one of the most controversial aspects of NPC is the recommendation for treatment of recurrent disease. A comparison of results from different centers is difficult without an understanding of standard criteria (staging sysTable 4. Acute toxicity (RTOG criteria) Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Skin Mucosa Xerostomia
29 (59.2) 16 (32.7)
19 (38.8) 10 (20.4) 26 (53.1)
1 (2.0) 21 (42.9) 23 (46.9)
— 2 (4.1) —
Abbreviation: RTOG ⫽ Radiation Therapy Oncology Group. Data presented as the number of patients, with the percentage in parentheses.
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tem, patient numbers, treatment period, and treatment modalities). For NPC patients with deep-seated disease at relapse, few salvage options are available other than reirradiation. Most patients with recurrent NPC have been treated with EBRT alone or EBRT combined with intracavitary brachytherapy (1, 2, 4, 6). Unfortunately, reirradiation with conventional EBRT is associated with a high risk of severe complications. Other treatment methods have been tried at several institutions, including interstitial implant, nasopharyngectomy, and stereotactic radiosurgery. Kwong et al. (11) reported their 13-year experience using radioactive gold grain implantation for local recurrent NPC. Fifty-three patients who had first recurrence in the nasopharynx were treated. The treatment was performed under direct vision with a split palate approach. The 5-year local control rate was 62.7%. The 5-year overall survival rate was 56.3%. Treatment-related complications included headache (28.3%), palatal fistula (18.9%), and mucosal radiation necrosis at the site of implantation (16%). However, the authors did not break down their complication results according to the subset of patients: persistent disease, first recurrence, and second recurrence. To date, their study is the longest follow-up report on recurrent NPC patients treated with interstitial radioactive implants. They concluded that gold grain implantation is an effective salvage treatment for recurrent disease confined to the nasopharynx. Investigators from various institutions (8, 10, 12) have agreed that nasopharyngectomy showed benefit only in T1 and T2 recurrent tumors. Supplemental postoperative RT was given in 21.6% (8 of 37) to 77.4% (24 of 31) of patients. However, the benefits of postoperative RT have not been consistently shown by all studies. Stereotactic radiosurgery has also been used in the treatment of recurrent NPC (9, 13, 14, 35). The dose and fractionation used in radiosurgery varied in different studies. Recognizing the substantial risk of radiation-induced morbidity of singlefraction, high-dose RT, Ahn et al. (13) used fractionated stereotactic RT (FSRT) to treat recurrent NPC. FSRT has the radiobiologic advantage of conventional fractionation in addition to the mechanical precision of stereotactic devices. In their report, the authors treated 12 recurrent NPC patients using FSRT as the sole modality. The tumor stage at recurrence was not detailed. The median total dose of FSRT was 54 Gy (range 45– 65), and the fractional FSRT dose was 2.5 Gy or 3.0 Gy. The local control and survival rate at 2 years was 92% and 60%, respectively. As IMRT emerges, this technique has shown a lot of advantages compared with conventional RT. Xia et al. (26) compared the NPC treatment plans with different techniques (conventional RT, three-dimensional conformal RT, and IMRT). They found that IMRT techniques provided improved tumor target coverage with significantly better sparing of sensitive normal tissue structures in the treatment of locally advanced NPC. Hsiung et al. (29) reported that for boost or salvage treatment of NPC, lower normal tissue doses and more homogeneous target doses were achieved
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with IMRT plans. Woo et al. (36) compared IMRT with stereotactic radiosurgery for the treatment of intracranial lesions. They found that a treatment plan generated using IMRT appears superior to a multiple isocenter plan using a conventional radiosurgery system for the treatment of a large (⬎4 cm) irregularly shaped intracranial target. IMRT has been used in the treatment of primary and recurrent NPC. Lee et al. (30) reported the largest series of primary NPC treated with IMRT. We now report the first and largest series of patients with recurrent NPC treated with IMRT. In our current study, all 49 NPC patients recurred after the initial conventional RT. Of these 49 recurrent patients, 36 (73.5%) had Stage T3 and T4 and had 55 adjacent anatomy site invasion (Table 1 and 2). The most frequent invasion sites were the skull base (40.8%) and cavernous sinus (30.6%), respectively. It is very difficult to achieve the treatment goal in this group of patients with advanced recurrent disease with conventional RT, brachytherapy, and surgery. In our IMRT treatment plan, the prescription dose was 68.8 Gy (range 66.0 –70.0) to GTV. The plans showed that D95-GTV was 68.1 Gy (range 64.0 – 72.2), and the V95-GTV was 98.5% (range 88.6 –100.0%) in nasopharynx. The mean dose of GTV was 71.4 Gy (range 68.7–75.4). The mean dose to the surrounding critical structures was much lower than the tolerable range. In some cases, the temporal lobes dose reached 61.0 Gy and 60.9 Gy, but the irradiated volume was very small. The reason for this high dose was that recurrent disease invaded the cavernous sinus and/or skull base. No acute brain and spinal cord radiation injuries have been observed thus far. Longterm follow-up is warranted to evaluate late toxicity.
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One of the interesting phenomena we found in this study was necrosis of the recurrent tumor and part of tumor shedding near the end of IMRT. This phenomenon was not common with conventional RT. In this study, tumor necrosis was observed in 14 patients (28.6%) toward the end of IMRT. None of them had bleeding, fistula, or ulceration of the nasopharynx. Oral antibiotics were given. No patients complained of headache or other neurologic symptoms. The shed tissues were sent to the pathologist and reported to be necrotic tissue and inflammatory change without any carcinoma. We postulated that the reasons of early tumor necrosis are that IMRT delivered a higher dose and fractionation size to the nasopharynx and the recurrent tumor in nasopharynx has a poorer blood supply than the primary.
CONCLUSION The improvement in tumor target coverage and significant sparing of adjacent critical structures allow the feasibility of IMRT as a retreatment option for recurrent NPC after initial RT. Our initial experience of high-dose IMRT for recurrent NPC has been promising with acceptable treatment-related toxicity profile and encouraging tumor response/control. In contrast to primary NPC, recurrent NPC reirradiated with high dose IMRT led to the shedding of tumor necrotic tissues toward the end of RT. Longer term follow-up of a larger cohort of patients is warranted to evaluate late toxicity and to confirm the early promising treatment outcome.
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CLINICAL INVESTIGATION
Head and Neck
INITIAL EXPERIENCE USING INTENSITY-MODULATED RADIOTHERAPY FOR RECURRENT NASOPHARYNGEAL CARCINOMA TAI-XIANG LU, M.D.,* WEI-YUAN MAI, M.D.,*† BIN S. TEH, M.D.,† CHONG ZHAO, M.D.,* FEI HAN, M.D.,* YIN HUANG, M.D.,* XIAO-WU DENG, PH.D.,* LI-XIA LU, M.D.,* SHAO-MIN HUANG, C.M.D.,* ZHI-FAN ZENG, M.D.,* CHENG-GUANG LIN, R.T.T.,* HSIN H. LU, M.D.,† J. KAM CHIU, M.D.,† L. STEVEN CARPENTER, M.D.,† WALTER H. GRANT III, PH.D.,† SHIAO Y. WOO, M.D.,† NAN-JI CUI, M.D.,* AND E. BRIAN BUTLER, M.D.† *Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China; † Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX Purpose: To report our initial experience on the feasibility, toxicity, and tumor control using intensity-modulated radiotherapy (IMRT) for retreatment of recurrent nasopharyngeal carcinoma (NPC). Methods and Materials: A total of 49 patients with locoregional recurrent carcinoma in the nasopharynx were treated with IMRT between January 2001 and February 2002 at the Sun Yat-Sen University Cancer Center, Guangzhou, China. The average time to the nasopharyngeal recurrence was 30.2 months after initial conventional RT. The median isocenter dose to the nasopharynx was 70 Gy (range 60.9 –78.0) for the initial conventional RT. All patients were restaged at the time of recurrence according to the 1992 Fuzhou, China staging system on NPC. The number of patients with Stage I, II, III and IV disease was 4, 9, 10, and 26, respectively. T1, T2, T3, and T4 disease was found in 4, 9, 11, and 25 patients, respectively. N0, N1, N2, and N3 disease was found in 46, 2, 0, and 1 patient, respectively. Invasion of the nasal cavity, maxillary sinus, ethmoid sinus, sphenoid sinus, and cavernous sinus and erosion of the base of the skull was found in 8, 1, 3, 8, 15, and 20 patients, respectively. The gross tumor volume (GTV) was contoured according to the International Commission on Radiation Units and Measurements (ICRU) Report 62 guidelines. The critical structures were contoured, and the doses to critical structures were constrained according to ICRU 50 guidelines. The GTV in the nasopharynx and positive lymph nodes in the neck received a prescription dose of 68 –70 Gy and 60 Gy, respectively. All patients received full-course IMRT. Three patients who had positive lymph nodes were treated with five to six courses of chemotherapy (cisplatin ⴙ 5-fluorouracil) after IMRT. Results: The treatment plans showed that the percentage of GTV receiving 95% of the prescribed dose (V95-GTV) was 98.5%, and the dose encompassing 95% of GTV (D95-GTV) was 68.1 Gy in the nasopharynx. The mean dose to the GTV was 71.4 Gy. The average doses of the surrounding critical structures were much lower than the tolerable thresholds. At a median follow-up of 9 months (range 3–13), the locoregional control rate was 100%. Three cases (6.1%) of locoregional residual disease were seen at the completion of IMRT, but had achieved a complete response at follow-up. Three patients developed metastases at a distant site: two in the bone and one in the liver and lung at 13 months follow-up. Acute toxicity (skin, mucosa, and xerostomia) was acceptable according to the Radiation Therapy Oncology Group criteria. Tumor necrosis was seen toward the end of IMRT in 14 patients (28.6%). Conclusion: The improvement in tumor target coverage and significant sparing of adjacent critical structures allow the feasibility of IMRT as a retreatment option for recurrent NPC after initial conventional RT. This is the first large series using IMRT to reirradiate local recurrent NPC after initial RT failed. The treatment-related toxicity profile was acceptable. The initial tumor response/local control was also very encouraging. In contrast to primary NPC, recurrent NPC reirradiated with high-dose IMRT led to the shedding of tumor necrotic tissue toward the end of RT. More patients and longer term follow-up are warranted to evaluate late toxicity and treatment outcome. © 2004 Elsevier Inc. IMRT, Reirradiation, Recurrent, Nasopharyngeal carcinoma.
LA, October 6 –10, 2002. Acknowledgments—The authors thank Shirley Clark for her assistance in the preparation of this manuscript. Received Mar 13, 2003, and in revised form Jul 3, 2003. Accepted for publication Jul 11, 2003.
Reprint requests to: Wei-Yuan Mai, M.D., Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, 6565 Fannin, MS 121-B, Houston, TX 77030. Tel: (713) 790-2637; Fax: (713) 793-1300; E-mail: [email protected] Presented at the 44th American Society for Therapeutic Radiology and Oncology (ASTRO) Annual Meeting, New Orleans, 682
IMRT for recurrent nasopharyngeal carcinoma
INTRODUCTION Local recurrent nasopharyngeal carcinoma (NPC) that has received previous full-dose radiotherapy (RT) poses a challenge to additional treatment options. Additional RT, especially with a conventional technique, could cause significant undesirable complications and side effects, because the normal tissue tolerance has previously been reached. In the past several decades, various treatment modalities, including external beam radiotherapy (EBRT), intracavitary brachytherapy, interstitial radioactive implantation, stereotactic radiosurgery, nasopharyngectomy, chemotherapy, and a combination of these methods, have been used (1–14). Despite the advances in surgery and chemotherapy, reirradiation remains the most effective modality for salvaging local recurrent NPC. High-dose reirradiation (ⱖ60 Gy) has been shown to be more effective than low-dose reirradiation (⬍60 Gy), with greater additional local control and survival rates (4, 15). However, the higher reirradiation dose is also associated with a greater risk of severe complications. Before the advent of conformal RT, the major modality used was conventional EBRT combined with brachytherapy to achieve the high-dose objective. Advancements in technology potentially offer improved precision in the delivery of RT. More than 30 years ago, the concept of conformal therapy using arc therapy and a continuously changing shape of the treatment port was first described by Takahashi (16). Through advances in computer software and hardware, a new concept of RT—intensity-modulated RT (IMRT)— has been developed. IMRT uses inverse treatment planning and computer controlled radiation deposition (17–19). The chief advantage of IMRT is its ability to precisely deliver radiation to the target tissue while relatively sparing the surrounding tissues. Recently, IMRT has gained popularity in the treatment of head-andneck cancer (20 –25). NPC, as a special type of head-andneck cancer, has gained attention in IMRT research. In the treatment of primary NPC, IMRT has been shown to provide an incremental improvement in both dose distribution (26 –29) and therapeutic result (30). In this study, we used a commercial IMRT system (NOMOS Peacock System, NOMOS Corp., Cranberry Township, PA) for planning and delivery in locoregional recurrent NPC. We found that IMRT is a feasible and safe option in this group of patients.
METHODS AND MATERIALS Patient characteristics Between January 2001 and February 2002, 49 patients (Karnofsky performance status ⱖ80) with locoregional recurrence in the nasopharynx were treated with IMRT at the Cancer Center, Sun Yat-Sen University, Guangzhou, China. Local failure was diagnosed by biopsy and/or CT/MRI evidence of progressive skull base erosion and clinical symptoms. Forty patients were diagnosed by biopsy. Nine patients had recurrence in the skull base only and were
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Table 1. Patient characteristics Gender (n) Male Female Age (y) Mean Range Median T stage (n) T1 T2 T3 T4 N stage (n) N0 N1 N2 N3 Previous RT dose (Gy) Mean Range Median Time to relapse (mo) Mean Range Median
37 (75.5) 12 (24.5) 46 28–70 45 4 (8.1) 9 (18.4) 11 (22.4) 25 (51.0) 46 (93.9) 2 (4.1) 0 (0.0) 1 (2.0) 71 66–78 70 30.2 6–184 19.5
Abbreviation: RT ⫽ radiotherapy. Numbers in parentheses are percentages.
diagnosed by CT/MRI and clinical symptoms. The average time for recurrent locoregional disease in the nasopharynx was 30.2 months after initial conventional RT. The median isocenter dose of the nasopharynx was 70 Gy (range 60.9 – 78.0) for initial conventional RT. All patients were restaged according to the 1992 Fuzhou, China staging system on NPC (31). This staging system is essentially similar to the recent TNM staging criteria for NPC (32). The number of patients with Stage I, II, III, and IV disease was 4, 9, 10, and 26 respectively. T1, T2, T3, and T4 disease was found in 4, 9, 11, and 25 patients, respectively. N0, N1, N2, and N3 disease was found in 46, 2, 0, and 1 patient, respectively (Table 1). Of these patients, invasion of the nasal cavity, maxillary sinus, ethmoid sinus, sphenoid sinus, and cavernous sinus and erosion of the skull base was found in 8, 1, 3, 8, 15, and 20 patients, respectively. RT details The gross tumor volume (GTV) was defined as the gross extent of the tumor shown by CT/MRI imaging studies and was contoured according to International Commission on Radiation Units and Measurements (ICRU) Report 62 (ICRU 62) guidelines (33). The clinical target volume was defined as the GTV plus a margin for potential microscopic spread. Two margins (margin 1 and margin 2) were set up for the subclinical disease in the nasopharynx. Margin 1 was defined as 0.5–1 cm away from the border of GTV. Margin 2 was defined as 1–1.5 cm away from the border of margin 1. The surrounding critical normal structures, namely the brainstem, spinal cord, optic nerves, chiasm, pituitary gland,
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Fig. 1. Axial and sagittal treatment plan with isodose lines. M1 ⫽ margin 1; M2 ⫽ margin 2; BS ⫽ brainstem; SC ⫽ spinal cord.
lens, temporal lobes, parotid gland, temporomandibular joints, and mandible bone were contoured, and the doses to these structures were constrained according to the ICRU 50 guidelines (34). All target volumes were outlined slice by slice on the treatment planning CT images. Inverse planning was created with the Corvus, version 3.0 (NOMOS Corp., Cranberry Township, PA) planning system, and the treatment was delivered with a dynamic multivane intensity modulating collimator called MIMiC using segmental tomotherapy techniques (NOMOS). The gantry rotation arc was 105–255°, and beamlet patterns changed every 5°. A treatment plan is shown in Fig. 1. The GTV in the nasopharynx and the positive lymph nodes in the neck received a prescription dose of 68 –70 Gy and 60 Gy, respectively. Our goal was to prescribe 1.8 –2.0 Gy/fraction/d, 5 d/wk to the clinical target volume. The GTV received a higher dose per fraction, typically 2.2–2.3 Gy/fraction/d. The dose–volume histogram parameters of the GTV and margins 1 and 2 are shown in Table 2. All patients received full-course IMRT. Three patients who had
positive lymph nodes were also treated with five to six courses of chemotherapy (cisplatin plus 5-fluorouracil) after IMRT. RESULTS Treatment planning dosimetry The plans showed that the percentage of the GTV receiving 95% of the prescribed dose (V95-GTV) was 98.5%, and the dose encompassing 95% of the GTV (D95-GTV) was 68.1 Gy in the nasopharynx. The mean dose of the GTV, margin 1, and margin 2 was 71.4, 68.2, and 63.1 Gy, respectively (Table 2). The average doses and volumes of critical structures in these 49 patients are shown in Table 3. At a median follow-up of 9 months (range 3–13), the locoregional control rate was 100%. Three cases (6.1%) of locoregional residual disease were seen in 49 patients by the end of IMRT, but they achieved a complete response at 3 months of follow-up. Tumor necrosis was seen in 14 patients (28.6%) toward the completion of IMRT. Three patients
Table 2. Dose–volume histogram summary for target volumes
Volume (cm3) Prescribed dose (Gy) Fractionation (Gy) Maximal dose (Gy) Mean dose (Gy) Minimal dose (Gy) D95 (Gy) V95 (%)
GTV
Margin 1
Margin 2
47.2 (7.0–158.9) 68.8 (66.0–70.0) 2.2 (2.0–2.8) 79.2 (72.5–89.1) 71.4 (68.7–75.4) 54.8 (33.1–66.8) 68.1 (64.0–72.2) 98.5 (88.6–100.0)
55.9 (23.0–132.3) 61.2 (60.0–66.0) 2.0 (1.8–2.2) 76.6 (72.3–83.9) 68.2 (65.4–71.3) 48.5 (27.6–59.1) 63.5 (60.3–67.1) 99.6 (98.5–100.0)
70.2 (16.1–120.7) 52.7 (50.0–58.0) 1.8 (1.4–2.0) 76.1 (70.2–83.4) 63.1 (57.5–69.2) 41.5 (25.3–51.0) 55.6 (50.3–64.9) 99.4 (96.2–100.0)
Abbreviations: GTV ⫽ gross target volume; D95 ⫽ dose encompassing 95% of volume of target; V95 ⫽ percentage of volume receiving 95% of prescribed dose. Numbers in parentheses are the range.
IMRT for recurrent nasopharyngeal carcinoma
Table 3. IMRT doses and volume of critical structures irradiated by IMRT in 49 patients with recurrent nasopharyngeal carcinoma Volume (cm3)
Mean dose (Gy)
23.0 (6.8–34.7) 5.4 (3.0–7.5) 0.9 (0.4–1.3)
28.5 (9.1–55.3) 20.2 (5.5–38.7) 21.6 (12.4–33.0)
0.6 (0.5–0.8) 0.6 (0.4–1.4)
19.6 (10.1–34.1) 19.2 (10.1–32.6)
0.2 (0.2–0.2) 0.2 (0.2–0.2)
3.9 (2.3–6.4) 4.1 (3.0–6.5)
40.5 (29.0–64.8) 39.2 (29.7–65.2)
21.0 (4.5–61.0) 22.1 (5.0–60.9)
11.0 (3.4–23.1) 14.2 (3.8–27.1)
21.0 (9.2–39.8) 18.4 (7.6–35.3)
1.8 (1.5–1.9) 1.8 (1.4–2.1)
27.9 (19.4–43.3) 28.8 (19.7–43.6)
36.3 (22.5–47.3) 35.8 (29.2–46.9) 0.2 (0.1–0.4)
20.2 (5.4–51.0) 19.7 (4.9–48.5) 32.6 (23.5–43.4)
Critical structure Brainstem Spinal cord Optical chiasm Optical nerves Left Right Lens Left Right Temporal lobes Left Right Parotids Left Right Temporomandibular joints Left Right Mandible bone Left Right Pituitary
Numbers in parentheses are the range.
developed metastases at a distant site at 13 months of follow-up: two in the bone and one in the liver and lung. Acute toxicity Acute toxicity in 49 patients was evaluated according to the RTOG radiation morbidity scoring criteria. Grade 0, 1, and 2 skin toxicity developed in 29, 19, and 1 patient, respectively. Grade 0, 1, 2, and 3 oral mucosa toxicity occurred in 16, 10, 21, and 2 patients, respectively, and 26 and 23 patients had Grade 1 and 2 xerostomia, respectively. Among the Grade 2 xerostomia patients, 18 had moderate dryness and 5 had complete dryness (Table 4). DISCUSSION Currently, one of the most controversial aspects of NPC is the recommendation for treatment of recurrent disease. A comparison of results from different centers is difficult without an understanding of standard criteria (staging sysTable 4. Acute toxicity (RTOG criteria) Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Skin Mucosa Xerostomia
29 (59.2) 16 (32.7)
19 (38.8) 10 (20.4) 26 (53.1)
1 (2.0) 21 (42.9) 23 (46.9)
— 2 (4.1) —
Abbreviation: RTOG ⫽ Radiation Therapy Oncology Group. Data presented as the number of patients, with the percentage in parentheses.
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tem, patient numbers, treatment period, and treatment modalities). For NPC patients with deep-seated disease at relapse, few salvage options are available other than reirradiation. Most patients with recurrent NPC have been treated with EBRT alone or EBRT combined with intracavitary brachytherapy (1, 2, 4, 6). Unfortunately, reirradiation with conventional EBRT is associated with a high risk of severe complications. Other treatment methods have been tried at several institutions, including interstitial implant, nasopharyngectomy, and stereotactic radiosurgery. Kwong et al. (11) reported their 13-year experience using radioactive gold grain implantation for local recurrent NPC. Fifty-three patients who had first recurrence in the nasopharynx were treated. The treatment was performed under direct vision with a split palate approach. The 5-year local control rate was 62.7%. The 5-year overall survival rate was 56.3%. Treatment-related complications included headache (28.3%), palatal fistula (18.9%), and mucosal radiation necrosis at the site of implantation (16%). However, the authors did not break down their complication results according to the subset of patients: persistent disease, first recurrence, and second recurrence. To date, their study is the longest follow-up report on recurrent NPC patients treated with interstitial radioactive implants. They concluded that gold grain implantation is an effective salvage treatment for recurrent disease confined to the nasopharynx. Investigators from various institutions (8, 10, 12) have agreed that nasopharyngectomy showed benefit only in T1 and T2 recurrent tumors. Supplemental postoperative RT was given in 21.6% (8 of 37) to 77.4% (24 of 31) of patients. However, the benefits of postoperative RT have not been consistently shown by all studies. Stereotactic radiosurgery has also been used in the treatment of recurrent NPC (9, 13, 14, 35). The dose and fractionation used in radiosurgery varied in different studies. Recognizing the substantial risk of radiation-induced morbidity of singlefraction, high-dose RT, Ahn et al. (13) used fractionated stereotactic RT (FSRT) to treat recurrent NPC. FSRT has the radiobiologic advantage of conventional fractionation in addition to the mechanical precision of stereotactic devices. In their report, the authors treated 12 recurrent NPC patients using FSRT as the sole modality. The tumor stage at recurrence was not detailed. The median total dose of FSRT was 54 Gy (range 45– 65), and the fractional FSRT dose was 2.5 Gy or 3.0 Gy. The local control and survival rate at 2 years was 92% and 60%, respectively. As IMRT emerges, this technique has shown a lot of advantages compared with conventional RT. Xia et al. (26) compared the NPC treatment plans with different techniques (conventional RT, three-dimensional conformal RT, and IMRT). They found that IMRT techniques provided improved tumor target coverage with significantly better sparing of sensitive normal tissue structures in the treatment of locally advanced NPC. Hsiung et al. (29) reported that for boost or salvage treatment of NPC, lower normal tissue doses and more homogeneous target doses were achieved
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with IMRT plans. Woo et al. (36) compared IMRT with stereotactic radiosurgery for the treatment of intracranial lesions. They found that a treatment plan generated using IMRT appears superior to a multiple isocenter plan using a conventional radiosurgery system for the treatment of a large (⬎4 cm) irregularly shaped intracranial target. IMRT has been used in the treatment of primary and recurrent NPC. Lee et al. (30) reported the largest series of primary NPC treated with IMRT. We now report the first and largest series of patients with recurrent NPC treated with IMRT. In our current study, all 49 NPC patients recurred after the initial conventional RT. Of these 49 recurrent patients, 36 (73.5%) had Stage T3 and T4 and had 55 adjacent anatomy site invasion (Table 1 and 2). The most frequent invasion sites were the skull base (40.8%) and cavernous sinus (30.6%), respectively. It is very difficult to achieve the treatment goal in this group of patients with advanced recurrent disease with conventional RT, brachytherapy, and surgery. In our IMRT treatment plan, the prescription dose was 68.8 Gy (range 66.0 –70.0) to GTV. The plans showed that D95-GTV was 68.1 Gy (range 64.0 – 72.2), and the V95-GTV was 98.5% (range 88.6 –100.0%) in nasopharynx. The mean dose of GTV was 71.4 Gy (range 68.7–75.4). The mean dose to the surrounding critical structures was much lower than the tolerable range. In some cases, the temporal lobes dose reached 61.0 Gy and 60.9 Gy, but the irradiated volume was very small. The reason for this high dose was that recurrent disease invaded the cavernous sinus and/or skull base. No acute brain and spinal cord radiation injuries have been observed thus far. Longterm follow-up is warranted to evaluate late toxicity.
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One of the interesting phenomena we found in this study was necrosis of the recurrent tumor and part of tumor shedding near the end of IMRT. This phenomenon was not common with conventional RT. In this study, tumor necrosis was observed in 14 patients (28.6%) toward the end of IMRT. None of them had bleeding, fistula, or ulceration of the nasopharynx. Oral antibiotics were given. No patients complained of headache or other neurologic symptoms. The shed tissues were sent to the pathologist and reported to be necrotic tissue and inflammatory change without any carcinoma. We postulated that the reasons of early tumor necrosis are that IMRT delivered a higher dose and fractionation size to the nasopharynx and the recurrent tumor in nasopharynx has a poorer blood supply than the primary.
CONCLUSION The improvement in tumor target coverage and significant sparing of adjacent critical structures allow the feasibility of IMRT as a retreatment option for recurrent NPC after initial RT. Our initial experience of high-dose IMRT for recurrent NPC has been promising with acceptable treatment-related toxicity profile and encouraging tumor response/control. In contrast to primary NPC, recurrent NPC reirradiated with high dose IMRT led to the shedding of tumor necrotic tissues toward the end of RT. Longer term follow-up of a larger cohort of patients is warranted to evaluate late toxicity and to confirm the early promising treatment outcome.
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