British Journal of Radiology 75 (2002),307-339 © 2002 The British Institute of Radiology
Nasopharyngeal carcinoma: treatments and outcomes in the 20th century
R F Mould, MSc, PhD1 and
T H P Tai, FRCR, FRCPC2
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
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Abstract
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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.
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Introduction
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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.
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Historical era (1896–1950)
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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.
Brachytherapy for NPC continues into the 21st century and, for example, in southern China, which has the highest incidence of NPC, the intracavitary method pioneered at the Institut du Radium 80 years ago continues in modified form. Today, CT and MRI are used for planning and moulage applicators are made individually (Figure 2). Brachytherapy is regularly used for cases with small primary T1–T2, N0–N3 tumours of thickness below 10 mm, with radium now replaced by remote afterloading 192Iridium. It is combined with external radiotherapy to total doses in the range 76–84 Gy and also with chemotherapy [31].
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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].
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X-ray therapy and teleradium (1921–1950)
Treatment techniques using several small fields, 200 kV X-rays or short source skin disease teleradium were common throughout the 1930s and 1940s with the Coutard, Paris method being the delivery over a 6–8 week period and the Radiumhemmet, Stockholm method delivering two 2-week external courses with an intracavitary radium application between the courses. In 1931 the Radiumhemmet results were quoted as a 5-year survival rate of 11.4% in 70 cases [27, 32]. In this period, such 5-year survival rate statements did not properly take into account losses to follow-up, or use an actuarial life-table method. Instead they quoted only a simple ratio of number of cases surviving/total number of cases treated. Another example of a 5-year outcome during this time is from the Mayo Clinic, reporting survival in 15.6% of 32 NPC patients presenting without neck metastases [33]. 5-year survival rates reviewed for six series in 1960 [34], and also calculated as simple fractions, were in the range 14.3–33.3% for total numbers of patients treated in the range 39–87. The six centres were: UCSF, San Francisco; Memorial, New York; Presbyterian & Montefiore, New York; Lahey Clinic, Boston; Middlesex Hospital, London; and the Radium Center, Copenhagen.
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.
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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.
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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].
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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].
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Graphical presentation of the measurement of skin erythema for these cases (Figure 5) is not too surprising because the use of biological effects (as distinct from chemical and physical effects, the latter including ionization) as the basis of proposals for units of measurement had been made for 30 years, between 1904 and 1934 [15]. The most well known of the biological units was the skin erythema dose (SED), which was used independently for both X-rays and radium for many years. In the 1930s the generally accepted equality of 1 SED=500 roentgen was used. The tolerance of skin to radiation was the limiting factor in determining the fractionation of the radiation dose. Table 1 is a 1936 attempt to relate total dose to daily single fractional dose [36]. That dose-fractionation was important had been recognized much earlier, notably by Colwell and Russ in 1915 at the Middlesex Hospital, London [37], and by Regaud in 1922 at the Institut du Radium, Paris [38]. In fact, the MRC study [35] was only one in a long series of radiological studies that extends to the present day.
Symptom-free outcome
The above section shows that by 1950 a more scientific approach was starting to be taken towards specifying treatment results in terms of survival and outcome. This was to continue and with the advent of 60Cobalt teletherapy was to significantly improve the prognosis of later NPC patients. Finally, Table 2 completes this historical era review by presenting a literature survey [32] for papers published between 1931 and 1944 that summarise treatment outcome in terms of the percentage of symptom-free NPC cases. It is also interesting to note that Hayes Martin, the first author of the Memorial Hospital, New York series was an oncological plastic surgeon, thus illustrating the existence of multidisciplinary teams from the early years.
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Table 2. Results of a world literature survey after Godtfredsen [32] tabulating "freedom from symptoms for five years or more", which the author equates to "five year cure rates". The number of cases in this material "comprise all cases followed and treated scientifically, by which the figures indicating the results become maximum figures"
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Transitional era (1951–1970)
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This period saw the widespread introduction of 60Cobalt teletherapy, which marked the real start of megavoltage radiotherapy. Earlier, a very few van de Graaf machines operating at 2 MV had been installed in radiotherapy departments and by 1970 linear accelerators had begun to be installed in several major centres throughout the world. However, these had not yet begun to generally replace the use of 60Cobalt teletherapy in the industrialized world. It must be remarked that, even at the start of the 21st century, telecobalt still has a role to play in developing countries where the infrastructure for maintenance of the technologically more complicated linear accelerators is virtually non-existent. This is seen in the current market for refurbished telecobalt machines.
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.
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Table 3. Results of a world literature survey after Rosemarie Albrecht of the Head & Neck Clinic,Jena, former German Democratic Republic [41]
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Elective neck irradiation
Douglas Quick of Memorial Hospital, New York was, in the 1920s, one of the first to suggest that radiotherapy could be used electively for possible subclinical disease, particularly for cancers of the buccal cavity and the lip [42, 43]. However, the external beam radiation machines then available were not able to deliver an adequate dose distribution to the lymph nodes of the neck; only relatively small sized fields were initially available and the depth dose characteristics were not optimal.
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.
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Figure 6. Schematic diagram of seven telecobalt treatment fieldpositions and shapes, including shielding blocks, for a typical 1960s two-phase treatment [5].
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Brachytherapy
By the 1950s and 1960s it had been realised that NPC, either primary, recurrent or residual disease, could be treated by intracavitary or interstitial brachytherapy. It was really only in Paris that the moulage method pioneered by Richard and Pierquin in the 1920s [12] continued to be routinely used, although patient numbers were small. For example, Mazeron [12] reported in 1987 that, for the years 1961–1975, a total of only 33 previously untreated NPC cases were treated by a combination of external beam therapy and intracavitary brachytherapy with 192Iridium wires.
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.
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Modern era (1971–2000)
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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).
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Table 4. Mean annual crude (CR) and age-standardized incidence (ASR) rates for nasopharyngeal carcinoma per 100 000 males or females for selected populations: data from [52]
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TNM staging systems: Ho and the UICC/AJCC
The series of NPC patients treated by John Ho over a large number of years at the Queen Elizabeth Hospital, Hong Kong forms the largest series of cases in the world [53–55]. In addition, Ho designed the staging system [11, 56, 57] still used throughout Hong Kong and elsewhere Table 5 [9]. It should be noted, however, that the UICC/AJCC system [10, 58] defines the T, N and M stages differently from that of Ho (Tables 6 and 7) [6, 7, 10, 59, 60].
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Table 5. Ho's staging system for nasopharyngeal carcinoma, classifying the apparent extent of the disease as a whole (I–V) and proposed as a guide to prognosis and treatment together with Ho's original T1–T3 and N0–N3 staging [9]
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Table 6(a) International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) recommendations for T and M staging, 1978, 1983, 1988, 1992 [6, 7, 10, 59]
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Table 7(a) N0–N3 staging according to the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) system, 1978 [59]
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In the old AJCC or UICC classification [10, 58, 59] T1 was defined as tumour confined to one subsite or region, and T2 to two subsites or regions. Ho felt that the limits of the primary tumour within the nasopharynx are not easy to ascertain. Furthermore, a carcinoma may extend submucosally and not be readily visible. Ho combined all tumours confined to the nasopharynx into T1, disregarding the subsites. This is compatible with the observation that the prognosis of the AJCC or UICC T1 and T2 are the same [61].
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.
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Table 8b 5-year actuarial survival by T stage from MD Anderson Cancer Center, 1954–1977. UICC/AJCC 1978 staging was used [71]
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The interpretation of data for T stage is easier than N stage, since there was no change in classification over the years before 1997 (Table 9).
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.
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Table 10. Actuarial disease-free survival rates by N stage after Lee et al [56] for a series of 4730 cases treated between 1976 and 1985. Cases were originally defined using the Ho system and then later re-staged using International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) 1988 stage
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For comparison with the 5-year local control rates from the Hong Kong results in Table 10, those from two American series are given in Table 11 [71, 73]. The numbers involved are far fewer than the 4730 from Hong Kong, and other parameters are not identical. It cannot therefore be concluded from Table 11 that the American results are superior to those of Hong Kong, whereas in Table 12 [56, 70, 74, 75] most of the American results fall within the range of the Hong Kong results. These tables are included in this review because there is very little in the literature on outcome as a function of NPC nodal status and therefore this data can be considered to be a best estimate.
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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
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WHO pathological classification
The WHO classification [76] is based on the degree of differentiation (Table 13) with the so-called lymphoepitheliomas as part of the unclassified group Type 3. The distribution of WHO histopathological types varies with geography. For Chinese populations the incidence of Type 1 has been recorded as only 0.3% in a review of 5037 cases in southern China, and as 3% in Hong Kong [77, 78]. In North America the incidence of type 1 is some 20% [78]. Type 2 incidence is similar for Hong Kong and North America at approximately 10% [78].
It has also been stated that "the distinctions among the three types are by no means sharp" [78], as there are similarities in epidemiology, serology, clinical features and natural history between the two latter WHO groups. It has also been suggested that NPC should be divided into two categories; squamous cell carcinoma and undifferentiated carcinoma of nasopharyngeal type (UCNT) [79]. Most of the non-keratinizing carcinomas (WHO Type 2) are to be found among UCNT. In other words, "the classification may be reduced to two, 1 and a combined 2+3, for clinical and prognostic purposes" [80].
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.
In a study from Hong Kong on stage I patients between 1969 and 1975, NPC was classified into two major types: undifferentiated carcinoma (102 of 137 cases) and squamous cell carcinoma (35 of 137 cases) [82]. The former was further divided into four sub-types: lymphoepithelioma of the Schmincke type (10 of 102 cases), lymphoepithelioma of the Regaud type (46 of 102 cases), spindle cell carcinoma (26 of 102 cases) and UCNT (20 of 102 cases). None of this histological typing was of value in predicting the clinical outcome. Overall survival was 75% vs 77% for undifferentiated carcinoma and squamous cell carcinoma, respectively. One explanation for this is the small sample size. Another possibility is that these results are for stage I patients only.
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.
External beam radiotherapy for primary NPC
The main modality of treatment for primary NPC is radiotherapy, although chemotherapy may have a role in advanced stage, i.e. III and IV (UICC/AJCC 1988). Surgery is not used as a primary treatment option because of anatomical difficulty, and only a few centres in the world have experience with nasopharyngectomy. Radiation treatment planning for NPC is complicated owing to the frequent spread of disease to the parapharyngeal space and cavernous sinus. Proximity to the optic nerve and chiasm is another problem, as is the difficulty to junction the high neck node(s) and oropharyngeal disease with the nasopharyngeal primary whilst avoiding undue irradiation to the spinal cord. The air–tissue interface in the nasopharynx can potentially result in underdosing the surface of the nasopharyngeal tumour.
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].
Dose–response relationship
Fletcher made an important observation between the tumour control probability and radiation dose [45] and it was estimated that 50 Gy could control 60% of T1 lesions of the nasopharynx [85]. However, owing to the small size of series in the Western world, the dose–response relationship cannot be determined accurately. At the MD Anderson Cancer Centre, there was a 20% local failure rate, a 13% regional failure rate and a 29% distant metastases rate when dose delivered to the nasopharynx was 60 Gy for T1–2 and 70 Gy for T3–4. Since 1972 an additional 5–7.5 Gy boost had been delivered to the nasopharynx for T1–2 disease, resulting in the reduction of the local recurrence rate to 6% [67]. In Asia, although case series are big, staging investigations varied widely since some patients did not have CT or MR scans. In addition, many of the Asian series used hypofractionation to save resources.
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].
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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.)
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A set of normal classical Ho's NPC views is shown in Figures 8a–e and a set of abnormal NPC views in Figures 9a–e. CT and MR scans of another patient are shown in Figures 10 and 11 and demonstrate that both are complementary investigations that can be used to show intracranial extension and bone involvement. The advantages of MR scans are availability of coronal and sagittal views, and better differentiation of tumour from normal tissue using different scan settings.
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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.
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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.
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Modern radiotherapy has also evolved from skin marks to different immobilization devices, e.g. cobex shell, aquaplast and stereotactic frames. Instead of front and back pointers, lasers from the wall and machine are used for positioning of the patient.
Modern 3D treatment planning is another way of dose escalation and also of sparing the normal tissue in a spatial manner (Figures 12–13).
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Figure 12. Three-dimensional representation of patient contour, with critical structures outlined: spinal cord and eyes.
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Figure 13. Three-dimensional radiotherapy planning for a tumour that extends from the nasopharynx to the nasal fossa.
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Ho's radiotherapy technique is unique in that non-coplanar fields are used. Doses were manually calculated in the earlier days and any air inhomogeneities for anterior fields are difficult to take into account. 3D treatment planning is also useful for the changing contour and oblique fields as shown in Figure 14, which illustrates the technique used in Hong Kong to boost the parapharyngeal space. The patient's neck is turned to one side, slightly extended, and skin marks are made to delineate the field.
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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.
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In the 1990s IMRT has been delivered using one of the following three techniques: (a) manually cut partial transmission blocks; (b) computer controlled auto-sequencing static multileaf collimator (MLC); and (c) Peacock system using a dynamic multivane intensity-modulating collimator (MIMiC). A forward 3D treatment planning system was used for the first two methods and an inverse treatment planning system was used for the third method [97]. One definite advantage of IMRT is the ability to avoid the spinal cord and parotid gland. In the best achievable plan of a cohort from Mallinckrodt Institute of Radiology, only 27%±8% of parotid gland volumes were treated to more than 30 Gy, whilst an average of 3.3%±0.6% of the target volume received less than 95% of the prescribed dose [98].
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].
The incidence of severe complications was related to the total cumulative dose of external beam irradiation; 4% for patients receiving doses less than or equal to 100 Gy compared with 39% for those patients who received doses greater than 100 Gy (p=0.066) [104]. The recommendation is an additional salvage 20–30 Gy in 10–15 fractions to the nasopharynx, to limit the total dose of external irradiation to less than 100 Gy. Intracavitary brachytherapy is then used to deliver an additional 40–50 Gy to the surface of the recurrent cancer. Interstitial placement of needles or seeds into recurrent tumours in the roof of the nasopharynx is often preferable to use of a paediatric endotracheal tube as this has a tendency to rest on the soft palate down away from the tumour. The above recommendation to add a brachytherapy boost of 40–50 Gy agrees with the results from Wang [103], and Yan et al [105]; overall survival is better with total salvage dose of 60 Gy or more by ERT plus brachytherapy.
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).
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Abstract
Introduction
