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Introduction: the significance of radiobiology for radiotherapy

THE ROLE OF RADIOTHERAPY IN THE MANAGEMENT OF CANCER

Radiotherapy is one of the two most effective treatments for cancer. Surgery, which of course has the longer history, is in many tumour types the primary form of treatment and it leads to good therapeutic results in a range of early non-metastatic tumours. Radiotherapy has replaced surgery for the long-term control of many tumours of the head and neck cervix, bladder, prostate and skin, in which it often achieves a reasonable probability of tumour control with good cosmetic results. In addition to these examples of the curative role of radiation therapy, many patients gain valuable palliation by radiation. Chemotherapy is the third most important treatment modality at the present time. Following the early use of nitrogen mustard during the 1920s, it has emerged to the point where upwards of 30 drugs are available for the management of cancer, although no more than 10-15 are in common use. Many patients receive chemotherapy at some point in their management and useful symptom relief and disease arrest are often obtained.

The following is a brief outline of the role of radiotherapy in six disease sites:

Bladder the success of surgery or radiotherapy varies widely with stage of the disease; both approaches give 5-year survival rates in excess of 50%.

Breast early breast cancers, not known to have metastasized, are usually treated by surgery and this has a tumour control rate in the region of 50-70%. Radiotherapy given to the chest wall and regional lymph nodes increases control by up to 20%. Hormonal therapy and chemotherapy also have significant impact on patient survival. In patients who have evidence of metastatic spread at the time of diagnosis, the outlook is poor.

Cervix: disease that has developed beyond the in situ stage is often treated by a combination of intracavitary and external-beam radiotherapy. The control rate varies widely with the stage of the disease, from around 70% in stage I to perhaps 7% in stage IV.

Lung: most lung tumours are inoperable and in them the 5-year survival rate for radiotherapy combined with chemotherapy is in the region of 5%.

Lymphoma: in Hodgkin's disease, radiotherapy alone achieves a control rate of around 50% and when combined with chemotherapy this may rise to 80%.

Prostate: where there is evidence of local invasion, surgery and radiotherapy have a similar level of effectiveness, with 10-year control rates in the region of 50%. Chemotherapy makes a limited contribution to tumour control.

Very substantial numbers of patients with common of cancers achieve long-term tumour control largely by the use of radiation therapy. Informed debate on the funding of national cancer programs requires data on the relative roles of the main treatment modalities. Broad estimates by De Vita et al. (1979) and Souhami and Tobias (1986) suggested that local treatment, which includes surgery and/or radiotherapy, could be expected to be successful in approximately 40% of these cases; in perhaps 15% of all cancers, radiotherapy would be the principal form of treatment. By contrast, many patients do receive chemotherapy but their contribution to the overall cure rate of cancer may be only around 2%, with some prolongation of life in perhaps another 10%. This is because the diseases in which chemotherapy does well are rare. If these figures are correct, it may be that around seven times as many patients currently are cured by radiotherapy as by chemotherapy. This is not to undervalue the important benefits of chemotherapy in a number of chemosensitive diseases, but to stress the greater role of radiotherapy as a curative agent (Tubiana, 1992).

Considerable efforts are being devoted at the present time to the improvement of radiotherapy and chemotherapy. Wide publicity is given to the newer areas of drug development such as lymphokines, growth factors, anti-oncogenes and gene therapy. But if we were to imagine aiming to increase the cure rate of cancer by, say, 2%, it would seem on a realistic estimation that this would more likely be achieved by increasing the results of radiotherapy from, say, 15% to 17% than by doubling the results achieved by chemotherapy.

There are three main ways in which such an improvement in radiotherapy might be obtained:

1 by raising the standards of radiation dose prescription and delivery to those currently in use in the best radiotherapy centres;

2 by improving radiation dose distributions beyond those that are conventionally achieved, either using techniques of conformal radiotherapy with photons, or ultimately by the use of proton beams;

3 by exploiting radiobiological initiatives

The proportion of radiotherapists world-wide who work in academic centres is probably less than 5%. They are the clinicians who may have access to large new treatment machines, for instance for proton therapy, or to new radiosensitizers or to new agents for targeted therapy. Chapters of this book allude to these exciting developments which may well have an impact on treatment success in the future. But it should not be thought that the improvement of radiation therapy lies exclusively with clinical research in the specialist academic centres. It has widely been recognized that by far the most effective way of improving cure rates on a national or international scale is by quality assurance in the prescription and delivery of a radiation treatment. Chapters 12-14 of this book deal with the principles on which fractionating schedules should be optimized, including how to respond to unavoidable gaps in treatment. For many radiotherapists this will be the most important part of this book, for in even the smallest department it is possible, without access to greatly increased funding, to move closer to optimum fractionating practices.

THE ROLE OF RADIATION BIOLOGY

Experimental and theoretical studies in radiation biology contribute to the development of radiotherapy at three different levels, moving in turn from the most general to the more specific:

Ideas: providing a conceptual basis for radiotherapy, identifying mechanisms and processes that underlie the response of tumours and normal tissues to irradiation and which help to explain observed phenomena. Examples are knowledge about hypoxia, reoxygenation, tumour cell repopulation or mechanisms of repair of DNA damage.

Treatment strategy: development of specific new approaches in radiotherapy. Examples are hypoxic cell sensitizing, high-LET radiotherapy, accelerated radiotherapy, hyperfractionation.

Protocols: advice on the choice of schedules for clinical radiotherapy, for instance conversion formulae for changes in fractionating or dose rate, or advice on whether to use chemotherapy currently or sequentially with radiation. We may also include under this heading methods for predicting the best treatment for the individual of patient (individualized radiotherapy).

There is no doubt that radiobiology has been very fruitful in the generation of new ideas and in the identification of potentially exploitable mechanisms. A variety of new treatment strategies have been produced, but unfortunately few of these have so far led to demonstrable clinical gains with regard to the third an of the levels listed above) the newer conversion formulae based on the linear-quadratic equation seem to be successful. But beyond this, the ability of laboratory the science to guide the radiotherapist in the choice of specific protocols is limited by the inadequacy of the theoretical and experimental models: it will always be by necessary to rely on clinical trials for the final choice of a protocol.

THE TIME-SCALE OF EFFECTS IN RADIATION BIOLOGY

Irradiation of any biological system generates a succession of processes that differ enormously in time-scale. This is illustrated in Figure 1.1 where these processes are divided into three phases (Boag, 1975).

The physical phase consists of interactions between charged particles and the atoms of which the tissue is composed. A high-speed electron takes about 10-18 seconds to traverse the DNA molecule and about 10-14 seconds to pass across a mammalian cell. As it does so, it interacts mainly with orbital electrons, ejecting some of them from atoms (ionization) and raising others to higher energy levels within an atom or molecule (excitation). If sufficiently energetic, these secondary electrons may excite or ionize other atoms near which they pass, giving rise to a cascade of ionization events. For 1 Gy of absorbed radiation dose, there are in excess of 105 ionizations within the volume to of every cell of diameter 10 micron.

The chemical phase describes the period in which these damaged atoms and molecules react with other to cellular components in rapid chemical reactions. Ionization and excitation lead to a breakage of chemical bonds and the formation of broken molecules, known as free radicals. These are highly reactive and they engage in a succession of reactions that lead eventually to the restoration of electronic charge equilibrium. Free-radical reactions are complete within approximately 1 ms of radiation exposure. An important characteristic of the chemical phase is the competition between scavenging reactions, for instance with sulphydryl compounds that inactivate the free radicals, and fixation reactions that lead to stable chemical changes in biologically important molecules.

The biological phase includes all subsequent processes. These begin with enzymatic reactions that act on the residual chemical damagers: vast majority of lesions, for instance in DNA, are successfully repaired. Some rare lesions fail to repair and it is these that lead eventually to cell death. Cells take time to die; indeed, after small doses of radiation they may undergo a number of mitotic divisions before dying.

It is the killing of stem cells and the subsequent loss of the cells that they would have given rise to that causes the early manifestations of normal-tissue damage during the first weeks and months after radiation exposure. Examples are breakdown of the skin or mucosa, denudation of the intestine and haemopoietic damage (see Section 4.4). A secondary effect of cell killing is compensatory cell proliferation, which occurs both in normal tissues and in tumours. At later times after the irradiation of normal tissues the so-called late reactions appear. These include fibrosis and telangiectasia of the skin, spinal-cord damage and blood-vessel damage. An even later manifestation of radiation damage is the appearance of second tumours (i.e. radiation carcinogenesis). The time-scale of the observable effects of ionizing radiation may thus extend up to many years after exposure.

RESPONSE OF NORMAL AND MALIGNANT TISSUES TO RADIATION EXPOSURE

Much of the text of this book focuses on effects high of radiation exposure that become apparent to the clinician or the patient during the weeks, months and years after radiotherapy. These effects are seen both in tumour tissues and in the normal tissues that surround a tumour and which are unavoidably exposed to radiation. The primary tasks of radiation biology as applied to radiotherapy are to explain observed phenomena, and to suggest improvements to existing therapies (as set out in Section 1.2).

The response of a tumour is seen by regression, often followed by regrowth (or recurrence), but perhaps with failure to regrow during the normal lifespan of the patient (which we term cure or local control). These italicized terms describe the tumour responses that we seek to understand. The relationship between regression and regrowth is illustrated graphically in Figure 2.6. The cellular basis of tumour response, including tumour control, is dealt with in Section 6.6.

The responses of normal tissues to therapeutic radiation exposure range from those that cause mild discomfort to others that are life threatening. The speed at which a response develops varies widely from one tissue to another and often depends on the dose of radiation that the tissue receives. Generally speaking, the haemopoietic and epithelial tissues manifest radiation damage within weeks of radiation exposure, whereas damage to connective tissues becomes important at later times. A major development in the radiobiology of normal tissues during the 1980s was the realization that early and late normal-tissue responses are differently modified by a change in dose fractionating and this has given rise to the current interest in hyperfractionation (Section 14.3).

The first task of a radiobiologist is to measure a tissue response accurately and reliably. The term assay is used to describe such a system of measurement. Assays for tumour response are described in Section 17.3. For normal tissues, the following three general types of assay are available.

Scoring of gross tissue effects. It is possible to grade the severity of damage to a tissue using an arbitrary scale as is done in Figure 4.1 or Figure 11.2. In superficial tissues this approach has been remarkably successful in allowing isoeffect relationships to be determined.

Assays of tissue function. For certain tissues, functional assays are available that allow radiation effects to be documented. Examples are the use of breathing rate as a measure of lung function in mice (see Figure 4.5), EDTA clearance as a measure of kidney damage (see Figure 12.4), or blood counts as an indicator of bone marrow function.

Clonogenic assays. In some tumours and some normal tissues it has been possible to develop methods by which the colony of cells that derives from a single irradiated cell can be observed. In tumours this is particularly important because of the fact that regrowth of a tumour after suppurative treatment is caused by the proliferation of a small number of tumour cells that retain colony forming ability. This important area of radiation-biology is introduced in Chapter 6.

RESPONSE CURVES, DOSE-RESPONSE CURVES AND ISOEFFECT RELATIONSHIPS

The damage that is observed in an irradiated tissue increases, reaches a peak and then may decline (Figure l.2A). How should we quantify the magnitude of this response? We could use the measured response at some chosen time after irradiation, such as the time of maximum response, but the timing of the peak may change with radiation dose and this would lead to some uncertainty in the interpretation of the results. A common device is to calculate the cumulative response by integrating this curve from left to right (Figure 1.2B). Some normal-tisuses responses give a cumulative curve that rises to a plateau, and the height of the plateau is a good measure of the total effect of that dose of radiation on the tissue. Other normal-tissue, in particular the late responses seen in connective and vascular tissues, are progressive and the cumulative response curve will continue to rise (Figures 11.3 and 11.4). The quantification of clinical late reactions is dealt with in section 11.4.

The next stage in a study of the radiation response of a tissue will be to vary the radiation dose and thus to investigate the dose-response relationship (Figure 1.2C). Many examples of such curves are given in this book, for instance Figures 5.4, 10.6 and 11.6. Cell survival curves (see section 6.3) are further examples of dose-response curves that are widely used in radiobiology. The position of the curve on the dose scale indicates the sensitivity of the tissue to radiation; its steepness also gives a direct indication of the change in response that will accompany an increase or decrease in radiation dose. These aspects of dose-response curves are dealt with in detail in Chapter 10.

The foregoing paragraphs have for simplicity referred to dose as though we are concerned only with single radiation exposures. It is a well-established fact that multiple radiation doses given over a period five of few weeks give a better curative response than can be achieved with a single dose. Diagrams similar to Figures 1.2A, 1.2B and etc can also be constructed for fractionally radiation treatment, although the results are easiest to interpret when the fractions are given over a time that is short compared with the time-scale of development of the response. If we change the schedule of dose fractionating, for instance by giving a different number of fractions, changing the fraction size or the radiation dose rate, we can then investigate the therapeutic effect in terms of an isoeffect plot (Figure 1.2D). Experimentally this is done by per forming multiple studies at different doses for each chosen schedule and calculating a dose-response curve. We then select some particular level of effect (T in Figure 1.2C) and read off the total radiation dose that gives this effect. For effects on normal tissues the isoeffect will often be some upper limit of tolerances of the tissue perhaps expressed as a probability of tissue failure (sections 5.1 and 10.1).The isoeffect plot shows how the total radiation dose for the chosen level of effect varies with dose schedule. Examples are Figures gore 12.3 and 14.3, and recommendations for tolerance calculations are set out in chapters 12 and 13. The dashed line in Figure 1.2D illustrates how therapeutic conclusions may be drawn from isoeffect curves. lf the curve for tumour response is flatter than for normal-tissue tolerance, then there is a therapeutic advantage in using large fraction numbers: a tolerance dose given using small fraction numbers will be far short of the tumour-effective dose, whereas for large fraction numbers it may be closer to an effective dose.

THE CONCEPT OF THERAPEUTIC INDEX

Discussion of the possible benefit of a change in treatment strategy must always consider simultaneously the effects on tumour response and on normal- tissue damage. A wide range of factors enter into this assessment. In the clinic, in addition to quantifiable aspects of tumour response and toxicity there may be a range of poorly quantifiable factors such as new forms of toxicity or risks to the patient, or practicability and convenience to hospital staff, also cost implications. These must be balanced in the clinical setting. The function of radiation biology is to address the quantifiable biological aspects Of a change in treatment.

In the laboratory this can be done by considering dose-response curves. As radiation dose is increased, there will be a tendency for tumour response to increase, and the same is also true of normal-tissue damage. If, for instance, we measure tumour response by determining the proportion of tumours that are controlled, then we expect a sigmoid relationship to dose (for fractionally radiation treatment we could consider the total dose or any other measure of treatment intensity). This is illustrated in the upper part of Figure 1.3. If we quantify normal-tissue damage in some way for the same treatment schedule, there will also be a rising curve of toxicity (lower panel). The shape of this curve is unlikely to be the same as that for tumour response and we probably will not wish to determine more than the initial part of this curve since a high frequency of severe damage is unacceptable. By analogy with that must be done in the clinic, we can then fix a notional upper limit of tolerance (see Section 5.1). This fixes, for that treatment schedule, the upper limit of radiation dose that can be tolerated, for which the tumour response is indicated by the point in Figure 1.3 labelled A.

Consider now the effect of adding treatment with a cytotoxic drug. We expect that this will be seen as a movement to the left of the curve tumour control (Figure l.3). There will probably also be an increase in damage to normal tissues, which will consist of a leftward movement of the toxicity curve. The relative displacement of the curves for the tumour and normal tissues will usually be different and this fact makes the amount of benefit very difficult to assess. How do we know whether there has been a real therapeutic gain? For studies on laboratory animals, there is a straightforward way of asking whether the combined treatment is better than radiation alone: for the same tolerance level of normal-tissue damage (the broken line), the maximum radiation dose (with drug) will be lower and the corresponding level of tumour control is indicated by point B in the figure. If B is higher than A, then the combination is better than radiation alone for it gives a greater level of tumour control for the same level of morbidity.

This example indicates the radiobiological concept of therapeutic index: it is the tumour response for a fixed level of normal-tissue damage (see Section 10.6). The term therapeutic window describes the (possible) difference between the tumour control dose and the tolerance dose. The concept can in principle be applied to any therapeutic situation or to any appropriate measures of tumour response or toxicity. Its application in the clinic is, however, not a straightforward a matter, as indicated in Section 20.1. Therapeutic index carries the notion of cost-benefit analysis. It is impossible to reliably discuss the potential benefit of a new treatment without reference to its effect on therapeutic index.

THE IMPORTANCE OF RADIATION BIOLOGY FOR THE FUTURE DEVELOPMENT OF RADIOTHERAPY

Many developments in radiotherapy have resulted from new technologies or have been made empirically by clinicians; there are few examples of developments that have begun in the radiobiological laboratory and been carried through to the point where patient survival has significantly improved. The role of oxygen is one positive example that has led to benefits (see Chapter 16), also the clinical gains obtained with accelerated fractionating and hyperfractionation (see Chapter 14).

Compared with chemotherapeutic drugs, radiation is now a well understood cytotoxic agent. Its access to tumour cells is just a matter of dosimetry, independent of the transport mechanisms that largely determine the effectiveness of chemical agents. The sequence of processes listed in Section 1.2 above are well described for radiation; some of them are equally relevant to the response of tissues to cytotoxic drug treatment, and thus research into radiation biology has brought benefits to other areas of therapeutic cancer research.

The future is likely to require greater and greater dependence on basic science. The simple empirical things have mostly been fully exploited and increasing knowledge about the cellular and molecular nature of radiation effects will undoubtedly lead to developments for which the radiotherapist will require grounding in fundamental mechanisms. That is the purpose of this book.

Organ Preservation with Concurrent Chemoradiation for Advanced Laryngeal Cancer

Purpose
To determine the rates of organ preservation and function in patients with advanced laryngeal and hypopharyngeal carcinomas treated with concurrent chemoradiotherapy (CRT).

Methods and Materials
Between April 1999 and September 2005, 82 patients with advanced laryngeal (67%) and hypopharyngeal carcinomas (33%) underwent conventional radiotherapy and concurrent platinum-based chemotherapy with curative intent. Sixty-two patients were male (75.6%). The median age was 59 years. Eighteen patients (22%) were in Stage III and 64 (78%) were in Stage IV. The median radiation dose was 70 Gy. The median potential follow-up was 3.9 years.

Results
Overall survival and disease-free survival were respectively 63% and 73% at 3 years. Complete response rate from CRT was 75%. Nineteen patients (23%) experienced significant long-term toxicity after CRT: 6 (7.3%) required a percutaneous endoscopic gastrostomy, 5 (6%) had persistent Grade 2 or 3 dysphagia, 2 (2.4%) had pharyngoesophageal stenosis requiring multiple dilations, 2 (2.4%) had chronic lung aspiration, and 7 (8.5%) required a permanent tracheostomy. Four patients (4.9%) underwent laryngectomy without pathologic evidence of disease. At last follow-up, 5 (6%) patients were still dependent on a gastrostomy. Overall, 42 patients (52%) were alive, in complete response, with a functional larynx and no other major complications.

Conclusions
In our institution, CRT for advanced hypopharyngeal and laryngeal carcinoma has provided good overall survival and locoregional control in the majority of patients, but a significant proportion did not benefit from this approach because of either locoregional failure or late complications. Better organ preservation approaches are necessary to improve locoregional control and to reduce long-term toxicities.

Larynx, Hypopharynx, Radiotherapy, Chemotherapy, Adverse effects, Late morbidity
Article Outline
• Abstract

• Introduction

• Methods and Materials

• Patient and tumor characteristics

• Radiotherapy

• Chemotherapy

• Surgery

• Toxicity assessment

• Statistical analysis

• Results

• Treatment outcome

• Late toxicities

• Discussion

• Conclusion

• Uncited reference

• References

• Copyright

Introduction
Larynx cancer is the most common cancer subsite in head and neck oncology. For patients with advanced tumors (Stage III or IV) of the larynx and hypopharynx, treatment options are concomitant chemoradiation (CRT) with surgery as salvage, or up-front surgery followed by adjuvant radiotherapy, with or without concurrent chemotherapy. These multimodal regimens are equivalent in terms of survival, but CRT offers the potential advantage of organ preservation 1, 2, 3, 4, 5, 6, 7.

Unfortunately, organ preservation treatment protocols are associated with significant acute and late adverse effects. Therefore, quality of life and morbidity should be considered when a treatment is proposed. Quality of life relates to overall well-being including the functional, emotional, mental, social, and economic components. The most common predictors of quality of life in surviving patients with advanced laryngeal cancer receiving CRT appear to be absence of pain and lower incidence of mood disorder rather than preservation of speech function (8).

Intensity-modulated radiotherapy (IMRT) is starting to be used in the larynx and hypopharynx substites (9). Although experience with this modality is accumulating, we wanted to review our current results with conventional radiotherapy. Our goal was to determine rates of functional organ preservation and late toxicities in patients treated for advanced laryngeal and hypopharyngeal cancer at our tertiary care health center.

Methods and Materials
Patient and tumor characteristics
Between August 1998 and September 2005, a total of 105 patients with histologically proven laryngeal and hypopharyngeal squamous cell cancer (SCC) were treated with concurrent CRT at the Centre Hospitalier de l'Université de Montréal. Pretreatment evaluations consisted of a complete history and physical examination including direct laryngoscopy using a flexible fiberoptic endoscope. Dental evaluation was mandatory in all except edentulous patients. All patients had a complete blood count and biochemical profile, chest X-ray, head-and-neck CT scan, and, in some cases, an MRI. All patients were presented to our multidisciplinary team, which includes head-and-neck surgeons, medical oncologists, radiation oncologists, nurses, nutritionists, speech and swallowing specialists, and pharmacists.

Of these patients, 23 were excluded from the analysis for the following reasons: retreatment (6 patients), use of IMRT (4 patients), follow-up less than 2 years (5 patients), or up-front laryngectomy (10 patients).

Of the remaining 82 eligible patients, 57 and 39 were Stage IVa and T3, respectively. All the data were reported according to the 1998 American Joint Committee on Cancer (AJCC). The distribution of the primary site was 55 larynx and 27 hypopharynx. Of the patients, 62 were male and 20 were female, with a median age of 59 years. Patient characteristics are shown in Table 1. Median potential follow-up was 3.9 years (10).

Table 1. Patient and tumor characteristics


Characteristic Value (%)
Total patients 82 (100)
Gender
Men 62 (76)
Women 20 (24)
Age (y)
Median 59
Range 42–77
Site
Larynx 55 (67)
Hypopharynx 27 (33)
Histological type (SCC) 82 (100)
T stage
T1–2 23 (28)
T3 39 (48)
T4a-b 20 (24)
N stage
N0 15 (18)
N1 12 (15)
N2 51 (62)
N3 4 (5)
Overall stage
III 18 (22)
IVA 57 (70)
IVB 7 (8)


Based on American Joint Committee on Cancer criteria.


Radiotherapy
Most patients were treated with conventional radiotherapy and standard fractionation, 2 Gy per day, five fractions per week for 7 weeks. Median dose was 70 Gy (16–72 Gy). Four patients received a concomitant boost to 72 Gy in 6 weeks. Nine patients did not receive the prescribed dose of radiotherapy (Table 2), including 4 patients who died during treatment, of which two deaths were from an unrelated cause. One of the 9 patients experienced recurrence in the treatment field.

Table 2. Treatment details


Treatment Value (%)
Radiation dose (Gy)
Median 70
Range 16–72
Chemotherapy
Cisplatin 46 (56)
Carboplatin 10 (12)
Carboplatin/5-fluorouracil 23 (28)
Unknown 3 (4)


A planning CT scan with a 5-mm slice thickness was performed in all patients. A thermoplastic head-to-shoulder mask was used for immobilization. Dosimetry was performed with Theraplan v3.8 (Nucletron, Veenendaal, the Netherlands); field arrangement consisted of half-beam blocked lateral opposed fields and supraclavicular field with 4-MV photons. Electrons fields were added as required to the spinal and tracheostomy regions. The target volumes and radiation doses were defined according to International Commission on Radiation Units (ICRU) 12, 13.

Chemotherapy
All patients underwent concurrent platinum-based chemotherapy. Most patients (56%) received cisplatin 100 mg/m2 every 3 weeks. A total of 23 (28%) had carboplatin-5FU given respectively 70 mg/m2/day and 600 mg/m2/day in continuous infusion, both for 4 days every 3 weeks (Table 2).

Surgery
A head-and-neck CT scan was performed 2 months after the completion of treatment. Neck dissection was performed in a patient with persistent clinical or radiographic evidence of residual nodal disease. A salvage total laryngectomy was performed if the primary tumor response was incomplete.

Toxicity assessment
Follow-up was done every 2 months for the first 2 years, then every 4 months up to 5 years, then annually. Patients with locoregional failure or death resulting from cancer were excluded from the assessment. Late toxicity was evaluated more then 3 months after the end of radiation treatment and defined as follow: Grade 2 or higher dysphagia according to the Common Terminology Criteria of Adverse Events (CTCAE) Version 3.0, requirement of a feeding tube/gastrostomy, pharyngoesophageal stenosis, chronic lung aspiration, and laryngectomy or tracheotomy without evidence of tumor recurrence.

Statistical analysis
Statistical analyses were performed with SAS version 8.2 (SAS Institute, Cary, NC). Disease-free survival and overall survival were calculated using the Kaplan-Meier method. Time variables were calculated from the start of radiotherapy. Freedom from local, regional, or distant progression was defined as the absence of demonstrable tumor on physical and radiographic examinations. Follow-up time was calculated using the method described by Schemper and Smith (10).

Results
Treatment outcome
Overall survival, disease-free survival, and the laryngectomy-free survival were respectively 63%, 73%, and 53% at 3 years (Fig 1, Fig 2). Complete response rate with CRT was 75%. The primary tumor response rate was higher, with 88% complete response vs. 79% for nodal complete response.




Fig 1. Kaplan-Meier estimate of overall survival.






Fig 2. Kaplan-Meier estimate of disease-free survival.




Late toxicities
Nineteen patients (23%) experienced significant complications after CRT corresponding to Grade 2, 3, or 4 on the CTCAE scale. Six (7%) required a percutaneous gastrostomy (PEG), 5 (6%) had persistent Grade 2 or 3 dysphagia, 2 (2%) had pharyngoesophageal stenosis requiring multiple dilations, 2 (2%) had chronic lung aspiration, and 7 (8.5%) required a permanent tracheostomy. Four patients (4.9%) underwent laryngectomy because of poor pain control or dysfunctional larynx, without pathologic evidence of disease (Table 3).

Table 3. Late complications


Complications and treatment n
Percutaneous endoscopic gastrostomy 6
Dysphagia Grade 2–3 5
Pharyngoesophageal stenosis 2
Chronic lung aspirations 2
Tracheostomy 7
Laryngectomy 4


At last follow-up, 5 (6%) patients were still dependent on their PEG for adequate intake for a mean duration of 43 months (range, 18–61 months) after radiation. Overall, 42 (52%) patients obtained a complete response and had a functional larynx with no other major complications.

Discussion
Few studies have addressed functional outcomes of larynx preservation protocols. The main goal of our study was to review the toxicity of laryngeal preservation treatments in our center for patient with advanced larynx or hypopharynx squamous cell carcinoma. Both subjective and objective swallowing problems are frequent and severe long-term side effects after radiotherapy for pharyngeal cancer. Swallowing dysfunction has been correlated with dose and volume parameters of the upper aerodigestive tract 14, 15, 16. Organ preservation treatment impairs movement of structures that are essential for effective swallowing 17, 18, 19.

With a median potential follow-up of 3.9 years, our 3-year laryngectomy-free survival, progression-free survival and overall survival are comparable four Phase III laryngectomy preservation trials 1, 2, 3, 7. Toxicity remains significant with this treatment option, as only half of surviving patients are able to return to pretreatment function. These findings are corroborated by Guadagnolo et al. (20) In a recent meta-analyses of 230 patients receiving CRT for SCC of the head and neck, the laryngeal and hypopharyngeal primary site was the strongest independent risk factor on multivariate analysis for severe late toxicity (21).

The successful management of swallowing dysfunction after chemoradiation is complex and difficult to achieve, requiring a multidisciplinary approach. Collaboration among different specialists (physicians, speech pathologists, dietitians, and psychologists) remains the key to a desirable outcome (22). Prophylactic swallowing exercises may benefit these patients and we reinforce this with our patients 23, 24. Moreover, Mekhail et al. reported more pharyngeal stenosis and duration of nutritional support with PEG vs. nasogastric tube at their institution when patients underwent concurrent chemoradiation for advanced head-and-neck carcinoma (25).

In our center, to decrease the incidence of pharyngeal stenosis and to prevent PEG dependency, we tend not to install PEG up front. We hypothesize that encouraging patients to use their swallowing mechanisms during treatment for the longest period of time might decrease those patients' likelihood of developing a PEG dependency as well as requiring pharyngeal dilation in the long run. Even with this approach, 15% of our patients experienced one of these late toxicities.

The present study has several limitations. First, it is a retrospective single-institution study on the long-term toxicities of concomitant chemotherapy and conventional radiotherapy in the treatment of advanced laryngeal and hypopharyngeal tumors. Toxicities were retrospectively determined from a review of the patient charts and thus possibly underreported for the lower grades. Nevertheless, severe complications were likely to be reported, as patient with Grade 2 or greater toxicities are closely followed weekly after treatment by our multidisciplinary team.

Preliminary studies have shown that IMRT can achieve encouraging locoregional control rates for advanced laryngeal and hypopharyngeal carcinomas (9). Xerostomia improves over time but pharyngoesophageal stricture with PEG dependency remains a problem, particularly for patients with hypopharyngeal carcinoma and, to a lesser extent, those with laryngeal cancer. Strategies using IMRT to limit the dose delivered to the esophagus/inferior constrictor musculature without compromising target coverage might be useful to further minimize these late complications (16). Moreover, the grade of laryngeal edema is correlated with mean dose to the larynx, which should ideally be kept to less than 43 to 45 Gy 26, 27. This dose constraint is difficult to achieve when one considers that the larynx is part of the radiation therapy target volume and that the tumoricidal dose usually is approximately 70 Gy.

One has to remember that total laryngectomy has psychological and social consequences, and the choice of the optimal treatment modality is largely dependent on the expertise and experience of the multidisciplinary team 28, 29. Given that survival appears equivalent between the two modalities, post-treatment quality of life becomes a decisive factor. Only a few studies compared qualilty of life between CRT for laryngeal preservation with total laryngectomy and postoperative radiation. Although some trials have shown an improvement in some components of quality of life 8, 30 many others have described equivalent results 31, 32, 33, 34. Furthermore, cost consideration may be an important factor in decision making for the treatment of advanced laryngeal cancer 35, 36.

Conclusion
In this study, half of all patients with advanced laryngeal or hypopharyngeal carcinomas treated with CRT, experienced either significant complications of laryngeal failure or locoregional relapse. For patients treated with the objective of preserving a functional larynx, PEG dependency and laryngectomy are frequent negative outcomes. More efforts and studies are necessary to further improve locoregional control, improve quality of life, and reduce late complications.

Given that survival appears equivalent between the two modalities, patient preference may be an important factor in decision making for the treatment of advanced laryngeal cancer, and clear and informed consent should be obtained. The incorporation of targeted biological therapies and IMRT may reduce long-term toxicities. Prospective Phase III studies are needed with quality of life assessment.

Defining the Clinical Target Volume for Bladder Cancer Radiotherapy Treatment Planning

Purpose
There are currently no data for the expansion margin required to define the clinical target volume (CTV) around bladder tumors. This information is particularly relevant when perivesical soft tissue changes are seen on the planning scan. While this appearance may reflect extravesical extension (EVE), it may also be an artifact of previous transurethral resection (TUR).

Methods and Materials
Eighty patients with muscle-invasive bladder cancer who had undergone radical cystectomy were studied. All patients underwent preoperative TUR and staging computed tomography (CT) scans. The presence and extent of tumor growth beyond the outer bladder wall was measured radiologically and histopathologically.

Results
Forty one (51%) patients had histologically confirmed tumor extension into perivesical fat. The median and mean extensions beyond the outer bladder wall were 1.7 and 3.1 mm, respectively. Thirty five (44%) patients had EVE, as seen on CT scans. The sensitivity and specificity of CT scans for EVE were 56% and 79%, respectively. False-positive results were infrequent and not affected by either the timing or the amount of tissue resected at TUR. CT scans consistently tended to overestimate the extent of EVE. Tumor size and the presence of either lymphovascular invasion or squamoid differentiation predict a greater extent of EVE.

Conclusions
In patients with radiological evidence of extravesical disease, the CTV should comprise the outer bladder wall plus a 10-mm margin. In patients with no evidence of extravesical disease on CT scans, the CTV should be restricted to the outer bladder wall plus a 6-mm margin. These recommendations would encompass microscopic disease extension in 90% of cases.

Bladder cancer, Radiation therapy, Clinical target volume
Article Outline
• Abstract

• Introduction

• Methods and Materials

• Results

• Discussion

• Conclusions

• References

• Copyright

Introduction
Radiotherapy, as a component of multimodality, organ-preserving treatment, remains a standard of care for treating bladder cancer in the United Kingdom, Scandinavia, and individual centers in North America. Modern series report complete response rates of ∼70% and actuarial 5-year local control in ∼50% of patients with muscle-invasive disease 1, 2. Technical developments in the planning and delivery of radiotherapy such as three-dimensional conformal radiation therapy (3D-CRT) and image-guided RT may further improve local tumor control. However, these technologies are predicated on the radiation oncologist being able to accurately define and target the tumor.

Attempts to improve the accuracy of radiotherapy for bladder cancer have, to date, focused on the planning target volume (PTV) expansion required to account for the variability in bladder filling and the uncertainty surrounding day-to-day patient position. As far as we are aware, there are no published data about the appropriate margin to be applied around the tumor to ensure coverage of microscopic disease, a prerequisite for defining the clinical target volume (CTV). A particular problem arises when extravesical stranding is seen on the planning scan. This appearance is commonly reported as tumor infiltration into the perivesical adipose tissue. However, it may also reflect local inflammation or edema following transurethral resection (TUR), particularly when macroscopic tumor clearance and deep muscle biopsies have been performed (3). The inability of computed tomography (CT) scans to accurately define the boundary between the tumor and perivesical fat may explain some of the interobserver variability reported in target contouring (4).

Defining the CTV for bladder tumors is likely to become increasingly important. Historically, the outer bladder wall and any solid extravesical extension have been outlined as the CTV. However, a recent trial has questioned the need to treat the whole bladder (5). Such partial bladder radiotherapy, when combined with modern image-guided techniques, will permit a marked reduction in target volumes (6). Thus, the accurate definition of microscopic extension will assume greater relative importance in the future. The primary purpose of this study was to quantify the magnitude of extravesical tumor extension (EVE) in cystectomy specimens and thereby define an appropriate CTV expansion for treatment planning. In addition, we wished to correlate radiological and pathological findings to determine the frequency with which perivesical CT changes result from either previous TUR or direct disease extension.

Methods and Materials
We conducted a retrospective review of patients who had undergone radical cystectomy for bladder cancer at our institution between 1998 and 2007. A total of 232 cases were initially identified from a departmental database. We excluded any patient who had a salvage cystectomy for disease recurrence following primary radiotherapy, received induction chemotherapy prior to surgery, or in whom the radiological investigations could not be retrieved. We also excluded patients who did not have muscle-invasive transitional cell carcinoma, squamous cell carcinoma, or sarcoma. In total, 80 cases were available for further analysis. Patient demographics and tumor characteristics are shown in Table 1.

Table 1. Tumor characteristics


Parameter Characteristic No. of patients
Histology TCC 46
TCC (squamoid differentiation) 16
TCC (sarcomatoid differentiation) 3
TCC (squamoid and sarcomatoid differentiation) 2
SCC 7
CIS† 2
No tumor identified† 4
Pathological stage pT0† 4
pTis 2
pTa† 1
pT1 5
pT2 16
pT3 41
pT4 11
Grade CIS 2
Grade 2 6
Grade 3 68
No tumor seen† 4
Radiological stage Tx† 2
T2 39
T3 35
T4 4
Anatomical position Lateral wall 46
Posterior wall 34
Anterior wall 24
Base 29
Fundus 17

Abbreviations: CIS = carcinoma in situ; SCC = squamous cell carcinoma; TCC = transitional cell carcinoma.


Data are from 61 male and 19 female patients with a median age of 69 years (range, 40-83 years). The median tumor size was 35 mm (range, 0–120 mm). Tumor histology, grade, and size refer to the analysis of the cystectomy specimen. A tumor could involve multiple sites within the bladder.

†
Muscle-invasive disease was previously confirmed on TUR.


All patients had their diagnoses confirmed by TUR biopsy and had undergone preoperative staging comprising examination under anesthesia, upper-tract imaging, CT scanning of the pelvis, and chest radiography. The median mass of tumor resected at TUR was 5 g (range, 1–151 g). In 65 patients, the tumor biopsy was performed prior to obtaining the staging CT scan. The median time interval between TUR and the scan was 27 days (range, 1–216 days). CT scans were performed with the bladder comfortably full. In 46 patients, intravenous contrast was also given. Images were reviewed by using soft tissue windows (window level, 40; window width, 400 Hounsfield units). EVE was considered to be present when the interface between the bladder cancer and perivesical fat was irregular or when the tumor showed solid growth beyond the outer wall of the bladder. Sagittal or coronal reconstructions were reviewed for tumors on the bladder dome wherever possible. For the purpose of this analysis, the local tumor stage was also defined on the basis of preoperative CT images, using the tumor-node-metastasis (1997) nomenclature. We modified this staging system to create four radiological T stages, namely, Tx, no tumor seen; T2, tumor confined within the bladder; T3, possible tumor extension into perivesical fat; and T4, possible tumor extension into adjacent organs or musculature.

The median interval from the staging scan to radical cystectomy was 25 days. Cystectomy specimens were inked before being placed in formalin. An important feature of this study is that the whole-mount specimens were then serially sectioned before being stained with hematoxylin and eosin and examined by two reporting pathologists. For the purpose this report, slides were further reviewed by a third pathologist, and the maximal extent of EVE was recorded with relation to the outermost muscle fibers of the bladder wall adjacent to the tumor (Fig. 1). In specimens with multiple tumors, the maximal distance was recorded. All measurements of EVE were made to the nearest 0.1 mm, using an optical micrometer. No adjustment was made to account for shrinkage resulting from tissue processing.




Fig. 1. Pathological assessment of extravesical extension. (Top) Tumor is destroying muscle and extending through the bladder wall into perivesical fat. The bar illustrates the measurement of extravesical spread. Original magnification x20. (Middle) A higher magnification view of the top panel shows tumor eroding through into the perivesical fat. Original magnification x40. (Bottom) A “tongue” of tumor (arrow) protrudes from the outer bladder wall. Original magnification x20. The stain is haematoxylin and eosin. M = muscle; T = tumor; A = adventitia.




The study was approved by the Gloucestershire Urological Audit and Research Group. SPSS (SPSS Inc. Chicago, IL) software was used for statistical analysis. The association of histological parameters with EVE was analyzed using Fisher's exact test for categorical variables and Student's t test for continuous variables (equal variances not assumed). All quoted p values are two tailed.

Results
Thirty five patients had T3 disease as seen on CT scanning, while 41 patients had tumor extension into the perivesical fat proven by pathological assessment. The sensitivity, specificity, and negative and positive predictive values of CT scans for predicting local disease extension into perivesical fat were 56%, 79%, 49%, and 83%, respectively. Understaging (29%) was more common than overstaging (10%). The overall accuracy of CT scanning relative to determination of the presence or absence of T3 disease was 44%.

For patients with histologically confirmed EVE, the tumor front was classified as being infiltrative in 35 (discontinuous strands and isolated tumor cells at edge) or pushing in 6 (solid tumor front). In patients with radiologically confirmed T3 disease which was subsequently confirmed on histology, the pattern of EVE seen on CT scanning was also classified (Fig. 2). In 20 patients, this had the appearance of perivesical stranding. Less commonly seen patterns were misting (3), nodular deposits (2), and solid tumor (2).




Fig. 2. Radiological patterns of extravesical extension. (Top left) Stranding; (top right) misting; (bottom left) nodular; (bottom right) solid.




The distribution of disease extension beyond the bladder wall, as measured histologically or radiologically, is shown in Fig. 3. Overall, the median, mean, and maximal EVE values, as measured on histology, were 1.7, 3.1, and 16 mm. For the patients with EVE seen on CT scans, there were eight false positives. For this group as a whole (n = 35), the median, mean, and maximal EVE values, as measured histologically, were 4.0, 4.4, and 16 mm, respectively. The 90th percentile was 9.6 mm. In the group of patients with organ-confined disease on CT, there were 23 false negatives. Taking this group as a whole (n = 45), the median, mean, and maximal histological EVE distances were 1.0, 2.1, and 12 mm, respectively. The 90th percentile in this group was 6.3 mm.




Fig. 3. The distribution of extravesical extension as measure histopathologically (top panel) or radiologically on CT scans (bottom panel).




The relationships between EVE as measured histologically and as measured by CT scan are shown in Fig. 4. There was a reasonable correlation between these two measurements (r = 0.51; p < 0.001). The linear correlation line is defined by the equation EVE (histological) = 1.71 + (0.31 × EVE [CT]). It is also evident from Fig. 4 that CT scans consistently overestimate the extent of spread beyond the bladder for patients with radiologically confirmed T3 disease.




Fig. 4. Correlation between extravesical extension as measured histologically and radiologically. The correlation line is described by the equation EVE (histological) = 1.71 + (0.31 x EVE [CT]).




A number of factors were analyzed for their ability to predict the presence and/or extent of histological EVE (Table 2). Squamoid differentiation, lymphovascular invasion (LVI), and tumor size were all significantly associated with more extensive extravesical tumor spread.

Table 2. Factors that predict extravesical extension


No. with EVE Extent of EVE (mm)
Tumor characteristics No. of tumors found No. with EVE/no. with characteristic No. with EVE/no. without characteristic p value No. with characteristic No. without characteristic p value
Squamoid differentiation† 25 15/25 26/55 0.29 5.1 2.2 <0.01
LVI 44 24/44 17/36 0.51 4.0 2.0 0.02
Necrosis 17 12/17 29/63 0.07 3.4 3.0 0.68
CIS 17 19/36 22/44 0.81 2.7 3.4 0.36
Tumor size >35mm 41 23/39 18/41 0.18 3.0 2.3 0.04
Grade 3 68 37/68 4/12 0.18 3.2 2.9 0.85

Abbreviations: CIS = carcinoma in situ; TCC = transitional cell carcinoma.


Values in bold type represent statistically significant associations.

†
TCC with squamoid differentiation and squamous cell carcinoma.


Sixty-five patients had a TUR performed prior to the staging scan. For the 6 patients in this group with false-positive CT scans, we tested for the possible influence of a TUR biopsy on overstaging. There were no differences in the timing of the TUR (31 vs. 35 days; p = 0.62) or the amount of tissue resected (10.9 g vs. 13.5 g; p = 0.63) between patients with false-positive CT scans and the rest of the sample.

Discussion
Radiotherapy remains a valuable modality in the treatment of muscle-invasive bladder cancer. Functional outcome and morbidity are equivalent or superior to surgery (7), and compared with similar cystectomy series, 5-year disease-specific survival is almost identical 1, 8. The addition of either induction (9) or concurrent (10) cisplatin-based chemotherapy further improves these results. However, despite these recent advances, there still remain the ∼30% of patients who either fail to attain a complete response or subsequently develop a local relapse in the bladder (2). It is noteworthy that up to 95% of recurrences occur at the original site of disease (11). The International Commission on Radiation Units and Measurements (ICRU) Report 50 has provided a conceptual framework for 3D-CRT to ensure adequate coverage of the tumor with the prescription dose (12). A margin is added around the radiologically visible tumor to account for possible microscopic disease extensions, which forms the CTV. A second expansion is then applied to account for tumor movement and the variability of patient setup, which forms the PTV. Although the ICRU report provided definitions of the margins to be used, actual quantitative determination of these expansions relies on clinical measurement. In the case of the CTV, current imaging technology is incapable of accurately identifying microscopic tumor extensions. Furthermore, for most tumors, these extensions are not uniform and can vary according to anatomical position or pathological characteristics (13). In the case of bladder cancer, the pragmatic solution adopted by many radiation oncologists is to add a composite safety margin of 1.5 to 2 cm around the outer wall of the empty bladder, to account for microscopic tumor extension, as well as factors such as daily setup error and variation in organ position. However, better quantification of the various components of this margin would enable the more conformal treatment plans afforded by modern 3D-CRT to be implemented with greater accuracy. To date, most of the research in this area has focused on interfraction organ motion, as this is undoubtedly the dominant source of error in the treatment of tumors within the bladder. For example, several studies have attempted to quantify bladder movement on serial imaging. Turner et al. showed that outward bladder wall movements of greater than 1.5 cm occurred at least once in over 60% of patients with maximal displacements of 2.7 cm (14). This variation compromised treatment margins in 33% of patients. Pos et al. reported that even when a 2-cm margin is allowed around the bladder, part of the tumor still fell outside the PTV on one or more occasions in 52% of patients (15). Finally, a comprehensive Dutch study found similar movements and concluded that anisotropic margins of 1 cm laterally/anteriorly, 1.4 cm posteriorly, and 2 cm for the bladder dome were required to ensure adequate coverage of bladder tumors (16). This variation in the size, shape and position of the bladder have reinforced the traditional view that large treatment margins are necessary when treating tumors in this organ. However, the development of image-guided RT technologies, which permit visualization of soft tissue at treatment, will result in a significant reduction in the internal margin component of the PTV. As a consequence, accurate definition of the CTV will acquire greater importance in the future.

In common with many previous studies, we found that CT scans are of limited value in the preoperative assessment of bladder cancer (17). A recent review by Zhang et al. reported that the overall accuracy of CT staging was only 60% (18). However, the figures quoted for the diagnostic accuracy of CT often amalgamate nodal staging and local tumor staging. In contrast to these studies, our report sought to assess the accuracy of modern CT scans in predicting tumor extension into the extravesical fat. In relation to EVE, the specificity and sensitivity of CT scans was 66% and 79%, respectively. Despite the limited accuracy of CT, our data have confirmed that when perivesical soft tissue changes are seen, they most commonly reflect local tumor extension rather than postbiopsy artifacts. This observation is important for target volume delineation and most likely reflects the long time interval (median, 27 days) between the initial biopsy and the scan in our series. Kim et al. have previously observed that the accuracy of CT scans in determining perivesical extension improves if the scanning is performed 7 days after the TUR (19).

We do not think that the correlation between EVE as measured on CT scans and histologically is sufficiently strong to permit a definition of the CTV based on radiology (Fig. 4). Even if a linear shrinkage factor of 4% is allowed for tissue processing 20, 21, CT scans tend to consistently overestimate the true extent of EVE. As a result, we would recommend that in the absence of radiologically overt T3 disease, an expansion margin of 6 mm beyond the outer wall of the bladder be used. However, for patients in whom extravesical stranding is visible on scanning, the CTV expansion should be increased to 10 mm beyond the outer wall of the bladder. These margins are sufficient to cover microscopic disease in 90% of cases. Where the bladder tumor itself can be visualized, it would seem reasonable for these margins to be added to the bladder wall along the tumor base alone. Finally, it should be emphasized that these recommendations apply to patients in whom the CT scan demonstrates the “stranding” or “misting” pattern of perivesical shadowing (Fig. 2).

Magnetic resonance imaging (MRI) is being used increasingly for the local staging of bladder cancer and is generally reported to be superior to CT, particularly with regard to local staging (22). Unfortunately, very few patients in our series had MRI performed, so we are unable to compare the two imaging modalities. However, we note that even with gadolinium enhancement, differentiating between residual tumor and edema, scar, or granulation tissue on MRI is difficult after the patient has undergone TUR (23).

We observed that EVE is more extensive in patients with LVI, squamoid differentiation, and larger tumors. LVI has recently been found to be an independent predictor for local recurrence in patients with negative lymph nodes at lymphadenectomy (24). Similarly, squamoid differentiation in bladder tumors has also been reported to be a predictor of local recurrence following cystectomy (25). Taken together, these data suggest that when squamoid cell differentiation or LVI is noted on the TUR specimen, larger CTV expansions may be required. The same is true for tumors with a maximum dimension greater than 3.5 cm.

Several limitations of our study methodology must be acknowledged. Staging CT scans were performed with the bladder comfortably full as opposed to planning scans which are usually undertaken with the bladder empty. Many patients in our series had CT scans performed with intravenous contrast, which has been shown to improve the accuracy of staging (26). Furthermore, the findings we report relate to CT scans performed at a median of 4 weeks after biopsy. The accuracy of radiological staging has been shown to be influenced by the interval postbiopsy (19). Finally our methodology for measuring EVE was not sufficiently sophisticated to account for fixation artifacts or the problem of tangential sectioning.

Conclusions
This is the first study that has systematically evaluated the radiological and pathological investigations of patients with bladder tumors to determine the extent of tumor spread into perivesical fat. There is a substantial variation in the degree of EVE. Using these data, we have made recommendations for the CTV margin that is required for treatment planning. This margin must be integrated with the other components of 3D-CRT to ensure coverage of the target. Future work will look at the effect of induction chemotherapy on these recommendations and the accuracy of staging MRI in predicting EVE.

Integration of Real-Time Internal Electromagnetic Position Monitoring Coupled with Dynamic Multileaf Collimator Tracking

Purpose
Continuous tumor position measurement coupled with a tumor tracking system would result in a highly accurate radiation therapy system. Previous internal position monitoring systems have been limited by fluoroscopic radiation dose and low delivery efficiency. We aimed to incorporate a continuous, electromagnetic, three-dimensional position tracking system (Calypso 4D Localization System) with a dynamic multileaf collimator (DMLC)–based dose delivery system.

Methods and Materials
A research version of the Calypso System provided real-time position of three Beacon transponders. These real-time three-dimensional positions were sent to research MLC controller with a motion-tracking algorithm that changed the planned leaf sequence. Electromagnetic transponders were embedded in a solid water film phantom that moved with patient lung trajectories while being irradiated with two different plans: a step-and-shoot intensity-modulated radiation therapy (S-IMRT) field and a dynamic IMRT (D-IMRT) field. Dosimetric results were recorded under three conditions: no intervention, DMLC tracking, and a spatial gating system.

Results
Dosimetric accuracy was comparable for gating and DMLC tracking. Failure rates for gating/DMLC tracking are as follows: ±3 cGy 10.9/ 7.5% for S-IMRT, 3.3/7.2% for D-IMRT; gamma (3mm/3%) 0.2/1.2% for S-IMRT, 0.2/0.2% for D-IMRT. DMLC tracking proved to be as efficient as standard delivery, with a two- to fivefold efficiency increase over gating.

Conclusions
Real-time target position information was successfully integrated into a DMLC effector system to modify dose delivery. Experimental results show both comparable dosimetric accuracy as well as improved efficiency compared with spatial gating.

Radiation therapy, Intensity modulation, Lung, Cancer, DMLC, Tracking
Article Outline
• Abstract

• Introduction

• Methods and Materials

• Experimental setup

• Gamma analysis

• Efficiencies

• Results

• Dosimetry

• Efficiency

• Discussion

• Conclusion

• Acknowledgment

• References

• Copyright

Introduction
Intensity-modulated radiation therapy (IMRT) is a widely used technique for delivering highly conformal radiation dose to a variety of tumor sites. The IMRT technique allows more accurate dose coverage and has been shown to improve clinical results in the prostate (1) as well as head and neck regions 2, 3. More recent efforts have focused on implementing IMRT delivery in the lung to limit the morbidity to healthy tissue (4).

Motion related to respiration, cardiac function, and the digestive system can all cause substantial tumor motion. Intrafraction motion is well documented to be problematic for radiation delivery to tumors in the abdomen, prostate (5), and thorax 6, 7. It has been shown via modeling (8) as well as experimentally (9) and clinically (10) that intrafraction motion can negate the benefits of using IMRT for delivering highly conformal dose gradients and therefore limit dose escalation because of unintentional irradiation of healthy tissue (11). Effectively managing intrafraction motion has led to development of radiation delivery techniques such as breath hold techniques 12, 13, 14, 15, 16, respiratory gating 17, 18, 19, 20, 21, 22, manual beam gating, and four-dimensional (4D) planning/tracking 23, 24, 25, 26, 27, 28.

Breath hold techniques and coached breathing have been implemented for treatment planning, imaging, and dose delivery. These works show promise for spatial localization of internal structures. However many patients with lung cancer are unable to perform the required regular breathing throughout treatment (19).

Respiratory gating conventionally relies on the use of an external surrogate to correlate volumetric imaging with a specific phase of respiration. When the target leaves a predetermined volume, the accelerator is “gated” and the beam is shut off until the target re-enters the volume. There is an inherent tradeoff between spatial accuracy and delivery efficiency. Decreasing the gating volume will lead to very precise dose delivery, but the duty cycle for the system will fall dramatically and treatment times will increase. Aside from patient throughput, increased treatment times can have dosimetric consequences, as the patient is more likely to move if the treatment times increase (29). Another potential limitation of gating is that if the tumor moves outside of the gating volume for an extended period (i.e., because of a non–respiratory-related shift in the patient), the gating system cannot account for this, and the treatment will pause until the patient is manually readjusted.

An ideal motion compensation solution would offer both dosimetric accuracy and efficient, flexible delivery. Here, we propose a solution using a dynamic multileaf collimator (DMLC) to track moving treatment targets. This system has the potential for delivering highly conformal and accurate IMRT treatments in an efficient manner.

To use DMLC tracking as an effector system, it is necessary to obtain accurate real-time low-latency information on the tumor position throughout the course of treatment. Although it has been shown that, for respiratory-related motion, correlation exists between the movements of external anatomy and internal tumor motion 28, 30, in some cases this correlation breaks down (31). Preferably, tumor positions would be continuously measured internally without the use of ionizing radiation, thus eliminating problems associated with changes in the relationship between the tumor and the position monitoring system without additional imaging dose to the patient.

Here we report the use of an electromagnetic position monitoring solution integrated with a DMLC effector system. We use a research version of the Calypso 4D Localization System (Calypso Medical, Seattle, WA) that provides real-time position monitoring of up to three internal fiducial transponders without the use of ionizing radiation. In a related study, we investigated the geometric accuracy of the combined system by measuring the ability of the system to center a circular aperture in response to motion. We have demonstrated that the system can “move” the treatment beam to compensate for target motion (32) with a mean geometric accuracy of 1.42 mm RMSE in the leaf direction and 0.60 mm RMSE orthogonal to the leaf direction when tracking a human patient–derived lung trajectory.

Even with known geometric accuracy of the system, there remain clinical questions regarding implementation. Interplay between the IMRT delivery technique and tumor motion can lead to dosimetric error 9, 33, 34, 35. Moreover, the addition of a motion tracking system to MLC movement during delivery adds complexity to the therapy quality assurance. Our hypothesis was that an integrated electromagnetic position measurement–DMLC tracking system should show similar dosimetric results to an electromagnetic position measurement–gating system, but with improved efficiency.

Methods and Materials
Experimental setup
A schematic diagram of the setup is shown in Fig. 1. A research version of the Calypso System provided real-time position data output of three Beacon electromagnetic transponders at an acquisition frequency of 25 Hz. This data stream containing 3D position information of the tracked centroid was sent to two effector systems. The first system used spatial gating and has been described previously (36). Spatial gating using electromagnetic transponders uses real-time internal position monitoring. The real-time 3D position of the implanted fiducials is compared with a predefined 3D volume. If the position is within the 3D volume, treatment commences. If the target leaves the volume, a BEAM_HOLD is enacted at the linear accelerator until the target returns and the real-time position is within the volume. In these experiments, the gating system received the 3D position and compared it with a predetermined 4 × 4 × 4-mm spatial volume.




Fig. 1. Four-dimensional (4D) phantom motion stage moves a film box containing dosimetric film. Three electromagnetic transponders are embedded in the film box provide real-time position output to a computer controlling the multileaf collimator (MLC) leaves. Leaf positions are updated to follow the motion of the target. 3D = three-dimensional.




The second effector system was the DMLC tracking system (37). The 3D position was input to a research MLC controller with a modified linear adaptive motion tracking algorithm (38). The algorithm altered the planned leaf sequence based on the real-time 3D position data and sent new leaf positions to the Millenium MLC controller on a Varian Trilogy (Varian Medical Systems, Palo Alto, CA) at 20 Hz. The prediction time for the algorithm was set at 220 ms based on previous latency estimates calculated for the system (32). Beacon electromagnetic transponders (Calypso Medical Technologies, Inc., Seattle, WA) were embedded in a solid water phantom along with dosimetric film (Kodak EDR2) located in the sagittal plane aligned at isocenter. The entire film box was placed on the Washington University 4D Phantom, a motion platform capable of recreating patient breathing trajectories to submillimeter accuracy (39).

The following settings were used for all cases: gantry 90°, collimator 90°, and 200 MU delivered via a 6-MV photon beam. The MLC leaves for both the S-IMRT and D-IMRT plans were aligned in the superior/inferior (primary) direction of motion. The delivered dose for each plan was approximately 100 cGy at isocenter. The moving phantom was loaded with a single film aligned in the sagittal plane at isocenter and irradiated as it moved with two different plans: (1) an S-IMRT field, and (2) a D-IMRT field. The phantom was programmed with no motion or with motion obtained from a lung cancer patient using the CyberKnife Synchrony (Accuray, Sunnyvale, CA) tracking system (40). The trajectory had a frequency of 23 breaths/min and had the following peak-to-peak amplitudes: 7 mm lateral, 23 mm superior/inferior, and 6 mm anterior/posterior. The breathing trajectory was relatively periodic, however, and not totally uniform throughout the treatment. Dosimetric results in the presence of motion were recorded for each plan using three different effector systems: no intervention, DMLC tracking, and a 4 × 4 × 4-mm spatial gating system. The comparators for the dosimetric results in the presence of motion were the dose results obtained with a static target.

The films in the presence of motion were registered to the static delivery case in the absence of motion. Once registered, the difference maps were calculated to determine the level of under- or overdosing.

Gamma analysis
Difference maps tend to break down in regions of high dose gradient because a small spatial offset can provide a relatively large dose difference. Conventionally, distance to agreement maps are complementary to difference maps in the sense that they work well in regions of high dose gradient and exhibit high dissimilarity for relatively low dosimetric differences in regions of low gradient. Here, we use the γ tool to evaluate each measurement (41). The γ tool effectively combines both dose difference and distance to agreement metrics which each break down in steep and shallow dose gradient regions respectively. The γ function is defined as the minimum generalized gamma function for all points:


Where are the positions on the evaluated and reference images respectively, is the spatial distance between the two points, is the difference between the evaluated dose and the reference dose at their respective positions, Δd is the distance to agreement criterion (here, 3 mm), and ΔD is the dose agreement criterion (here, 3% of the maximum dose). We leave out the details for the sake of brevity; however, further information on the γ tool can be found in the literature (41).

Efficiencies
In addition to dosimetric accuracy, the delivery efficiencies were recorded for each case. The “Beam-On Time” and “Total Time” displayed on the console of the Linac were recorded for each delivery. These metrics are used to determine the efficiency of delivery for each effector system. Delivery without intervention requires Beam Holds as the leaves in the MLC move from position to position. Our metric for efficiency uses a normalized duty cycle in which 100% matches the efficiency of delivery without intervention.

Results
Dosimetry
Figure 2 displays the raw films for each delivery case. Dose blurring is evident for the film irradiated in the presence of motion with no intervention. Gating and DMLC tracking significantly reduce the dosimetric artifacts associated with irradiating a moving target. For all dosimetric analysis, the static film irradiated in the absence of motion serves as the control.




Fig. 2. Dosimetric films were aligned at isocenter in the sagittal plane were used to observe the delivered dose. Intensity-modulated radiation therapy (IMRT) plans were delivered via step and shoot (A) and dynamic IMRT (D-IMRT) (B) delivery methods in the following scenarios: no motion, motion with no intervention, motion with dynamic multileaf collimator tracking, and motion with a 4-mm gating window. Sup/inf = superior/inferior.




Figure 3 shows the dose difference maps between each of the effector systems and the static “gold standard” film. For the S-IMRT case (Fig. 3A), the DMLC tracking difference map and gating difference map show similar amounts of mismatch, although the locations of the mismatch differ.




Fig. 3. Difference maps were produced after registering dose profiles in the presence of motion with film obtained via static delivery (the “gold standard”). Control is given as reference in each case. Sup/inf = superior/inferior.




For the single field D-IMRT difference maps (Fig. 3B), the gating and DMLC tracking films are comparable. The dose in the interior of the region is relatively homogeneous, and as a result a difference map is not the best metric for observing dose artifacts caused by motion.

In the S-IMRT delivery, the percentage of points with a difference of ±3 cGy from the static case were 10.91% and 7.53% for gating and DMLC tracking, respectively; for the D-IMRT, 3.30% failed for gating, whereas 7.20% failed for DMLC tracking (Table 1).

Table 1. Dosimetry failure rates for two types of intensity-modulated radiation therapy (IMRT) plan


Plan Intervention 3%, 3 mm 6%, 6 mm ±3 cGy ±5 cGy
S-IMRT Gating 0.18% 0.00% 10.91% 3.26%
S-IMRT DMLC 1.21% 0.00% 7.53% 2.73%
S-IMRT None 2.45% 0.16% 10.86% 5.02%
D-IMRT Gating 0.22% 0.00% 3.30% 0.64%
D-IMRT DMLC 0.24% 0.20% 7.20% 2.02%
D-IMRT None 1.55% 1.09% 13.06% 4.99%

Abbreviations: D-IMRT = dynamic IMRT; S-IMRT = step-and-shoot IMRT.

Note: Gamma failure rates were reported for all cases. Failure rates for D-IMRT plans were comparable for gating and DMLC tracking. S-IMRT gating outperformed DMLC tracking. Gating and DMLC tracking outperformed no intervention in both plans.


Analysis of the gamma output for 3 mm and 3% shows that gating outperforms DMLC tracking for the S-IMRT case, with failure rates of 0.18% and 1.21%, respectively (Fig. 4). For the D-IMRT case, the two intervention methods were comparable, with failure rates of 0.22% for gating and 0.24% for DMLC tracking (Table 1). Both methods of intervention outperform no intervention, which produced failure rates of 2.45% and 1.45% in the presence of motion for the S-IMRT and the D-IMRT plan.




Fig. 4. Gamma values were calculated for each of moving image. Values for distance to agreement criterion Δd = 3 mm and dose agreement criterion ΔD = 3% of maximum dose. Control is given as reference for each case. Sup/inf = superior/inferior.




Efficiency
The study results show that DMLC tracking allows drastic improvement in delivery efficiency when compared with beam gating (Table 2). The DMLC tracking showed no decrease in efficiency for both S-IMRT and D-IMRT plans (100% efficiency). Beam gating exhibited efficiency values of 38% for the S-IMRT plan and 22% for the D-IMRT plan.

Table 2. Efficiency values for two types of intensity-modulated radiation therapy (IMRT) plan


Plan Intervention Beam on time (min) Total time (min) Duty cycle (normalized)
S-IMRT None 0.32 0.64 100%
S-IMRT DMLC 0.32 0.60 100%
S-IMRT Gating 0.30 1.68 38%
D-IMRT None 0.33 0.35 100%
D-IMRT DMLC 0.32 0.36 100%
D-IMRT Gating 0.30 1.53 22%

Abbreviations: D-IMRT = dynamic IMRT; S-IMRT = step-and-shoot IMRT.

Note: Delivery efficiencies were recorded in the form of beam on time and total time for each of the delivery conditions. Values along with associated duty cycles are displayed. Duty cycle values are normalized to the static delivery case (100% indicates no efficiency drop caused by intervention).


Discussion
We have successfully implemented a tracking system that does not rely on ionizing radiation or an external tumor surrogate for the detection of internal targets. The DMLC tracking solution shows promise for the reduction of motion-related dosimetric errors. However there are several details that still need to be addressed.

For the case of the D-IMRT plan, the gating solution produced comparable dosimetric output when compared with the DMLC tracking. The D-IMRT plan shows relatively few high dose gradient regions in the center of the dose distribution. As a result, in the interior of the target, the dosimetric errors associated with superior inferior motion are not as evident from a difference map.

The S-IMRT delivery to the moving phantom with no intervention corresponds to a convolution of the beam profile for each step-and-shoot segment with the motion of the phantom during delivery of that segment. With gating, the delivery corresponds to a convolution with the residual motion within the gating window. Therefore, one would expect small blurring of the dose profiles with dosimetric errors related to the size of the gating volume. The errors associated with DMLC tracking are not as clear. Here, the discrepancy with the static case is caused by failure to align instantaneously to the target position and the coarse (one-leaf width) aperture resolution orthogonal to the leaf direction. It is possible that the target motion oscillated in a fashion that dictated a shift back and forth of one leaf position in the anterior/posterior direction; this could lead to substantial dosimetric error on the order of the size of the one leaf (5 mm). It should be noted that our algorithm did not use subleaves to estimate motion orthogonal to the leaf direction (37). As a result, a shift in the anterior/posterior direction is “all or nothing,” which could potentially have led to the dosimetric error seen in the S-IMRT DMLC tracking films.

It is notable that increased efficiency has potential for dosimetric implications, not just patient throughput. If the patient is on the table for a considerably greater duration (i.e., using a gating solution with a very small gating window), it is possible the patient will move because of discomfort. Although not in the scope of this experiment, this motion has potential dosimetric consequences.

There is further work to be done on the system. Currently there is variable latency in the position monitoring which is not taken into account by the prediction algorithm. Setting a fixed latency for the position monitoring, or accounting for the variable latency in the MLC tracking algorithm would provide for better geometric (and hence dosimetric) results. In addition, reducing the overall latency of the system as a whole would provide for better dosimetric results. Incorporating target deformation and rotation into the beam shaping is another potential improvement for the system. Work needs to be done to evaluate a variety of treatment plans to ensure that the MLC tracking algorithm is robust and accurate when applied to any conventionally generated treatment plan.

There are plans for commercialization of this system. It may be safer to implement the system for prostate cancer management, as there are currently approved uses for Calypso Beacon implantation for that location. Further uses, such as lung tumor tracking, will need a new transponder design that can be safely inserted in the thorax. It is not clear whether changes in treatment planning software will be necessary, although they may be desirable to fully take advantage of the DMLC tracking capability. The tools for quality assurance of the system will have to be developed and may include motion phantoms such as the one used in this work. Safety and reliability of a commercial implementation will have to be investigated in a more thorough manner than in this preliminary work.

Conclusion
In summary, we have integrated a system that senses real-time internal anatomy positions without the use of ionizing radiation with a DMLC tracking system to deliver continuous dose to a moving target. The dose profiles are comparable with an idealized gating algorithm, eliminate the uncertainties inherent in the use of chest wall surrogates for tumor position, and show much higher delivery efficiencies as well as the promise of increased clinical confidence of the radiation dose delivery to the treatment target during radiation delivery. More work is left to be done in further improving the dosimetric results in an effort to create a system that delivers accurate radiation with submillimeter intrafraction motion management.

Imaging After GliaSite Brachytherapy

Purpose
In this study, we analyzed the magnetic resonance imaging (MRI) changes in patients after GliaSite treatment and characterized the prognostic MRI indicators in these patients.

Methods and Materials
A total of 25 patients with recurrent glioblastoma multiforme were treated with the GliaSite Radiation Therapy System. Patients at the Johns Hopkins Hospital with recurrent glioblastoma multiforme underwent surgical resection followed by GliaSite balloon implantation. Available MRI scans for 20 patients were obtained throughout the post-GliaSite treatment course. These were reviewed and analyzed for prognostic significance.

Results
After GliaSite treatment, all patients developed some degree of T1-weighted contrast and T2-weighted hyperintensity around the resection cavity. The development of enhancement on T1-weighted contrast-enhanced imaging and the size of these lesions, in the absence of increasing T2-weighted hyperintensity, before clinical progression was not associated with decreased survival. Patients with T1-weighted enhancement >1 cm had a median survival of 13.6 months and those with T1-weighted lesions ≤1 cm had a median survival of 8.5 months (p = .014). In contrast, the development of larger areas of T2-weighted hyperintensity surrounding the resection cavity was significantly associated with poorer survival (p = .027).

Conclusion
After GliaSite treatment, characteristic T1- and T2-weighted changes are seen on MRI. Greater T1-weighted changes in the absence of increasing edema appears not to indicate disease progression; however, greater T2-weighted changes were associated with decreased survival. These findings suggest that T1-weighted enhancement in the absence of concomitant edema after GliaSite treatment might represent pseudoprogression. Conversely, increasing T2-weighted hyperintensity might reflect infiltrative disease progression. These results provide a framework for the analysis of disease control in future prospective studies of GliaSite treatment.

Glioblastoma multiforme, Recurrent glioma, GliaSite, Brachytherapy, Imaging
Article Outline
• Abstract

• Introduction

• Methods and Materials

• Results

• Discussion

• Conclusion

• References

• Copyright

Introduction
In the United States, glioblastoma multiforme (GBM) is nearly universally fatal and occurs at a frequency of approximately 8,500 cases annually (1). The disease constitutes about 80% of all malignant gliomas (2). The infiltrative nature of GBM prohibits cure with surgery alone. Despite surgical resection and adjuvant external beam radiotherapy, GBMs typically recur within 1 year. Local failure is the predominant mode of failure, and most relapses occur within 2 cm of the margin of surgical resection (3). In nearly all cases, disease progression is followed shortly by death.

In randomized trials, adjuvant external beam radiotherapy has been shown to result in a modest increase in survival in patients with newly diagnosed GBM 4, 5. The use of systemic chemotherapy such as carmustine provides an additional marginal benefit in survival for selected patients, resulting in an absolute increase in the 1-year survival rate from 40% to 46% (6). Adjuvant therapy with oral temozolomide, an oral alkylating agent with some activity against glioma, during and after RT increases the median survival to approximately 15 months (7). Likewise, the use of local chemotherapy regimens such as biodegradable carmustine wafers (Gliadel) has been shown to increase survival by about 2 months, with fewer toxicities than systemic chemotherapy (8).

The GliaSite device allows the delivery of a radiation dose to areas most at risk of recurrence while addressing some of the potential limiting factors of interstitial brachytherapy. The GliaSite Radiation Therapy System (RTS) makes use of a silicone balloon catheter and an aqueous iodinated radiation source (Iotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]). Immediately after surgery, the distal balloon portion of the GliaSite device is placed inside the resection cavity. After placement of the balloon, the injection port is brought to the surface of the skull to allow subcutaneous access to the balloon. Intracavitary brachytherapy is then performed by filling the balloon with Iotrex using the subcutaneous port. The balloon is left filled for a predetermined dwell time to deliver the prescribed radiation dose. After treatment, the Iotrex is taken out of the balloon, and the implanted device is surgically removed. Tatter et al. (9) described the safety and feasibility of the GliaSite RTS.

The GliaSite RTS has now been used to treat recurrent high-grade glioma, primary high-grade glioma (as a boost), and brain metastases in the adjuvant setting 10, 11, 12, 13. The treatment of recurrent glioblastoma after repeat resection has resulted in survival that is favorable compared with that after surgery alone. Proper patient selection is important because favorable results are seen in patients with a Karnosfky performance status of ≥70 at GliaSite treatment but not for patients with a lower Karnosfky performance status (10). The rate of symptomatic radionecrosis was low—3–4%—and the treatment was well tolerated 10, 11. Prospective trials have been conducted to determine the efficacy of GliaSite treatment for patients with recurrent GBM, as well as for patients newly diagnosed with glioblastoma. However, the results from these trials have proved difficult to interpret, because the magnetic resonance imaging (MRI) characteristics during the post-treatment period were difficult to interpret. In the weeks after GliaSite treatment, it was common for symmetric contrast enhancement to be seen on T1-weighted images. This enhancement was at times accompanied by symptoms, and it was unclear whether these findings indicated disease progression or post-RT change. As such, the duration of disease control afforded by GliaSite treatment has been difficult to determine accurately owing to these uncertainties, and the patients might be subject to unnecessary neurosurgical procedures. In the present study, we analyzed the post-GliaSite MRI studies for patients with recurrent GBM who were treated with repeat resection followed by GliaSite brachytherapy at Johns Hopkins Hospital. This analysis was performed to determine the prognostic value of MRI findings for patients in the post-treatment period.

Methods and Materials
We retrospectively analyzed the survival and MRI imaging data for 20 patients with recurrent GBM (World Health Organization Grade IV malignant glioma). Between February 2000 and April 2004, patients at Johns Hopkins Hospital with recurrent GBM, who had previously undergone surgery and external beam radiotherapy, underwent surgery for a gross total resection followed by GliaSite balloon implantation. The primary tumor site for all patients was supratentorial. All primary and recurrent tumors were histologically proven to be GBM. All patients had previously been treated for newly diagnosed GBM with surgical resection and adjuvant external beam radiotherapy. The patient characteristics are listed in Table 1. The median patient age was 48 years (range, 25–69). The mean Karnofsky performance status at initial diagnosis was 80 (range, 50–100). Patients had undergone gross total resection for their initial surgical resection. At repeat resection, 18 patients (90%) underwent gross total resection and 2 (10%) underwent subtotal resection (90% tumor removal).

Table 1. Patient characteristics

Patients (n) 20
Gender (n)
Male 6 (30)
Female 14 (70)
Age (y)
Median 48
Range 25–69
Age (n)
<50 y 11 (55)
≥50 y 9 (45)
KPS at diagnosis
Median 80
Range 50–100
KPS at GliaSite
Median 80
Range 60–100
KPS ≥70 (n) 18 (90)
KPS <70 (n) 2 (10)
RPA class at diagnosis (n)
3 5 (25)
4 8 (40)
5 6 (30)
6 1 (5)
Surgical resection extent (n)
Biopsy 0 (0)
Subtotal 2 (10)
Gross total 18 (90)
Postoperative external beam radiotherapy (cGy)
Mean dose 5,972
Mean dose per fraction 190.7
Chemotherapy (n)
Yes 13 (65)
No 7 (35)

Abbreviations: KPS = Karnofsky performance status; RPA = recursive partitioning analysis.

Data in parentheses are percentages.


All patients who underwent repeat resection and placement of the GliaSite balloon after recurrence of their GBM were found to have recurrence as determined by both clinical and radiographic (MRI) progression. The GliaSite balloon implantation technique and criteria for treatment have been previously described (10). The appropriate candidates were patients with tumors ≤30 cm3 that did not extend across the midline. After resection of the GBM, a GliaSite balloon catheter with a diameter of 2, 3, or 4 cm was placed in the resection cavity. During the post-GliaSite period, all patients were given a standard taper of dexamethasone for 30 days. No patients received antiangiogenic therapy before GliaSite treatment.

Follow-up was performed with serial MRI scans and clinical assessments. Post-GliaSite MRI scans were obtained at 6 and 12 weeks after treatment and at clinical progression. We obtained all MRI scans for the 20 patients with GBM after GliaSite brachytherapy. All MRI scans were performed using 4-mm-thick, T1-weighted imaging after administration of 0.1 mmol/kg Magnevist (gadopentetate dimeglumine), T2-weighted imaging, and 4-mm-thick, axial fast fluid-attenuated inversion recovery (FLAIR) imaging. The imaging studies were analyzed with particular attention to changes in contrast enhancement and signal intensity surrounding the resection site. The assessment of T1-weighted contrast-enhanced images included measurement of the lesion size by measuring the maximal thickness of T1 enhancement around the surgical cavity. The size of the lesions seen on the T2-weighted images was determined by measuring the elliptical area of the T2 lesion at the image slice, with the largest area of T2 size. The measurements were performed using the Merge eFilm Workstation software. The MRI scans were read and interpreted by a neuroradiologist.

Four patients underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) of the brain to evaluate for disease progression after GliaSite therapy. The agent administered during this test was intravenous 10.06 MCI F-18 fluoro-deoxy-d-glucose. A neuroradiologist analyzed the PET images for abnormal activity and interpreted the results. Deaths were confirmed using the U.S. Social Security Death Index and patient records.

Survival estimates were obtained using the Kaplan-Meier method. Statistical analysis was performed using the Stata software suite. Survival estimates were calculated using the Kaplan-Meier method and the log–rank statistic for univariate analysis. Spearman's test was used for correlation analysis.

Results
A total of 20 patients with recurrent GBM underwent repeat resection and subsequent GliaSite brachytherapy. At the analysis, all 20 patients had died. We defined overall survival as the interval from the initial tissue diagnosis to death. The Kaplan-Meier curve for overall survival is shown in Fig. 1. Survival after GliaSite was defined as the interval from the end of GliaSite treatment to death. The Kaplan-Meier curve for survival after GliaSite is shown in Fig. 2.




Fig. 1. Kaplan-Meier survival curve for all patients treated with GliaSite and included in our imaging analysis (n = 20). Survival defined as interval from pathologic diagnosis to death.






Fig. 2. Kaplan-Meier curve for survival after GliaSite therapy for patients in our imaging analysis.




Follow-up was performed with clinical assessments and serial MRI scans after GliaSite therapy. We defined clinical progression as recurrent disease initially determined by clinical assessment (e.g., increasing headache, steroid dependence, and/or new neurologic symptoms) and then confirmed by MRI findings (e.g., development of mass effect and/or dramatic increase in T1-weighted positive contrast/T2-weighted hyperintensity compared with the previous scan). All 20 patients in the study had had clinical progression using these criteria before death. The median interval from GliaSite brachytherapy to clinical progression was 4 months. The median survival after clinical progression was 5.8 months.

We analyzed a total of 79 MRI studies for 20 patients after GliaSite treatment for recurrent GBM. The MRI characteristics of the patients are summarized in Table 2.

Table 2. MRI characteristics of patients with GBM after treatment with GliaSite

Interval from GliaSite to first post-GliaSite MRI (mo)
Median 1.5
Range 0.1–17.6
Interval between consecutive MRI scans (mo)
Median 1.6
Range 0.2–10.4
Changes observed on MRI
Maximal thickness of T1-weighted contrast enhancement (cm) 1.2 ± 0.4
Interval to maximal thickness of T1 contrast enhancement (mo)
Median 2.8
Range 0.3–21.7
Maximal elliptical area of T2/FLAIR hyperintensity (cm2) 240 ± 104
Interval to maximal elliptical area of T2/FLAIR hyperintensity (mo)
Median 3.8
Range 0.2–20.7
Interval from GliaSite to clinical progression (mo)
Median 4.0
Range 0.6–17.6
Changes observed on MRI before clinical progression
Maximal thickness of T1 contrast enhancement (cm) 0.86 ± 0.40
Interval to maximal thickness of T1 contrast enhancement (mo)
Median 2.6
Range 0.3–11.3
Maximal elliptical area of T2/FLAIR hyperintensity (cm2) 196 ± 88.5
Interval to maximal elliptical area of T2/FLAIR hyperintensity (mo)
Median 2.6
Range 0.3–11.3

Abbreviations: MRI = magnetic resonance imaging; GBM = glioblastoma multiforme; FLAIR = fast fluid-attenuated inversion recovery.


Data presented as mean ± standard deviation.


For all 20 patients, T1-weighted contrast-enhanced and T2-weighted/FLAIR MRI scans were analyzed for prognostic significance. After GliaSite therapy, all patients developed some degree of enhancement around the resection cavity on T1 and T2/FLAIR imaging. The mean maximal thickness of the T1-weighted contrast enhancement was 1.2 ± 0.4 cm, with a median time to maximal thickness of 2.8 months after GliaSite therapy. For the T2-weighted/FLAIR images, the mean maximal elliptical area of hyperintensity was 240 ± 104 cm2. The MRI studies were also analyzed in relation to the time to clinical progression. For T1-weighted images, the mean maximal thickness of enhancement attained before clinical progression was 0.86 ± 0.40 cm. The median interval between GliaSite therapy and maximal thickness before clinical progression was 2.6 months. For the T2-weighted/FLAIR images, the mean maximal elliptical area attained before clinical progression was 196 ± 88.5 cm2, with a median time of 2.6 months after GliaSite therapy. At clinical progression, the common findings on MRI included increased T2 signal hyperintensity, vasogenic edema, and mass effect. Figure 3 shows a representative patient's T1-weighted and T2-weighted/FLAIR changes after GliaSite therapy.




Fig. 3. Magnetic resonance imaging scans from representative patient after GliaSite therapy showing concomitant increases in lesion size on both T1- and T2-weighted magnetic resonance imaging. (a) Axial contrast-enhanced T1-weighted image showing resection cavity and surrounding enhancement. Image taken 36 days after GliaSite therapy. (b) Corresponding axial T2/fast fluid-attenuated inversion recovery image showing signal hyperintensity. Image obtained 36 days after GliaSite therapy. (c) Axial contrast-enhanced T1-weighted image showing increased thickness of rim of enhancement surrounding resection cavity at clinical progression of glioblastoma multiforme, 78 days after GliaSite therapy. (d) Corresponding axial T2/fast fluid-attenuated inversion recovery image showing increased signal hyperintensity at clinical progression of glioblastoma multiforme, 78 days after GliaSite therapy.




In general, FDG-PET or MRI spectroscopy results confirmed progressive disease at clinical progression. At clinical progression, 4 of the 20 patients with GBM underwent FDG-PET imaging after GliaSite therapy. These patients underwent FDG-PET imaging after they had clinical progression of their GBM. The median interval from clinical progression to FDG-PET imaging was 16 days. In 3 patients, the FDG-PET studies confirmed tumor recurrence in the region of their resection site; the fourth patient had a FDG-PET result that was indeterminate but progression could not be ruled out. Figure 4 shows FDG-PET images from a representative patient with tumor recurrence. MRI spectroscopy imaging was performed in 1 patient 20 days after the date of clinical progression. The patient's spectroscopy results showed reduced N-acetylaspartate/choline ratios in the region surrounding the resection cavity suggestive of tumor recurrence.




Fig. 4. Fluorodeoxyglucose-positron emission tomography (FDG-PET) cerebral glucose scans for representative patient at clinical progression of glioblastoma multiforme (GBM) after GliaSite therapy. (a) Enhancement on axial FDG-PET scan surrounding resection cavity. (b) Enhancement on coronal FDG-PET scan in corresponding region.




The MRI data were analyzed for prognostic significance on the basis of the thickness of the maximal T1 enhancement and the size of the T2/FLAIR hyperintensity. Patients with T1 enhancement >1 cm had a median survival after GliaSite treatment of 13.5 months and those with T1 enhancement of ≤1 cm had a median survival of 8.4 months (p = .014). We also analyzed the changes before clinical progression for all patients. Patients with T1-weighted enhancement >1 cm before clinical progression had a median survival of 19.3 months, but those with T1 enhancement of <1 cm before clinical progression had a median survival of 8.4 months (p = .004). In contrast, the development of larger T2-weighted lesions was associated with poorer survival, with Spearman's correlation test yielding r = −0.45 (p = .027). Table 3 summarizes the results for the MRI findings and prognostic factors. The measurements before clinical progression were unlikely to have been related to differences in steroid use because no difference was found in the amount of steroids taken by the patients throughout the range of measurements during this period.

Table 3. Prognostic MRI findings after treatment with GliaSite


Prognostic factor Survival (mo) p
Maximal T1 enhancement (cm)
>1 13.5 (5.6–27.3) .014
≤1 8.4 (4.5–12.9)
Maximal T1 enhancement before clinical progression
>1 19.3 (13.8–23.3 .004
≤1 8.4 (4.5–12.9)
Maximal T2 enhancement elliptical area r = −0.45 .027†

Abbreviation: MRI = magnetic resonance imaging.

Data in parentheses are ranges.

For T2 area as continuous variable in proportional hazards model, p value likelihood ratio statistic) was < .05 after elimination of other variables (i.e., dose, duration of steroid use), none of which were significant.


Log–rank test.

†
Spearman's test for correlation, significant as continuous variable.


We next attempted to evaluate post-GliaSite T2 changes in relationship to the T1 changes. Although the numbers of patients available for investigation did not allow for meaningful multivariate analysis, we did perform a subgroup analysis of the survival of patients with or without significant increases in T2 hyperintensity during the period before clinical progression. Significant increases in T2 hyperintensity were defined as an increase of >30% in the maximal diameter of the area of T2 hyperintensity surrounding the resection cavity during the period of interest. Patients with T1 enhancement >1 cm during the period before clinical progression had a median survival of 19.3 months. In contrast, those with T1 enhancement <1 cm before clinical progression had a median survival of 8.4 months (p = .004). However, the subset of patients with T1 enhancement >1 cm and a concomitant significant increase in T2 hyperintensity before clinical progression had a median survival of only 10.1 months (19.3 vs. 10.1 months, p = .04). Thus, it appears that the development of T1-positive contrast enhancement alone at the treatment site does not necessarily indicate disease progression. Large areas of T1-positive contrast enhancement in the absence of T2 changes were associated with longer progression-free survival. Thus, T1-positive contrast lesions might often correspond to areas of radiation change and not proliferating tumor. In contrast, progressive increases in T2 hyperintensity likely signifies infiltrative disease and disease recurrence.

Discussion
The GliaSite RTS enables the delivery of a high, homogeneous radiation dose to the tissues most at risk after surgical resection of brain lesions. This treatment is currently in use by a number of institutions for recurrent glioma and as a boost for the initial adjuvant treatment of GBM 11, 12. The survival of patients treated with GliaSite has appeared favorable, but data from well-controlled, prospective studies are lacking. Successful completion of such studies have been hampered by difficulty in interpreting post-GliaSite MRI data, which is required for accurate determination of the clinical endpoints required to gauge the efficacy of the treatment.

We conducted the present study to gain a better understanding of the MRI changes that occur after patients with recurrent GBM are treated with the GliaSite. Our analysis has indicated that distinct imaging changes exist, evident on MRI scans, that are associated with a better or worse outcome in the post-GliaSite treatment period. The development of a contrast-enhancing area around the treatment site is not, in and of itself, indicative of recurrence in the absence of significantly increased vasogenic edema. These lesions might represent post-RT changes in the area of the brain that received the greatest radiation doses or, alternatively, postoperative scarring (14). The cycling endothelium is a sensitive target for radiation damage that promotes blood–brain barrier breakdown (15). This breakdown can present as an area of contrast enhancement on T1-weighted images. Thus, it is not surprising that patients who developed large T1-positive contrast changes after GliaSite treatment might not all have had disease progression.

The presence of T1-positive contrast lesions at the GliaSite treatment location does not necessarily indicate disease progress; however, in some patients, it can. Our analysis has indicated that in patients with progression in this setting, the MRI scans from these patients will often demonstrate a concomitant increase in T2 signal surrounding the T1-weighted contrast-enhancing lesion. It appears that T2 lesion increases, together with T1-weighted contrast enhancement, are more indicative of disease progression. The increased T2 signal is consistent with the development of progressive infiltrative disease into the surrounding brain parenchyma. This imaging finding was also described in a smaller study reported by Matheus et al. (16) to be associated with poorer progression-free survival. They also concluded that progressive hyperintense abnormalities on T2-weighted images were due to tumor recurrence, although the low numbers analyzed in their study did not allow for statistical evaluation. Patients with the largest T1-positive contrast lesions without increasing vasogenic edema appeared to have a better survival than those with progressively increasing edema.

Currently, distinguishing between residual tumor and radiation necrosis is not feasible with MRI alone. In our experience, the incidence of symptomatic radionecrosis in patients with recurrent GBM treated with GliaSite is 8% (2 of 25) (10). The 2 patients with symptomatic radionecrosis at our institution were not included in the present analysis, because they had both undergone repeat resection and extended imaging was not available. Of the patients analyzed in our study, there were no cases of symptomatic radionecrosis. Nevertheless, it is possible that some of our patients did experience some level of subclinical radionecrosis after GliaSite treatment. Definitive documentation of this would require pathologic verification, which was not feasible at the time. Additional study is required to determine how the presence or absence of radionecrosis affects the prognostic MRI findings we have identified.

The use of PET and/or MRI spectroscopy might aid in differentiating between progressive disease and radionecrosis. Five patients underwent either PET or MRI spectroscopy at suspected clinical progression. On the MRI studies, all 5 patients had developed contrast-enhancing lesions on T1-weighted imaging accompanied by a ≥30% increase in the size of the T2-FLAIR enhancement. Of the 5 patients, 4 had PET or spectroscopy results indicative of disease progression, and 1 patient had indeterminate study findings. This suggests that PET and/or MRI spectroscopy, although not definitive, might be useful in detecting disease progression. It should be noted, however, that FDG-PET can yield false-positive results in this setting. Thus, although helpful, PET alone cannot reliably distinguish radionecrosis from tumor recurrence (17).

The finding that T1-weighted contrast-enhancing lesions might not herald local recurrence is increasingly being documented in GBM patients treated with external beam radiotherapy. This so called “pseudoprogression” usually manifests itself as the development of contrast enhancement in the treatment site shortly after adjuvant radiotherapy (18). This phenomenon is due to treatment-associated scarring or regional necrosis, resulting in the disruption of the hematoencephalic barrier and passage of contrast medium (19). Given that GliaSite treatment often treats the adjoining resection cavity surface to a high radiation dose, our findings are consistent with the T1-enhancing lesions we observed as being a type of pseudoprogression that does not signify disease recurrence. The time course in which we see these imaging effects was similar to that seen for central nervous system tumors treated with radiosurgery or interstitial brachytherapy 20, 21, 22. For example, Moringlane et al. (22) noted that a ring-like signal on T1-positive contrast images developed as early as 1 month in most of their glioma patients treated with interstitial 125I. This timing is very consistent with our own observations after GliaSite treatment.

Conclusion
We have identified several useful MRI factors that can aid in the interpretation of the imaging findings from patients with recurrent GBM who have undergone GliaSite radiotherapy. Post-GliaSite patients often present with complex MRI findings, often with a large compendium of changes that occur over time. Because of the difficulty in interpreting these images, the determination of whether a patient has developed recurrence or not is often empirical. Although not definitive, the prognostic imaging factors we have identified can aid the clinician with interpretation of the MRI changes that occur during the post-GliaSite period. These factors should be considered in any future prospective studies of the GliaSite RTS.