PET–CT functional imaging

Diagnostic imaging has witnessed enormous changes in the past twenty years. Notably, the introduction of CT scanners and virtual simulation have supported the development of 3D conformal radiotherapy (3DCRT) and fundamentally changed radiotherapy practice.Reference Aird and Conway⁵

Despite these advances, Carey argues that there is still no reliable imaging method to distinguish those cancers that are ‘biologically aggressive from those that may have a more indolent clinical course’.Reference Carey⁶ This, surely, remains the challenge for imaging technology.

For the detection of metabolic as well as morphological changes, magnetic resonance spectroscopy (MRS) has been suggested.Reference Kurhanewicz, Vigneron, Hricak, Narayan, Carroll and Nelson^7,Reference Mizowaki, Cohen, Fung and Zaider⁸

Internationally, however, it is the emergence of PET–CT that is significantly advancing functional imaging. The UK National Cancer Research Institute believes its future contribution will influence treatment management and advance our understanding of cancer mechanisms.⁹

PET–CT’s contribution is, perhaps, most notable in the diagnosis and treatment of lung cancers. ErdiReference Erdi, Rosenzweig and Erdi¹⁰ argued that the incorporation of PET–CT fused images improved tumour definition, reduced geographical misses and improved local control. RuysscherReference De Ruysscher, Wanders and Minken¹¹ supports these findings, arguing that the use of combined PET–CT enables significant dose escalation while preserving normal-tissue complications. NICE¹² recommends that all lung patients eligible for radical radiotherapy should have a PET–CT scan.

It is not just in lung cancer where PET–CT is making an impact. HeronReference Heron, Gerszten and Selvaraj¹³ reviews PET–CT’s use across a variety of tumour sites. Some key findings are summarized in Table 1. HeronReference Heron, Gerszten and Selvaraj¹³ argues that these developments within PET–CT functional imaging, combined with advances in molecular and genetic science, will enable image-guided radiotherapy to advance.

Table 1. PET–CT: a review of the current evidenceReference Heron, Gerszten and Selvaraj¹³

The impact of PET–CT in the UK is less advanced. Postcode lotteries remain. At present, there are only approximately 15 PET–CT scanners in the UK, mostly located around London. Access to PET–CT imaging technology is hampered both by capital costs, estimated at approximately £1.5 million per scanner,Reference Metherall¹⁴ and geographical access to a cyclotron, owing to the rapid half-life of the FDG-18 isotope.Reference Kumar and Jana^15,Reference Griffiths¹⁶

IMRT and tomotherapy

The development of increasingly conformal treatments has seen the emergence of IMRT. These precise treatment techniques are being assisted by more robust planning algorithms, such as the Monte Carlo algorithm.Reference Solberg, DeMarco, Holly, Smathers and DeSalles¹⁷

Inverse-planning systems are being developed, supporting IMRT implementation, optimizing treatment accuracy and integrating volumetric imaging into on-line validation of treatments.Reference Budgell¹⁸

BeavisReference Beavis¹⁹ describes the emergence of helical tomotherapy, arguing that this represents the future of IMRT. KupelianReference Kupelian, Ramsey, Meeks, Willoughby, Forbes, Wagner and Langen²⁰ believes developments within tomotherapy and serial megavoltage CT imaging will enable PTVs to be monitored during treatment and to be further reduced through tumour shrinkage. SuitReference Suit²¹ concurs, describing a fourth-dimensional planning stage, namely time, whereby tumour motion and shrinkage are corrected on-line during treatment and updated throughout the patient’s course of radiotherapy.

Concerns, however, have been raised with integral dose levels. Hall and WuuReference Hall and Wuu²² warn of the risk in secondary radiation-induced carcinomas as a result of increased integral doses from the multiple field arrangements used with IMRT treatment techniques. Similarly, MuticReference Mutic and Low²³ reports an increase in whole-body dose equivalent using tomotherapy treatments, with consequent possible increases in radiation-induced fatalities.

Access to tomotherapy units within the UK remains very limited. Interestingly, though, the Cromwell Hospital in London has recently announced its intention to migrate entirely to this technology, with a second tomotherapy unit having been commissioned in Summer 2006.²⁴

Hadron therapy

Hadron therapy, using protons, neutrons and light ions to treat complex and advanced tumours, is attracting increasing interest. Charged hadrons have a much more defined distribution of dose at depth, characterized by their Bragg Peak, which is high and narrow because of their monoenergic release of the highest dose towards the end of their energy range.Reference Orecchia²⁵

In a keynote lecture on the future of radiotherapy in the twenty-first century, SuitReference Suit²¹ argued that proton beams are likely to replace photon beams in the next 20–30 years owing to their superior physical characteristics. Certainly, several reports demonstrate much higher levels of conformality and avoidance of normal tissue than is possible using even the most sophisticated IMRT techniques.Reference Suit^21,Reference Orecchia^25,Reference Jones and Burnet²⁶

Worldwide, there are relatively few hadron facilities operational. To date, clinical studies have been limited to phase-I and phase-II trials.Reference Jones and Burnet²⁶ Clinical results do appear impressive, as demonstrated in Table 2. However, some of these studies remain unpublished. LennoxReference Lennox²⁷ is perhaps more cautious than Suit,Reference Suit²¹ arguing that there is not yet enough long-term experience, derived properly through randomized clinical trials, to demonstrate the superiority of hadron treatment.

Table 2. Advantages of hadron therapy: a review of the current evidenceReference Suit²¹

Any belief that protons will replace the photon plays down the practical obstacles to their implementation – notably, the costs associated with commissioning such centres. SuitReference Suit²¹ argues that history demonstrates that ‘perceived efficacy and not the cost primarily determine the fate of new technology’. As I argue later, such a view is unlikely to find favour within the context of current NHS funding constraints.

The costs of commissioning a hadron facility are considerable. Goitein and JermannReference Goitein and Jermann²⁸ estimate them to be 2.4 times the costs of photon treatments, but argue that they will reduce over the next 10 years. Costs could be reduced further if treatments were offered over longer hours, or over shorter fractionation regimes.Reference Goitein and Jermann²⁸

There are other, indirect practicalities to be considered. A hadron facility requires a significant amount of space, precluding building within many current hospital sites. Moreover, as these accelerators are served from a single energy source, if the cyclotron develops problems, this will halt all treatments within the facility.Reference Goitein and Jermann²⁸

Jones and BurnetReference Jones and Burnet²⁶ argue strongly for the presence of a hadron facility within the UK. It is noteworthy that their demands are being considered as part of the current ‘radiotherapy stock-take’ exercise.Reference Beardmore²⁹

Pharmaceutical research and the emergence of pharmacogenomics

Systemic treatment has developed during the past 20 years as an integral element of cancer management. With lung cancer, for example, chemotherapy advances have been cited as improving response rates, although these have since largely plateaued.Reference Chua, Steer and Yip³⁰ Similarly, with breast cancer, the use of both chemotherapy drugs and hormone treatments, such as tamoxifen, are now recommended for early-stage treatment.³¹ However, progress has been slow, steady and very costly, with clinical outcomes rarely achieving those purported by their manufacturers.

Current pharmaceutical research is focusing on developing new strategies within genetic and biological oncology. Pharmacogenomics is emerging to develop drugs that are ‘personalized’ to a specific patient’s genetic profile.Reference Ginsburg and McCarthy³² For many cancers, critical proteins affecting tumour growth are now being targeted using monoclonal antibodies.

Such developments, of course, bring added cost pressures. The annual NHS drugs bill is estimated at £7 billion, with the UK pharmaceutical industry being cited as the third most profitable economic activity.³³ However, conflicts exist between the interests of the NHS, patients and the pharmaceutical industry.

Recent reports regarding the benefits and funding of the monoclonal antibody Herceptin (trastuzumab) provide an interesting illustration of this conflict.

Two studies demonstrated benefits from Herceptin for early-stage breast cancer.Reference Piccart-Gebhart, Procter and Leyland-Jones^34,Reference Romond, Perez and Bryant³⁵ An editorial, commenting on these studies, described their results as ‘simply stunning … and revolutionary’, suggesting ‘maybe even a cure’.Reference Hortobagyi³⁶

Unsurprisingly, this editorial sparked media attention, with international demands for Herceptin. Within the UK, NICE and the Department of Health both experienced pressure to license and fund the drug.

The Lancet highlighted several flaws in the research, notably merged clinical trial data, a lack of overall and disease-free survival data and no analysis of cardiotoxicity.³⁷ The Lancet concluded that the evidence for Herceptin in early-stage breast cancer remained unclear and argued that bodies such as NICE should be allowed to consider their decisions properly on the basis of clinical evidence. MossReference Moss³⁸ concurred, arguing that the evidence presented suggested only modest improvements for a minority of early-stage patients. Interestingly, Moss also highlighted a potential conflict of interest, with Dr. Hortobagyi also being a paid consultant for the leading US distributor of this drug.Reference Moss³⁸

Consequently, within the UK, in addition to recommending increased funding for NICE to enable more timely analysis of new drugs, the Health Committee also recommends that professional bodies declare their members’ interests through a public register.³³

Health care rationing: what can the NHS afford to buy?

The NHS Cancer Plan established a 10-year strategy to improve cancer care and treatment outcomes in the UK.¹ Since then, significant additional investment has been directed towards cancer services, as highlighted in Table 3.

Table 3. Additional NHS investment in UK cancer services (£millions)⁷⁶

A review of progress indicated that mortality rate predictions for the under 75’s are slightly ahead of schedule to meet the 20% reduction target by 2010.⁴⁰ The National Audit Office further supported this analysis in its report on progress against the Cancer Plan targets.⁴¹ Both these reports have received criticism for too optimistic an analysis.

Sikora argues that the UK still lags behind most other countries in Europe and the USA in its cancer services, believing the answer is to introduce a more pluralist solution, with the private sector competing with the NHS to deliver cancer services.Reference Sikora, Slevin and Bosanquet⁴² Although this view is seen by some as controversial, there is speculation that such options may be supported as part of the current National Radiotherapy Advisory Group’s (NRAG’s) ‘radiotherapy stock-take’.Reference Revill⁴³

Such funding debates do highlight wider health economics questions concerning what NHS services the UK can now afford to provide. The twenty-first century NHS is a vastly different institution from that envisaged back at its inception in 1948. The pace of medical advances since then means we do need to revisit properly the notion of a health care service free at the point of delivery for all. Not all scientific advances can be afforded and, consequently, choices will have to be made.

Against a backdrop of significant government investment, and in the absence of such an explicit debate, there has been much media attention to the latest NHS funding crisis and redundancies. Some radiography departments have already experienced redundancies, and included amongst these have been reductions in therapy radiographer establishments.Reference Carvel^44,Reference Kelly⁴⁵

Health care funding pressures are not unique to the UK. Schueren argues they are common across most Western countries, and that, as a consequence, explicit health economics choices now need to be made.Reference Schueren, Kesteloot and Cleemput⁴⁶

Future investment and advances in cancer therapy, therefore, need to be considered in the context of this more explicit health care rationing debate. Without such a debate, there is a very real danger that many of the current capital investment programmes under way within cancer services across the UK will instead be attacked in media headlines, alluded to by critics such as Sikora, citing wastage of taxpayers’ money owing to a failure to invest properly in the revenue, as well as the capital, consequences of such developments.Reference Sikora, Slevin and Bosanquet⁴²

The need to reduce waiting times for cancer treatment

In addition to these economic pressures, increasing waiting times represent challenges to improving treatment outcomes.

The Cancer Plan established two specific targets to be met by December 2005.¹ Nationally, neither target has been achieved (Table 4). Meeting these targets has been described as ‘an enormous challenge’. Failure to achieve waiting times is largely attributable to the national shortage of therapy radiographers, which, despite investment, will take time to resolve.⁴⁰

Table 4. Progress towards the 2005 waiting time targets⁴⁰

A UK audit of radiotherapy centres, however, suggests waiting times have risen. Reasons cited are a combination of increased patient numbers, insufficient equipment and increasingly complex treatments.Reference Ash, Barrett, Hinks and Squire⁴⁷

A number of studies have directly cited radiotherapy delays as having an adverse impact on treatment outcomes. O’Rourke and Edwards demonstrated that delays, in both referral and treatment, resulted in patients initially eligible for radical treatment having to be treated palliatively.Reference O’Rourke and Edwards⁴⁸

It would be wrong to presume that this is just a UK problem. International studies demonstrate similar problems.Reference Fortin, Bairati, Albert, Moore, Allard and Couture^49,Reference Waaijer, Terhaard, Dehnad, Hordijk, van Leeuwen, Raaymakers and Lagendijk⁵⁰ Both these studies cite similar reasons to those given by AshReference Ash, Barrett, Hinks and Squire⁴⁷ for these delays and demonstrate that such delays have an adverse impact on tumour control and treatment outcomes.Reference Fortin, Bairati, Albert, Moore, Allard and Couture^49,Reference Waaijer, Terhaard, Dehnad, Hordijk, van Leeuwen, Raaymakers and Lagendijk⁵⁰ Similarly, Huang et al. reported a three-fold increase in local recurrence for head and neck tumours when waiting times rose above six weeks.Reference Huang, Barbera, Brouwers, Browman and Mackillop⁵¹

In response to calls for a UK hadron facility,Reference Jones and Burnet²⁶ Dodwell and Crellin caution that such investment will merely divert scarce resources from tackling this larger problem of increased waiting times, thereby further adversely affecting outcomes. They argue that these strategic issues need to be addressed first.Reference Dodwell and Crellin⁵²

Equipment replacement and proper manpower planning

Despite the significant investment highlighted in Table 3, the Royal College of Radiologists argues that the benefits of much replacement equipment are being countered by the deteriorating age profile of existing stock. This also, through machine breakdown and unplanned treatment interruptions, affects treatment outcomes.⁵³Table 5 highlights the relative proportion of new and replacement equipment.⁴⁰

Table 5. Investment in UK cancer equipment⁴⁰

Furthermore, many departments are operating with significant vacancy levels such that they are unable to staff their normal working sessions at full capacity.⁵³ A UK audit of head and neck radiotherapy provision concurs. James et al. cite both ongoing shortages of radiotherapy and medical-physics staff and the need for further investment in equipment.Reference James, Robertson, Squire, Forbes, Jones and Cottier⁵⁴ More recently, Dodwell and Crellin have argued that, despite investments, staff shortages mean many radiotherapy centres are unable to cope with increasing workloads.Reference Dodwell and Crellin⁵²

Meanwhile, Sikora depicts an image of new linear accelerators ‘lying around in boxes’ within the NHS owing to the inability properly to fund the staff for their use.Reference Sikora, Slevin and Bosanquet⁴² Certainly, it has proved easier to secure capital investment, through programmes such as the New Opportunity Funds, than the revenue investment required to staff and run such machines on a ongoing basis.

Proper manpower planning for key staff groups within cancer services remains critical to future improvements in treatment outcomes. The attempt to address recruitment shortages with the introduction of the four-tier service has been one response. Initial reports, however, describe its implementation as haphazard and lacking uniformity.Reference Woodford⁵⁵

Expansion of radiotherapy training places offers a further solution. These are reported to have doubled since 2000, and attrition rates have also reduced.⁴¹ Beardmore, however, reports concerns that overall attrition rates remain at nearly one-third.Reference Beardmore²⁹ Surprisingly, attrition rate analyses seem to focus purely on student radiotherapists, with little research or comment made on attrition rates of experienced staff within the profession generally.

All the manpower planning effort towards expanding the number of therapy radiographers is, however, being countered by the present NHS implementation of the ‘Agenda for Change’ (AfC). It had been envisaged that this would establish a uniform national pay and conditions programme across the NHS for all staff groups. It fails, however, to recognize and accommodate those key staff groups where there are national shortages. Indeed, its implementation has meant that salaries for therapy radiographers and medical dosimetrists have fallen across all grades of staff nationally. This has happened despite the national shortage. In consequence, many UK radiotherapy centres’ expansion programmes are now being thwarted by high vacancy levels and inadequate staffing establishments.Reference Griffiths, Craig and Abraham⁵⁶

AfC has, in addition, been criticized for being locally interpreted, such that pay disparities persist across different grades of staff and between different radiotherapy centres. Consequently, some of those (foundation) hospitals that are able to, have chosen to drop the AfC pay and conditions structure in favour of pre-existing agreements.Reference Kelly⁵⁷

AfC is not conducive to attracting and retaining key staff in therapy radiography and medical dosimetry. For progress to be made towards the achievement of the NHS Cancer Plan targets, the national implementation of AfC among these staff groups needs urgent reconsideration.

Meeting increased capacity demands means continued investment in equipment and staffing. The Royal College of Radiologists argues for the need to plan accounting for future capacity requirements and not just for present-day requirements.⁵³

The Society of Radiographers published two position papers recently in an attempt to influence future workforce planning: one to establish initial baseline establishment requirements;⁵⁸ the other to define better the future role of the therapy radiographer.⁵⁹

There is much that the UK could learn from the approach taken in Australia in radiotherapy utilization modelling. Delaney et al.Reference Delaney, Barton, Jacob and Jalaludin⁶⁰ suggest a much more scientifically robust model to develop an evidence-based benchmark to measure the use of radiotherapy for specific cancers. Involving the country’s leading clinical oncologists and epidemiologists, an expert committee reviewed the evidence for specific cancers and compared the optimum rate of radiotherapy use with current radiotherapy utilization.

Delaney’s utilization model has now been used to map more than 23 of Australia’s major cancer sites, reviewing the evidence from more than 1,400 scientific papers in the process to advise the Australian government on demand for radiotherapy. With such a robust model, and the active involvement of the country’s leading clinicians, the Australian government could not ignore such advice and has already implemented most of the recommendations.Reference Griffiths, Craig and Abraham⁵⁶ Although it falls short of making specific recommendations on manpower planning, such a methodology could be extended to define more conclusively the current and future manpower requirements in cancer services.

Significantly, the NRAG has been established to undertake a ‘radiotherapy stock-take’ considering all aspects of planning and delivery of radiotherapy services, including equipment requirements, service delivery, workforce requirements and future developments.Reference Beardmore²⁹ These recommendations, expected to be published in 2007, are likely to have a major influence on the future strategic development of UK cancer therapy.

The impact of differing fractionation regimes

Increasingly complex treatments have already been cited here as contributory causes of rising waiting times.Reference Ash, Barrett, Hinks and Squire^47,Reference Fortin, Bairati, Albert, Moore, Allard and Couture^49,Reference Waaijer, Terhaard, Dehnad, Hordijk, van Leeuwen, Raaymakers and Lagendijk⁵⁰ In addition, combined equipment and staffing pressures, compounded by financial pressures, suggest that additional capacity must be identified to improve treatment outcomes. Within these increasingly complex treatments, the impact of the fractionation regimes adopted needs to be considered.

Ash reported a reduction in the number of fractions prescribed for palliative treatment, but this was offset by an increased fractionation for radical treatments.Reference Ash, Barrett, Hinks and Squire⁴⁷ Kirkbride believes these changes represent qualitative changes in radiotherapy practice that ultimately will improve outcomes.Reference Kirkbride, Roberts and Craig⁶¹ However, Kirkbride also argues that urgent consensus is required on fractionation regimes, highlighting that 85 different palliative fractionation regimes were reported as part of the audit undertaken by Ash.Reference Ash, Barrett, Hinks and Squire^47,Reference Kirkbride, Roberts and Craig⁶¹

Ongoing clinical trials, notably START, are investigating the optimum fractionation regime for breast treatments. Breast irradiation represents approximately 40% of the workload of UK radiotherapy departments.Reference Winfield, Deighton, Venables, Hoskin and Aird⁶² Given this, reductions in fractionation here as a result of such research could have a major impact on waiting times and, in consequence, treatment outcomes.Reference Probst and Griffiths⁶³

Bentzen argues that fractionation also needs to be considered from this more pragmatic, rather than radiobiological, viewpoint when looking at its impact on treatment outcomes.Reference Bentzen³⁹

To date, progress by the Royal College of Radiologists in agreeing clinical protocols to consolidate the number of different fractionation regimes has been slow. This slow progress may well also be hindering improvements in clinical outcomes. It is notable, therefore, that NRAG has also highlighted fractionation as one aspect to focus on in their future strategic recommendations.Reference Beardmore²⁹