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Preliminary data suggest that circulating cell-free DNA of EBV may be another useful tool for early detection of treatment failure. A longitudinal study by Lo et al. (151) showed that elevation of EBV-DNA titer was noted in patients with relapse up to 6 months before detectable clinical disease. However, this measurement is more sensitive for distant metastases than locoregional recurrence; up to one third of patients with locoregional recurrence did not show elevated EBV-DNA copies (229).

Additional Radiation for Persistent Disease

Brachytherapy has been widely used for locally persistent disease after a full course of EBRT (Table 38.16, part A). Excellent results with 5-year L-FFR in the range of 87% to 95% for patients with initial T1-2 a tumors have been reported (101,109,140,209,246). There is preliminary evidence suggesting that patients with initial T2b tumors could also be effectively treated by brachytherapy (143).
Stereotactic RT is a valuable advance for delivering additional EBRT. Yau et al. (239) studied 755 patients with T1-4 tumors and showed that 7% had positive biopsies 8 weeks after completion of primary RT. The 21 patients treated with fractionated stereotactic RT to a median dose of 15 Gy achieved a 3-year L-FFR of 82%, a result that was very close to corresponding L-FFR of 86% in the contemporary cohort with complete remission, and was substantially better than corresponding L-FFR of 71% in 24 patients treated with high dose-rate brachytherapy to a median dose of 20 Gy.

Reirradiation for Recurrent Disease

Aggressive salvage treatment should be attempted because long-term survival can be achieved for a substantial proportion of patients with early locoregional recurrence and useful palliation for those with extensive disease. However, there is a high risk of normal tissue damage. It is crucial to restrict the irradiation of normal tissue to a minimum.
The most important prognostic factor is the TNM stage of the tumor at the time of recurrence. Thorough restaging,
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including metastatic work-up, is needed. A study of 891 patients with local recurrence by Lee et al. (125) showed that 54% of patients also developed regional and/or distant failures. Another significant factor is reirradiation dose: Most series using EBRT with conventional 2D technique showed that doses ≥60 Gy were associated with better outcome (119,186,221).
A retrospective comparison by Lee et al. (116) of the symptomatic late toxicity rate in 487 patients with two courses of EBRT versus 3,635 patients with one course showed that the summated total biologic dose tolerated (BED-Σ) was higher than that expected with a single-course treatment (BED-1), suggesting partial recovery of normal tissues (particularly for patients with reirradiation after an interval >2 years). Assuming an α/β ratio of 3 Gy, the BED-Σ that incurred 20% toxicity at 5 years was 129% that of BED-1.
Brachytherapy has been widely used for treatment of recurrent NPC (Table 38.16, part B). Early-stage recurrent NPC could be effectively salvaged by brachytherapy alone (101,109). Kwong et al. (101), using interstitial implants with radioactive gold grains, reported a 5-year L-FFR of 63%; complications included headache (28%), palatal fistula (19%), and mucosal necrosis (16%). Law et al. (109), using iridium mold, achieved excellent local salvage up to 89%, but the complication rate was 53%.
The combination of brachytherapy and EBRT is useful, particularly when conventional 2D technique is used. Lee et al. Lee et al. (119) showed that patients reirradiated by combined modes had higher salvage rate than those by EBRT or brachytherapy alone: The 5-year L-FFR was 45%, 32%, and 29%, respectively. Similar pattern of superiority by combined method was reported by other investigators (64,141,186,219,221).

Stereotactic radiosurgery or fractionated stereotactic radiotherapy is another useful tool for retreatment of local recurrence. Control rates ranging from 53% to 86% have been reported (22,44,50,178). For advanced recurrence with extension beyond the nasopharynx, this method will give better dose coverage than brachytherapy. A higher salvage rate by adding stereotactic radiation (17,44,236) as a boost after EBRT has been reported. Although most series reported a low risk of complications, massive hemorrhage with potential fatal outcome has been described (44). To minimize this risk, radiosurgery should be avoided when there is direct tumor encasement of the carotid artery or when a high cumulative dose has already been delivered.
Table 38.17 summarizes the treatment outcome and severe late complications by external reirradiation. Past series using 2D technique achieved 5-year survival rates in the range of 21% to 41%, and the incidence of temporal lobe necrosis ranged from 2% to 27%. The use of 3D conformal radiotherapy showed improving results. Chang et al. Chang et al. Chang et al. Chang et al. (17) showed that none of the patients reirradiated by 3D technique developed temporal lobe necrosis compared with 14% in those reirradiated by 2D technique. Zheng et al. (247), reported a very encouraging 5-year local salvage rate of 71%, but the actuarial rate of late toxicities (grade 4) was still as high as 49%.
Preliminary reports using IMRT for reirradiation show encouraging short-term results. Using IMRT to deliver 68–70 Gy, Lu et al. (155) reported 100% salvage rate without any
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severe late complications in a series of 49 patients with a median follow-up of 9 months. Using IMRT to a median dose of 54 Gy in 31 patients (with or without induction chemotherapy and stereotactic boost), Chua et al. (48) reported a locoregional salvage rate of 56% and late complications (grade 3) of 25% at 1 year. Longer follow-up is clearly needed.
Chemoradiotherapy may also improve treatment outcome for recurrent NPC. Using gemcitabine and cisplatin as induction chemotherapy followed by reirradiation with IMRT in 20 patients (95% rT3-4), Chua et al. (42) reported a 1-year local salvage rate of 75%. In a study of 35 patients (66% rT3-4), Poon et al. (185) reported a 1-year EFS of 42% by concurrent cisplatin followed by adjuvant chemotherapy with cisplatin and 5-fluorouracil.

Surgical Treatment Trattamento chirurgico

For patients who develop local or nodal persistent/recurrent disease without distant metastasis, surgical salvage is an important option to consider. For patients with nodal failure following RT, lymph node involvement is often extensive, Radical neck dissection is the recommended salvage procedure (224). A study by Wei et al. (226) showed that salvage with radical neck dissection could achieve a 5-year nodal control rate of 66% and a disease-free survival of 37%. For those with tumor extending beyond the lymph node confines and involving nearby structures, addition of after-loading brachytherapy to the tumor bed following radical neck dissection might be useful (225).
For selected patients with persistent/recurrent disease localized in the nasopharynx, surgical salvage by nasopharyngectomy is an option. As the nasopharynx is located in the center of the head, adequate exposure for oncologic extirpation of the tumor is a great challenge. A number of approaches have been employed. These include an infratemporal approach from the lateral aspect (60), transpalatal, transmaxillary and transcervical approaches from the inferior aspect (58,166), and an anterolateral approach (227). As all the patients concerned have undergone prior radical RT, the associated morbidities of trismus and palatal fistula are common, but the mortalities associated with these surgical procedures have been low.
Recurrent NPC is frequently located in the pharyngeal recess on the lateral wall. Direct access to this region is essential for complete tumor extirpation. Wei and Sham (228) advocated the anterolateral approach or the maxillary swing approach for surgical salvage of localized failure in the nasopharynx. Following facial incisions and the appropriate osteotomies, the maxilla bone is swung laterally while attached to the anterior cheek flap as one osteocutaneous unit (Figs. 38.28 and 38.29). The nasopharynx with the persistent/recurrent tumor and its vicinity including the paranasopharyngeal region are then widely exposed for oncologic resection. At completion of nasopharyngectomy, the maxilla is returned and fixed to the rest of the facial skeleton with miniplates.

Wei et al. (228) studied 161 patients with salvage nasopharyngectomy using this approach performed at Queen Mary Hospital (Hong Kong) for recurrent NPC following primary treatment by radical RT. Twelve patients also had prior brachytherapy as a salvage procedure. Preoperative assessment showed the tumors of all patients were recurrent stage T1. Negative tumor resection margins, confirmed by frozen section, were achieved in 78% of patients, and the remaining patients had microscopic tumor at the internal carotid artery or the skull base detected during surgery, making further resection impossible. All patients recovered from this anterolateral approach nasopharyngectomy and were discharged. Associated morbidities included trismus of different degrees in 60% and palatal fistula in 25% of patients. Recent modification of the palatal incision has eliminated the problem of palatal fistula (168). In concurrence with other reports, satisfactory long-term results could be achieved for persistent/recurrent tumor that can be completely removed surgically. The 5-year local salvage rate was around 65% and disease-free survival was 54% (57,223).

Results of Treatment Risultati del trattamento

The specific results of various new treatments have been summarized in the preceding respective sections. This section focuses on the overall results in major series of patients treated in the past two decades (Table 38.18).
Two of the representative series from the past, 5,037 patients treated at Queen Elizabeth Hospital (Hong Kong) during 1976–1985 (129) and 378 patients treated at MD Anderson Cancer Center (United States) during 1954–1992 (67,192), both reported very similar results with DSS of around 50% at 5 years


and 45% at 10 years. The risk of delayed “relapse” is another feature of NPC that is distinct from other head and neck cancers; long-term follow-up is needed.

Almost all retrospective analyses have demonstrated steady improvement in treatment results when compared with historical data at the same institution. Taking the series that includes only patients treated from 1985 onward as contemporary series, the average 5-year survival now achieved is up to 70% (range in OS, 57% to 75%; DSS, 67% to 80%). Such encouraging results were reported not only from Asia (4,130,142), but also from Europe (180) and Australia (52).
Retrospective analyses by Su and Wang (202) of patients with NPC of different histologic types treated at Massachusetts General Hospital (United States) during 1979–1996 showed that Chinese race per se was not a significant prognostic factor. The 5-year OS for Chinese versus non-Chinese patients was 49% versus 56%. The study by Corry et al. (52) of patients with nonkeratinizing NPC treated at Peter MacCallum Cancer Institute (Australia) during 1985–1999 also showed that race had no significant impact. The 5-year OS for Asian versus non-Asian patients was 75% versus 63%.
A representative contemporary series reported by the HKNPCSG (130) of 2,687 patients treated in all public centers in Hong Kong during 1996–2000, with 53% of patients staged III-IVB by the current AJCC/UICC system, showed that a 5-year OS of 75% and DSS of 80% could now be achieved. Figure 38.30 shows the OS achieved for different stages during this era. Treatments during this period were not state of the art because of resource constraints; only 32% of the series were staged by MRI (the rest by CT), 90% were irradiated with conventional 2D technique to a median total dose of 66 Gy, and
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only 14% had additional treatment with concurrent chemotherapy and 9% sequential chemotherapy. Hence, similar, if not better, results should be achievable at least for nonkeratinizing NPC.

Review of contemporary series (Tables 38.18) shows that the average 5-year L-FFR was 80% (range, 74% to 85%), nodal-FFR was 90% (range, 80% to 94%), and D-FFR was 77% (range, 75% to 83%).
Excellent nodal control can usually be achieved. Based on the contemporary series with detailed results for different N-categories (130,142), the average 5-year nodal-FFR was 97% for N0, 95% for N1, 90% for N2, and 75% for N3. Routine surgery is not indicated; radical neck dissection should be reserved for those with nodal persistence or recurrence after RT.
T category is the most important prognostic factor for local control. Based on the contemporary series treated mostly by conventional 2D technique (4,130,142,158,159), the average 5-year L-FFR varied from 90% (range, 82% to 93%) for T1, 82% (range, 77% to 87%) for T2, 70% (range, 69% to 80%) for T3, to 68% (range, 58% to 77%) for T4 tumors. With all the technological development, dose escalation, and/or addition of concurrent chemotherapy, 3-year local control close to 100% has been reported (7,111,189).
Distant failure remains the most challenging problem. The risk correlates significantly with both T and N category, but N category is by far the most significant predicting factor. The study from the HKNPCSG (112) showed that the HR of distant failure in patients with N3b disease was as high as 6.26 (95% CI: 4.42 to 8.88) when compared with N0.
Based on the contemporary series with detailed results for different stages (49,130,142), the average 5-year D-FFR varied from 93% for stage I, 85% for stage II, 78% for stage III, to 60% for stage IVA-B. A study of 2,070 patients treated by RT alone in the HKNPCSG series (130) showed that both the presenting stage and achievement of locoregional control were significant predictors for distant failure. The 5-year D-FFR for stages I-IIB versus stages III-IVB were 90% versus 75% for patients who achieved locoregional control, but 81% versus 65% for those with locoregional failure (Fig. 38.31).

One difficulty in the interpretation of treatment results for different stages is that the phenomenon of stage migration inevitably occurs with changing investigation methods. Detailed analyses of the HKNPCSG series (130) showed that, together with simultaneous changes in treatment provisions, the MRI-staged patients achieved significantly better results for corresponding stages than those who were CT-staged. The treatment results of different stages in the two differently staged groups are shown in Table 38.19 as a reference for contemporary results.
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Sequelae of Treatment Esiti di trattamento

Overall Incidence and Types

With the anatomic proximity to critical structures, the need for high radiation doses and adequate field coverage, the risks of radiation-induced toxicities are substantial. The diagnosis of irradiation injury can be difficult. A high degree of awareness is demanded and every effort must be made to exclude other possible causes (tumor recurrence in particular).
Table 38.20 lists the incidence of late toxicities following radical RT with conventional technique (without any concurrent chemotherapy) in five representative series with long-term follow-up. Both the studies on patients treated by RT alone at MD Anderson Cancer Center during 1954–1992 (192) and those treated at Mallinckrodt Institute of Radiology during 1956–1991 (19) showed an overall treatment mortality rate of 3%. Both showed encouraging reduction of severe toxicity in later years, even with the use of higher radiation doses. Sanguineti et al. (192) reported that the 10-year actuarial rate of severe toxicity (grade 4–5) decreased from 14% in 1954–1971 to 5% in 1983–1992. Chao and Perez (19) reported a similar reduction rate of toxicity (grade ≥3) from 17% in 1956–1965 to 4% in 1986–1991.

To minimize the risk of late damage, the importance of maximum conformity and precision in RT delivery cannot be overemphasized. The advent of IMRT enhances the feasibility of protecting normal tissues. All the studies using this technique have shown substantial sparing of parotid glands (90,97,135). However, it should be cautioned that attempts at dose escalation together with concurrent chemotherapy might lead to severe toxicities (100).
The extensive use of concurrent CRT increases the risk of toxicities. Preliminary data from NPC-9901 and NPC-9902 trials (124,132) showed significant increase in toxicities (grade ≥3) when patients treated with CRT using the Intergroup regimen were compared with those with RT alone (Table 38.14). Hearing loss is the most common problem with cisplatin-based regimens; RT technique with sparing of cochlea should be attempted as far as possible.

Temporal Lobe Necrosis

Temporal lobe necrosis (TLN) is the most worrisome complication; the study by Lee et al. (126) of 4,527 patients treated during 1976–1985 showed that this accounted for 65% (40/62) of all irradiation-induced deaths. In a study of 1,008 patients with T1 tumors, Lee et al. (115) showed that the 10-year actuarial incidence of TLN ranged from 4.6% to 18.6% for schedules
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with fraction sizes of 2.5 to 4.2 Gy. The fractional effect is the most significant risk factor.
In a subsequent study of 1,032 patients with T1-2 tumors treated with conventional 2D technique during 1990–1995, Lee et al. (123) showed that the incidence of symptomatic TLN ranged from 0% (with 2 Gy/fraction, five fractions/week, for 33 fractions) to 24% (3.5 Gy/fraction, three fractions/week, for 17 fractions), and 33% for an altered fractionation schedule (71.2 Gy in 5 weeks). Besides fractional effect, overall treatment time was also found to be a significant factor. Overacceleration and fractional dose >2 Gy should be avoided.
The presenting features in 102 patients with TLN were summarized by Lee et al. (127). Thirty-nine percent presented with vague symptoms (dizziness, poor memory, or behavioral changes); hence, diagnosis was often delayed. Only 31% had classic temporal lobe epilepsy with absence attacks, hallucinations, or déjà vu, and 14% had symptoms of headache, confusion, convulsion, or hemiparesis. Sixteen percent were asymptomatic.
The early classic radiologic feature is fingerlike white matter edema confined to the inferomedial part of the temporal lobes, followed by contrast-enhancing necrosis involving the grey matter (35) (Fig 38.32). Some lesions may resolve spontaneously; others remain stationary or progress to massive edema, cyst formation (Fig 38.33), acute hemorrhage (26), or develop brain abscess (27).
Control of temporal lobe epilepsy by anticonvulsants and close monitoring of symptoms or signs of increased intracranial pressure are the main treatments. Early promising results with high-dose steroids for more than 4 months were hampered with severe and sometimes fatal infection (127), and the apparent high remission rate shown on CT was not confirmed with MRI (114). Hence, intervention with steroids and/or surgery is usually reserved for markedly symptomatic patients.
The possible risk of Kluver-Bucy syndrome is a serious concern when considering bilateral temporal lobectomy (128). A study in Queen Elizabeth Hospital of 520 patients with TLN showed that 9% (49 patients) had temporal lobe surgery performed, and their postsurgery 5-year OS was 32%. Among the six patients who had bilateral lobectomy, none have had Kluver-Bucy syndrome thus far (SCK Law, unpublished data, 2006).
The degree of cognitive dysfunction with TLN correlates with the volume and site of radionecrosis (31). Lesions predominantly in the right and the left side are associated with loss of visual and verbal memory, respectively. General intelligence is usually intact (30).

Brainstem Encephalopathy/Cervical Spinal Cord Myelopathy

In the past, this was a common neurologic sequelae leading to spastic paraparesis or quadriparesis. In the study by Lee et al. (126), 59% of the 44 affected patients progressed rapidly to a debilitated state and 34% died. There was no effective treatment to arrest this pathologic process. Fortunately, this sequela has become rare with improving RT technique and accuracy in delivery. Lee et al. Lee et al. (126) showed that all affected patients were treated before 1983.

Cranial Neuropathy

The last four cranial nerves, especially the twelfth, are the most frequently injured (126,142,149). This is related to marked fibrosis, particularly among patients with an additional boost
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dose to parapharyngeal space. Affected patients usually present with slurring of speech, twitching of neck muscles, and/or swallowing difficulties that can lead to fatal aspiration pneumonia. Wu et al. (233) studied 31 patients with post-RT dysphagia in NPC and found that 77% aspirated after the act of swallowing.
The sixth nerve is another commonly affected nerve, and is frequently associated with TLN (126). Isolated palsy of branches of the fifth nerve is less common, and optic neuropathy is rare with careful attention to the RT technique. Intracranial recurrence must be excluded before making a clinical diagnosis of radiation injury.

Endocrine Dysfunction

Amenorrhea and/or galactorrhea from hyperprolactinemia in female patients are the commonest presenting feature(s), followed by hypothyroidism and hypoadrenalism. Very few male patients complain of impotence or decreased libido.
Symptomatic hypothalamic-pituitary dysfunction was clinically observed in 5% of patients after a median latency of 5 years in the series reported by Lee et al. (126). However, detailed endocrine assessment and longitudinal study by Lam et al. (105) showed that biochemical dysfunction might be detected as early as 1 year after RT, and the 5-year incidence was up to 62% (104). The deficiency of releasing or inhibitory factors suggests that the main damage occurs at the hypothalamus (103,106). Deficiencies in growth hormone, gonadotropins, corticotrophin, and thyrotropin were found, in decreasing order of frequency.
Sham et al. (195), in a randomized trial of 152 patients treated with 2D technique using a hypofractionation schedule (3.5 Gy/fraction, three daily fractions/week, for 17 fractions), showed that additional shielding could significantly reduce the incidence of symptomatic endocrine dysfunction from 11% to 0%, and TLN from 21% to 0%. The importance of maximum conformity for protection of normal tissues cannot be overemphasized.
Aural Toxicity
Hearing loss is a common sequela, particularly for patients treated with concurrent CRT using cisplatin-based regimens. Kwong et al. (102) followed 132 NPC patients with serial audiograms for a median period of 30 months after RT, showed that 24% of patients developed sensorineural deafness (mainly affecting the high-frequency range). Grau et al. (69) further showed significant correlation between hearing loss and the cochlear dose. It should be noted that sudden deafness with late onset (more than 5 years) might result from vascular insufficiency and recover after treatment with a vascular expander like dextran 40 (243).
Another major mechanism of ear complications is dysfunction of eustachian tube (244), causing otitis media with effusion. Lau et al. (108) showed that tinnitus developed in 49% of patients, and persisted in 29% at 1 year. The benefit of prophylactic insertion of ventilation tubes is controversial. Chowdhury et al. (40) showed that patients with tubes inserted had less conductive hearing loss, tinnitus, and/or otitis. However, Skinner et al. (198) showed that this did not lead to long-term benefit for hearing. Chen et al. Chen et al. (21) showed that this might even worsen postirradiation otitis media, with increased risk of ascending infection from all adjacent irradiated areas.

Oral Complications

Xerostomia is almost universal with conventional RT using 2D technique. Jen et al. (84) showed that the salivary flow dropped by half after dose of 7.2 Gy, reached the nadir after 36 Gy, and then further dropped after completion of RT without recovery during the following 2 years. However, with parotid sparing by IMRT (mean parotid dose, 34 Gy), Lee et al. (135) from University of California, San Francisco, reported marked recovery, with grade 2 xerostomia decreasing from 64% at 3 months to 2.4% at 2 years.
Dental decay is commonly associated with xerostomia. Appropriate dental care with prophylactic fluoride treatment and extractions of decayed teeth prior to commencement of RT can help to reduce the risk of dental sequelae (6). Cheng et al. (28) showed that 2.7% of 1,758 patients developed osteoradionecrosis at the maxilla and 1.7% developed it at the mandible. They found no difference in the risk of oesteonecrosis between extractions performed before and after RT. Tong et al. (214) reported that the incidence of complications following post-RT extraction of posterior maxillary teeth could be as high as 29%, with 10.5% developing osteonecrosis.

Carotid Artery Injury/Epistaxis

Stenosis of the extracranial and pseudoaneurysm of the intracranial portion of carotid arteries are two potentially fatal complications. Cheng et al. (29) studied 96 patients with a mean follow-up of 6.7 years after RT for NPC and 96 healthy controls by color flow duplex ultrasonography. Severe stenosis with ≥70% occlusion at the internal or the common carotid artery was found in 16% of patients, but none among the controls. Ultrasound screening of carotids for high-risk patients (age more than 60 years, history of smoking, heart disease, cerebrovascular symptoms) was advocated.
Lam et al. Lam et al. (107) also detected carotid stenosis with ≥50% occlusion in 24 (30%) of 80 patients, 9 of whom had a history of stroke or transient ischemic attack. A high index of suspicion is required. Carotid endarterectomy or endoplasty may be needed for severe cases.
Ruptured pseudoaneurysm presents acutely with massive epistaxis/hemoptysis or severe otalgia, often with a catastrophic outcome (25). This has been reported following IMRT with dose escalation (100) and reirradiation for local recurrence (25). It usually affects the heavily irradiated petrous portion of the internal carotid artery. Urgent diagnosis with angiography and emergency intervention by endovascular occlusion or stenting could be life-saving.
Other causes of intractable epistaxis include severe telangiectasia and hypervascularization in the internal maxillary artery territory. Emergency embolization may also be considered.

Second Malignancies

Radiation-induced malignancy is a rare sequela. In one study, the incidence was 0.04% and the latency was more than 10 years (126). Maxillary osteosarcoma (54) and soft tissue sarcoma (92) are the usual histologic types. Surgery is the only chance of cure, but the prognosis is often poor. A second primary head and neck cancer is relatively uncommon for NPC patients, but Teo et al. (206) reported an excessive risk of tongue cancer at 0.13% per patient-year. The possibility of radiation carcinogenesis cannot be excluded.

Final Remarks Osservazioni finali

In summary, the current standard recommendation for NPC is RT alone for stages I-II, combined RT and concurrent chemotherapy for stages III-IVB (± bulky stage IIB). Intensity-modulated RT technique is preferred if resources allow. A total dose of about 70 Gy is generally recommended. The Intergroup-0099 regimen of cisplatin-based concurrent and adjuvant chemotherapy with RT at conventional fractionation remains the chemoradiotherapy regimen with the most
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supporting data. Further enhancement of efficacy by using accelerated fractionation for T3-4 tumors and/or changing the timing of chemotherapy to induction-concurrent sequence for stage IV is worth considering. Verification of these new strategies by randomized trials is awaited.
Patients should be duly informed that, with improving results achievable by modern RT techniques, the absolute magnitude of survival benefits by adding chemotherapy might not be large and that the new treatments do incur higher risk of toxicities. Yet the prognosis for patients with relapse is so gloomy that achieving radical eradication of the cancer by best-quality primary treatment is crucially important. Patients should be encouraged to consider the treatment option that could maximize the chance of tumor control. More accurate prognostication is needed for further refinement of treatment strategies tailored to individual risk patterns.
Medical progress in the battle against NPC is one of the most gratifying successes. This peculiar cancer was invariably lethal before the advent of megavoltage RT, and it was not until the mid-1960s that we saw the first reports showing 25% of patients alive at 5 years (167). Contemporary results show that 5-year overall survival 75% and above can be achieved. Furthermore, the age-standardized incidence rate (per 100,000 male populations) in Hong Kong (one of the most prevalent sites) has steadily decreased from the peak of 40 in 1978 to 16 in 2003. With concerted efforts by all, we are highly optimistic that even greater global success in reducing the health burden by this notorious cancer can be achieved in the near future.