British Journal of Radiology (2005) 78, S131-S137
© 2005 British Institute of Radiology
doi: 10.1259/bjr/22543935
Advances in chemoradiation therapy in rectal cancer: the impact of imaging
D Tait, MD, FRCP, FRCR
Department of Radiotherapy, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
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Introduction
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The vast modern speciality of oncology, clinical and medical, was borne out of the more mature parent discipline of radiology and its allied sciences. The infant radiotherapy service rapidly established its value in the care of cancer patients and was quick to adopt medical developments, which provided a systemic approach to complement local management with surgery and radiotherapy. Clinical and medical oncology are now major specialties, critically reliant on modern imaging, itself a much mutated descendant of radiology. The diversity and detail of imaging approaches makes modern diagnostic imaging almost as removed from parent radiology as oncology. Now, the two descendants meet as partners in the management of patients with rectal cancer and this relationship has been hugely facilitated by the establishment of multidisciplinary team meetings (MDTM).
Rectal cancer is an excellent example of the contribution of multi-modality therapy [1–3]. The role of the component modalities is now being extended so that whereas before, surgery and radiotherapy were mostly applied to the primary and systemic treatment employed for metastases, all modalities are now contributing to all stages of disease. A particularly obvious example of this is the application of surgery to metastatic disease, most commonly for liver metastases [4, 5], but also in the setting of lung disease [6, 7]. Conversely, chemotherapy is increasingly being used as part of the strategy for downstaging locally advanced primary tumours [8, 9].
Rectal cancer, like gastrointestinal (GI) malignancy in its entirety, was a "Cinderella" subject during the phases of marked oncology development in the 1960s and 1970s. The picture has changed over the past 15–20 years and there is now huge activity in this area. Advances have been adopted from both randomized trial evidence and also from technical work. In the former, most studies have concentrated on the adjuvant setting and investigated chemotherapy, radiotherapy or both, with there also being a large research effort directed at second and subsequent lines of chemotherapy as palliation for patients with relapsed disease. The Scandinavian groups have been particularly productive, in terms of addressing the role of radiotherapy in randomized trials and have put pre-operative radiotherapy high up on the international research agenda [10, 11]. This has progressed to a strategy of neoadjuvant treatment, comprising of induction chemotherapy and radiotherapy for locally advanced tumours. Technical advances in surgery and radiotherapy do not lend themselves so easily to assessment in randomized trials. However, there has been meticulous work on developing surgical technique and disseminating this information internationally, so that the standard of surgery has improved dramatically and total mesorectal excision (TME) has become the standard procedure [12, 13]. Radiotherapy advances have gained less prominence, but the gradual increase in sophistication, in terms of radiotherapy planning and exclusion of normal tissues, ought to make the delivery of radiotherapy safer, particularly in this multimodality setting with overlapping toxicities.
These advances in management of rectal cancer have been both facilitated and paralleled by developments in imaging. These are covered in another section of this edition, but it needs to be stressed that radiology research has allowed a fresh look at the management of rectal cancer in general, and is key to planning a treatment strategy for individual patients. Despite the ubiquitous influence of imaging on rectal cancer management, there are four main functions in the patient's pathway where this influence is very clear. These are staging, monitoring response to treatment, treatment precision and surveillance.
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Staging
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Staging continues to be a process in evolution as refinement in imaging allows better identification of disease status. In addition to the conventional staging mechanisms of clinical examination, endoscopy and barium enema, MRI and anorectal ultrasound now provide much more detail on the extent of the spread of the primary into the mesorectal fascia, the precise location of the tumour within the rectum and the relationship to the levator plate and sphincter muscles. In addition, MRI allows identification of lymph nodes within the pelvis and CT completes staging by assessing for metastatic disease. Positron emission tomography (PET) has not been systematically assessed as a staging tool for rectal cancer, but it is highly likely that it will have a role in detecting early metastatic disease in those patients at high risk for this. Mostly these approaches are complementary or supplementary, and allow us to define increasingly homogeneous patient groups. This is critical in research terms, so that assessment of new approaches can be managed and also so that comparisons can be made between different series, institutions and countries.
Assessment of primary tumour
The management of rectal cancer is also a process in evolution, with the introduction of induction/neoadjuvant strategies being one of the most fundamental changes. It is fortunate that in rectal cancer three main treatment modalities, surgery, chemotherapy and radiotherapy, are all effective and that this is the case has been established in many randomized trials. The development in staging techniques allows the better selection of patients to a particular treatment strategy. The first, most important, decision is whether or not the patient has metastatic disease, which will not be amenable to radical surgery. Once this has been established, it allows tumours to be allocated to either operable low risk, operable high risk or inoperable. On the basis of this, patients are likely to be offered primary surgery or a neoadjuvant strategy. Examples of MRI defined operable, operable but high risk and inoperable tumours are shown in Figure 1
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Figure 1. (a) MRI of a T2 N0 tumour deemed operable by MR appearance, with no poor prognostic features. (b) MRI of a bulky, circumferential, rectal cancer with features indicating invasion into the mesorectal fascia and close circumferential resection margins. (c) MRI appearance of locally advanced rectal cancer with extension of disease to the left pelvic side wall, making this an inoperable cancer.
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The MDTM provides a forum for the discussion of all newly diagnosed patients with rectal cancer, where the imaging, pathology and clinical features can be presented and the recommendation for the appropriate treatment strategy made. At these meetings, every patient has the benefit of the opinion of specialists from all diagnostic and treatment groups, prior to having the discussion about management with the clinical team that the patient has been referred to. This constitutes an enormous change in practice from the days when patients who were fit for surgery, in general medical terms, underwent a primary surgical procedure and were then referred to an oncologist for a further, isolated, opinion. Not only does the MDTM advantage individual patients, it also provides a forum for learning between the specialities and for the development of rapid and effective communications. The impact of the MDTM on clinical outcomes is very difficult to gauge and there will never be a randomized study to measure this. However, data from the colorectal MDTM at the Royal Marsden Hospital provide supporting evidence. When the MDTM was relatively newly established, there were still patients who underwent surgery alone without the benefit of discussion at this meeting. A comparison has been made between MDTM discussed and non-discussed patients during this early phase and has defined a group of 178 patients who went straight to surgery; 63 of these did so without pre-operative discussion and some of these patients also had no pre-operative MRI; 115 patients had both pre-operative MRI and MDTM discussion. In the latter group all patients had complete resection of tumour with histopathologically confirmed clear margins, whereas for the patients not discussed in this way 27% had incomplete surgical resection. These data indicate that MRI staging, with discussion at the MDTM, allows more appropriate allocation of patients to either a primary surgical approach or a neoadjuvant strategy [14].
Imaging metastatic disease
The increasingly aggressive approach to limited metastatic disease has had a positive impact on outcome. There are, of course, patients with multiple sites of metastases or multiple lesions within one organ, which make a radical approach unfeasible. Imaging is the major tool by which patients are identified for metastectomy, most commonly with disease in the liver, but also with pulmonary metastasis. There are a few patients who will have limited disease in both liver and lung and who are suitable for resection of both. Before embarking on these procedures, it is critical that the full extent of disease in the organ is appreciated and, as far as liver is concerned, the progression from CT to MRI and then to contrast enhanced MRI has had a major influence; the identification of multiple sites of unsuspected disease may exclude the patient from the approach (Figure 2). Alternatively, a suspected diagnosis of metastatic disease may be confirmed or refuted and the response to chemotherapy appreciated. Patients undergoing metastectomy can now expect a reasonable prognosis, with 5 year survival rates in the order of 30–50%, depending on series and selection criteria, and those with pulmonary resection experiencing a similar outcome.
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Figure 2. (a) CT appearance of liver showing suspicious solitary metastasis. (b) Tesla MRI of equivalent slices confirming the CT suspected lesion and identifying a further lesion in the left lobe.
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Monitoring tumour response
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A critical function, in terms of the use of chemotherapy in rectal cancer, is to be able to monitor tumour response as a measure of the effectiveness of treatment. This applies both to locally advanced primary tumours and to metastases and allows the description of response rates in a research setting, and also the appropriateness of continuing with a particular regimen in the individual patient [15]. Randomized trials have been particularly prolific in the setting of second line chemotherapy for relapsed disease, and imaging, particularly CT, has been crucial in providing the data to establish best practice. For locally advanced disease, a number of studies have used radiological criteria to establish response rates to neoadjuvant chemoradiation and these have subsequently been validated by histopathological correlation.
The adoption of objective tumour shrinkage as a standard end-point for assessment of new chemotherapy agents and other anti-cancer approaches, has necessitated the availability of means to report changes in tumour status in a consistent manner. Standardized criteria were first established about 25 years ago [16] with the recent emergence of a new set of criteria termed RECIST (response evaluation criteria in solid tumours). These criteria have now become standard for the evaluation of objective tumour response in anti-cancer drug trials and the diagnostic implications have been reported on [18, 19].
Although CT has been the main mechanism by which tumour response has been measured, this function has been taken up by MRI and more recently, by functional imaging [20]. There is considerable interest, in PET/CT in all branches of oncology and this has recently been applied to locating pelvic recurrence after surgery for rectal cancer. The interpretation of CT and MRI is notoriously difficult with the tissue changes that occur after surgery and radiotherapy [21].
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Local treatment precision
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For local treatment approaches to rectal cancer, imaging provides crucial information for planning and executing both surgery and radiotherapy. The enormous impact of imaging on the development of surgical procedure for rectal cancer is detailed in another article in this edition [22]. The contribution of imaging to radiotherapy precision has been no less important and is the fundamental basis for the development, first of conformal therapy and more recently of intensity-modulated radiotherapy (IMRT). These technologies rely on accurate delineation of a target volume, with maximum exclusion of normal tissue structures. Clinical examination, surgical findings and histopathological analysis, will all contribute to this process, but imaging techniques are the vehicle by which radiotherapy planning and dose calculations are performed.
Radical radiotherapy for rectal tumours is usually given in two phases. Phase I covers the primary tumour, or surgical bed, and also includes the pelvic lymph nodes to which rectal tumours are known to spread. This mainly involves the internal and common iliac chains. The aim is to give these potential sites of micrometastatic disease sufficient dose to sterilize small volume disease and the aim is therefore to deliver around 45 Gy in daily fractions of 1.8–2 Gy. The Phase II is a reduced volume to cover either the primary tumour or surgical bed, with a small margin in the order of 2 cm. This will receive a further 5–9 Gy, depending on the proximity of the more sensitive small bowel. Traditionally, the two phases were defined using bony pelvic anatomy on orthogonal simulator radiographs films. This allowed the application of simple lead blocking to the corners of the fields used to deliver the treatment. The use of CT planning in rectal cancer allows the possibility of conforming the treatment volume to the desired target volume more closely and thus facilitates the exclusion of some of the bowel. However, the constraints of planning, even using a conformal technique, do not allow the treatment volume to follow the concave distribution of the nodes around the pelvic side wall. This means that although on lateral beams, blocking can be used to exclude bowel, posterior or anterior beams can not achieve this. Figure 3a shows a transaxial CT slice from a CT planning scan and demonstrates the Phase I volume with an anterior border parallel to the anterior abdominal wall. Figure 3b shows the corresponding lateral view with a concavity on the anterior aspect of the target volume allowing exclusion of some normal bowel. The desired shape of the lateral field is achieved by multileaf collimation as shown in Figure 4. The smaller volume Phase II can be appreciated in the lateral view of the reconstructed target volume (Figure 5).
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Figure 3. (a) Transaxial CT planning scan slice showing the Phase I volume with the achievable anterior border, without the desired concavity. (b) Sagittal CT reconstruction showing a Phase I volume with an achievable concavity on the anterior aspect.
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IMRT has provided the capability for producing a target volume with a concavity from right to left (Figure 6). This, combined with further sophistication in the production of a concavity from superior to inferior, allows the extent of the target volume better exclusion of unwanted small bowel. Combined Phase I and Phase II dosimetry for an IMRT treatment is shown in Figure 7. At the present time, nearly all conformal and IMRT treatments are planned using a CT planning scan. The better definition of tumour and normal tissues structures on MRI makes this the obvious development in planning for rectal cancer. This is likely to particularly apply to the Phase II volume and to low tumour where CT poorly identifies the inferior extent of disease.
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Figure 6. Transaxial CT planning slice showing the target volume achievable with intensity-modulated radiotherapy, in particular the anterior border has a concavity not achievable with standard conformal techniques.
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Figure 7. Transaxial CT planning scan showing combined Phase I and II dosimetry for an intensity-modulated radiotherapy treatment plan.
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Surveillance
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On completion of radical treatment, patients enter a follow up programme of surveillance for early detection of disease recurrence. The surveillance strategy may be clinical, most appropriate for low rectal cancers, biochemical, or based on imaging. There remains discordance as to the most appropriate strategy and frequency of follow up on conclusion of radical treatment. Data from a large adjuvant chemotherapy trial provide some interesting information on a group of patients who had 3 monthly clinical and biochemical follow up in the first year and 6 monthly in the second year, post completion of treatment, with CT being performed at 12 months and 24 months [23]. At the time of reporting median follow up was 5.6 years and disease relapses had been observed in 154 patients. Of these, relapse was detected by symptoms in 65, carcinoembryonic antigen (CEA) rise in 45, CT abnormality in 49 and by some other means in 9 patients. 14 of the 49 patients whose relapse was detected by CT had a concomitant elevation of CEA and were included in both groups. The CT detected group had a better survival, compared with those whose relapse was diagnosed from symptoms, as measured from the time of relapse. 33 patients (21%) underwent potentially curative surgery for the relapsed disease, and had a better survival than those whose disease was not suitable for surgery. Of those patients who underwent hepatic or pulmonary metastatic resection, 13 (26.5%) and 8 (17.8%) were in the CT and CEA group, respectively, whereas only 2 (3.1%) were in the symptom detected group. Within the setting of this carefully defined and closely monitored protocol therefore, surveillance CT, along with CEA measurement, were valuable components of follow up in stage 2 and 3 colorectal cancer.
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Conclusion
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Colorectal cancer management has advanced significantly over the past 20 years and continues to do so. The contribution of imaging to this development, has been enormous and would not have taken place without the parallel development of imaging techniques. This article has concentrated on four main aspects of that contribution, accurate staging, leading to selection for appropriate management, monitoring of tumour response to ensure continuation of effective treatment, delineation of tumour extent for treatment precision in surgery and radiotherapy and surveillance imaging for the detection of early recurrence. Some of these functions have already established their worth in terms of improved outcomes and research continues to progress the partnership of oncology and imaging in tandem.
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Introduction
Staging
