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Reirradiation of Locally Recurrent Nasopharynx Cancer With External Beam Radiotherapy With or Without Brachytherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 76, No. 1, pp. 130–137, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/10/$–see front matter
doi:10.1016/j.ijrobp.2009.01.055
CLINICAL INVESTIGATION
Head and Neck
REIRRADIATION OF LOCALLY RECURRENT NASOPHARYNX CANCER WITH EXTERNAL BEAM RADIOTHERAPY WITH OR WITHOUT BRACHYTHERAPY LAWRENCE KOUTCHER, M.D.,* NANCY LEE, M.D.,* MICHAEL ZELEFSKY, M.D.,* KELVIN CHAN, B.A.,* GILAD COHEN, M.SC.,y DAVID PFISTER, M.D.,z DENNIS KRAUS, M.D.,x AND SUZANNE WOLDEN, M.D.* Departments of *Radiation Oncology, y Medical Physics, z Medicine, and x Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Purpose: To determine survival rates of patients with locally recurrent nasopharynx cancer (LRNPC) treated with modern therapeutic modalities. Methods and Materials: From July 1996 to March 2008, 29 patients were reirradiated for LRNPC. Thirteen patients received combined-modality treatment (CMT), consisting of external beam radiotherapy (EBRT) followed by intracavitary brachytherapy, whereas 16 received EBRT alone. The median age was 50 years, 59% were male, 38% were Asian, 69% had World Health Organization Class III histology, and 86% were treated for their first recurrence. Nine, 6, 8, and 6 patients had recurrent Stage I, II, III, and IV disease, respectively. Patients in the EBRT-alone group had more advanced disease. Median time to reirradiation was 3.9 years. In total, 93% underwent imaging with positron emission tomography and/or magnetic resonance imaging before reirradiation, 83% received intensity-modulated radiotherapy, and 93% received chemotherapy, which was platinum-based in 85% of cases. Results: The median follow-up for all patients was 45 months and for surviving patients was 54 months. Five-year actuarial local control, event-free survival, and overall survival rates were 52%, 44%, and 60%, respectively. No difference was observed between patients treated with EBRT or CMT. Overall survival was superior in patients who achieved local control (p = 0.0003). The incidence of late Grade $3 events in patients re-treated with EBRT alone was significantly increased compared with those receiving CMT (73% vs. 8%; p = 0.005). Conclusions: In this modern reirradiation series of patients with LRNPC, favorable overall survival compared with historical series was achieved. Patients treated with CMT experienced significantly fewer severe late effects compared with those treated with EBRT. Ó 2010 Elsevier Inc. Reirradiation, Locally recurrent nasopharynx cancer, Intracavitary brachytherapy, Late complications.
reirradiating LRNPC, the significant majority of them were performed in previous eras without the full benefit of modern technology. Consequentially, long-term survival generally has been poor, prompting one study (8) to conclude, ‘‘After modern primary radical radiotherapy for NPC, local failures can seldom be salvaged . . . and morbidity is significant and outweighs the benefit.’’ Fortunately, there have been many advances in recent times, including new imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) for target volume delineation, the use of modern chemotherapeutic regimens, and the advent of intensity-modulated radiotherapy (IMRT), which enables the delivery of radiation to the target area with relative sparing of normal tissue. One study found a 4-year local–regional progressionfree rate of 98% with IMRT for primary NPC (9).
INTRODUCTION Patients with locally recurrent nasopharynx cancer (LRNPC) have an extremely poor prognosis without treatment (1, 2). Many treatment options exist, including stereotactic radiosurgery, external beam radiation therapy (EBRT), interstitial radioactive seed implantation, intracavitary brachytherapy, nasopharyngectomy, chemotherapy, and various combinations of these modalities. Chemotherapy alone is palliative and does not result in cure (3). Nasopharyngectomy is typically performed only in patients who have recurrent T1 and T2 disease because it is difficult to perform an en bloc resection of LRNPC when there is skull-base involvement (4–7). In light of these considerations, reirradiation remains the standard of care for LRNPC. Although many series have reported their results on Reprint requests to: Lawrence Koutcher, M.D., Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Tel: (212) 639-5148; Fax: (212) 639-2417; E-mail: [email protected]
Presented in abstract and poster form at the 50th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, September 21–25, 2008, Boston, MA. Conflict of interest: none. Received Nov 5, 2008, and in revised form Jan 23, 2009. Accepted for publication Jan 29, 2009. 130
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Table 1. Patient and tumor characteristics at reirradiation Gender Male Female Age (y), median (range) Race Caucasian East Asian Other Histology WHO I WHO II WHO III Not specified Negative biopsy 2002 AJCC T-stage at recurrence: CMT group 1 2 3 4 2002 AJCC T-stage at recurrence: EBRT group 1 2 3 4 2002 AJCC stage at recurrence: CMT group I II III IV 2002 AJCC stage at recurrence: EBRT group I II III IV Recurrent sites Primary only Primary + neck First recurrence? Yes No
17 (59) 12 (41) 50 (34–74) 15 (52) 11 (38) 3 (10) 3 (10) 4 (14) 20 (69) 1 (3) 1 (3) 9 (69) 2 (15) 2 (15) 0 4 (25) 1 (6) 5 (31) 6 (38) 6 (46) 5 (38) 2 (15) 0 3 (19) 1 (6) 6 (38) 6 (38) 22 (76) 7 (24) 25 (86) 4 (14)
Abbreviations: WHO = World Health Organization; AJCC = American Joint Committee on Cancer; CMT = combined-modality treatment; EBRT = external beam radiotherapy. Values are number (percentage) unless otherwise noted.
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Table 2. Treatment details Initial radiation dose (cGy), median (range) Years between reirradiation 0–<2 2–<5 $5 Time to reirradiation (y), median (range) EBRT-alone group Conventional technique 3D-CRT IMRT CMT group Conventional technique 3D-CRT IMRT PET and/or MRI performed Both MRI PET Neither Brachytherapy details LDR HDR Ir-192 I-125
6800 (6000–7750) 6 12 11 3.9 (0.7–13.8) 0 2 14 1 2 10 16 7 4 2 12 1 3 10
Abbreviations: EBRT = external beam radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiotherapy; CMT = combined-modality treatment; PET = positron emission tomography; MRI = magnetic resonance imaging; LDR = low dose rate; HDR = high dose rate. Values are number unless otherwise noted.
2008. One patient who refused treatment after 30 Gy and died approximately 1 month later was excluded. Of the 29 patients included, 59% were male, 38% were East Asian, 69% had World Health Organization Class III histology, and the median (range) age was 50 (34–74) years. Twenty-five patients (86%) were treated for their first recurrence. Patients were restaged at recurrence, with 52% recurrent (r)-Stage I/II, and 48% r-Stage III/IV. Among patients who were re-treated with combined-modality treatment (CMT)—EBRT and brachytherapy—85% were Stage I/II, whereas among those reirradiated with EBRT alone, 25% were Stage I/II. All
Table 3. Chemotherapy administered at recurrence
Data are scant on the survival outcomes of patients with LRNPC when treated with the benefits of all of these modern techniques. Furthermore, although there has never been a consensus on the role of brachytherapy in the treatment of LRNPC, in the era of IMRT it is perhaps even more unclear because IMRT allows dose escalation in a manner that was not possible with conventional radiation. To address this gap in the literature, we report the Memorial Sloan-Kettering Cancer Center (MSKCC) experience of patients with LRNPC reirradiated in the modern era. METHODS AND MATERIALS Patient characteristics We identified 30 patients without distant metastatic disease who underwent reirradiation for LRNPC from July 1996 to March
Received chemotherapy Yes No Chemotherapy regimen Induction alone Concurrent alone Adjuvant alone Induction and concurrent Concurrent and adjuvant Induction, concurrent, and adjuvant Chemotherapy used for induction Platinum-based Chemotherapy used for concurrent Platinum-based Taxol Cetuximab Chemotherapy used for adjuvant Platinum-based
27 2 3 16 0 2 5 1 6 20 3 1 6
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Chemotherapy Chemotherapy was administered to 27 of 29 patients (93%) (Table 3). A platinum-based regimen was used in 23 of 27 (85%).
Radiation technique: EBRT
Fig. 1. Nasopharynx applicator set (Mick Radionuclear Instruments, Mount Vernon, NY) consisting of (A) two catheters and a lead shield embedded in a rectangular silastic mold, (B) applicator without lead shield for simulation, (C) insertion catheters, and (D) dummy ribbons used for simulation and localization. 29 patients had failed locally. Seven patients (23%) also failed in the neck, 4 of whom underwent neck dissection (Table 1).
Radiotherapy details The median (range) initial radiation dose was 6800 (6000–7750) cGy. The median time to reirradiation was 3.9 (0.7–13.8) years. Eighty-three percent underwent IMRT, 14% three-dimensional conformal radiotherapy, and 3% conventional radiation. The median reirradiation doses were 4500 (3960–7000) cGy and 5940 (3960– 6100) cGy for those treated with CMT and EBRT alone, respectively. Twelve of the 13 patients treated with CMT received low-dose-rate brachytherapy to a dose of 2000 cGy. Ten of these 12 were treated with 125I, and the remaining 2 received 192Ir (Table 2).
All patients were treated with 6-MV photons using a linear accelerator. One also received 6-MeV electrons. For the patient treated with conventional radiation, the portal consisted of parallel-opposed fields to the nasopharynx. For the remaining 28 patients treated with three-dimensionally based planning, the gross tumor volume (GTV) was defined as any tumor visible on either physical examination or imaging studies. To account for organ motion and setup error, the GTV was expanded into a planning target volume (PTV), typically by 1 to 2 cm, although less in areas adjacent to vital structures such as the brainstem. Target volumes and vital structures were outlined on each axial computed tomography (CT) slice. PET and/or MRI were available in the majority of patients for fusion for treatment planning purposes.
Radiation technique: Brachytherapy Brachytherapy was typically administered 1–4 weeks after EBRT. On the day of simulation, after the administration of lidocaine, an in-house applicator without lead shielding was inserted, which was then connected to a pair of rubber catheters (Fig. 1). Localization films were taken to determine the position of the applicator. Most patients were treated with CT planning techniques; they underwent CT simulation, after which target contours were drawn and seed activity determined. On the day of treatment, the applicator, now containing lead shielding for the soft palate, was reinserted, and localization films were again taken to verify positioning. The patient was then brought to the hospital floor and placed in an isolation room. The seeds were loaded into two ribbons, and each ribbon was inserted through a catheter. The seeds
Fig. 2. Sagittal, axial, and coronal views of isodose distributions for intracavitary low-dose-rate brachytherapy using 125I are displayed.
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dose-rate brachytherapy alone to 15 Gy to her nasopharynx, as well as a neck dissection. Because her principal course of reirradiation was delivered at the time of her first recurrence, her survival data were calculated from the first day of her first reirradiation course.
Toxicity assessment Charts were reviewed to retrospectively assess the incidence of late Grade $3 complications. For the toxicity analysis, we assessed local complications of therapy only in patients who had a follow-up visit at least 6 months after the last day of radiation, which resulted in 23 analyzable patients. The Common Terminology Criteria for Adverse Events v3.0 was used to grade late complications. We did not assess ototoxicity because it was typically impossible to determine from which course of radiation it developed; there were very few patients who had audiograms both before and after reirradiation.
Statistical methods The primary endpoints examined were 5-year actuarial LC, EFS, and OS. Actuarial data for these parameters were determined using the Kaplan-Meier technique (10). The log–rank test was used to assess differences between curves, and c2 analysis to identify the difference in toxicity between patients re-treated with EBRT vs. CMT (11).
RESULTS LC, EFS, and OS The median follow-up for the entire cohort was 45 months (range, 2–127 months), for the CMT group 50 months, for the EBRT group 44 months, and for all surviving patients 54 months. The median time to LF has not yet been reached. The 5-year LC rate for the entire cohort was 52% (Fig. 3a). The 5-year LC rate for the CMT and EBRT groups was 52% and 53%, respectively (p = 0.60). The median EFS was 25 months. The 5-year EFS rate for the entire cohort was 44% (Fig. 3b). The 5-year EFS rate for the CMT and EBRT groups was 41% and 44%, respectively (p = 0.31). The median OS was 78 months. The 5-year OS rate for the entire cohort was 60% (Fig. 3c). The 5-year OS rate for the CMT and EBRT groups was 60% and 57%, respectively (p = 0.36). Fig. 3. (a) Local control; (b) event-free survival; (c) overall survival. typically delivered 20 Gy over approximately 2 days (Fig. 2). The use of 125I seeds and lead shielding enabled relative sparing of the soft palate.
Local control, event-free survival, and overall survival Local control (LC), event-free survival (EFS), and overall survival (OS) were calculated from the first day of reirradiation. Among the 4 patients who were not being treated for their first recurrence, 2 had previously been reirradiated. One had undergone a nasopharyngectomy at the time of first recurrence and underwent postoperative brachytherapy. Survival data were calculated from the first day of his second reirradiation course. The second patient had undergone chemoradiation to a dose of 7000 cGy at the time of her first recurrence. For her second recurrence, she was treated with high-
Prognostic factors for OS and LC Patients who achieved LC had an improved 5-year OS compared with those who did not (93% vs. 18%, p = 0.0003; Fig. 4). Reirradiation modality was not prognostic for OS. The 5-year OS rate for patients treated between 2002 and 2008 vs. between 1996 and 2001 was 63% vs. 50%, which was not statistically significant (p = 0.58). Patients with r-Stage I/II disease had a trend toward improved 5-year OS compared with those who had r-Stage III/IV disease (74% vs. 44%, p = 0.13). For LC, these corresponding numbers were 65% vs. 38% (p = 0.11; Fig. 5). Toxicity Late Grade $3 complications included temporal lobe necrosis, syncope in the presence of temporal lobe hemorrhage, cranial neuropathy, and severe trismus. In the EBRT-alone
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Table 4. Grade $3 local late toxicity in patients with $6 months follow-up (n = 23)
Toxicity
Fig. 4. Overall survival by local control.
group, Grade $3 late complications occurred in 73% of patients, compared with 8% in the CMT group (p = 0.005). In the EBRT-alone group, 10 events occurred in 8 patients, whereas in the CMT group, there was 1 event in 1 patient (Table 4). Of the 11 total events, 9 were Grade 3 and 2 were Grade 4. Both Grade 4 events were temporal lobe necrosis, occurring in patients reirradiated with EBRT alone.
DISCUSSION In this study in which patients with LRNPC were reirradiated with modern techniques, patients had a median OS of 78 months and a 5-year OS rate of 60%, which compares favorably with other published series (Table 5) (6, 8, 12–27). One study did report a 74% 3-year OS rate among patients with isolated local failure. However, this series initiated survival time from the start of the primary radiation course, which markedly differs from nearly all other studies and results in an artificially increased follow-up time for a given survival. Another study reported a 61% 5-year OS rate. Among the 86% of patients who were restaged, 80% had rT1 lesions, and 97% #rT2a (18). Furthermore, 23 of 118 patients had locally persistent disease, which has a better prognosis. Another series reported a 3-year OS rate of 65.6–77.5%, but 70% of patients had rT1/T2 disease, and there were no rT4 patients (27).
Fig. 5. Local control by r-stage.
Temporal lobe necrosis Syncope associated with temporal lobe hemorrhage Cranial neuropathy Trismus Total events Proportion of patients with Grade $3 late effects
Reirradiation with EBRT and Reirradiation brachytherapy with EBRT alone 1 0
3 1
0 0 1 1/12 (8)
2 4 10* 8/11 (73)y
Abbreviation: EBRT = external beam radiotherapy. Values in parentheses are percentages. * Two patients had multiple events. y p = 0.005.
One factor accounting for the improved survival observed in our series is that nearly all patients were re-treated with chemotherapy. Intergroup 0099 demonstrated the superiority of concurrent chemoradiation over radiation alone for primary NPC, and in our study 24 patients had concurrent chemotherapy (28). In many studies the percentage of patients receiving chemotherapy is very low or is not reported (6, 8, 12–16, 18–20, 22, 24–27). In one recent study all patients received chemotherapy, but the 5-year OS rate was only 26% (21). This may be in part because no patients received IMRT. In another study, 68% of patients received chemotherapy and 100% received IMRT, but the 2-year OS rate was <40% (23). This poor outcome is likely because nearly half of the patients had rT4 disease. A second factor accounting for the improved outcome was the use of IMRT in 83% of our patients. Lee et al. (29) showed that for patients undergoing reirradiation for head-and-neck cancer, patients treated with IMRT had improved 2-year locoregional progression-free probability compared with those not treated with IMRT. One promising study reported 100% locoregional control in 49 patients with LRNPC treated with IMRT, although median follow-up was only 9 months (19). Intensity-modulated radiotherapy likely improves outcomes by enabling dose escalation to the tumor. Multiple studies have demonstrated improved outcomes when treating to >60 Gy in the setting of LRNPC (12, 16, 20, 30). With conventional radiation, achieving a high reirradiation dose safely is limited by the vital surrounding normal structures, including the brain stem, spinal cord, cranial nerves, temporal lobe, optic apparatus, and the pituitary fossa. In our study, among the 3 patients in the EBRT-alone group who received <58.8 Gy, by 9 months all had failed locally. Moreover, for patients to have any realistic chance of long-term survival, LC must be achieved. In our series, among patients who failed locally, at 5 years only 18% were alive, and no one was alive by 73 months. A third factor leading to the improved outcome in our series is that more than 90% of patients had an MRI and/or PET scan performed, and more than 50% had both. One study found that in patients with locally persistent NPC, PET impacted salvage
Table 5. Comparison of LRNPC reirradiation studies (>20 patients) published after 1995 in which patients were restaged Reirradiation series (reference)
Years in which patients were treated
654 97 74 123y 186 91 41z 118k 36 49 41 35 21 31 159 31 56 74 29
3-y actuarial survival (%)
1.4 — 1.5 46 1.7 49 1.7 — 3.5 22 2.25/2.9/4.6 — 7 48 (2-y) 6.5{ — 1.8 54 0.75 100 LRC (0.75 y) 1.9 48 (2-y) 1.5 45 (2-y) 4.1 — .92 30-40 (2-y) Unclear 74# 4.2x — 13.3 46 DSS 3.5x 78 (SRS); 66 (BT) 3.75 71
5-y actuarial T1/T2 or T3/T4 or Patients treated Patients re-treated with survival (%) Stage I/II (%) Stage III/IV (%) with IMRT (%) chemotherapy (%) 16 36 37 9 12 30 30 61 31 — 28 26 32 — — 53 — — 60
52 34 35 49 37 56 46 $97 64 27 39 34 48 26 50** 100 68 70 52
48 66 65 51 63 44 49x #3 36 73 61 66 52 74 50 0 32 30 48
0 0 0 0 0 0 BT BT SRS 100 0 0 FSRT 100 Not discussed SRSyy FSRT SRS/BT 83
Not discussed 18 28 13 44 19 61 13 Not discussed 6 42 100 Not discussed 68 Not discussed Not discussed 30 Not discussed 93
Abbreviations: IMRT = intensity-modulated radiotherapy; BT = brachytherapy; SRS = stereotactic radiosurgery; LRC = locoregional control; FSRT = fractionated stereotactic radiotherapy; DSS = disease-specific survival. * Sixty-four of 74 patients received reirradiation. y Six patients did not undergo reirradiation; 14 underwent nasopharyngectomy followed by reirradiation. Excludes 43 patients who underwent ‘‘palliative treatments,’’ defined as reirradiation <60 Gy and/or chemotherapy and/or supportive treatment. z Includes 34 patients with recurrent or persistent disease and 7 patients with prior radiation to the nasopharynx for head-and-neck cancer. The median follow-up includes an additional 15 patients treated for primary nasopharynx cancer. x Five percent were unknown. k Includes 23 patients with locally persistent disease; re-staging includes 101/118 patients. { Median follow-up for all surviving patients. # Overall survival time was counted from the start of primary radiation; 74% represents the 3-y overall survival among all 275 patients with isolated local failure. ** Fifty percent among all 319 patients who failed locally. yy Also received intracavitary irradiation.
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Lee, 1997 (12) 1976–1992 Chua, 1998 (13) 1984–1995 Hwang, 1998* (14) 1957–1995 Teo, 1998 (8) 1984–1989 (primary radiation) Chang, 2000 (15) 1982–1995 Leung, 2000 (16) 1990–1999 Syed, 2000 (17) 1978–1997 Law, 2002 (18) 1989–1996 Pai, 2002 (6) 1994–1999 Lu, 2004 (19) 2001–2002 Oksuz, 2004 (20) 1979–2000 Poon, 2004 (21) 1994–2002 Shin, 2004 (22) 1995–2000 Chua, 2005 (23) 2001–2004 Yu, 2005 (24) 1996–2000 (primary radiation) Low, 2006 (25) 1995–2003 Wu, 2007 (26) 1999–2005 Chua, 2007 (27) 1994–2005 Present series 1996–2008
No. of Median patients follow-up (y)
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treatment by enhancing the accuracy of GTV delineation in the treatment planning process (31). Compared with CT, MRI is superior at demarcating the extent of soft-tissue disease, allowing more accurate target delineation. Multiple studies have shown that r-stage is prognostic of outcome, which our series supports (8, 12, 13, 20, 30). The outcome of studies reporting on reirradiation for LRNPC is significantly impacted by the proportion of patients included with early-stage vs. advanced-stage disease. Excluding the stereotactic radiotherapy studies in which most patients had early-stage disease, among the studies listed in Table 5, early-stage recurrences accounted for 26–56% of patients. In our series, 52% of patients had early-stage recurrence, indicating a relatively favorable group of patients. The greater proportion of early-stage patients is partially a reflection of stage migration across different staging systems; a T3 lesion in the American Joint Committee on Cancer (AJCC) 1992 system would be a T2 lesion in the AJCC 2002 system. However, it is likely that the patients in our series, do, in fact, have somewhat earlier-stage disease. In the current era patients are typically followed by MRI, which is able to differentiate postradiation fibrosis from tumor recurrence, potentially leading to earlier diagnosis at recurrence and hence earlier disease stage (32). Therefore, improved imaging may be enhancing outcome not only by improving target volume delineation but by enabling recurrences to be detected and treated at an earlier stage. An important finding of this study is that patients reirradiated with EBRT alone were far more likely to develop Grade $3 late complications compared with those reirradiated with CMT. Although this can be partly explained by the fact that patients in the CMT group had earlier-stage disease, it is also likely because the median dose delivered by EBRT was 1440 cGy lower in the CMT group, resulting in lower doses to critical structures, such as the temporal lobes. Moreover, there is evidence that the cumulative doses delivered may be on the steep portion of the toxicity dose–response curve. Pryzant et al. (33) demonstrated that patients who received #100 Gy of cumulative EBRT dose had a 5-year incidence of severe complications of 4%, whereas those who received >100 Gy had a 39% risk (p = 0.066). They further reported that 8 of 44 patients reirradiated with EBRT alone developed severe complications, compared with 0 of 9 in those who received EBRT with intracavitary cesium. Lee et al. (12) showed that among patients with rT1 disease, patients reirradiated with
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CMT had a lower complication rate than those treated with either EBRT alone or brachytherapy alone. Leung et al. (16) found that patients treated with CMT had a decreased rate of central nervous system and major complications compared with those treated with EBRT alone, which was statistically significant on univariate analysis but not on multivariate analysis. Whereas patients in these series were not treated with IMRT, our study supports the notion that even IMRT is not enough to compensate for the inherent dosimetric advantages of brachytherapy because we also observed significantly higher complication rates in those treated with EBRT alone compared with those treated with CMT. There was no difference in LC, EFS, and OS in patients treated with CMT vs. EBRT alone. This is in agreement with a large study that found that reirradiation technique—EBRT alone, EBRT with brachytherapy, or brachytherapy alone— did not statistically significantly affect local control (12). The biggest strength of this study is the uniformity of patient treatment. Except for 1 patient, all patients who received brachytherapy were treated with a low dose rate to a dose of 20 Gy. More than 80% were treated with IMRT, more than 90% received chemotherapy, and more than 90% underwent imaging with PET and/or MRI before reirradiation. Additionally, most other studies have a considerably shorter median follow-up (6, 8, 12–14, 19–21, 23, 26). Finally, the significant majority of these studies have been published by Chinese groups on Chinese patients, and there are far fewer data for non-Chinese populations. Weaknesses of this study include the small number of patients and the fact that many came from overseas for reirradiation, thereby making follow-up more sporadic. CONCLUSION This study demonstrates that patients with LRNPC treated with the full complement of modern modalities of care, including IMRT, contemporary chemotherapeutic regimens, and high-quality imaging for both detecting early recurrences and for improved target delineation during treatment planning, can achieve relatively long-term OS with acceptably low toxicity. Patients who were treated with CMT developed significantly fewer late Grade $3 complications compared with those treated with EBRT. For patients who have earlystage disease and are candidates for CMT, strong consideration should be given to this treatment modality.
REFERENCES 1. Yan JH, Hu YH, Gu XZ. Radiation therapy of recurrent nasopharyngeal carcinoma. Report on 219 patients. Acta Radiol Oncol 1983;22:23–28. 2. Lee AWM, Law SCK, Foo W, et al. Retrospective analysis of patients with nasopharyngeal carcinoma treated 1976-1985: Survival after local recurrence. Int J Radiat Oncol Biol Phys 1993;26:773–782. 3. Decker DA, Drelichman A, Al-Sarraf M, et al. Chemotherapy for nasopharyngeal carcinoma. A ten-year experience. Cancer 1983;52:602–605.
4. King WW, Ku PK, Mok CO, et al. Nasopharyngectomy in the treatment of recurrent nasopharyngeal carcinoma: A twelveyear experience. Head Neck 2000;22:215–222. 5. Hsu MM, Hong RL, Ting LL, et al. Factors affecting the overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site: Experience with 60 cases. Arch Otolaryngol Head Neck Surg 2001;127:798–902. 6. Pai PC, Chuang CC, Wei KCW, et al. Stereotactic radiosurgery for locally recurrent nasopharyngeal carcinoma. Head Neck 2002;24:748–753.
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7. Fee WE Jr., Moir MS, Choi EC, et al. Nasopharyngectomy for recurrent nasopharyngeal cancer: A 2- to 17-year follow-up. Arch Otolaryngol Head Neck Surg 2002;128:280–284. 8. Teo PML, Kwan WH, Chan ATC, et al. How successful is highdose reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 1998;40:897–913. 9. Lee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53:12–22. 10. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 11. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 1966; 5:163–170. 12. Lee AW, Foo W, Law SC, et al. Reirradiation for recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 1997; 38:43–52. 13. Chua DTT, Sham JST, Kwong DLW, et al. Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 1998;41:379–386. 14. Hwang JM, Fu KK, Phillips T. Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1998;41:1099–1111. 15. Chang JTC, See LC, Liao CT, et al. Locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2000;54:135–142. 16. Leung TW, Tung SY, Sze WK, et al. Salvage radiation therapy for locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2000;48:1331–1338. 17. Syed AMN, Puthawala AA, Damore SJ, et al. Brachytherapy for primary and recurrent nasopharyngeal carcinoma: 20 years’ experience at Long Beach Memorial. Int J Radiat Oncol Biol Phys 2000;47:1311–1321. 18. Law SCK, Lam WK, Ng MF, et al. Reirradiation of nasopharyngeal carcinoma with intracavitary mold brachytherapy: An effective means of local salvage. Int J Radiat Oncol Biol Phys 2002;54:1095–1113. 19. Lu TX, Mai WY, Teh BS. Initial experience using intensitymodulated radiotherapy for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004;58:682–687. 20. Oksuz DC, Meral G, Uzel O, et al. Reirradiation for locally recurrent nasopharyngeal carcinoma: Treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2004;60:388–394.
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21. Poon D, Yap SP, Wong ZW, et al. Concurrent chemoradiotherapy in locoregionally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004;59:1312–1318. 22. Shin SS, Ahn YC, Lim DH, et al. High dose 3-dimensional reirradiation for locally recurrent nasopharyngeal cancer. Yonsei Med J 2004;45:100–106. 23. Chua DTT, Sham JST, Leung LHT, et al. Reirradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy. Radiother Oncol 2005;77:290–294. 24. Yu KW, Leung SF, Tung SW, et al. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck 2005;27:397–405. 25. Low JS, Chua ET, Gao F, et al. Stereotactic radiosurgery plus intracavitary irradiation in the salvage of nasopharyngeal carcinoma. Head Neck 2006;28:321–329. 26. Wu SXW, Chua DTT, Deng ML, et al. Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69:761–769. 27. Chua DTT, Wei WI, Sham JST, et al. Stereotactic radiosurgery versus gold grain implantation in salvaging local failures of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69: 469–474. 28. Al-Sarraf M, LeBlanc M, Giri PGS, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310–1317. 29. Lee N, Chan K, Bekelman JE, et al. Salvage reirradiation for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2007;68:731–740. 30. Wang CC. Reirradiation of recurrent nasopharyngeal carcinoma. Treatment techniques and results. Int J Radiat Oncol Biol Phys 1987;13:953–956. 31. Zheng XK, Chen LH, Wang QS, et al. Influence of 18F fluorodeoxyglucose positron emission tomography on salvage treatment decision making for locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;65:1020–1025. 32. Olmi P, Fallai C, Colagrande C, et al. Staging and follow-up of nasopharyngeal carcinoma: Magnetic resonance imaging versus computed tomography. Int J Radiat Oncol Biol Phys 1995;32: 795–800. 33. Pryzant RM, Wendt CD, Delclos L, et al. Re-treatment of nasopharyngeal carcinoma in 53 patients. Int J Radiat Oncol Biol Phys 1992;22:941–947.
doi:10.1016/j.ijrobp.2009.01.055
CLINICAL INVESTIGATION
Head and Neck
REIRRADIATION OF LOCALLY RECURRENT NASOPHARYNX CANCER WITH EXTERNAL BEAM RADIOTHERAPY WITH OR WITHOUT BRACHYTHERAPY LAWRENCE KOUTCHER, M.D.,* NANCY LEE, M.D.,* MICHAEL ZELEFSKY, M.D.,* KELVIN CHAN, B.A.,* GILAD COHEN, M.SC.,y DAVID PFISTER, M.D.,z DENNIS KRAUS, M.D.,x AND SUZANNE WOLDEN, M.D.* Departments of *Radiation Oncology, y Medical Physics, z Medicine, and x Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Purpose: To determine survival rates of patients with locally recurrent nasopharynx cancer (LRNPC) treated with modern therapeutic modalities. Methods and Materials: From July 1996 to March 2008, 29 patients were reirradiated for LRNPC. Thirteen patients received combined-modality treatment (CMT), consisting of external beam radiotherapy (EBRT) followed by intracavitary brachytherapy, whereas 16 received EBRT alone. The median age was 50 years, 59% were male, 38% were Asian, 69% had World Health Organization Class III histology, and 86% were treated for their first recurrence. Nine, 6, 8, and 6 patients had recurrent Stage I, II, III, and IV disease, respectively. Patients in the EBRT-alone group had more advanced disease. Median time to reirradiation was 3.9 years. In total, 93% underwent imaging with positron emission tomography and/or magnetic resonance imaging before reirradiation, 83% received intensity-modulated radiotherapy, and 93% received chemotherapy, which was platinum-based in 85% of cases. Results: The median follow-up for all patients was 45 months and for surviving patients was 54 months. Five-year actuarial local control, event-free survival, and overall survival rates were 52%, 44%, and 60%, respectively. No difference was observed between patients treated with EBRT or CMT. Overall survival was superior in patients who achieved local control (p = 0.0003). The incidence of late Grade $3 events in patients re-treated with EBRT alone was significantly increased compared with those receiving CMT (73% vs. 8%; p = 0.005). Conclusions: In this modern reirradiation series of patients with LRNPC, favorable overall survival compared with historical series was achieved. Patients treated with CMT experienced significantly fewer severe late effects compared with those treated with EBRT. Ó 2010 Elsevier Inc. Reirradiation, Locally recurrent nasopharynx cancer, Intracavitary brachytherapy, Late complications.
reirradiating LRNPC, the significant majority of them were performed in previous eras without the full benefit of modern technology. Consequentially, long-term survival generally has been poor, prompting one study (8) to conclude, ‘‘After modern primary radical radiotherapy for NPC, local failures can seldom be salvaged . . . and morbidity is significant and outweighs the benefit.’’ Fortunately, there have been many advances in recent times, including new imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) for target volume delineation, the use of modern chemotherapeutic regimens, and the advent of intensity-modulated radiotherapy (IMRT), which enables the delivery of radiation to the target area with relative sparing of normal tissue. One study found a 4-year local–regional progressionfree rate of 98% with IMRT for primary NPC (9).
INTRODUCTION Patients with locally recurrent nasopharynx cancer (LRNPC) have an extremely poor prognosis without treatment (1, 2). Many treatment options exist, including stereotactic radiosurgery, external beam radiation therapy (EBRT), interstitial radioactive seed implantation, intracavitary brachytherapy, nasopharyngectomy, chemotherapy, and various combinations of these modalities. Chemotherapy alone is palliative and does not result in cure (3). Nasopharyngectomy is typically performed only in patients who have recurrent T1 and T2 disease because it is difficult to perform an en bloc resection of LRNPC when there is skull-base involvement (4–7). In light of these considerations, reirradiation remains the standard of care for LRNPC. Although many series have reported their results on Reprint requests to: Lawrence Koutcher, M.D., Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Tel: (212) 639-5148; Fax: (212) 639-2417; E-mail: [email protected]
Presented in abstract and poster form at the 50th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, September 21–25, 2008, Boston, MA. Conflict of interest: none. Received Nov 5, 2008, and in revised form Jan 23, 2009. Accepted for publication Jan 29, 2009. 130
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Table 1. Patient and tumor characteristics at reirradiation Gender Male Female Age (y), median (range) Race Caucasian East Asian Other Histology WHO I WHO II WHO III Not specified Negative biopsy 2002 AJCC T-stage at recurrence: CMT group 1 2 3 4 2002 AJCC T-stage at recurrence: EBRT group 1 2 3 4 2002 AJCC stage at recurrence: CMT group I II III IV 2002 AJCC stage at recurrence: EBRT group I II III IV Recurrent sites Primary only Primary + neck First recurrence? Yes No
17 (59) 12 (41) 50 (34–74) 15 (52) 11 (38) 3 (10) 3 (10) 4 (14) 20 (69) 1 (3) 1 (3) 9 (69) 2 (15) 2 (15) 0 4 (25) 1 (6) 5 (31) 6 (38) 6 (46) 5 (38) 2 (15) 0 3 (19) 1 (6) 6 (38) 6 (38) 22 (76) 7 (24) 25 (86) 4 (14)
Abbreviations: WHO = World Health Organization; AJCC = American Joint Committee on Cancer; CMT = combined-modality treatment; EBRT = external beam radiotherapy. Values are number (percentage) unless otherwise noted.
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Table 2. Treatment details Initial radiation dose (cGy), median (range) Years between reirradiation 0–<2 2–<5 $5 Time to reirradiation (y), median (range) EBRT-alone group Conventional technique 3D-CRT IMRT CMT group Conventional technique 3D-CRT IMRT PET and/or MRI performed Both MRI PET Neither Brachytherapy details LDR HDR Ir-192 I-125
6800 (6000–7750) 6 12 11 3.9 (0.7–13.8) 0 2 14 1 2 10 16 7 4 2 12 1 3 10
Abbreviations: EBRT = external beam radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiotherapy; CMT = combined-modality treatment; PET = positron emission tomography; MRI = magnetic resonance imaging; LDR = low dose rate; HDR = high dose rate. Values are number unless otherwise noted.
2008. One patient who refused treatment after 30 Gy and died approximately 1 month later was excluded. Of the 29 patients included, 59% were male, 38% were East Asian, 69% had World Health Organization Class III histology, and the median (range) age was 50 (34–74) years. Twenty-five patients (86%) were treated for their first recurrence. Patients were restaged at recurrence, with 52% recurrent (r)-Stage I/II, and 48% r-Stage III/IV. Among patients who were re-treated with combined-modality treatment (CMT)—EBRT and brachytherapy—85% were Stage I/II, whereas among those reirradiated with EBRT alone, 25% were Stage I/II. All
Table 3. Chemotherapy administered at recurrence
Data are scant on the survival outcomes of patients with LRNPC when treated with the benefits of all of these modern techniques. Furthermore, although there has never been a consensus on the role of brachytherapy in the treatment of LRNPC, in the era of IMRT it is perhaps even more unclear because IMRT allows dose escalation in a manner that was not possible with conventional radiation. To address this gap in the literature, we report the Memorial Sloan-Kettering Cancer Center (MSKCC) experience of patients with LRNPC reirradiated in the modern era. METHODS AND MATERIALS Patient characteristics We identified 30 patients without distant metastatic disease who underwent reirradiation for LRNPC from July 1996 to March
Received chemotherapy Yes No Chemotherapy regimen Induction alone Concurrent alone Adjuvant alone Induction and concurrent Concurrent and adjuvant Induction, concurrent, and adjuvant Chemotherapy used for induction Platinum-based Chemotherapy used for concurrent Platinum-based Taxol Cetuximab Chemotherapy used for adjuvant Platinum-based
27 2 3 16 0 2 5 1 6 20 3 1 6
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Chemotherapy Chemotherapy was administered to 27 of 29 patients (93%) (Table 3). A platinum-based regimen was used in 23 of 27 (85%).
Radiation technique: EBRT
Fig. 1. Nasopharynx applicator set (Mick Radionuclear Instruments, Mount Vernon, NY) consisting of (A) two catheters and a lead shield embedded in a rectangular silastic mold, (B) applicator without lead shield for simulation, (C) insertion catheters, and (D) dummy ribbons used for simulation and localization. 29 patients had failed locally. Seven patients (23%) also failed in the neck, 4 of whom underwent neck dissection (Table 1).
Radiotherapy details The median (range) initial radiation dose was 6800 (6000–7750) cGy. The median time to reirradiation was 3.9 (0.7–13.8) years. Eighty-three percent underwent IMRT, 14% three-dimensional conformal radiotherapy, and 3% conventional radiation. The median reirradiation doses were 4500 (3960–7000) cGy and 5940 (3960– 6100) cGy for those treated with CMT and EBRT alone, respectively. Twelve of the 13 patients treated with CMT received low-dose-rate brachytherapy to a dose of 2000 cGy. Ten of these 12 were treated with 125I, and the remaining 2 received 192Ir (Table 2).
All patients were treated with 6-MV photons using a linear accelerator. One also received 6-MeV electrons. For the patient treated with conventional radiation, the portal consisted of parallel-opposed fields to the nasopharynx. For the remaining 28 patients treated with three-dimensionally based planning, the gross tumor volume (GTV) was defined as any tumor visible on either physical examination or imaging studies. To account for organ motion and setup error, the GTV was expanded into a planning target volume (PTV), typically by 1 to 2 cm, although less in areas adjacent to vital structures such as the brainstem. Target volumes and vital structures were outlined on each axial computed tomography (CT) slice. PET and/or MRI were available in the majority of patients for fusion for treatment planning purposes.
Radiation technique: Brachytherapy Brachytherapy was typically administered 1–4 weeks after EBRT. On the day of simulation, after the administration of lidocaine, an in-house applicator without lead shielding was inserted, which was then connected to a pair of rubber catheters (Fig. 1). Localization films were taken to determine the position of the applicator. Most patients were treated with CT planning techniques; they underwent CT simulation, after which target contours were drawn and seed activity determined. On the day of treatment, the applicator, now containing lead shielding for the soft palate, was reinserted, and localization films were again taken to verify positioning. The patient was then brought to the hospital floor and placed in an isolation room. The seeds were loaded into two ribbons, and each ribbon was inserted through a catheter. The seeds
Fig. 2. Sagittal, axial, and coronal views of isodose distributions for intracavitary low-dose-rate brachytherapy using 125I are displayed.
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dose-rate brachytherapy alone to 15 Gy to her nasopharynx, as well as a neck dissection. Because her principal course of reirradiation was delivered at the time of her first recurrence, her survival data were calculated from the first day of her first reirradiation course.
Toxicity assessment Charts were reviewed to retrospectively assess the incidence of late Grade $3 complications. For the toxicity analysis, we assessed local complications of therapy only in patients who had a follow-up visit at least 6 months after the last day of radiation, which resulted in 23 analyzable patients. The Common Terminology Criteria for Adverse Events v3.0 was used to grade late complications. We did not assess ototoxicity because it was typically impossible to determine from which course of radiation it developed; there were very few patients who had audiograms both before and after reirradiation.
Statistical methods The primary endpoints examined were 5-year actuarial LC, EFS, and OS. Actuarial data for these parameters were determined using the Kaplan-Meier technique (10). The log–rank test was used to assess differences between curves, and c2 analysis to identify the difference in toxicity between patients re-treated with EBRT vs. CMT (11).
RESULTS LC, EFS, and OS The median follow-up for the entire cohort was 45 months (range, 2–127 months), for the CMT group 50 months, for the EBRT group 44 months, and for all surviving patients 54 months. The median time to LF has not yet been reached. The 5-year LC rate for the entire cohort was 52% (Fig. 3a). The 5-year LC rate for the CMT and EBRT groups was 52% and 53%, respectively (p = 0.60). The median EFS was 25 months. The 5-year EFS rate for the entire cohort was 44% (Fig. 3b). The 5-year EFS rate for the CMT and EBRT groups was 41% and 44%, respectively (p = 0.31). The median OS was 78 months. The 5-year OS rate for the entire cohort was 60% (Fig. 3c). The 5-year OS rate for the CMT and EBRT groups was 60% and 57%, respectively (p = 0.36). Fig. 3. (a) Local control; (b) event-free survival; (c) overall survival. typically delivered 20 Gy over approximately 2 days (Fig. 2). The use of 125I seeds and lead shielding enabled relative sparing of the soft palate.
Local control, event-free survival, and overall survival Local control (LC), event-free survival (EFS), and overall survival (OS) were calculated from the first day of reirradiation. Among the 4 patients who were not being treated for their first recurrence, 2 had previously been reirradiated. One had undergone a nasopharyngectomy at the time of first recurrence and underwent postoperative brachytherapy. Survival data were calculated from the first day of his second reirradiation course. The second patient had undergone chemoradiation to a dose of 7000 cGy at the time of her first recurrence. For her second recurrence, she was treated with high-
Prognostic factors for OS and LC Patients who achieved LC had an improved 5-year OS compared with those who did not (93% vs. 18%, p = 0.0003; Fig. 4). Reirradiation modality was not prognostic for OS. The 5-year OS rate for patients treated between 2002 and 2008 vs. between 1996 and 2001 was 63% vs. 50%, which was not statistically significant (p = 0.58). Patients with r-Stage I/II disease had a trend toward improved 5-year OS compared with those who had r-Stage III/IV disease (74% vs. 44%, p = 0.13). For LC, these corresponding numbers were 65% vs. 38% (p = 0.11; Fig. 5). Toxicity Late Grade $3 complications included temporal lobe necrosis, syncope in the presence of temporal lobe hemorrhage, cranial neuropathy, and severe trismus. In the EBRT-alone
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Table 4. Grade $3 local late toxicity in patients with $6 months follow-up (n = 23)
Toxicity
Fig. 4. Overall survival by local control.
group, Grade $3 late complications occurred in 73% of patients, compared with 8% in the CMT group (p = 0.005). In the EBRT-alone group, 10 events occurred in 8 patients, whereas in the CMT group, there was 1 event in 1 patient (Table 4). Of the 11 total events, 9 were Grade 3 and 2 were Grade 4. Both Grade 4 events were temporal lobe necrosis, occurring in patients reirradiated with EBRT alone.
DISCUSSION In this study in which patients with LRNPC were reirradiated with modern techniques, patients had a median OS of 78 months and a 5-year OS rate of 60%, which compares favorably with other published series (Table 5) (6, 8, 12–27). One study did report a 74% 3-year OS rate among patients with isolated local failure. However, this series initiated survival time from the start of the primary radiation course, which markedly differs from nearly all other studies and results in an artificially increased follow-up time for a given survival. Another study reported a 61% 5-year OS rate. Among the 86% of patients who were restaged, 80% had rT1 lesions, and 97% #rT2a (18). Furthermore, 23 of 118 patients had locally persistent disease, which has a better prognosis. Another series reported a 3-year OS rate of 65.6–77.5%, but 70% of patients had rT1/T2 disease, and there were no rT4 patients (27).
Fig. 5. Local control by r-stage.
Temporal lobe necrosis Syncope associated with temporal lobe hemorrhage Cranial neuropathy Trismus Total events Proportion of patients with Grade $3 late effects
Reirradiation with EBRT and Reirradiation brachytherapy with EBRT alone 1 0
3 1
0 0 1 1/12 (8)
2 4 10* 8/11 (73)y
Abbreviation: EBRT = external beam radiotherapy. Values in parentheses are percentages. * Two patients had multiple events. y p = 0.005.
One factor accounting for the improved survival observed in our series is that nearly all patients were re-treated with chemotherapy. Intergroup 0099 demonstrated the superiority of concurrent chemoradiation over radiation alone for primary NPC, and in our study 24 patients had concurrent chemotherapy (28). In many studies the percentage of patients receiving chemotherapy is very low or is not reported (6, 8, 12–16, 18–20, 22, 24–27). In one recent study all patients received chemotherapy, but the 5-year OS rate was only 26% (21). This may be in part because no patients received IMRT. In another study, 68% of patients received chemotherapy and 100% received IMRT, but the 2-year OS rate was <40% (23). This poor outcome is likely because nearly half of the patients had rT4 disease. A second factor accounting for the improved outcome was the use of IMRT in 83% of our patients. Lee et al. (29) showed that for patients undergoing reirradiation for head-and-neck cancer, patients treated with IMRT had improved 2-year locoregional progression-free probability compared with those not treated with IMRT. One promising study reported 100% locoregional control in 49 patients with LRNPC treated with IMRT, although median follow-up was only 9 months (19). Intensity-modulated radiotherapy likely improves outcomes by enabling dose escalation to the tumor. Multiple studies have demonstrated improved outcomes when treating to >60 Gy in the setting of LRNPC (12, 16, 20, 30). With conventional radiation, achieving a high reirradiation dose safely is limited by the vital surrounding normal structures, including the brain stem, spinal cord, cranial nerves, temporal lobe, optic apparatus, and the pituitary fossa. In our study, among the 3 patients in the EBRT-alone group who received <58.8 Gy, by 9 months all had failed locally. Moreover, for patients to have any realistic chance of long-term survival, LC must be achieved. In our series, among patients who failed locally, at 5 years only 18% were alive, and no one was alive by 73 months. A third factor leading to the improved outcome in our series is that more than 90% of patients had an MRI and/or PET scan performed, and more than 50% had both. One study found that in patients with locally persistent NPC, PET impacted salvage
Table 5. Comparison of LRNPC reirradiation studies (>20 patients) published after 1995 in which patients were restaged Reirradiation series (reference)
Years in which patients were treated
654 97 74 123y 186 91 41z 118k 36 49 41 35 21 31 159 31 56 74 29
3-y actuarial survival (%)
1.4 — 1.5 46 1.7 49 1.7 — 3.5 22 2.25/2.9/4.6 — 7 48 (2-y) 6.5{ — 1.8 54 0.75 100 LRC (0.75 y) 1.9 48 (2-y) 1.5 45 (2-y) 4.1 — .92 30-40 (2-y) Unclear 74# 4.2x — 13.3 46 DSS 3.5x 78 (SRS); 66 (BT) 3.75 71
5-y actuarial T1/T2 or T3/T4 or Patients treated Patients re-treated with survival (%) Stage I/II (%) Stage III/IV (%) with IMRT (%) chemotherapy (%) 16 36 37 9 12 30 30 61 31 — 28 26 32 — — 53 — — 60
52 34 35 49 37 56 46 $97 64 27 39 34 48 26 50** 100 68 70 52
48 66 65 51 63 44 49x #3 36 73 61 66 52 74 50 0 32 30 48
0 0 0 0 0 0 BT BT SRS 100 0 0 FSRT 100 Not discussed SRSyy FSRT SRS/BT 83
Not discussed 18 28 13 44 19 61 13 Not discussed 6 42 100 Not discussed 68 Not discussed Not discussed 30 Not discussed 93
Abbreviations: IMRT = intensity-modulated radiotherapy; BT = brachytherapy; SRS = stereotactic radiosurgery; LRC = locoregional control; FSRT = fractionated stereotactic radiotherapy; DSS = disease-specific survival. * Sixty-four of 74 patients received reirradiation. y Six patients did not undergo reirradiation; 14 underwent nasopharyngectomy followed by reirradiation. Excludes 43 patients who underwent ‘‘palliative treatments,’’ defined as reirradiation <60 Gy and/or chemotherapy and/or supportive treatment. z Includes 34 patients with recurrent or persistent disease and 7 patients with prior radiation to the nasopharynx for head-and-neck cancer. The median follow-up includes an additional 15 patients treated for primary nasopharynx cancer. x Five percent were unknown. k Includes 23 patients with locally persistent disease; re-staging includes 101/118 patients. { Median follow-up for all surviving patients. # Overall survival time was counted from the start of primary radiation; 74% represents the 3-y overall survival among all 275 patients with isolated local failure. ** Fifty percent among all 319 patients who failed locally. yy Also received intracavitary irradiation.
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Lee, 1997 (12) 1976–1992 Chua, 1998 (13) 1984–1995 Hwang, 1998* (14) 1957–1995 Teo, 1998 (8) 1984–1989 (primary radiation) Chang, 2000 (15) 1982–1995 Leung, 2000 (16) 1990–1999 Syed, 2000 (17) 1978–1997 Law, 2002 (18) 1989–1996 Pai, 2002 (6) 1994–1999 Lu, 2004 (19) 2001–2002 Oksuz, 2004 (20) 1979–2000 Poon, 2004 (21) 1994–2002 Shin, 2004 (22) 1995–2000 Chua, 2005 (23) 2001–2004 Yu, 2005 (24) 1996–2000 (primary radiation) Low, 2006 (25) 1995–2003 Wu, 2007 (26) 1999–2005 Chua, 2007 (27) 1994–2005 Present series 1996–2008
No. of Median patients follow-up (y)
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treatment by enhancing the accuracy of GTV delineation in the treatment planning process (31). Compared with CT, MRI is superior at demarcating the extent of soft-tissue disease, allowing more accurate target delineation. Multiple studies have shown that r-stage is prognostic of outcome, which our series supports (8, 12, 13, 20, 30). The outcome of studies reporting on reirradiation for LRNPC is significantly impacted by the proportion of patients included with early-stage vs. advanced-stage disease. Excluding the stereotactic radiotherapy studies in which most patients had early-stage disease, among the studies listed in Table 5, early-stage recurrences accounted for 26–56% of patients. In our series, 52% of patients had early-stage recurrence, indicating a relatively favorable group of patients. The greater proportion of early-stage patients is partially a reflection of stage migration across different staging systems; a T3 lesion in the American Joint Committee on Cancer (AJCC) 1992 system would be a T2 lesion in the AJCC 2002 system. However, it is likely that the patients in our series, do, in fact, have somewhat earlier-stage disease. In the current era patients are typically followed by MRI, which is able to differentiate postradiation fibrosis from tumor recurrence, potentially leading to earlier diagnosis at recurrence and hence earlier disease stage (32). Therefore, improved imaging may be enhancing outcome not only by improving target volume delineation but by enabling recurrences to be detected and treated at an earlier stage. An important finding of this study is that patients reirradiated with EBRT alone were far more likely to develop Grade $3 late complications compared with those reirradiated with CMT. Although this can be partly explained by the fact that patients in the CMT group had earlier-stage disease, it is also likely because the median dose delivered by EBRT was 1440 cGy lower in the CMT group, resulting in lower doses to critical structures, such as the temporal lobes. Moreover, there is evidence that the cumulative doses delivered may be on the steep portion of the toxicity dose–response curve. Pryzant et al. (33) demonstrated that patients who received #100 Gy of cumulative EBRT dose had a 5-year incidence of severe complications of 4%, whereas those who received >100 Gy had a 39% risk (p = 0.066). They further reported that 8 of 44 patients reirradiated with EBRT alone developed severe complications, compared with 0 of 9 in those who received EBRT with intracavitary cesium. Lee et al. (12) showed that among patients with rT1 disease, patients reirradiated with
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CMT had a lower complication rate than those treated with either EBRT alone or brachytherapy alone. Leung et al. (16) found that patients treated with CMT had a decreased rate of central nervous system and major complications compared with those treated with EBRT alone, which was statistically significant on univariate analysis but not on multivariate analysis. Whereas patients in these series were not treated with IMRT, our study supports the notion that even IMRT is not enough to compensate for the inherent dosimetric advantages of brachytherapy because we also observed significantly higher complication rates in those treated with EBRT alone compared with those treated with CMT. There was no difference in LC, EFS, and OS in patients treated with CMT vs. EBRT alone. This is in agreement with a large study that found that reirradiation technique—EBRT alone, EBRT with brachytherapy, or brachytherapy alone— did not statistically significantly affect local control (12). The biggest strength of this study is the uniformity of patient treatment. Except for 1 patient, all patients who received brachytherapy were treated with a low dose rate to a dose of 20 Gy. More than 80% were treated with IMRT, more than 90% received chemotherapy, and more than 90% underwent imaging with PET and/or MRI before reirradiation. Additionally, most other studies have a considerably shorter median follow-up (6, 8, 12–14, 19–21, 23, 26). Finally, the significant majority of these studies have been published by Chinese groups on Chinese patients, and there are far fewer data for non-Chinese populations. Weaknesses of this study include the small number of patients and the fact that many came from overseas for reirradiation, thereby making follow-up more sporadic. CONCLUSION This study demonstrates that patients with LRNPC treated with the full complement of modern modalities of care, including IMRT, contemporary chemotherapeutic regimens, and high-quality imaging for both detecting early recurrences and for improved target delineation during treatment planning, can achieve relatively long-term OS with acceptably low toxicity. Patients who were treated with CMT developed significantly fewer late Grade $3 complications compared with those treated with EBRT. For patients who have earlystage disease and are candidates for CMT, strong consideration should be given to this treatment modality.
REFERENCES 1. Yan JH, Hu YH, Gu XZ. Radiation therapy of recurrent nasopharyngeal carcinoma. Report on 219 patients. Acta Radiol Oncol 1983;22:23–28. 2. Lee AWM, Law SCK, Foo W, et al. Retrospective analysis of patients with nasopharyngeal carcinoma treated 1976-1985: Survival after local recurrence. Int J Radiat Oncol Biol Phys 1993;26:773–782. 3. Decker DA, Drelichman A, Al-Sarraf M, et al. Chemotherapy for nasopharyngeal carcinoma. A ten-year experience. Cancer 1983;52:602–605.
4. King WW, Ku PK, Mok CO, et al. Nasopharyngectomy in the treatment of recurrent nasopharyngeal carcinoma: A twelveyear experience. Head Neck 2000;22:215–222. 5. Hsu MM, Hong RL, Ting LL, et al. Factors affecting the overall survival after salvage surgery in patients with recurrent nasopharyngeal carcinoma at the primary site: Experience with 60 cases. Arch Otolaryngol Head Neck Surg 2001;127:798–902. 6. Pai PC, Chuang CC, Wei KCW, et al. Stereotactic radiosurgery for locally recurrent nasopharyngeal carcinoma. Head Neck 2002;24:748–753.
Reirradiation of locally recurrent nasopharynx cancer d L. KOUTCHER et al.
7. Fee WE Jr., Moir MS, Choi EC, et al. Nasopharyngectomy for recurrent nasopharyngeal cancer: A 2- to 17-year follow-up. Arch Otolaryngol Head Neck Surg 2002;128:280–284. 8. Teo PML, Kwan WH, Chan ATC, et al. How successful is highdose reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 1998;40:897–913. 9. Lee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002;53:12–22. 10. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 11. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 1966; 5:163–170. 12. Lee AW, Foo W, Law SC, et al. Reirradiation for recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 1997; 38:43–52. 13. Chua DTT, Sham JST, Kwong DLW, et al. Locally recurrent nasopharyngeal carcinoma: Treatment results for patients with computed tomography assessment. Int J Radiat Oncol Biol Phys 1998;41:379–386. 14. Hwang JM, Fu KK, Phillips T. Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1998;41:1099–1111. 15. Chang JTC, See LC, Liao CT, et al. Locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2000;54:135–142. 16. Leung TW, Tung SY, Sze WK, et al. Salvage radiation therapy for locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2000;48:1331–1338. 17. Syed AMN, Puthawala AA, Damore SJ, et al. Brachytherapy for primary and recurrent nasopharyngeal carcinoma: 20 years’ experience at Long Beach Memorial. Int J Radiat Oncol Biol Phys 2000;47:1311–1321. 18. Law SCK, Lam WK, Ng MF, et al. Reirradiation of nasopharyngeal carcinoma with intracavitary mold brachytherapy: An effective means of local salvage. Int J Radiat Oncol Biol Phys 2002;54:1095–1113. 19. Lu TX, Mai WY, Teh BS. Initial experience using intensitymodulated radiotherapy for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004;58:682–687. 20. Oksuz DC, Meral G, Uzel O, et al. Reirradiation for locally recurrent nasopharyngeal carcinoma: Treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2004;60:388–394.
137
21. Poon D, Yap SP, Wong ZW, et al. Concurrent chemoradiotherapy in locoregionally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2004;59:1312–1318. 22. Shin SS, Ahn YC, Lim DH, et al. High dose 3-dimensional reirradiation for locally recurrent nasopharyngeal cancer. Yonsei Med J 2004;45:100–106. 23. Chua DTT, Sham JST, Leung LHT, et al. Reirradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy. Radiother Oncol 2005;77:290–294. 24. Yu KW, Leung SF, Tung SW, et al. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck 2005;27:397–405. 25. Low JS, Chua ET, Gao F, et al. Stereotactic radiosurgery plus intracavitary irradiation in the salvage of nasopharyngeal carcinoma. Head Neck 2006;28:321–329. 26. Wu SXW, Chua DTT, Deng ML, et al. Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69:761–769. 27. Chua DTT, Wei WI, Sham JST, et al. Stereotactic radiosurgery versus gold grain implantation in salvaging local failures of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69: 469–474. 28. Al-Sarraf M, LeBlanc M, Giri PGS, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310–1317. 29. Lee N, Chan K, Bekelman JE, et al. Salvage reirradiation for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2007;68:731–740. 30. Wang CC. Reirradiation of recurrent nasopharyngeal carcinoma. Treatment techniques and results. Int J Radiat Oncol Biol Phys 1987;13:953–956. 31. Zheng XK, Chen LH, Wang QS, et al. Influence of 18F fluorodeoxyglucose positron emission tomography on salvage treatment decision making for locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;65:1020–1025. 32. Olmi P, Fallai C, Colagrande C, et al. Staging and follow-up of nasopharyngeal carcinoma: Magnetic resonance imaging versus computed tomography. Int J Radiat Oncol Biol Phys 1995;32: 795–800. 33. Pryzant RM, Wendt CD, Delclos L, et al. Re-treatment of nasopharyngeal carcinoma in 53 patients. Int J Radiat Oncol Biol Phys 1992;22:941–947.