Computed tomography findings of bony regeneration after radiotherapy for nasopharyngeal carcinoma with skull base destruction: implications for local control

Int. J. Radiation Oncology Biol. Phys., Vol. 44, No. 2, pp. 305–309, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter

PII S0360-3016(99)00004-8

CLINICAL INVESTIGATION

Head and Neck

COMPUTED TOMOGRAPHY FINDINGS OF BONY REGENERATION AFTER RADIOTHERAPY FOR NASOPHARYNGEAL CARCINOMA WITH SKULL BASE DESTRUCTION: IMPLICATIONS FOR LOCAL CONTROL FU-MIN FANG, M.D.,* STEPHEN WAN LEUNG, M.D., M.S.,* CHONG-JONG WANG, M.D.,* CHIH-YING SU, M.D.,† CHUN-CHUNG LUI, M.D.,‡ HUI-CHUN CHEN, M.D.,* LI-MIN SUN, M.D.,* § AND TSUNG-MIN LIN, M.D. Departments of *Radiation Oncology, †Otolaryngology, ‡Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; §Department of Radiotherapy, Jen Ai Hospital, Pintung, Taiwan Purpose: To evaluate the response of bony destruction (BD) of the skull base following radiotherapy in nasopharyngeal carcinoma (NPC) and investigate the implications of bony regeneration (BR) on local control and its related factors. Methods and Materials: Ninety patients with NPC with skull base destruction clearly demonstrated on computed tomography (CT) were reviewed. These patients have completed the prescribed treatment and received regular CT follow-up. A total of 338 sets of CT images of the head and neck were reviewed. The tumor response and the appearance of BR in the previous destructive part of the skull base were recorded and analyzed. The tumor response was divided into complete, partial, or no response. BR was defined as recalcification or sclerotic change with partial or complete healing in the previous osteolytic bony defect. Local failure was confirmed either by pathological or merely by imaging studies showing progression of tumor in consecutive radiological pictures. Results: The distribution of specific sites of bony destruction (BD) in these patients included the sphenoid bone (68%), paracavernous sinus area (48%), petrous apex (47%), clivus (44%), pterygoid plates (20%), and others (7%). The CT showed 57 patients (63%) had BR. All were observed within 1 year after treatment. Sixty-two patients (69%) had complete tumor response after treatment. Analyzed by logistic regression method, tumor response after treatment was found to have a statistically significant correlation with BR (p 5 0.0004). Most BR (55/57) was demonstrated in patients with complete tumor response. The 3-year actuarial local control rate was 54 % in these patients. The local control was quite different in the comparison of patients with BR versus those with persistent BD (77% vs. 21%, p < 0.0001). Multivariate analysis showed that patients with complete tumor response or with BR on imaging had statistically better local control than those without either of the two findings (p < 0.05). Conclusion: Appearance of BR at previous destructive skull base following radiotherapy for NPC patients could be clearly demonstrated on CT. Bony regeneration significantly correlated with treatment response and local control. Although the underlying significance of BR was unknown, to predict the outcome after treatment, the appearance of BR shown on CT may imply the complete eradication of tumor in this area. © 1999 Elsevier Science Inc. Computed tomography, Bony regeneration, Nasopharyngeal carcinoma, Radiation therapy.

INTRODUCTION Bony destruction (BD) of the skull base is frequently seen in nasopharyngeal carcinoma (NPC) and believed to be a significant prognostic factor. Prior to the era of computed tomograghy (CT), bony change of the skull base after treatment was evaluated by plain skull films (1– 4). Nowadays, CT scans are routine examinations for tumor staging and follow-up in NPC. With the coronal sections and bone window, CT clearly delineates the response of tumor and adjacent bony structures to treatment. Bony regeneration (BR) following radiotherapy or che-

motherapy at sites of malignant tumors in head, neck cancer, and breast cancer with osseous metastasis has been demonstrated in certain imaging studies such as plain radiography, and radionuclide bone scanning (1– 8). CT has been used to monitor bony changes responding to treatment in only some cases of head and neck cancer (9). Some correlation between BR and tumor response or local control was observed in these reports. In the present study, pre- and post-treatment CT scans of patients with nasopharyngeal carcinoma with bony destruction were reviewed. The appearance of BR after treatment, its related factors, and its implications on local control were analyzed.

Reprint requests to: Fu-Min Fang, M.D., Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, 123,

Ta-Pei Rd., Niao Sung Hsian, Kaohsiung Hsien, Taiwan. Accepted for publication 4 January 1999. 305

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Table 1. Patient characteristics Number of patients (%) Age (yr) Median: 48 Range: 18–81 Sex Male Female Stage (AJCC 1997) T3 T4 N0 N1 N2 N3 Specific sites of skull base Sphenoid bone Paracavernous sinus area Petrous apex Clivus Pterygoid plate Others

90 (100%)

67 (74%) 23 (26%) 37 (41%) 53 (59%) 25 (28%) 17 (18%) 24 (27%) 24 (27%) 61 (68%) 43 (48%) 42 (47%) 40 (44%) 18 (20%) 7 (7%)

METHODS AND MATERIALS Patients’ characteristics From 1989 to 1994, 90 patients with pathologically proven NPC with skull base destruction clearly demonstrated on pretreatment CT were enrolled in the review. All patients received radical radiotherapy with curative intent in the Department of Radiation Oncology. All patients completed the treatment schedule and received regular CT follow-up. The anatomic composition of the skull base is complex. The structures described here mainly include the sphenoid bone, clivus, petrous apex, pterygoid plates, the paracavernous sinus area, and other unspecified bone surrounding the roof of the nasopharynx. All patients were restaged according to the 1997 NPC staging system of the American Joint Committee on Cancer. The age, sex, T and N stages, and specific sites of skull base destruction of these patients are listed in Table 1. CT scan A total of 338 sets of CT images of the head and neck were reviewed, including 90 sets for pretreatment tumor staging, and 248 sets for follow-up. Plain and contrastenhanced images were performed on third-generation scanners (GE 9800, USA). Iodinated contrast agents, 90 to 150 ml were used. The axial and coronal sections in soft tissue and bone windows were the standard requirements. The slice thickness was 5 to 10 mm whenever possible. All original films were reviewed and reported by diagnostic radiologists. To assess the tumor and bony changes, CT slices were reviewed and details of changes were recorded. Radiotherapy The technique of radiotherapy is generally uniform in our department. Initially, the clinical target volume covered the

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nasopharynx, skull base, and regional lymphatics. Radiation was delivered with 6 MV photon via bilateral opposed fields, matching onto an anterior low neck field. To spare the spinal cord after 45 or 46.6 Gy, the primary tumor site was boosted by a 10 MV photon beam and any residual neck mass was further treated by electron beam. The fractionation schedule was 1.8 Gy per fraction per day, and 5 or 6 fractions per week. The total dose ranged from 70.2 Gy to 81 Gy, median 75.6 Gy. The radiation duration ranged from 51 to 90 days, median 67 days. Eighteen patients received chemotherapy in either adjuvant or neoadjuvant setting. Salvaged radiotherapy or chemotherapy was attempted in 23 patients for either local failure or distant metastasis.

Definition of treatment response According to CT, the tumor response was divided into complete, partial, and no response. Complete response was defined as complete or nearly complete disappearance of tumor density with clear demarcation of the anatomic landmarks of the nasopharynx and adjacent tissue planes. Partial response was defined as more than 50% tumor regression but with some persistent or suspected tumor density. No response was defined as an unchanged or progressed tumor. BD was identified when tumor invaded the adjacent bony cortex causing demineralization, erosion, or fragmentation (Fig. 1a). BR was defined as recalcification or sclerotic change with partial or complete healing in the previous osteolytic bony defect (Fig. 1b). No questionable BD or BR was recorded. The presentations of BD or BR on CT varied in different cases. We did not attempt to detail classification of the patterns of BD or BR in this study.

Follow-up and statistics Patients received regular follow-up in the Department of Radiation Oncology. All patients were followed for 2 to 7 years (median: 3.6 years). Patients with no regular visits were followed by telephone and/or letter. Nasopharyngoscopy was routinely performed at every visit. The first CT follow-up was usually done within 3 months of treatment. The next CT follow-up was done according to individual clinical demands. Seventy-eight patients (86%) received two or more CT follow-up examinations. In some cases magnetic resonance imaging was also done to better determine local status. Local failure was confirmed either by pathological or merely imaging studies showing progression of the suspected tumor in consecutive radiographic pictures. Distant metastasis was detected by physical examination, or radiographic means. The software package SPSS for Windows was used to carry out the data processing and statistics. Statistical analysis of the data was done by the chisquared test and logistic regression methods; survival curves were calculated by the Kaplan-Meier method. Comparison between curves was performed using the log-rank test. Multivariate analysis was done by the Cox regression model.

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Table 2. Factors analyzed for their correlation with bony regeneration (BR) after treatment Number of patients Factors Age (yr) , 48 . 48 Sex Male Female T stage (AJCC 1997) T3 T4 Radiation dose , 75.6 Gy . 75.6 Gy Radiation duration , 67 days . 67 days Chemotherapy Y N Tumor response Complete Partial or No

p-value

BR (1)

BR (2)

USA

MVA

24 33

21 24

0.05

0.09

40 17

27 6

0.22

0.4

25 32

12 21

0.48

0.7

26 31

20 13

0.17

0.97

25 32

17 16

0.48

0.07

8 49

10 23

0.06

0.26

55 2

7 26

0.00001

0.0004

UVA 5 univariate analysis; MVA 5 multivariate analysis.

sistent BD in the first CT follow-up. In the next CT, 3 of them developed BR, and 21 still presented with either stationary or progressive BD. Ten patients who did not have a second CT follow-up were considered having persistent BD since all expired on follow-up. Factors related to BR Factors including age, sex, radiation dose, radiation duration, chemotherapy, and tumor response were analyzed for their correlation with BR. The results are listed in Table 2. A statistically significant correlation with BR was observed in age, and tumor response by univariate analysis. Further assessment by multivariate analysis based on logisFig. 1. (a) Osteolytic destruction of the petrous apex, pterygoid plates, and clivus by direct invasion of nasopharyngeal carcinoma is clearly demonstrated on CT scans. (b) Bony regeneration at previous destructive sites shown in (a) appears 6 months after radiotherapy.

RESULTS Changes in BD after treatment After treatment, 57 patients (63%) developed BR in the area of BD. Most BR (53/57) was demonstrated on the first or next CT follow-up within 1 year after treatment. Four patients had BR identified on follow-up CT 1 to 3 years post-treatment. In all cases with BR, it became better identified with longer follow-up. Four patients with BR experienced re-destruction either at the original or new sites because of tumor regrowing. Thirty-four patients had per-

Fig. 2. Local control rate for NPC patients with and without BR after treatment.

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Table 3. Prognostic factors affecting 3-year local control rates Local control rates (%) Age (yr) , 48 . 48 Sex Male Female T stage (AJCC 1997) T3 T4 Radiation dose , 75.6 Gy . 75.6 Gy Radiation duration , 67 days . 67 days Tumor response Complete Partial or No Bone regeneration Y N

p-value (UVA)

p-value (MVA)

47 61

0.23

0.73

54 58

0.48

0.63

59 51

0.99

0.96

46 63

0.02

0.11

50 57

0.83

0.81

72 21

,0.0001

0.03

77 21

,0.0001

0.005

UVA 5 univariate analysis; MVA 5 multivariate analysis.

tic regression models showed only tumor response after treatment was significantly correlated with BR (p 5 0.0004). Most BR (55/57) was demonstrated in patients with complete tumor regression, and most patients (55/62) with complete tumor regression had BR. Local control and BR The 3-year actuarial local control rate was 54%. Forty patients had local failure, either recurrence or persistence of tumor. Distant metastasis was found in 27 patients, and in 12 of them it was combined with local failure. Of the 40 patients with local failure, 16 (40%) were proven by biopsy and 24 were diagnosed by image studies. Figure 2 shows the correlation between BR and local control. The 3-year actuarial local control rates for patients with BR and persistent BD were 77% and 21% respectively (p , 0.0001). We also evaluated the influence of gender, age, T stage, radiation dose, radiation duration, tumor response, and BR on local control. Table 3 summarizes the results. Only BR and tumor response were independent predictors of local control on both univariate and multivariate analysis (p , 0.05). Patients with complete tumor response after treatment or with BR had better local control rates than those without. DISCUSSION Tumor invasion of the skull base is difficult to detect early and is usually not recognized until a large amount of tumor is present in the nasopharynx or when neurologic symptoms are observed. Due to the complex anatomy and numerous overlying bony structures of the skull base, CT is

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superior to plain radiography and radionuclide bone scan. However, because of obscure demarcation of the anatomic landmarks caused by previous tumor invasion and radiation therapy, the tumor status in the skull base is usually difficult to assess clearly on CT. More sensitive methods such as single-photon emission tomography and planar bone scintigraphy have been reported to detect skull base lesions early in pretreatment NPC (10). However, the high falsepositive rates for patients after treatment make the value of these radionuclide methods doubtful for routine follow-up. Appearance of BR in NPC with skull base destruction after treatment has been reported. Estrin et al. (9) stressed the value of CT not only in detecting initial osseous invasion, but also in monitoring treatment response of head and neck cancer. However, the implication of BR following treatment has not been emphasized previously. Assessment of the CT appearance of BR may give us additional information on tumor status in this area. In our study, 63% patients with NPC with skull base destruction developed BR after treatment. Most could be clearly identified on CT within 1 year after treatment. By plain radiography, in 1944, Godtfredsen (1) observed BR in 8 of 154 patients with NPC within 3 to 5 months after disappearance of the primary tumor. In 1948, Graham and Meyer (2) reported their experience with NPC with 26 cases and found some patients had striking regeneration at the previous destructive skull base after irradiation. In 1978, Unger et al. (3) demonstrated BR of the skull base in 11 patients with NPC after radiotherapy. Recalcification or reactive osteitis could be identified within 4 to 6 months. Recently, using serial CT examinations during and after treatment, Estrin et al. (9) reported the changes of BD in 4 patients with head and neck tumors. BR was demonstrated at sites of initial osteolytic destruction in 2 patients who responded to therapy, and regeneration was observed at 4 and 7 months after the start of treatment. The relationship between BR and tumor response after treatment or local control has not been discussed in detail before. In our analysis, BR was observed to have statistically significant correlation with tumor response and local control. BR usually appeared consequentially in patients with good treatment response and showed better local control. It could be speculated that the appearance of BR might indicate complete eradication of tumor in this area. Similar results have been reported. Koukourakis et al. (11) treated 32 patients with NPC by radiotherapy and found the local recurrence rate was 30% if abnormal CT findings still persisted after treatment, but the rate went up to 100% in three cases with persistent skull base destruction. Estrin et al. (9) reported that osseous regeneration of bone previously destroyed by tumor should indicate a favorable response to therapy. In the textbook Nasopharyngeal Carcinoma, Kreel et al. (12) mentioned the following observation in 15 patients with NPC with skull base destruction followed with regular CT scans after radiotherapy (RT): “Following RT two patients showed bony reconstitution and remained free of tumor. Eight patients showed no change although two of

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these had proven recurrence. Five patients showed new bone erosion. All of these patients had biopsy proven recurrences...” Only 40% (16/40) of patients in our series had biopsyproven recurrences. Failure to biopsy the right area is not uncommon when the tumor cells situated in deep-seeded regions such as the skull base. Skull base biopsy is too invasive and comparison of consecutive image studies in suspicious tumor areas is an acceptable alternative for patients in clinical practice. When CT showed BD persisted or progressed, a high local failure rate was observed. It was probable that surviving tumor cells still existed in the destructive bone area. More concern should be paid to such patients even though smooth mucosa of the nasopharynx is found on CT or nasopharyngoscopy. Close observation or biopsy at deeper sites is needed for early detection of recurrence. The mechanisms of BD and BR are not clearly understood. Tumor cells may cause bone loss by directly resorbing bone mineral and matrix. It is understood tumor cells can activate osteoclasts either by directly releasing osteoclastic stimulating factors such as transforming growth factor, or indirectly activating immune cells which, in turn, release osteoclast-stimulating cytokines, such as tumor necrosis factor-alpha (TNF-a) and interleukin-1 (13). For ex-

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ample in head and neck cancer, it was observed TNF-a may promote tumor invasion by stimulation of collagenase production, with consequent bone and connective tissue destruction (14). As shown in Fig. 1b, the trabecular pattern of regenerated petrous apex and clivus was abnormally present on CT compared with other areas of normal bone. On plain radiography, Libshitz and Hortobagyi (6) described the pattern of healing of osteolytic breast metastasis in the axial skeleton responding to chemotherapy. They found four sequential steps in the healing process in the osteolytic area: development of a sclerotic rim around the lytic area, osteoblastic filling in the sclerotic rimmed lesions, formation of abnormal trabecular pattern, and osteoblastic fading to form a more normal bone density and trabecular pattern. In the repair of the bony defect of the skull base, the calvarial periosteum and dura play an important role (15). The calvarial periosteum was found to have less bone-producing capacity than that of long bones (15). We doubted whether the osteoblastic healing process seen in long bones could be used to conjecture about the causes of the abnormal appearance of the regenerated skull base on CT. Further biochemical research into bone turnover and more detailed imaging studies of the bony changes are needed to explain the phenomena.

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