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Nasopharyngeal carcinoma: treatments and outcomes in the 20th century

¹ 41 Ewhurst Avenue, Sanderstead, South Croydon, Surrey CR2 0DH, UK and ² Department of Radiation Oncology, Allan Blair Cancer Centre, 4101 Dewdney Avenue, Regina, Saskatchewan, S4T 7T1 Canada

Correspondence: Dr T H P Tai, Department of Radiation Oncology, Allan Blair Cancer Center, 4101 Dewdney Avenue, Regina, Saskatchewan, S4T 7T1 Canada

	Abstract

Top Abstract Introduction Historical era (1896-1950) Transitional era (1951-1970) Modern era (1971-2000) References

 
Nasopharyngeal carcinoma (NPC), although rare in Europe and North America, is not uncommon in parts of Asia such as southern China and Hong Kong. Consequently, very few oncologists in the Western world have extensive experience in treating this neoplasm. Treatment using external beam therapy and/or brachytherapy evolved greatly during the 20th century and is still evolving, particularly with the use of adjunctive chemotherapy regimes. Diagnosis of NPC has also improved with the availability of CT and MRI. This worldwide review is divided into historical, transitional and modern eras, with the latter concerning 1971–2000. Currently, the most controversial aspects of NPC are recommendations for treatment of recurrent disease and the role of chemotherapy in the overall framework of treatment. Comparison of results from different centres is not possible without an understanding of the various staging systems that are, and have been, used; a comparison is given in this review. In the future, early diagnosis, adequate radiation dose to the primary with boost to bulky disease, and regular follow-up with biopsy of any suspicious residual or recurrent disease, are likely to become key issues to improve outcome. Also, apart from direct/indirect nasopharyngoscopy, the role of follow-up CT needs to be studied for early detection of residual or recurrent disease. More clinical trials on chemo-radiation are also required, in order to study optimum doses and agents.

	Introduction

Top Abstract Introduction Historical era (1896-1950) Transitional era (1951-1970) Modern era (1971-2000) References

 
Nasopharyngeal carcinoma (NPC) has multi-factorial risks including occupational, environmental and viral risk. Worldwide, NPC has by far the highest incidence in southern China in the provinces of Guandong (formerly Kwantung, which is why NPC is sometimes called Kwantung tumour), Guang Xi and Fujian, and in Hong Kong. It has the lowest incidence of all pharyngeal cancers (naso, oro and hypo) in North America and Europe, with only a relatively small number of cases seen annually within individual cancer centres [1–3]. Exceptions include those centres in which there are the few radiation oncologists who have made a particular study of the disease [4–8].

John Ho of the Queen Elizabeth Hospital, Hong Kong is the pre-eminent radiation oncologist in the field of study of the natural history of NPC. Ho, whose NPC staging system developed in the late 1960s [9] was used internationally for many years, has treated more cases than any other oncologist. The staging system, based on the natural history of the disease, was constructed by Ho after observations of many autopsies (J Ho, personal communication). The latest staging system for NPC is the 1997 International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) system [10], which is approximately the 20th different system reported in the literature [11] since the early 1950s. This makes direct comparisons of outcomes between different centres rather difficult, and a statement of which staging system has been used is considered essential for retrospective comparative review studies.

NPC is one of the most technically difficult sites within the head and neck region to treat with radiotherapy because of the close proximity to the primary site of radiation sensitive structures such as the eyes and spinal cord. Also, when irradiating the neck nodes either prophylactically or because of the presence of regional disease, the skin surface anatomy relative to the nodal locations is far from simple geometry. This has led to the proposal of many different types of field arrangements, treatment phases with or without coning down field sizes and organ shielding techniques. These range from the use of orthovoltage X-rays to telecobalt to photons from linear accelerators with or without the use of electron beams and with different time–dose fractionation schedules. Chemotherapy is also an integral part of treatment protocols and, with the advent of high dose rate (HDR) remote afterloading machines, such as the microSelectron-HDR (Nucletron B. V., Veenendaal, The Netherlands) with its small ¹⁹²Iridium source, the use of HDR brachytherapy for residual or recurrent disease is more often used today than in the past. Low dose rate (LDR) brachytherapy using a moulage technique [12] has been in regular use in France for many years, formerly with radium but now using ¹⁹²Iridium.

Presentation of cancer treatment outcomes, not only for NPC but for all cancers, has also varied widely over the years, from photographs of the patient before and after treatment, to a statement of a t-month or t-year survival. Standard methods such as Kaplan–Meier [13] have not always been used, different assumptions have been made for cases lost to follow-up and rates have sometimes been age-corrected.

Partly because of such problems of interpretation of survival rates, outcome results and even of radiotherapeutic technique, which is not always clearly specified, and also because past treatments bear no resemblance to those of today, this review commences with the period 1896–1950, which we have arbitrarily called the "Historical era". This is followed by the "Transitional era" (1951–1970) during which orthovoltage X-ray therapy and teleradium therapy were to become obsolete and be replaced by telecobalt therapy. The third and final section is called the "Modern era" (1971–2000) as this is the era which has seen the wide use of megavoltage photons using linear accelerators, electron beams, computer treatment planning, three-dimensional (3D) dose distributions, improved imaging procedures with CT and MR, HDR remote afterloading brachytherapy, some (although not many) clinical trials, widespread use of chemotherapy, applications of radiation biology in clinical practice (including the use of the linear-quadratic model), more standardization in survival rate calculations using life table methods and, relatively recently, the use of multileaf collimators (MLC).

NPC treatment in the 21st century will also, no doubt, see the routine use of intensity modulated radiation therapy (IMRT). Perhaps though, we have almost reached the final level of technological advances in radiation oncology, both for treatment delivery and treatment planning. However, advances can still be expected in radiochemotherapy regimes and in time–dose fractionation. It is, therefore, an opportune time to review the treatments and outcomes of NPC over the last 100 years.

	Historical era (1896–1950)

Top Abstract Introduction Historical era (1896-1950) Transitional era (1951-1970) Modern era (1971-2000) References

 
Röentgen discovered X-rays on 8 November 1895. However, the first proven successful X-ray treatment of histologically verified cancer was not until June 1899, reported at the Swedish Society of Medicine meeting in December 1899. There were, in fact, two cases reported, treated by general practitioners Tor Stenbeck and Tage Sjögren [14, 15], later also presented by Elis Berven at the 1961 annual meeting of the Radiological Society of North America [16]. The Stenbeck case was a basal cell carcinoma of the nose with 30-year follow-up and the Sjögren case was a squamous cell carcinoma of the cheek with 30-month follow-up; both were documented by photographs [15].

There were, however, several earlier unsubstantiated claims for priority for successful X-ray therapy. The most infamous of these, because it has been proven to be false, was that of Emil Grubbé, variously described as an X-ray manufacturer and a pharmacist–homeopath [17, 18] who claimed to have successfully treated a breast cancer patient in Chicago on 29 January 1896.

First successful X-ray therapy relief of pain: NPC (1896)
Another early claim for treatment success was at a meeting of the Society of Physicians of Hamburg, Germany on 3 February 1896 and concerned treatment of an 89-year-old patient with NPC. The physician was a Dr Voigt [19] and the report was first made in English by Leopold Freund of Vienna [20]. Fruend is considered to be the first physician ever to treat a patient therapeutically and to incontrovertibly document the evidence [21]; a 4-year-old girl with a hairy pigmented naevus in November 1896, who was subsequently followed up in 1956 [15]. Freund reported the treatment outcome described by Voigt as "relief of pain". This is not an exaggerated claim and, unlike Grubbé, Stenbeck and Sjögrens' claims were not for a cure of cancer. Thus, although it was nevertheless reported by Freund, it is therefore not too unreasonable to postulate that an NPC patient provided the first evidence of relief of pain as an outcome of X-ray treatment.

This case predates the only other early claim, that of V Despeignes of Lyon, France who in July 1896 reported relief of pain for a stomach cancer patient who underwent 80 treatments of 15–30 min duration twice daily [22].

Radiotherapy not considered for NPC (1900–1920)
X-ray therapy in the first decade of the 20th century was typically described in the 545 page textbook of 1907 by Mihran Kassabian [23], Director of the Roentgen Ray Laboratory of the Philadelphia Hospital, and the 1115 page textbook of 1910 by Sinclair Tousey [24], Consulting Surgeon to St. Bartholomew's Clinic, New York. Kassabian considered X-rays to have therapeutic value only for cancers of the breast, sternum, oesophagus, larynx, stomach and bowels, and uterus. Tousey gave the very similar list of breast, larynx, tongue, shoulder, mediastinum, stomach and intestines, and uterus. No text in the USA during this period mentioned NPC and nor did any European standard textbook such as that of Robert Knox [25] of the Royal Cancer Hospital, London (later renamed the Royal Marsden Hospital) in 1915. Neither was NPC mentioned as a site suitable for treatment using radium [23–25]. This is not surprising owing to the rarity of NPC. Indeed, in a 1901 JAMA paper [26, 27] only 13 cases were found to have been reported in the medical literature before the 20th century.

Radium brachytherapy (1921–1950)
It was not until the 1920s that NPC was considered to be practicable for radiation treatment, in part because, prior to this decade, X-ray tubes could seldom operate at 200 kV or above and consequently had extremely poor depth dose characteristics. With radium sources it was a different matter and in the early 1920s Georges Richard and Jean Pierquin [12] at the Institut du Radium (now the Institut Curie), Paris first employed an intracavitary method using a cork containing a tube of radium for the treatment of primary NPC. This cork was held in the nasopharynx by retaining strings in the same manner as a posterior nasal pack for epistaxis.

Many other radium brachytherapy techniques were described, including variants of the original Paris method. Some used gauze packs on which were sewn three or four radium tubes [28], or a catheter containing a row of radium sources inserted into the nasopharynx via the nose [29]. The Christie Hospital, Manchester method (Figure 1) of Ralston Paterson [30] was very similar to that used in Paris and used a single 15 mg radium tube in a sponge rubber cork of diameter 15–20 mm with a string at each end. It was described as "a useful alternative to a small field X-ray technique but not superior to the use of X-rays" [30]. The dose prescribed was 80 rad in 7 days delivered at about 0.5 cm depth within the tumour.

View larger version (38K): [in this window] [in a new window]   Figure 1. Christie Hospital, Manchester, technique of the 1940s [30].

View larger version (131K): [in this window] [in a new window]   Figure 2. Four examples of Fuzhou-developed nasopharyngeal carcinoma applicators. The microSelectron-HDR (Nucletron B. V., Veenendaal, The Netherlands) catheters are inserted into the rubber tubes shown, which have an outer diameter of 5 mm and an internal diameter of 2.5 mm. The rubber-type material spacer between the tubes ensures that the catheters are kept at 10–15 mm distance from the soft palate. Only topical anaesthesia is required and the applicators are cheap and easy to construct, as with the designs of the 1920s, and therefore reliance does not have to be placed on expensive, commercially available applicators [31].

In the UK, the Medical Research Council (MRC) undertook a clinical comparative study of 185 kV X-rays vs teleradium with a 10 gm radium bomb and units fitted with similar sized applicators for head and neck cancers. A total of more than 700 patients were treated between 1934 and 1945, only 20 of whom were NPC cases. The final report was published in 1950 [35].

Skin erythema outcome
Another interesting feature of this 1950 report [35] is the classification of skin reaction as an "immediate response to treatment" and the inclusion of a diagram of the "typical arrangement of fields for treating NPC and the isodose distribution" (Figure 3). Also included were three pairs of colour photographs of an NPC patient for both X-ray and radium treatment taken at 2 days after the start of treatment, on the 34 days of treatment (with the fields marked on the patient's face) and at 10 days after the end of treatment (Figure 4). The graph in Figure 5 shows the degree of skin erythema over time, with the tumour dose in roentgens on the left-hand scale and the skin reaction on the right-hand scale. This latter scale is not numbered but the numerical value of degree of erythema is classified as equal between slight and severe erythema and between severe and moist desquamation. Figures 4 and 5 are included because they are almost certainly the only pictorial information on the treatment outcome of NPC in the 1940s that now exist in the literature.

View larger version (52K): [in this window] [in a new window]   Figure 3. Typical arrangement of four treatment fields for nasopharyngeal carcinoma in the 1940s together with isodose distributions. The isodose curves numbered 4, 8, 12, 16 and 20 are in units of roentgen min-1. Displaying the dose distributions in sagittal and coronal planes is an early attempt at trying to produce a three-dimensional (3D) view [35]. Even in the late 1960s manual calculation (maybe using an analogue computing device as distinct from a digital computer) in two or three orthogonal planes was the only way of showing a 3D distribution.

View larger version (64K): [in this window] [in a new window]   Figure 4. Nasopharyngeal carcinoma patient with radium fields (left) and X-ray fields (right) 2 days after treatment (top), on the 34th day of treatment (centre) with three fields clearly marked on the patient's skin on both sides of the face, and 10 days after the end of treatment (bottom). The study involved one side of the face being treated using teleradium and the other side of the face being treated using X-rays [35].

View larger version (37K): [in this window] [in a new window]   Figure 5. Skin reaction graph for the nasopharyngeal carcinoma (NPC) patient in Figure 4, for bothradium and X-ray fields for the skin of the temple. Treatment was described as follows. "A 5 cm field was placed in each preauricular region, a 5 cm field in each superior labial region, and an 8 cm field in each superior cervical region" [35]. The total dose received by the skin of the neck in 40 days was 7400 roentgen (r) from the radium beam and 5500 r from the X-ray beam. The total dose received on the skin of the temple in 46 days from the radium beam was 8700 r and from the X-ray beam 6500 r. Of the 20 cases of NPC treated, the "percentage cured" was estimated to be 25% with a 95% confidence interval of 9–51%. This, as expected from the small number of cases, is very wide [35].

	Transitional era (1951–1970)

Top Abstract Introduction Historical era (1896-1950) Transitional era (1951-1970) Modern era (1971-2000) References

Prognosis and survival
Results from one such 2 MV series of NPC treatments were published in 1963 from Massachusetts General Hospital [39] and quoted 48% 5-year survival results. This study was one of the first to take into account the stage of the disease and to analyse the sites of failure. For example, they reported that a poor prognosis was associated with those cases with involvement of the cranial nerves, the paranasal sinuses or the base of skull. This observation was confirmed, also in the 1960s, for base of skull involvement and also for involvement of the cranial nerves in an MD, Anderson Hospital series reported by Fletcher and Million [40]. Table 3 gives the results of a world literature survey [41] published in 1959.

The natural history of NPC was also well documented by the end of the 1930s including the anatomy of the nasopharynx in relation to the origin and spread of cancer and including cranial nerve involvement, orbital invasion and metastatic routes [32]. In particular, a knowledge of the lymph drainage of the nasopharynx [44] was available for treatment planning purposes. After telecobalt machines were available, several treatment planning schemes were proposed to prophylactically irradiate the neck nodes, and data on the frequency of particular nodal involvement was also reported [5, 9, 40, 45, 46].

Radiation field arrangements
As with the field arrangements for elective neck irradiation, many different variants of field arrangements, including shielding to minimize dose to the eyes and spinal cord, have been proposed. The sketch diagrams in Figure 6 are typical of the use of telecobalt in the 1960's, and also typical in that treatment was divided into two phases with the lateral face fields coned down for the second phase of treatment. For this particular treatment, doses from the two phases for the primary midline tumour dose were 4000 rad+2000 rad and for two neck nodal dosimetry points totalled 5400 rad and 4800 rad from both phases combined [5]. Field arrangements are discussed in more detail for the modern era for photon only treatment and mixed photon plus electron beam treatment.

View larger version (50K): [in this window] [in a new window]   Figure 6. Schematic diagram of seven telecobalt treatment fieldpositions and shapes, including shielding blocks, for a typical 1960s two-phase treatment [5].

All primary tumours were limited to the nasopharynx without evidence of bone or neurological involvement and 20 of 33 tumours were squamous cell carcinoma, with the remainder being undifferentiated neoplasms. The external dose was 45 Gy and the total combined dose to the nasopharynx was 75 Gy. 23 of the 33 cases presented with clinically involved cervical nodes and received electron boosts to the neck following 45 Gy to the bilateral cervical regions. Only two patients were lost to follow-up. Overall survival is 13 of 31 (42%), which although 31 is only a small number is an improvement on the results in Tables 2 and 3. Nevertheless, 11 of 13 patients have been continuously disease free, although 13 of the 31 patients have died with active disease [12]. In addition, Mazeron reported on 14 cases treated for recurrent NPC in which local tumour control was achieved in 7 of 12 patients who could be followed-up. The total doses delivered varied widely in the range 40–98.5 Gy. This series of 33+14 NPC cases has also been reported on by Gerbaulet et al [47] in 1994 as part of a review of brachytherapy in the treatment of 1140 head and neck cancer patients at the Institut Gustave-Roussy, Villejuif, France. No changes in survival results are given when further follow-up is available.

In the UK and North America during this period, the experience of the French school of brachytherapy was seldom followed. For example, in London only individualized moulage applicators incorporating single sources were used, but for very few NPC patients. Lederman's [4] design of radium applicator incorporated a 50 mg capsule delivering a dose rate of 700 rad h^-1 at 0.5 cm, which was enclosed in a plastic cylinder and drawn up into the nasopharynx via the mouth. The cylinder was designed to fill the nasopharyngeal lumen, but in practice the source tended to rest on the superior surface of the soft palate and was therefore unsatisfactory.

A more invasive technique was designed by Windeyer [48] of the Middlesex Hospital, London, which required resection of the posterior portion of the hard palate. This technique used a single ⁶⁰Cobalt source, but it was generally considered [49], because of the rapid fall-off of dose below the mucosal surface, that the method was ineffective for treating any infiltrating lesion.

Interstitial brachytherapy as a treatment for NPC did not start until after 1970 and although ²²²Radon seeds were temporarily implanted in many different cancer sites [15] they were never implanted in the nasopharynx. For this brachytherapy method implants were permanent, using ¹⁹⁸Gold [50] or ¹²⁵Iodine [51]. However, this was not performed until the modern era.

	Modern era (1971–2000)

Top Abstract Introduction Historical era (1896-1950) Transitional era (1951-1970) Modern era (1971-2000) References

 
By far the highest incidence of NPC is in southern China, including Hong Kong, as indicated from cancer incidence data [52] (Table 4). The publications on NPC treatment and outcome analysis are far fewer from mainland China than from Hong Kong. However, for future research and development of radiochemotherapy treatment protocols, and because clinical trials are more practical owing to large numbers of NPC patients, we should also look towards China, as well as to groups such as the Eastern Cooperative Oncology Group (ECOG) and the Radiation Therapy Oncology Group (RTOG).

Comparing the 1988 and the 1997 UICC/AJCC staging systems [60], T1 and T2 become T1 on the new staging system, and T3 becomes T2. A study from Taiwan of chemo-radiation from 1990 to 1997 staged patients in both systems [62]. This is likely to be more accurate than other studies owing to homogeneous staging investigations. In addition, the time of data collection is not too distant from the time of reporting. Using the 1988 system, the study had 12 stage III and 95 stage IV patients. These became 32 stage II, 44 stage III and 31 stage IV patients if staged by the 1997 system. This highlights the problem of intercomparison between results from different centres when a different staging system is used.

Unfortunately, this is likely to continue for the forseeable future and, for instance, the most widely used staging system in mainland China is neither that of Ho nor the UICC/AJCC but that of Ming and Hong of Changsha [31, 63]. In the latter, paranasal sinus involvement is classified as T4, which is different from other staging systems. There is no apparent differentiation between a small tumour invading into the maxillary sinus and a large tumour invading into the sphenoid sinus. A comparison of the Chinese 1992 system of Ming and Hong and the 1997 UICC/AJCC system was made and it was concluded that the predictive power of the Chinese 1992 T-classification was superior [64]. Conversely, however, it was concluded that the UICC/AJCC N classification was more reasonable. Patients were categorized more evenly by the UICC/AJCC stages than by the Chinese 1992 stages. The 5-year disease-specific survival rates for patients in corresponding stages of both systems were almost identical, despite differences in the criteria defining T and N classifications. Statistical analysis showed that the rate of agreement was 72% between the two staging systems.

As a result of the work from Asia, the 1997 AJCC/UICC classification now divides T2 into T2a and T2b, with the absence or presence of parapharyngeal extension, respectively [61]. Parapharyngeal extension denotes posterolateral infiltration of tumour beyond the pharyngo-basilar fascia. One way to classify parapharyngeal extension is Grade 1 (into the retrostyloid space), Grade 2 (into the prestyloid space) and Grade 3 (into the anterior part of the masticator space) [65].

T stage: local control, patterns of failure and survival
Since the nasopharynx is a small volume with a curved surface, and the tumour may spread submucosally, division into one or two subsites is difficult. In the UICC/AJCC staging systems prior to 1997, T1 (one subsite) and T2 (more than one subsite) do not show any difference in local or distant failure and cancer deaths (Tables 8 and 9) [60, 66–72]. The only possible slight difference one may expect is that a T1 tumour may have a smaller bulk than a T2 tumour.

N stage: local control, patterns of failure and survival
The main feature of Ho's N staging is that it goes by the level of involvement down the neck. In the UICC/AJCC systems prior to 1997, N staging is similar to other head and neck cancers. However, for a non-surgically treated tumour with frequent submucosal infiltration in a midline organ, the relevance of differentiating between ipsilateral and contralateral nodal involvement is doubtful. Furthermore, for a tumour with orderly spread, ignoring the level of the lymph node would result in a significant loss of predictive power. Presence of supraclavicular nodes increases the chances of distant spread. Hence, in the UICC/AJCC 1997 classification, N3a is defined as the presence of lymph node(s) greater than 6 cm in dimension and N3b as lymph node(s) in the supraclavicular fossa [60].

Lee et al [56] have retrospectively analysed their data using both types of N classification and found that "both N staging systems showed a strong significant overall correlation with distant failures and cancer-specific deaths and a significant trend was also shown for nodal failures in node positive patients". They also found that "Ho's system was superior in predicting distant failures, while the UICC/AJCC system was superior for nodal failures" [56]. Therefore, the bulk of lymph node(s) predicts nodal failure better. Table 10 gives to the nearest 0.5%, from published graphs [56], actuarial disease-free survival rates for the Queen Elizabeth Hospital, Hong Kong series, for patients treated between 1976 and 1985, for different N stages as defined by Ho and UICC/AJCC [56]. However, as stated by the authors, it should be noted that this is a retrospective study in terms of staging by UICC/AJCC and that, in addition, only 14% of the patients were staged with the benefit of CT. Also, the study was based entirely on non-keratinizing or undifferentiated carcinoma.

View this table: [in this window] [in a new window]   Table 12. 5-year disease–free survival rates as a function of cervical node status for two American series and for the Hong Kong series in Table 11

Pathology: patterns of failure and survival
Even though they have higher rates of distant metastases, the Type 2 and Type 3 NPC carcinomas are more radiosensitive and therefore more easily controlled, with the result that they have a better prognosis when survival is analysed by stage than does Type 1 (Table 14) [8, 81]. Patients with keratinizing squamous cell carcinoma had a higher incidence of T3 and T4 tumours than those with non-keratinizing and undifferentiated tumours. However, it must be noted that the patient numbers are small, the staging system used was UICC/AJCC 1988 and the treatment period for these 50 NPC cases was 1971–1986.

5-year survival rates by cell type are given in Table 15. This shows that, as mentioned earlier, apart from the series by Frezza et al [74], survival is better for lymphoepitheliomas that are WHO Type 3 than for squamous cell carcinoma that are WHO Type 1. The series from Stanford combined the undifferentiated carcinoma into squamous cell carcinoma group in the analysis [83]. This diluted the favourable prognosis of lymphoepithelioma as opposed to that for squamous cell carcinoma.

We emphasize that it is very important when reviewing the literature to note the time period of the study, staging system used, patient population and stage distribution, investigations, treatment methods and intent. Survival results can be disease free survival, cause-specific survival or overall survival. Some series only include radically treated patients whilst others also include the metastatic and palliative cases (Table 16) [54, 71, 84].

To overcome this, Teo et al [72] calculated the total uncorrected biological effective dose (BED₁₀), and the total BED₁₀ corrected for tumour repopulation during the whole period of radiotherapy to the last fraction of intracavitary treatment (ICT). It was found that patients with early T stage NPC given higher dose ICT after external radiotherapy (ERT) had the best local control rate, whilst those with intermediate dose ICT after ERT had intermediate local control rate, and those without any ICT after ERT had the worst results.

Yan et al [86] performed a randomized study on 78 T1 (involving one wall), T2 (involving two or more walls) and T3 (primary tumour extending to the surrounding tissues but no palsy of the cranial nerves or destruction in the base of skull) patients after 70 Gy to the nasopharynx. A total of 30 patients with a positive biopsy after a post-irradiation time interval of 10–14 days were randomized to receive an external boost dose of 20 Gy in 5 fractions over 2.5 weeks. Local recurrence rates of the biopsy negative group were 4% (2 of 48 patients). Local recurrence rates of the biopsy positive group were 6% (1 of 16 patients) for those given boost radiotherapy and 36% (5 of 14 patients) for those not given boost radiotherapy.

The time frame of this study is of interest compared with the study from Queen Mary Hospital, Hong Kong [87] since some of the positive biopsies may turn negative at 12 weeks. Yan et al's trial could not infer that the benefit of dose escalation above 70 Gy applies also to the complete responders to the primary radiotherapy at 10–14 days.

All these studies serve as circumstantial evidence suggestive of a dose–response relationship for early T stage NPC. It forms the basis of dose-escalation studies with 3D conformal radiotherapy and different boost techniques in the modern era.

Altered fractionation and concomitant boost
Altered fractionation is one way of achieving dose escalation and also sparing the normal tissue in a temporal manner. A few large series of altered fractionation had been performed with adequate follow-up. The Massachusetts General Hospital used 1.6 Gy, twice daily fractionation and a 2-week rest period between cases [7, 69]. The study was performed during 1970–1994 and was not randomized. The results showed that twice daily fractionation significantly improves local control and disease-specific survival [7, 69]. Amongst all cases, once daily fractionation gives a 5-year actuarial local control rate of 60% and disease-specific survival of 49%. The corresponding figures for a twice daily fractionation scheme were, respectively, 69% (p=0.008), and 69% (p=0.0001).

A split-course radiotherapy regimen was reported by RTOG [88]. It delivered 30 Gy in 10 fractions over 2 weeks, with a rest period of 3 weeks before another course of the same dose. No statistically significant differences were observed in the two arms with regard to acute or late toxicities incidence of distant metastases, disease-free survival (DFS) or overall survival (OS). A considerably greater fraction of the split-course group (79% vs 56%, p=0.01) completed therapy as planned and had less severe reactions compared with a group receiving 60–66 Gy in 6–7 weeks with daily fractions of 2–2.2 Gy continuous treatment. In the Intergroup study [89], only 63% of patients received three courses of chemotherapy concurrent with irradiation, and 55% received all three courses of adjuvant chemotherapy given after the completion of radiotherapy. Methods to reduce treatment reactions would mean a higher chance of completing treatment as planned. In fact, the success of the twice daily regimen of Massachusetts General Hospital may also be related to the 2-week break and allow a higher total radiation dose to be completed.

Another reported concomitant infusion cisplatin (5 mg m^-2 per 24 h) and hyperfractionated radiotherapy (1.2 Gy per fraction twice daily) was from the Health Science Center at Brooklyn, New York [90]. Again, acute reactions are minimized by splitting the treatment with a 1–2 week break after each 2 weeks of radiation treatment. Experience with all the split course radiotherapy so far does not diminish disease control, indicating that NPC is not a very fast growing tumour and that repopulation may occur during the rest period. Split course radiotherapy should be tested further during the continuing search for the optimal chemo-radiation regimen.

The Memorial Sloan–Kettering Cancer Center, New York, added on cisplatin based chemotherapy to an accelerated concomitant boost radiotherapy for stage II–IVb nasopharyngeal cancer [91]. The radiotherapy regime was 70 Gy concomitant boost ERT (1.8 Gy per day during weeks 1–6 and 1.6 Gy per day as a second daily fraction during weeks 5 and 6) and two cycles of concurrent cisplatin 100 mg m^-2 days 1 and 22. A total of 37 patients also received three cycles of cisplatin based adjuvant chemotherapy. These 50 patients were compared with a non-randomized cohort of 51 patients with NPC treated with 70 Gy conventional fractionation ERT (1.8 Gy per day) without chemotherapy from 1988 to 1995. The groups were well matched for prognostic factors except stage, for which the concomitant boost radiotherapy/chemotherapy group was more advanced (54%, T3–4; 54%, N2–3; 44%, stage IV) compared with the conventional radiotherapy group (31%, T3–4, p=0.03; 22%, N2–3, p<0.001; 20%, stage IV, p<0.01). With a median follow-up of 42 months (range 12–129 months), the 3-year actuarial local control, progression-free survival and survival rates were, respectively, 89% vs 74% (p<0.01), 66% vs 54% (p=0.01), and 84% vs 71% (p=0.04) for the concomitant boost ERT/chemotherapy group and the conventional ERT patients, respectively. Acute grade 3 mucositis was more prevalent with combined therapy, 84% vs 43% (p<0.001), resulting in a higher rate of temporary gastrostomy tube placement, 46% vs 20% (p<0.01). Hence this concomitant boost ERT with cisplatin based chemotherapy is feasible and improves local-regional control as well as survival for patients with advanced NPC compared with conventional ERT alone.

Another group from Baylor College of Medicine, Houston used simultaneous modulated accelerated radiation therapy (SMART) with acceptable toxicity [92]. Radiation was delivered via IMRT with three to five arcs. A total of 20 patients with primary head and neck carcinomas were treated with the SMART boost technique. Treatment fields encompassed two simultaneous targets. The primary target included palpable and visible disease sites. The secondary target included regions at risk for microscopic disease. Daily fractions of 2.4 Gy and 2 Gy were prescribed and delivered to the primary and secondary targets to a total dose of 60 Gy and 50 Gy, respectively. Lower neck nodes were treated with a single conventional anterior portal. This fractionation schedule was completed in 5 weeks with five daily fractions weekly.

An interesting study from Lee et al [93] in Hong Kong, which covered the period January 1994 to October 1997, used six daily fractions per week. It was possible to perform this study since Hong Kong clinics routinely work on Saturday mornings. 325 patients were treated to a total dose of 66 Gy in 33–37 fractions: 167 patients (irradiated before mid-January 1996) were treated with five daily conventional fractions (CF) and a subsequent 158 patients were treated with six daily accelerated fractions (AF) per week. Their median treatment times were 46 days and 39 days, respectively. Additional boost to parapharyngeal extensions had been given to 181 patients and cisplatin-based chemotherapy to 57 patients (24 concurrent with radiotherapy). The AF group had a significantly higher progression-free rate than the CF group (74% vs 63% at 3 years, p=0.02 by the log-rank test). However, the difference in disease-specific survival (86% vs 80%, p=0.39) and overall survival (81% vs 78%, p=0.9) did not reach statistical significance. Strongly significant improvement in local failure-free rate was achieved for patients with T3–4 tumours (87% vs 62%, p<0.01).

Caution should be exercised when developing the best fractionation scheme. Teo et al [94] reported a study that had to be prematurely terminated owing to toxicities. Arm I was the conventional arm, receiving 60 Gy in 24 fractions over 30 days. Arm II was the accelerated hyperfractionated arm starting with a pair of lateral opposing fields covering the nasopharynx and upper neck with 20 Gy in 8 fractions over 10 days (once daily treatment) and then 22.4 Gy in 14 fractions over 9 days (1.6 Gy twice daily per day). This is followed by a three-field technique (two lateral and one anterior facial fields) for 28.8 Gy in 18 fractions over 11 days (twice daily treatment). There were no intended treatment breaks. Incidences of neural complicatons were 23.2 vs 49.4% for arm I and II, respectively (p=0.001).

Modern radiotherapy treatment techniques
Figure 7 summarizes overall 5-year survival rates for 3233 NPC patients treated at the Cancer Hospital of the Shanghai Medical University from 1955 [95], and is unique in presenting a comparison of results for 180 kV orthovoltage X-rays vs telecobalt without computer treatment planning (TPS) facilities vs telecobalt with TPS. This illustrates that with telecobalt the results have been improved by a factor of two when compared with orthovoltage; 27.7% vs 54.0%, respectively. This may also reflect better technical accuracy, better understanding of the mode of spread of the disease, and better diagnostic methods to stage the tumour [96].

View larger version (32K): [in this window] [in a new window]   Figure 7. Overall 5-year survival rates for nasopharyngeal carcinoma cases treated at the Cancer Hospital of the Medical University of Shanghai, to show improvement of treatment results with differenttreatment periods. (Courtesy of Professor Liu Taifu, Cancer Hospital of the Medical University of Shanghai.)

View larger version (81K): [in this window] [in a new window]   Figure 8. A set of normal classical Ho's nasopharyngeal carcinoma views for (a) lateral, (b) submento-vertical, (c) occipito-submental, (d) 25° occipital-mental and (e) occipito-maxillary views.

View larger version (56K): [in this window] [in a new window]   Figure 9. A set of abnormal classical Ho's nasopharyngeal carcinoma views showing (a) lateral, (b) submento-vertical, (c) Towne's (30° fronto-occipital), (d) 25° occipital-mental and (e) occipito-maxillary views.

View larger version (124K): [in this window] [in a new window]   Figure 10. CT scan of a patient who presented with right-sided ptosis.

View larger version (116K): [in this window] [in a new window]   Figure 11. MR scans of the same patient as Figure 10, to show the corresponding axial scan as Figure 10. Sagittal scans are a useful adjunct for tumour localization.

Modern 3D treatment planning is another way of dose escalation and also of sparing the normal tissue in a spatial manner (Figures 12–13).

View larger version (177K): [in this window] [in a new window]   Figure 12. Three-dimensional representation of patient contour, with critical structures outlined: spinal cord and eyes.

View larger version (53K): [in this window] [in a new window]   Figure 13. Three-dimensional radiotherapy planning for a tumour that extends from the nasopharynx to the nasal fossa.

View larger version (104K): [in this window] [in a new window]   Figure 14. The Hong Kong technique to boost parapharyngeal space. The patient's neck is turned to one side, slightly extended, and skin marks are made to delineate the field.

Accuracy is greatly improved by these modern technologies. With the advances in computing power, comparison of plans is easier than in the past when using only dose-volume histograms [99].

Stereotactic radiosurgery is another modern development and is given in a single large fraction. Fractionated stereotactic radiotherapy has also been reported for use in NPC [100, 101]. This can be used as a boost for bulky disease, or treatment of residual or recurrent disease.

External beam radiotherapy for recurrent NPC
Traditionally, staging should always refer to the disease extent at the initial presentation. However, many NPC authors now restage the patients at relapse and use the notation "r" to signify it. Studies from Hong Kong employed Ho's T stage distribution at recurrence (rT). For persistent disease after ERT, brachytherapy is recommended [102]. Wang [103] of Massachusetts General Hospital reported 38 patients with recurrent disease treated with radical radiotherapy consisting of 60 Gy or more, by external beam with or without intracavitary brachytherapy. The actuarial 5-year and 10-year survival rates after re-treatment were, respectively, 45% and 39% [103]. For most modern series with adequate follow-up, the high incidence of major late complications (9–39%) is of serious concern (Table 17) [56, 103–6].

In Table 17, Teo et al's [106] results of re-irradiation can be explained by two factors. First, his primary radiotherapy employed adequate dose and modern planning techniques to avoid any geographical miss. Therefore his recurrent patients may have a more radioresistant tumour than series with less modern and adequate radiotherapy techniques. Second, the cumulative dose from the primary hypofractionated radiotherapy is high (60 Gy in 24 fractions over 6 weeks or 62.5 Gy in 29 fractions over 6 weeks, with or without boost to the parapharyngeal space of 20 Gy in 10 fractions over 2 weeks, and/or brachytherapy of 24 Gy in 3 fractions over 15 days), and the salvage treatment was 54–60 Gy in 27–30 fractions over 5.5–6 weeks and brachytherapy dose of 10–24 Gy in 1–3 treatments. The high cumulative nasopharyngeal dose accounts for the high complication rate of at least 61%, since some patients had more than one severe complication and all had some complication of different severity.

In practice, patients should be carefully selected by taking into account prognosis and high rate of late tissue toxicity, especially soft tissue necrosis, fistula formation and potential nerve damage. Several criteria may be used to select patients for curative re-irradiation. These include limited tumour size, a relatively long period since previous irradiation (a suitable, though arbitrary, minimal time period may be 1 year), good performance status and lack of evidence of skin or soft tissue damage (skin fibrosis, atrophy or telangiectasis) from the previous irradiation course [107]. If recurrence is less than 1 year after initial treatment, palliative chemotherapy is sometimes used because the tumour is deemed radioresistant [106].

To summarize, the more modern series from Teo et al, Hong Kong [106] likely reflects the benefits and risks of repeated radiotherapy courses better than the older series [55]. With the availability of IMRT and better planning systems to avoid normal structures, many of the severe complications may now be avoidable. Chemotherapy can also be given to eradicate any metastases. A combined approach with chemotherapy, nasopharyngectomy (in selected cases), reduced cumulative external radiotherapy dose and brachytherapy or stereotactic radiotherapy boost may become potential areas for further research.

Molecular markers for prediction of radiation response
Another development in the modern era is the use of molecular markers to predict treatment response and outcome. Among them p53, proliferating cell nuclear antigen (PCNA), Ki-67, c-erbB2 and angiogenesis factors have been tested. The clinical response rate of primary tumour was 85.1% (40 of 47 cases) in positive p53 immunostaining and 95.2% (20 of 21 cases) in those with no immunostaining. The former has lower loco-regional tumour response than the latter, but there was no significant difference (p>0.05, ² test) [108]. Another study found that p53 positivity correlated with the presence of lymph nodes, but it was not a significant factor in predicting outcome [109]. PCNA expression was not found to be a prognostic indicator. On the other hand, the proliferative value of Ki-67 staining helps to predict prognosis. A Ki-67 proliferation index of less than 10% indicated longer survival (p=0.03). There was no correlation between Ki-67 staining and PCNA index.

Strong c-erbB2 expression correlated with a shorter overall survival (p=0.02) and disease-free survival (p=0.02) [110]. Intense tumour angiogenesis, defined as microvessel, counts for 60 or more microvessels per 200 x field correlated with the development of distant metastasis (p=0.03), shorter overall survival (p=0.02) and disease free survival (p=0.05) [110]. RTOG 95-05 trial evaluated the prognostic value of tumour angiogenesis as measured by microvessel density. This trial was closed in June 2000 and is currently pending analysis.

Brachytherapy for primary, residual and recurrent NPC
Brachytherapy is a special radiotherapy technique that delivers dose at a short distance with a rapid dose fall-off. Brachytherapy is a useful addition to external beam irradiation in the treatment of patients with head and neck cancer. The advantage of limiting the high dose region to the tumour bearing area owing to the rapid dose fall-off is of particular interest because of the proximity of critical dose limiting structures to the nasopharynx. This is especially true when treating recurrent or residual NPC because the region will already have received a high dose from the initial treatment using external beam radiotherapy.

Brachytherapy can be given as an interstitial implant or intracavitary treatment. A retrospective series seems to suggest that interstitial implant is better than intracavitary radiotherapy owing to certainty of dose delivery and higher tissue dose [111]. However, only a prospective randomized trial can properly answer the question of whether interstitial implant is better than intracavitary treatment. The disadvantages of an interstitial implant are the essential requirements of technical skill, which cannot be obtained without a high patient workload, and the possibility of dislodgement of the sources, especially when the tumour is friable. In permanent implants, for good exposure of the nasopharynx, retraction of the soft palate [51, 112], a posteriorly based transpalatal flap [113] or transverse or longitudinal splitting of the soft palate [50, 114, 115] can be used. Often quoted studies of intracavitary study include that of Wang from Massachusetts General Hospital [116], Syed et al from Long Beach Memorial Medical Center [117] and Teo et al from Prince of Wales Hospital, Hong Kong [72].

It is still controversial as to whether brachytherapy should routinely be given as part of initial therapy. It is favoured in studies by Teo et al, Wang, Levendag et al and Chang et al [72, 116, 118, 119]. An alternative method is to give brachytherapy only when residual or recurrent disease is documented or strongly suspected. The time trend for tumour regression had been studied by Nicholls et al [120]. Post-treatment biopsy should be performed twice, as four patients in Nicholls et al's study had negative biopsy findings owing to sampling error. In an update of their data in 1999 [87], the authors suggested a confirmatory biopsy at 10 weeks before initiation of salvage treatment.

There is no standard recommendation for brachytherapy dose. This will depend on the dose-fractionation and total dose of the previous external radiotherapy. In the series of Teo et al [121] of Hong Kong, an external radiotherapy dose of 60.0–62.5 Gy in 6 weeks was given. Local persistence in 99 patients was treated additionally by intracavitary brachytherapy to 24 Gy in three fractions over 15 days. 51 of 99 patients with early stage primary disease (Ho Stage T1 and T2n (nasal)) who responded completely to external radiotherapy were given adjuvant intracavitary brachytherapy to 18 Gy in three fractions over 15 days. In another study from Taiwan [119], after external beam irradiation of 64.8–68.4 Gy, a boost was given by HDR brachytherapy of 5–16.5 Gy in 1–3 fractions. Owing to complications of foul odour, palate or sphenoid sinus floor perforation or nasopharynx necrosis, these authors suggested fraction size be decreased.

Chemotherapy for primary NPC
Chemotherapy was first used in the 1970s as a component for the primary curative treatment. Even in patients who failed ERT, or those with systemic metastasis, high response rates are reported with the use of chemotherapy, with many patients alive and well more than 2 years after chemotherapy [122]. This review will only discuss its use in primary NPC.

Value of chemotherapy
Chemotherapy can be divided according to timing with respect to whether it is neoadjuvant, concurrent or adjuvant to radiotherapy. Chemotherapy acts as a radiosensitizer and helps to decrease the rate of distant metastases. Owing to conflicting results in the literature, it is difficult to assess its benefit and develop the best chemotherapy regimen. The impact of chemotherapy on survival is controversial. The different staging systems and investigations further confound the interpretation of data. Some studies are not randomized and sample sizes are small. Currently the optimum number of chemotherapy cycles is unknown. Many published series do not specify the rates of distant metastases as the first site or as the sole site of failure. It is important that these rates be interpreted in the light of histological subtypes since the lymphoepithelial or undifferentiated subtype has a higher distant metastases rate. Owing to the relative inexperience with this rare tumour in the Western world, the disease may be diagnosed late with greater tumour bulk (even if they belong to the same TNM staging) and higher rate of distant metastases than that in Asia. The overall incidence of distant metastases was 36% clinically and 51% pathologically (post-mortem) among 256 patients from a series in Illinois [123]. The influence on the sensitivity to chemotherapy and radiotherapy of oncogenes, molecular markers or other factors in different races, is also unknown.

The survival benefit of induction chemotherapy is controversial. Chan et al's study was based on Ho's N3 or any N stage with a nodal diameter of more than 4 cm [124]. This is equivalent to N2a (size >3 cm) or N3 in UICC/AJCC staging system of 1987, and hence Stage IV. All patients had WHO grade 3 carcinoma (undifferentiated) .Hence there are two possibilities that their induction chemotherapy did not confer survival advantage. First, the lower 5-fluorouracil dosage (1 g m^-2 infusion over 24 h for 3 days) decreased the response rate and hence the benefit [122, 124]. Second, neoadjuvant chemotherapy does not work as well as concurrent chemotherapy [125–129], possibly owing to delay in the start of radiotherapy [130], accelerated repopulation induced by neoadjuvant chemotherapy and the lack of radiosensitization effect, since it is not given concurrently with radiotherapy. The majority of neoadjuvant chemotherapy cases do not have any survival benefit, as analysed by the review from the Prince of Wales Hospital, Hong Kong [131].

Concomitant radiotherapy and chemotherapy (CCRT) followed by adjuvant chemotherapy is more effective than radiotherapy alone for advanced stage NPC from a large North American Phase III randomized Intergroup study [89]. However, this combined modality treatment for advanced NPC has not been accepted to a significant extent in endemic southeast Asia, because the survival rate of the CCRT group in the Intergroup study is not superior to the results of radiotherapy alone from Hong Kong, Toronto or from other series in the Western world [72, 131–135].

The Toronto series had 172 patients with stage III/IV (UICC/AJCC 1992 system) who received radiotherapy alone to a median dose of 66 Gy (range 18–66 Gy) [134]. The 5-year OS and 5-year DFS for these 172 patients were 64% and 48%, respectively. The 3-year OS and DFS were 74% and 58%, respectively, as compared with the Intergroup 0099 results of an OS of 47% and a DFS of 24% for ERT alone, and an OS of 78% and a DFS of 69% for the chemoradiotherapy arm.

The Intergroup study used 70 Gy total external beam radiotherapy dose, without any brachytherapy or parapharyngeal boost. The results of their radiotherapy-alone arm is poor. Hong Kong and Toronto have a larger Asian population than other cities and, owing to the prevalence of NPC, clinicians may have more experience with its management. Treatment inexperience can lead to geographical miss and suboptimal treatment planning. One further note is the composition of WHO histological subtypes (I, 22%; II, 37%; and III, 41%) in the Intergroup 0099 [89]. This can be compared with the MD Anderson Cancer Center (MDACC) series of squamous cell carcinoma 50% (125 of 251 cases) and lymphoepithelioma 45% (113 of 251 cases) [71]. The MDACC series has overall 5-year actuarial DFS rates of, respectively, 42% and 65% for squamous and lymphoepithelioma [71].

In 1996 the MDACC reported that among the 101 stage IV patients the 5-year actuarial rates for those who did and did not receive induction chemotherapy were, respectively, 68% vs 56% OS (p=0.02), and 64% vs 37% freedom from relapse (p=0.01) [136]. Cooper et al of New York University Medical Center used the same chemoradiotherapy scheme of Intergroup 0099 on 35 stage III and IV patients and produced an actuarial 3-year OS rate of 93% and 3-year DFS rate of 65% [135]. The Institut Gustave-Roussy, Villejuif, France used cisplatin (100 mg m^-2 on day 1), epirubicin (80 mg m^-2 on day 1) and bleomycin (15 mg bolus on day 1), followed by 16 mg m^-2 per day continuous infusion for 5 days, repeated every 21 days for three cycles on one subgroup of previously untreated locoregionally advanced disease (UICC/AJCC 1987, N2–3, M0) [137]. After a median follow-up time of 77 months (range 53–94 months), the 4-year OS and DFS rates were 66% and 60%, respectively.

Only 63% and 55% of patients in the Intergroup study completed the concurrent and adjuvant chemotherapy, respectively [89]. As discussed in the section of altered fractionation, split-course radiotherapy with a rest period is well tolerated. A regimen of induction chemotherapy with three courses of epirubicin 90 mg m^-2 on day 1 and cisplatin, 40 mg m^-2 on days 1 and 2, every 3 weeks was reported [138]. This was followed by three courses of cisplatin, 20 mg m^-2 per day on days 1–4 and fluorouracil, 200 mg m^-2 per day on days 1–4, iv bolus, (weeks 1 4 and 7) alternated to three courses of radiation (weeks 2–3, 5–6, and 8–10), with a single daily fractionation. All the patients but one had the planned number of chemotherapy courses in the alternating phase and all received the planned radiation dose. The 3-year actuarial progression-free survival and OS rates were 64% and 83%, respectively.

A phase II study in Singapore used 66–70 Gy with cisplatin 25 mg m^-2 on days 1–4 given by infusion over 6–8 h daily on weeks 1, 4 and 7 of the ERT [139]. This was followed by a further three cycles of adjuvant chemotherapy starting at week 11 from the first dose of radiation, cisplatin 20 mg m^-2 per day and 5-fluorouracil 1 gm m^-2 per day on days 1–4 every 28 days. The relative dose intensity of cisplatin and 5-fluorouracil of greater than 0.8 was achieved in 58% concurrent and 60% adjuvant chemotherapy patients.

The role of concomitant chemotherapy and radiotherapy has been explored for stage II NPC as well. Cheng of Taiwan treated 32 stage II (UICC/AJCC 1997) patients with cisplatin, 5-fluorouracil and 70 Gy per 35 fractions per 7 weeks of radiotherapy [140]. All 11 stage I and 1 stage II, patients had radiotherapy alone. The 3-year DFS was 96.9% vs 91.7% (p=0.66) for the radiotherapy group vs the chemoradiotherapy group. This shows that stage II, with a greater tumour burden, can achieve similar DFS with chemotherapy compared with stage I patients treated with radiotherapy alone.

Ongoing trials include a randomized study of concurrent chemotherapy and radiotherapy vs radiotherapy alone in the Prince of Wales Hospital, Hong Kong. It finished accrual in 2001. Lee in Hong Kong and Chua in Singapore are independently conducting concurrent and adjuvant chemoradiotherapy trials.

To conclude, there is increasing evidence in the Western world that concurrent chemotherapy and radiotherapy improves survival, although it needs to be proven in Asia. Induction chemotherapy is less effective. The commonly quoted large series with good results, using modern staging and chemotherapy are listed in Tables 18 and 19 [89, 92, 124–130, 135, 136, 140–142].

Radical surgery was reported on 20 patients in the series from Prince of Wales Hospital, Hong Kong [106]. Patients were selected for radical surgery rather than high dose re-irradiation based on the following criteria. (a) Patients must have satisfactory cardiopulmonary status for the surgery; (b) the tumour must be resectable, thus excluding tumours with extensive skull base infiltration and/or cranial nerve palsy; (c) the presence of cervical nodal disease in addition to the nasopharyngeal tumour rendered surgery a better treatment option because re-irradiation of the neck was too morbid to be justified; and (d) a short disease-free interval of less than 1 year between primary radiotherapy and local±regional failure was believed to be a sign of intrinsic tumour radioresistance and also may have severe acute radiation toxicities, and so it constituted a relative indication for radical surgery. At 2 years, freedom from further relapse was approximately 45% of the 20 nasopharyngectomy patients vs 20% of the 103 radical re-irradiation patients [106].

Restricting the comparison to rT1 and rT2 patients, nasopharyngectomy still had a result superior to re-irradiation. This could not be explained by stage or performance status [106]. Teo considered that although surgery was associated with soft tissue fibrosis (after radical neck dissection) and trismus, its late complications were, in general, less morbid than re-irradiation complications. Thus, for the fit patient with resectable local failures (mainly rT1 and rT2), nasopharyngectomy should be preferred to high dose re-irradiation.

Future research may focus on the role of adjunctive external radiotherapy, brachytherapy and chemotherapy after nasopharyngectomy when residual tumour is likely to remain.

Clinical trials
The information in this section cannot be considered complete since there may be other ongoing single or multi-institutional trials. Also, owing to publication bias, many trials may not be reported. However, listing the following 10 trials in this section may help the reader to link future published findings to our existing knowledge of NPC.

• Dana-Farber Cancer Insitute (DFCI)-99132, National Cancer Institute (NCI)-G99-1631, RP-DFCI-99132. Phase II study of docetaxel, cisplatin, fluorouracil and leucovorin calcium in patients with carcinoma of the nasopharynx. Trial closed.
  
• European Organisation for Research and Treatment of Cancer (EORTC)-24761-NPC-1, UICC-77055. Long-term cyclophosphamide chemotherapy following radiotherapy for advanced nasopharyngeal carcinoma. Trial closed.
  
• EORTC-24761-NPC-2, UICC-77056. Adriamycin chemotherapy, alone or combined with vinblastine/bleomycin, for metastatic carcinoma of the nasopharynx. Trial closed.
  
• EORTC-24863. Phase II study of chemotherapy with adriamycin/lomustine in patients with recurrent or metastatic nasopharyngeal carcinoma. Trial closed.
  
• EORTC-24881. Phase II study of cisplatin/epirubicin in patients with advanced nasopharyngeal carcinoma. Trial closed.
  
• Memorial Sloan–Kettering Cancer Centre (MSKCC)-91023, NCI-V91-0118. Phase I study of three-dimensional conformal radiotherapy in patients with locally advanced (T3 and T4) carcinoma of the nasopharynx. Trial closed.
  
• National Cancer Institute of Canada (NCIC)-HN3. A comparison of acute oral mucosities between morning and afternoon radiotherapy in patients receiving radiation treatment of the head and neck. Trial still open.
  
• National Medical Research Council, Singapore (NMRC)-SQNP01, EU-98047. Phase III randomized study of radiotherapy alone vs concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with previously untreated, locally advanced, non-metastatic nasopharyngeal cancer. Trial still open.
  
• Pediatric Oncology Group (POG)-9486. Phase II study of methotrexate/cisplatin/5-fluorouracil followed by radiotherapy for stage III/IV disease and of radiotherapy alone for stage I/II disease in children with nasopharyngeal carcinoma. Trial closed.
  
• Radiation Therapy Oncology Group (RTOG)-9505. Evaluation of tumour angiogenesis measured with microvessel density (MVD) as a prognostic indicator in nasopharyngeal carcinoma. Trial closed.
  

Treatment complications
The experience of chemotherapy is still limited and requires longer follow-up. Complications are largely owing to effects of bone marrow suppression, hearing loss and renal impairment from cisplatin based chemotherapy. Theoretically, as a radiosensitizer, chemotherapy also potentially accentuates the complications of radiotherapy.

Complications of radiotherapy are well documented. Xerostomia is the most common chronic side effect. Dysphagia can be owing to tumour recurrence, xerostomia, loss of gag reflex, and muscular incoordination [147]. Hearing loss can be owing to tumour invasion or mixed conductive and neurosensory problems, such as effusion in the middle ear [148].

Impaired cognitive function has been documented [149, 150]. A comprehensive neuropsychological battery was administered to 53 patients with nasopharyngeal carcinoma who had completed their radiotherapy at least 1 year previously in the Chinese University of Hong Kong [150]. As evidenced by MRI, 31 patients developed necrosis after treatment. A total of 31 age-matched and education-matched individuals were recruited as normal control subjects. Whereas the performance of patients without temporal lobe necrosis was similar to that of normal control subjects, patients with temporal lobe necrosis demonstrated significant impairment on tests of verbal ability (p<0.001), visual memory (range, p<0.001 to p=0.03), language (range, p<0.001 to p=0.01), motor ability (p=0.02), planning (p=0.02), cognitive ability (p=0.007) and abstract thinking (range, p=0.009 to p=0.04).

With temporal lobe necrosis, the potential of anaerobic infection from the necrotic mucosa, and bony defects between the brain and paranasal sinuses, brain abscesses can develop [151].

Radiation-induced malignancies documented in the literature include glioblastoma, sarcoma and carcinoma of the tongue [152, 153]. Obviously, malignancies developing within the radiation field can be radiation induced or coincidental. A series from Queen Mary Hospital, Hong Kong does not find any significant association between other malignancies with NPC [154]. The nasopharynx is distinct from other head and neck sites in that there is no field effect or increased rate of second head and neck primaries. Table 20 lists documented complications in the literature.

The high morbidity of patients treated for a nasopharyngeal cancer compared with other head and neck cancer, as reported by a EORTC QLQ-C30 core questionnaire [158], may be explained by the location of the target volume which included the bilateral temporo-mandibular joints and the salivary glands.

Probably the major improvement is in the prevention of xerostomia by the use of pilocarpine and conformal radiotherapy to decrease the dose to the salivary glands [157]. A prospective study is currently underway at the Mallinckrodt Institute of Radiology, St Louis to address the optimal parotid dose-volume with IMRT.

Future directions
From the above discussion, early diagnosis, adequate radiation dose to the primary with boost to any bulky disease and frequent follow-up with biopsy of any suspicious residual or recurrent disease will become the key methods to improve outcome.

The International Commission on Radiation Units and Measurements' reports 50 and 62 were introduced in 1993 and 1999, respectively, to guide prescription, recording and reporting of photon beam therapy [162, 163]. As 3D CT planning is increasingly used, attention should be paid to details like set-up margins, since patients may lose weight with chemo-radiation. Planning target volume uncertainty is partly related to unpredictable submucosal spread of the primary tumour. The dose to organs at risk, e.g. optic nerve, optic chiasm, brainstem, spinal cord and temporal lobes, should be determined. A clear reporting of total dose, dose per fraction and target volume dose variation in all scientific publications of nasopharyngeal cancer would enhance future communications to improve its treatment.

Apart from direct/indirect nasopharyngoscopy, the role of follow-up CT and/or MR scan needs to be studied for the assessment of early detection of residual or recurrent disease. Follow-up CT and/or MR scan may show asymmetry of the nasopharynx (Figure 15). This has to be correlated with other clinical findings and direct/indirect nasopharyngoscopy. Generally, biopsy is performed and, if negative, a stable asymmetry may be observed provided there are no new clinical findings on follow-up.

View larger version (122K): [in this window] [in a new window]   Figure 15. Follow-up CT scan may show asymmetry of the nasopharynx. This has to be correlated with other clinical findings and direct/indirect nasopharyngoscopy.

Finally, it is emphasized that more trials on chemo-radiation are required to examine the optimum chemotherapy doses and agents, in combination with the optimal radiotherapy techniques and quality assurance, to achieve better treatment results, including improved quality of life for NPC patients.

Received for publication August 20, 2001. Revision received December 4, 2001. Accepted for publication January 17, 2002.

	References

Top Abstract Introduction Historical era (1896-1950) Transitional era (1951-1970) Modern era (1971-2000) References

 

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