Coming of Age

Personalized cancer care, such as using theragnostic radiation oncology to deliver individualized treatment plans, holds promise.

Conventional radiotherapy has relied on delivering relatively homogenous radiation doses to visible or measurable tumor, referred to as gross target volume (GTV), and lower doses to surrounding normal tissues at risk of containing microscopic disease, known as the clinical target volume (CTV). These doses have largely been derived from, and driven by, the recognition of the tolerance of normal surrounding tissues. Consequently, almost all patients with a given stage of a particular tumor receive a relatively similar dose prescription, a paradigm that is effectively a population-based prescription.

This approach has two inherent flaws. First, these population-based prescriptions ignore tumor heterogeneity, and therefore, a single common prescription would treat potentially radiosensitive tumors to doses higher than necessary, and conversely radioresistant tumors would be underdosed. Since the majority of the prescriptions are driven by concerns regarding the toxicity level for normal tissue, the actual prescribed dose reflects and respects the possibility that a relatively small minority of patients could develop toxicities at modest doses. But since these patients cannot be identified a priori, all patients receive the same dose, with the assumption that everyone is at equal risk of toxicity. An improving appreciation of normal tissue biology, physiology and genetics suggests that there is likely considerable variability in terms of risk, and therefore population-based prescriptions subject the majority of patients to doses lower than they can actually tolerate, in order to ensure that no major toxicities develop in the vast majority of patients.

The advent of advanced imaging, intensity modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT) has opened up the possibility of personalizing radiotherapy prescriptions. By doing so, clinicians can migrate away from the routine practice of population-based prescriptions, leading to innovative concepts, such as adaptive radiotherapy, dose-painting, and theragnostic radiation oncology.

The Impact of Advanced Imaging

Advanced imaging, including PET and MR, has revolutionized the practice of radiotherapy. First, routine use of these modalities has resulted in “stage migration.” For example, patients deemed to have stage III (loco-regionally advanced) non-small cell lung cancer (NSCLC) on the basis of CT imaging are often “upstaged” to Stage IV on the basis of asymptomatic brain metastases identified by MR, or systemic metastases identified by PET. This stage migration has been proposed to have considerable economic implications. Inaccurately staged patients frequently end up receiving therapies that are not ideal for their true staging, and this often leads to overutilization of certain therapeutic modalities. Appropriate staging saves resources by avoiding unnecessary treatment. Although precise numbers are not readily available, it is estimated by some that anywhere from 5% to 20% of CT-defined Stage III NSCLC patients are upstaged to Stage IV on the basis of PET and MR.

To prospectively examine the impact of hybrid PET/CT imaging on overall oncologic impact, with a focus on radiotherapy planning, we performed a prospective, blinded trial in 111 patients. Patients with lung cancer (n=38), head-and-neck squamous cell carcinoma (n=23), breast (n=8), cervix (n=15), esophageal (n=9), and lymphoma (n=18) underwent hybrid PET/CT imaging at the time of radiation therapy planning. A physician blinded to the PET dataset designed a treatment plan using all clinical information and the CT dataset. The treating physician subsequently designed a second treatment plan using the hybrid PET/CT dataset. The two treatment plans were compared to determine if a major alteration in overall oncologic management occurred (see Table 1).

In patients receiving potentially curative radiotherapy, the concordance between CT-based and PET/CT-based GTVs was quantified using a conformality index (CI). In 76 of 111 (68%) of patients, the PET/CT data resulted in a change in one or more of the following: GTV volume, regional/local extension, prescribed dose or treatment modality selection. In 35 of these 76 cases (46%; 31.5% of the entire cohort), the change resulted in a major alteration in oncologic management (dose, field design, or modality change). Thus, nearly a third of all cases had a major alteration in oncologic management as a result of the PET/CT data, and 29 of 105 patients (27.6%) who underwent potentially curative radiotherapy had major alterations in either dose or field design (see Figure 1 below). Hybrid PET/CT imaging at the time of treatment planning therefore may be highly informative and an economical manner in which to obtain PET imaging, with the dual goals of staging and treatment planning.¹

Assuming that a definitive course of radiotherapy is estimated to cost $20,000 (considerable regional variation in this exists), and that 6,000 of the estimated 60,000 patients with CT-identified Stage III NSCLC are upstaged to Stage IV, in this simple example there would be a cost saving of $120 million by avoiding definitive radiotherapy. Extrapolated to all cancers, these numbers can rapidly assume considerable significance.

However, this simplistic example does not reflect societal reality, which must factor in the cost of incorporating advanced imaging, as well as the costs of alternative therapies that would replace radiotherapy. For example, assuming that the added imaging cost per patient is $5,000, this imaging would need to be applied to the entire population of patients at risk for upstaging, and in our example, this would amount to $300 million, which would negate any cost savings from avoiding radiotherapy in 6,000 patients. Realistically, the need to screen large groups of patients to identify smaller subsets whose therapy can be avoided or altered does not appear to lead to immediate meaningful reductions in the overall cost of cancer care. The genuine benefit that accrues from this is therefore not fiscal, but medical, in that a greater proportion of patients receive a more appropriate form of therapy.

From a radiotherapeutic perspective, advanced imaging has had a significant impact in “tailoring” the radiotherapy fields away from the “population-based” designs, which include vast swathes of regional nodes—assuming that they were all at equal risk—to avoidance of such “prophylactic nodal irradiation.” Several NSCLC clinical trials have now explored this concept, primarily treating nodal areas that are deemed to be abnormally enlarged on CT, or normal in size, but demonstrating increased FDG-uptake on PET imaging.² These trials have resulted in overall reductions in the total volume of tissue treated, thereby affording the opportunity to diminish toxicities. Such an opportunity logically provides the possibility of increasing total tumor dose, and several clinical trials have indeed accomplished this.^3,4 Preliminary institutional data suggest the ability to considerably escalate total dose, and at least one randomized trial from China also shows a survival improvement with this approach.⁵

The Impact of IMRT and IGRT

IMRT utilizes multiple beams of varying intensity delivered from several angles to very precisely shape the high radiation isodoses to the CTV, thereby precisely limiting and avoiding normal critical structures. An inherent risk in such an approach is the use of multiple small beamlets, and this potentially increases delivery inaccuracy. The combination of image guidance just before or during treatment (IGRT) substantially improves the accuracy of IMRT delivery. Therefore, IMRT combined with IGRT is more likely to provide accurate dose deposition with high precision. Once again, this inherently opens up opportunities for further dose-escalation, and avoidance of normal tissue toxicities.

We performed a comprehensive assessment of patient set-up using daily MVCT imaging by tumor site from more than 3,800 helical TomoTherapy treatments. This was done to assess the need for IGRT for patient setup in different anatomic treatment sites. Translational and rotational setup corrections per-fraction were analyzed for more than 1,414 lung, 1,274 prostate, and 1,179 head and neck and brain treatment fractions. Frequencies of 3D vector lengths, overall distributions of setup corrections, and patient-specific distributions of setup errors were analyzed in order to assess differences in patient positioning. 3D vector translational shifts of larger magnitudes occurred more frequently for lung and prostate than for brain and H&N treatments. Global systematic errors were minimal for all treatment sites except prostate, which had an error of 5.0 mm in the vertical direction. Patient-to-patient variations in systematic errors and magnitudes of random translational errors ranged from 1.6-2.6 mm for brain and head and neck and 3.2-7.2 mm for lung and prostate. Roll rotational errors ranged from 0.8-1.2? for brain and head and neck and 0.5-1.0? for lung and prostate (see Table 2). Daily imaging for each patient within each treatment site can improve treatment by correcting setup errors.6 However, the utilization of both IMRT and IGRT increases the cost of delivering radiotherapy, and can be justified only if corresponding improvements in clinical results are obtained.

A study by Konski et al presented at the 2004 ASTRO meeting found that IMRT is cost-effective due to the reduction in adverse effects and extended rates of disease-free survival, which means that fewer additional treatments with either hormone therapy or chemotherapy are required. The researchers developed a Markov model to compare IMRT and 3D conformal radiation therapy in a 70-year-old man with prostate cancer at intermediate risk for cancer recurrence or progression. The disease states modeled included:

1. no disease progression;
2. disease progression that responded to hormone therapy;
3. disease progression that did not respond or stopped responding to hormone therapy and therefore required chemotherapy; and
4. complete failure of therapy and death.

The study adjusted years of survival to reflect quality of life, thereby measuring quality-adjusted life years. The dose of radiation used to calculate cost was 81 Gy in 1.8 Gy fractions for IMRT and 78 Gy in 2 Gy fractions for conformal radiation therapy. The expected mean cost of IMRT was $52,170, with a survival of 7.62 quality-adjusted life years. The expected mean cost of 3D conformal radiation therapy was $27,357 with a survival of 6.65 quality-adjusted life years. Therefore, the incremental cost-effectiveness of IMRT was $25,580 for the additional quality-adjusted life year, well below the limit of $50,000 per quality-adjusted life year commonly accepted by health economists to determine cost-effectiveness.⁷

At the University of Wisconsin, Ritter et al have been delivering biologically comparable radiation doses using a much shorter schedule, which would further enhance the cost-effectiveness. In this phase I/II study, a dose per fraction escalation strategy is used in three steps, with late rectal bleeding the escalation-limiting factor. The design results in predicted late effects expected to remain relatively constant (at a level consistent with about 76 Gy delivered in 2 Gy fractions) even as fraction size escalates. The trial design also includes a nested fractions-per-week escalation/de-escalation to monitor for and prevent unacceptable acute toxicities that might result from too extreme a shortening of treatment duration. Preliminary results from this phase I/II trial have indicated acceptably low rates of GI and GU toxicity (2 years grade 2 GI and GU toxicity rates of 8.8% and 3%, respectively, even after 5-day-per-week treatment and preliminary biochemical control rates that are high and in the expected range). The trial has now been completed with 300 patients accrued, demonstrating the substantial capacity of IMRT/IGRT to permit safe dose escalation.⁸

Another analysis by Strauss et al examined the cost issue for breast cancer, using data from a case-control trial and a recent randomized controlled trial showing that IMRT reduces the incidence of moist desquamation. They performed an analysis to estimate the cost-effectiveness of breast IMRT to prevent moist desquamation. The direct medical costs of conventional whole breast radiotherapy and IMRT were estimated using the 2006 Medicare Fee Schedule. Moist desquamation rates of 31% to 48% were used in the model, based on known published rates in the literature. The cost-effectiveness ratio (additional dollars spent per case of desquamation avoided) was calculated under two circumstances:

1. every patient received IMRT, or
2. only those patients destined to desquamate were treated with IMRT.

The direct medical costs of conventional versus IMRT were $7,948 versus $29,790. Thus, the marginal cost of IMRT is $22,142. In circumstance 1, the marginal cost to avoid one case of desquamation is $130,247. In circumstance 2, this cost is $62,518. Patient risk factors for desquamation, such as large breast size, can be used to identify high risk patients, obviating the need to treat all patients with IMRT.⁹

To improve local control for inoperable non-small cell lung cancer, a phase I dose escalation study for locally advanced and medically inoperable patients was devised by us to escalate tumor dose while limiting the dose to organs at risk including the esophagus, spinal cord, and residual lung. Helical TomoTherapy provided image-guided IMRT, delivered in a 5-week hypofractionated schedule to minimize the effect of accelerated repopulation; 46 patients judged not to be surgical candidates with Stage I-IV NSCLC were treated. Concurrent chemotherapy was not allowed. Radiotherapy was delivered via helical TomoTherapy and limited to the primary site and clinically proven or suspicious nodal regions without elective nodal irradiation.

Patients were placed in one of five dose bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. The bin doses of 57 to 80.⁵ Gy result in 2 Gy/fraction normalized tissue dose (NTD) equivalents of 60 to 100 Gy. In each bin, the starting dose was determined by the relative normalized tissue mean dose modeled to cause < 20% Grade 2 pneumonitis. Dose constraints included spinal cord maximum NTD of 50 Gy, esophageal maximum NTD < 64 Gy to = 0.5 cc volume, and esophageal effective volume of 30%. No grade 3 RTOG acute pneumonitis (NCI-CTC v.3) or esophageal toxicities (CTCAE v.3.0 and RTOG) were observed at median follow-up of 8.1 months. Pneumonitis rates were 13% grade 2 and 0% grade 3 or greater.

Only seven patients (15%) required narcotic analgesics (RTOG grade 2 toxicity) for esophagitis, with only 2.3% average weight loss during treatment. Best in-field gross response rates were 17% complete response, 43% partial response, 26% stable disease, and 6.5% in-field thoracic progression. The out-of field thoracic failure rate was 13%, and distal failure rate was 28%. The median survival was 18 months with 2-year overall survival of 46.8 ? 9.7% for this cohort, 50% of whom were stage IIIB and 30% stage IIIA. Our preliminary results therefore show that dose escalation can be safely achieved in NSCLC with lower than expected rates of pneumonitis and esophagitis using hypofractionated image-guided IMRT.¹⁰

Moving Forward: Theragnostic Radiation Oncology

The examples above illustrate the potential of IMRT and IGRT to safely escalate dose, and all of these examples are based on the concept of homogenous dose escalation within the entire GTV. IMRT provides the opportunity to deliberately generate inhomogenous dose distributions, and these could be exploited therapeutically. The inherent concept here is that radiation resistance is mediated by biological heterogeneity within a tumor. In addition, the distribution of tumor cells into radiosensitive and radioresistant compartments highlights the value of inhomogenous radiation dose distributions, as long as the resistant compartment receives the higher dose and the sensitive compartment the lower dose. Such “dose-painting” can be performed using some baseline predictive imaging methodology, and FDG PET SUV is sometimes considered as a possible tool for this. However, as defined by Bentzen, theragnostic imaging for radiation oncology is the use of molecular and functional imaging to prescribe the distribution of radiation in four dimensions—the three dimensions of space plus time in an individual patient. Several new imaging targets for PET, SPECT, and MR allow variations in microenvironmental or cellular phenotypes that modulate the effect of radiation to be mapped in three dimensions. Dose-painting by numbers is a strategy by which the dose distribution delivered by IMRT is prescribed. This approach currently remains investigational but holds considerable promise.¹¹

---

Minesh P. Mehta, MD, FASTRO, is professor, radiation oncology at Ohio State University, James Cancer Hospital, and a consultant for TomoTherapy Inc.

References

1. Kruser TJ, Bradley KA, Bentzen SM, et al. The impact of hybrid PET-CT scan on overall oncologic management, with a focus on radiotherapy planning: a prospective, blinded study. Technol Cancer Res Treat. 2009;8:149-158.
2. Sura S, Gupta V, Yorke E, et al. Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol. 2008;87:17-23.
3. Kong FM, Ten Haken RK, Schipper, MJ, et al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 2005;63:324-333.
4. Belderbos JS, Heemsbergen WD, De Jaeger K, et al. Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:126-134.
5. Yuan S, Sun X, Li M, et al. A randomized study of involved field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer. Am J Clin Oncol. 2007;30:239-244.
6. Schubert LK, Westerly DC, Tom? WA, et al. A comprehensive assessment of patient setup using daily MVCT imaging by tumor site from more than 3,800 helical tomotherapy treatments, Med Phys. 2009;73:1260-1269.
7. Konski A, Watkins-Bruner D, Feigenberg S, et al. Using decision analysis to determine the cost-effectiveness of intensity-modulated radiation therapy in the treatment of intermediate risk prostate cancer. Int J Radiat Oncol Biol Phys. 2006;66:408-415.
8. Ritter MA, Forman JD, Kupelian PA, et al. A phase I/II trial of dose-per-fraction escalation for prostate cancer. Int J Radiat Oncol Biol Phys. 2007;69:S174.
9. Strauss JB, Chen SS, Dickler AT, Griem KL. Cost effectiveness of whole breast IMRT for reduction of moist desquamation. J Clin Oncol. 2007;25(June 20 suppl):18S.
10. Adkison JB, Khuntia D, Bentzen SM, et al. Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I dose escalation study. J Cancer Res Technol. 2008;7:441-448.
11. Bentzen S. Theragnostic imaging for radiation oncology: dose-painting by numbers. Lancet Oncol. 2005;6:112-117.