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On the cost-effectiveness of Carbon ion radiation therapy for skull base chordoma
Radiotherapy and Oncology 83 (2007) 133–138 www.thegreenjournal.com
Cost of hadrontherapy
On the cost-effectiveness of Carbon ion radiation therapy for skull base chordoma Oliver Ja ¨kela,*, Beate Landa, Stephanie Elisabeth Combsb, Daniela Schulz-Ertnerb, Ju ¨rgen Debusb a
Department of Medical Physics in Radiation Oncology, Heidelberg, Germany, bUniversity Hospital, Department for Radiation Oncology, Heidelberg, Germany
Abstract Aim: The cost-effectiveness of Carbon ion radiotherapy (RT) for patients with skull base chordoma is analyzed. Materials and Methods: Primary treatment costs and costs for recurrent tumors are estimated. The costs for treatment of recurrent tumors were estimated using a sample of 10 patients presenting with recurrent chordoma at the base of skull at DKFZ. Using various scenarios for the local control rate and reimbursements of Carbon ion therapy the costeffectiveness of ion therapy for these tumors is analyzed. Results: If local control rate for skull base chordoma achieved with carbon ion therapy exceeds 70.3%, the overall treatment costs for carbon RT are lower than for conventional RTI. The cost-effectiveness ratio for carbon RT is 2539 Euro per 1% increase in survival, or 7692 Euro per additional life year. Conclusion: Current results support the thesis that Carbon ion RT, although more expensive, is at least as costeffective as advanced photon therapies for these patients. Ion RT, however, offers substantial benefits for the patients such as improved control rates and less severe side effects. c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 83 (2007) 133–138.
Keywords: Radiation therapy; Carbon ion; Skull base; Cost-effectiveness
The total number of newly diagnosed tumors in Germany is increasing by 3–4% per year [1]. Due to the expected further increase of the expectancy of life and better diagnostic possibilities in the industrialized countries, this trend is expected to continue. The increasing costs for tumor therapies will therefore soon become a major burden for the health care systems. In the US, the NCI (National Cancer Institute) estimated the total treatment costs for cancer patients to amount to 18 billion US $ in 1985 and 41 billion US $ in 1995. These numbers do not include any indirect costs, which were estimated to be around 100 billion US $ for 1995. In view of these facts, the introduction of new cost intense therapy modalities is discussed very critically. It has even been stated that technology has been the primary driver of the increase in healthcare costs in the last 50 years [18]. Concerning new methods in cancer therapy, even the allegation has been made that ‘‘The distinctions between evidence-based medicine and if-it’s-reimbursable-we’lldo-it medicine have been lost’’ [7]. Before new expensive therapy modalities can be introduced into clinical practice, it is therefore important, to demonstrate not only the effectiveness of the therapy,
but to assess also the cost-effectiveness of the modality in comparison with conventional methods. In this article an attempt is made to analyze the costeffectiveness of Carbon ion radiotherapy (RT) using currently available data for the largest clinical trial performed in Germany. The German pilot project on Carbon ion radiotherapy is carried out by the University Hospital of Heidelberg, Department of Radiation Oncology, in cooperation with the Department of Medical Physics at the German Cancer Research Center (DKFZ, Heidelberg) and the Gesellschaft fu ¨r Schwerionenforschung (GSI) in Darmstadt.
Materials and methods Heavy ion radiotherapy Within the last two decades particle therapy with protons and Carbon ions has gained increasing interest worldwide. The primary rationale for RT with heavy charged particles is the sharp increase of dose in a well defined depth (Bragg peak) and the rapid dose fall-off beyond that maximum. The ratio of Bragg peak dose vs. dose in the entrance region is larger for Carbon ions than for
0167-8140/$ - see front matter c 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2007.03.010
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On the cost-effectiveness of Carbon ion radiation therapy
protons. Due to their larger mass, angular and energy straggling can be neglected with the use of Carbon ions as compared to protons. Carbon ions therefore offer an improved dose conformation as compared to photon and proton RT with better sparing of normal tissue structures close to the target. In addition, Carbon ions exhibit a strong increase of the linear energy transfer (LET) in the Bragg peak as compared to the entrance region. The radiobiological advantage of high LET radiation in tumor therapy is well known from neutron therapy. Unlike in radiotherapy with neutron beams, in Carbon ion radiotherapy the high LET region can also be conformed to the tumor. First clinical experiences with heavy ions (mainly Helium and Neon) have been made between 1977 and 1992 at the Lawrence Berkeley Laboratory [2,3]. Currently, Carbon ion RT is available at 3 facilities: two hospital based facilities in Japan (HIMAC/Chiba and HIBMC/Hyogo) and a physics research facility at GSI (Darmstadt, Germany). There is, however, an increasing interest in ion radiotherapy especially in Europe, where new facilities are being built in Heidelberg (Germany) and Pavia (Italy) or are in an advanced planning phase like in Wiener Neustadt (Austria), Lyon and Caen (France), Marburg and Kiel (Germany) [16]. The clinical experience with Carbon ions is still limited. At HIMAC, about 2400 patients have been treated within a series of clinical trials mainly for patients with tumors of the lung, liver, prostate, head and neck as well as for bone and soft tissue sarcoma patients since 1994. At the German facility, more than 330 patients have been treated since 1997 using a spot-scanning technique, the majority with chordoma and chondrosarcoma located at the base of skull, cervical spine and sacrum [11]. A smaller group of patients with adenoid-cystic carcinoma was treated with a combination of conventional and Carbon ion RT [14]. In these studies the observed radiation induced side effects after Carbon ion therapy were generally less pronounced as compared to conventional or even proton therapy. For skull base tumors, acute radiation induced effects (mainly mucositis) of grade 3 CTC were observed only in very few patients. The rate of late toxicity (temporal lobe injury) was reduced by about a factor of 2 as compared to proton RT [12,13]. The dose sparing potential of a scanned ion beam in RT is of special importance for patients with recurrent tumors that already received a course of RT. Using the spot-scanning beam delivery technique the dose can be confined to the target even if only a single field of ions is used. Commonly only two fields are used for the treatment of a skull base tumor, but in some cases treatments with even a single field are possible. The amount of involved normal tissue can therefore be reduced to a minimum.
Estimate of treatment costs The cost analysis was performed for patients with chordoma at the base of skull, which is the largest group of patients treated with Carbon ions in Germany. In total 96 patients with this indication have been treated with Carbon ions in Germany. In order to assess the cost-effectiveness of
Carbon ion radiotherapy, the primary treatment costs1 for conventional and Carbon ion RT were evaluated first. In a second step, the costs resulting from the treatment of recurrent tumors after primary treatment were assessed. In order to calculate the costs for the treatment of recurrent tumors, a sample of ten patients presenting at the DKFZ with recurrent chordoma at the base of skull was selected randomly and the medical records were analyzed. The overall costs of RT with photons and ions were calculated by adding the reimbursement for the primary treatment and the mean reimbursement for the treatment of a patient with a recurrent chordoma, weighted by the probability of recurrence.
Primary treatment costs According to common therapy standards, the primary treatment of patients with chordoma of the base of skull was assumed to be a combination of a neurosurgical resection of the tumor followed by a definitive radiation therapy [4]. In order to assess the treatment costs, only the major cost drivers were taken into account: surgical treatment, hospitalization and radiation therapy. Further costs for diagnostic investigations (biopsy, pathological examinations, imaging), supportive therapy (e.g. analgesics) or consequential costs (nursing, diagnostic follow-up, rehabilitation costs) were disregarded. The reason for doing so is twofold: first, only the medical records of the treatment performed in our institutions were available with all requested details, whereas treatments performed at other institutions were documented, however, not all details were at our disposal; second, the costs, especially for rehabilitation, may be substantial. A great difference between these costs for either RT modality is, however, not expected. Furthermore, as ion RT leads to a reduction of side effects, this cost factor will probably be smaller for ion therapy. The costs taken into account are only direct treatment related costs. All indirect costs (like e.g. loss of economic productivity during and after treatment, costs for treatments of late effects induced by radiation) were neglected. These indirect costs may be substantial and may be very different for the various modalities (as discussed below) but they could not be evaluated for the patients in this study. Neurosurgical resection of a tumor at the base of skull is a very demanding surgery that leads to a strong strain for the patient and requires long hospitalization. An inquiry at the department for neurosurgery at the Heidelberg University hospital resulted in an average reimbursement for a neurosurgical intervention at the base of skull of approximately 11 000 € (status June 2004). According to the same inquiry, the mean duration of the hospitalization following the surgical intervention is 3 weeks. The standard reimbursement paid by the assurance 1
The term treatment cost does not always refer to the real costs of the treatment. In the case of conventional RT or neurosurgical treatment this term refers to the reimbursement paid by the insurance companies. In the case of heavy ion RT, this value refers to an estimate of the real costs, taking into account all connected costs.
¨kel et al. / Radiotherapy and Oncology 83 (2007) 133–138 O. Ja
companies for a single day of hospitalization in a university hospital is 600 €. The additional mean reimbursement for the hospitalization therefore amounts to 12 600 €. This number is probably too low, since it is neglected that after such a resection, patients often need intensive care for several days, which is considerably more expensive. Rehabilitation treatment of the patients is only necessary in cases where neurosurgical deficits appear after treatment. Since again these data were not available, the rehabilitation costs were also omitted. The reimbursement for conventional radiotherapy with photons was estimated according to the common scale of charges and fees defined within the German health care system. For a full course of high precision radiotherapy a maximum fee of approximately 3500 € can be charged. This includes the fees for the irradiation (2300 €) as well as fees for three-dimensional computer-based treatment planning, including CT and MR imaging (1200 €). Very similar figures were found in the literature for Belgium [8] and various European countries [9]. Carbon ion radiotherapy in Germany is currently reimbursed as a standard treatment only for a few indications after individual consent has been obtained from the patient’s health insurance. The reimbursement for a full course of Carbon ion irradiation of 20 fractions (as performed for the patients treated for skull base tumors) is 20 000 €. For the new clinical ion facility in Heidelberg a reimbursement of 19 500 € was agreed upon with the insurance companies. This is consistent with estimated costs of around 1000 € per fraction, as calculated within the proposal written for the clinical particle therapy facility in Heidelberg [6]. Again these figures are very similar to estimates performed for the Italian [9], French and Austrian projects [10].
Costs for recurrent tumors In order to estimate the mean costs for patients treated with recurrent chordoma, the medical records of 10 chordoma patients, presenting at the DKFZ with recurrences, were analyzed. The available medical records only covered the treatment given at DKFZ in detail; other treatments and procedures performed were documented (including any prior diagnoses, information on nursing or rehabilitation), however, were commonly not performed at our institution and therefore not all required details for the present analysis were readily available. In order to calculate the overall treatment costs, the costs for repeated surgery, hospitalization and repeated radiotherapy were added according to the medical records. In doing so the treatment costs were taken as specified above. This number was calculated for each patient individually. All patients in the investigated group received conventional RT with photons, before the tumor recurred. The treatment of the recurrent tumors mainly was performed using repeated surgical approaches, while a second course of conventional RT was performed only for a single patient using a restricted target volume and dose in order not to exceed the radiation tolerances of the normal tissues. The majority of patients (6/10), however, were consequently treated with the more expensive Carbon ion RT for the
135
recurrent tumor, which was possible due to the high degree of dose conformation achievable with the spot-scanning technique. One of the patients could even be treated with a third course of RT. The treatment of recurrent tumors with Carbon ions was performed using single or two fields. The prescribed doses were limited by the radiation tolerances of the pre-irradiated normal tissues. From these overall individual costs, the cost for the primary treatment (neurosurgery plus conventional RT) is subtracted in order to obtain the additional costs for the treatment of the recurrencies. The cost for treatment of patients with recurrent tumors was averaged over all patients to obtain the mean cost for the treatment in the case of a recurrence. Without such a correction, the mean treatment costs for recurrent tumors would be exaggerated. In order not to overestimate the costs for these patients, the above correction was applied, in such a way, that only the reduced costs were taken into account that would result from conventional therapy, rather than the costs from Carbon ion RT.
Analysis of the cost-effectiveness Given the above numbers, the total treatment costs resulting from various scenarios with different outcomes of RT can be analyzed. To do so, the costs for the primary treatment and the mean cost for the treatment of a patient with a recurrent chordoma, weighted by the probability of recurrence, were added. If the local control (LC) rate is assumed to be the probability for a cure of the patient, then the quantity (1-LC) is an estimate for the probability of recurrent tumor. The resulting total treatment costs are then valid for a population of patients similar to the one presented in Table 2. The control rate for chordoma patients after conventional radiotherapy has been shown to be between 23% and 38% [15]. Best results with photons have been achieved using high precision stereotactically guided fractionated RT providing a local control rate of 50% [4]. In contrast to this, the 5-year local control rates for the treatment of chordoma patients with Carbon ion RT which have recently been analyzed [12] are at 70%. In addition to the best achievable control rates for conventional RT and ion RT (50% and 70%, respectively) and in order to study the effect of the local control rate on the cost-effectiveness, the calculations were also performed using a local control rate of 35% (assuming conventional RT) and 60% (assuming Carbon ion RT). Carbon ion RT has the potential of reducing further the overall number of fractions as is demonstrated by the results of the HIMAC facility [17]. Therefore, a second scenario (B) was introduced, where the overall treatment costs for Carbon ions were reduced by 20% equivalent to a moderate reduction of the total number of fractions to 16.
Results Costs for primary treatments and treatment of recurrent tumors The cost for the primary treatment as given in the text is summarized in Table 1. The resulting overall costs for the
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On the cost-effectiveness of Carbon ion radiation therapy
Table 1 Primary cost drivers and composition of treatment costs for the primary treatment of a patient with a skull base chordoma as described in the text Treatment
Treatment costs in €
Conventional photon RT Carbon ion RT Neurosurgical resection
Treatment planning Treatment delivery Planning + delivery Surgery Hospitalization
Total costs for conv. RT Total costs for ion RT
1200 2300 20 000 11 000 12 600 27 100 43 600
primary treatment using conventional photon RT and Carbon ion RT are 27 100 € and 43 600 €, respectively. The individual treatment costs for each patient and overall costs as calculated from the data in the medical records are summarized in Table 2. The mean overall cost for the treatment of a patient in this collective amounted to 121 770 €. If the individual cost for the primary treatment (neurosurgery plus conventional RT) is subtracted, the remaining mean cost for treatment in the case of recurrences amounts to 94 670 €. If the costs for patients receiving Carbon ion therapy were corrected, the mean costs for the treatment of recurrences thus amounted to 81 470 €.
Cost-effectiveness The overall treatment costs resulting from the sum of the costs for the primary treatment and the costs for the treatment of recurrent tumors, weighted with the probability of recurrence have been calculated for various scenarios. The results of the overall costs using local control rates for RT of 35%, 50%, 60%, and 70% are presented in column (A) of Table 3. The presented data only depend on the local control rate and treatment modality used to achieve them. It has to be stressed that the calculations for 35% and 50% local control were performed assuming conventional RT, while for the results at 60% and 70% local control, Carbon RT was assumed to be the primary RT modality. This affects only the primary treatment costs, as the costs for recurrent tumors are independent, due to the correction explained above.
The results for the second scenario (B), with the reduced number of fractions (16 instead of 20) and a 20% reduction of the overall costs, are given in column (B) of Table 3. As compared to results of standard conventional RT not using conformal stereotactic techniques, it is obvious that Carbon ion RT is certainly more cost-effective and yields much better local control. Looking at the best achievable results with conventional RT, the break-even point for Carbon RT applied in 20 fractions is reached at a control rate of 70.3%, where the saving of costs for recurrent tumors compensates for the more expensive ion RT. If the number of fractions can be reduced to 16 the costs of the primary treatment including carbon ion RT are 39 600 and this break-even is reached already at a control rate of 65.3%. The cost-effectiveness ratio (CER) is expressed as the additional treatment costs of the new technique weighed by gain in outcome. The CER can be based either on the gain in local control, which can be used as a measure of disease free survival, or on the overall survival rates. Taking the mean local control rates of 50% and 70% (for 5 years) for conventional and ion RT, the CER in terms of disease free survival is 16 500 €/year of disease free survival. The reported overall survival rates for precision RT using photons are 82% (at 5 years) [4] and 88.5% after Carbon RT [15]. The CER therefore is 2539 € per 1% increase in survival rate. Given the mean age of the patients in the analysis (47 years), a remaining lifespan of at least 33 years can be expected. In terms of additional life years the CER becomes 7692 €/year.
Discussion Skull base chordoma are tumors, where a complete surgical resection is rarely possible due to the anatomical structures in close vicinity including brain stem, optic system as well as bony structures. The standard for the primary treatment is therefore a combination of surgery and RT, which is a very common situation in tumor therapy. The major cost driver in the primary therapy consequently is surgery and not RT. Due to this fact, the primary therapy including ion RT is only roughly a factor of 2 more expensive than conventional RT, although ion RT is roughly 6.5 times more expensive than conventional RT.
Table 2 Treatments and costs for the health care of 10 patients presenting with recurrent chordoma of the skull base at the DKFZ in 2002/2003 Patient 1 2 3 4 5 6 7 8 9 10
No. of surgeries
Days of hospitalization
No. of RT treatments
Overall treatment costs
4 5 4 7 4 3 4 3 2 4
84 105 124 147 144 74 84 68 63 84
1 1 2 3 2 1 2 2 1 2
114 400 € 138 000 € 125 400 € 208 700 € 153 900 € 97 400 € 101 400 € 97 300 € 79 800 € 101 400 €
¨kel et al. / Radiotherapy and Oncology 83 (2007) 133–138 O. Ja
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Table 3 Overview of total costs of therapy for different local control rates of Carbon ion RT and different cost scenarios (A: current costs, B: reduced costs for Carbon RT) 5-Year local control rate
35% 50% 60% 70%
(conv. RT) (conv. RT) (Carbon RT) (Carbon RT)
Cost of primary therapy in €
27 100 27 100 43 600 43 600
Furthermore, since recurrent tumors are a rather common phenomenon in patients with skull base chordoma, the cost for the treatment of recurrent tumors is roughly 3 times higher than the cost for the primary treatment (based on conventional RT). It is certainly a common feature for tumors that are difficult to control, that the overall treatment costs are dominated by the costs for the treatment of the recurrent tumors. Any improvement in the local control rate therefore has a potential to decrease this large fraction of the overall treatment costs. The calculated CER in terms of gain in overall survival probability due to Carbon ion RT is 2539 € per 1% increase. If not only the primary treatment costs but also the costs for treatment of recurrent tumors are taken into account, carbon RT is not more expensive than conventional RT, but yields considerably better outcome. The analysis therefore shows clearly that Carbon ion RT is more cost-effective than a conventional RT treatment for chordoma patients. The analysis, however, suffers from large uncertainties in the cost estimates, which are mainly due to a lack of patient specific data and a lack of transparency in the system of charges and fees in the German health care system. Since realistic treatment costs for conventional RT or neurosurgical treatments are not accessible, the costs were assumed to be given by the standard reimbursement for these treatments (see also footnote 2). Any additional cost factor which is independent from the RT modality (like e.g. rehabilitation) would further increase the non-RT related costs and lead to an even higher cost-effectiveness of ion RT. If as an example, additional costs of 3000 € were assumed as additional costs after each neurosurgical treatment, the mean costs for recurrent tumors would increase by 12 000 € (for a mean of 4 surgeries) and the overall treatment costs for conventional RT would increase by 9000 € towards 76 835 € (at 50% local control), while for carbon RT the increase would be 6600 € towards 74 641 € (70% local control). Concerning additional costs, which are RT-related, it can be assumed that these costs are even lower for ion RT as compared to photon RT. For example, treatment related morbidity is generally much lower in the case of ion RT as compared to conventional RT (see e.g. [13,12]). Consequently the cost for additional supportive therapy and medication is lower. The lower iatrogenic morbidity together with an overall shortened therapy (20 fractions instead of 40 fractions) and the fact that ion RT can be administered on an outpatient basis lead to a significant reduction of the loss of economic productivity. In the group of patients being treated with Carbon ion RT there have been several patients that were working regularly even during the course
Cost of recurrencies in €
52 956 40 735 32 588 24 441
Total costs in € Scenario A
Scenario B
80 056 67 835 76 188 68 041
— — 72 188 64 041
of RT. The reason for this may be found in the low grade (and sometimes the absence) of even mild side effects like alopecia or skin erythema in these patients. It should also be pointed out that the reimbursement for high precision conventional RT is fixed at a rather low level by German governmental regulations, while for ion RT the true costs were estimated. For the US it was estimated [5] that the cost of a high precision conventional RT is around 10 000 €. The current reimbursement for a modern precision RT with photons (like stereotactically guided RT or IMRT) in Germany is probably not covering the true costs. Moreover, there is still a potential for ion RT to be even more cost-effective, if the number of fractions can be reduced further, as has been done quite successfully at the Japanese facility HIMAC for a number of tumors [17]. Another aspect that is not included in the cost analysis is the fact that an increased local control and reduced side effects of the treatment are of course invaluable benefits for the patient, which cannot easily be evaluated in terms of costs.
Conclusions In view of the numerous hospital based ion facilities which are currently planned or are already under construction, the question about cost-effectiveness of ion RT inevitably appears. Our analysis provides some evidence that ion RT can be more cost-effective in the treatment of some tumors, which are typically treated by a combination of surgery and RT and for which a clear increase of the control rates can be shown, when ion RT is used. In order to identify other more common tumor entities, for which ion RT can be used with increased cost-effectiveness, it is very important to perform clinical studies on the clinical effectiveness of ion beams as compared to photon RT. In addition it is also necessary to improve the accuracy of the calculated direct and indirect treatment costs. This can only be achieved, however, if realistic treatment costs become available and if the health care system becomes generally more transparent. * Corresponding author. Oliver Ja ¨kel DKFZ, Abt. Medizinische Physik in der Strahlentherapie (E040), 69120 Heidelberg, INF 280, Germany. E-mail address: [email protected] Received 10 October 2006; received in revised form 8 March 2007; accepted 19 March 2007; Available online 8 May 2007
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References [1] Becker N, Wahrendorf J, editors. Atlas of cancer mortality in the Federal Republic of Germany. Heidelberg: Deutsches Krebsforschungszentrum; 1998. [2] Castro JR, Linstadt DE, Bahary J-P, et al. Experience in charged particle irradiation of tumors of the skull base 1977– 1992. Int J Radiat Oncol Biol Phys 1994;29:647–55. [3] Castro JR. Clinical Programs: a review of past and existing hadron protocols. In: Amaldi U, Larrson B, Lemoigne Y, editors. Advances in hadron therapy. Amsterdam, Netherlands: Elsevier Science; 1997. p. 79–94. [4] Debus J, Schulz-Ertner D, Schad L, et al. Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys 2000;47:591–6. [5] Goitein M, Jermann M. The relative costs of proton and X-ray radiation therapy. Clin Oncol 2003;15:37–50. [6] Groß KD, Pavlovic M, editors. Proposal for a dedicated ion beam facility for cancer therapy. Darmstadt: GSI; 1998. [7] Halperin E. Overpriced technology in radiation oncology. Int J Radiat Oncol Biol Phys 2000;48:917–8. [8] Kesteloot K, Lievens Y, van der Schueren E. Improved management of radiotherapy departments through accurate cost data. Radiother Oncol 2000;55: 251–62. [9] Orecchia R, Zurlo A, Loasses A, et al. Particle beam therapy (Hadrontherapy): basis for interest and clinical experience. Eur J Cancer 1998;34:459–68.
[10] Pommier P et al. Light ion facility projects in Europe: methodological aspects for the calculation of the treatment cost per protocol; ENLIGHT-Meeting, Novarra, 2004. (Available from: http://www.estro.be). [11] Schulz-Ertner D, Nikoghosyan A, Thilmann C, et al. Results of Carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Phys 2004;58:631–40. [12] Schulz-Ertner D, Karger CP, Feuerhake A, Morath A, Nikoghosyan A, Combs SE, Ja ¨kel O, Edler L, Scholz M, Debus J. Effectiveness of Carbon ion radiotherapy in the treatment of skull base chordomas. Int J Radiat Oncol Biol Phys 2007 [in press]. [13] Schulz-Ertner D et al. Acute radiation-induced toxicity of heavy ion radiotherapy delivered with intensity modulated pencil beam scanning in patients with base of skull tumors. Radiother Oncol 2002;64:189–95. [14] Schulz-Ertner D, Nikoghosyan A, Didinger B, et al. Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation therapy techniques. Cancer 2004;104:338–44. [15] Schulz-Ertner D et al. Radiotherapy of chordomas and lowgrade chondrosarcomas of the skull base with Carbon ions. Int J Radiat Oncol Biol Phys 2002;53:36–42. [16] Sisterson J, editor. Particle newsletter, 36. Cambridge: Harvard; 2005. [17] Tsujii H, Mizoe JE, Kamada T, et al. Overview of clinical experiences on Carbon ion radiotherapy at NIRS. Radiother Oncol 2004;73(Suppl. 2):S41–9. [18] Wells PNT. Can technology truly reduce healthcare costs? IEEE Eng Med Biol Mag 2003;22:20–5.
Cost of hadrontherapy
On the cost-effectiveness of Carbon ion radiation therapy for skull base chordoma Oliver Ja ¨kela,*, Beate Landa, Stephanie Elisabeth Combsb, Daniela Schulz-Ertnerb, Ju ¨rgen Debusb a
Department of Medical Physics in Radiation Oncology, Heidelberg, Germany, bUniversity Hospital, Department for Radiation Oncology, Heidelberg, Germany
Abstract Aim: The cost-effectiveness of Carbon ion radiotherapy (RT) for patients with skull base chordoma is analyzed. Materials and Methods: Primary treatment costs and costs for recurrent tumors are estimated. The costs for treatment of recurrent tumors were estimated using a sample of 10 patients presenting with recurrent chordoma at the base of skull at DKFZ. Using various scenarios for the local control rate and reimbursements of Carbon ion therapy the costeffectiveness of ion therapy for these tumors is analyzed. Results: If local control rate for skull base chordoma achieved with carbon ion therapy exceeds 70.3%, the overall treatment costs for carbon RT are lower than for conventional RTI. The cost-effectiveness ratio for carbon RT is 2539 Euro per 1% increase in survival, or 7692 Euro per additional life year. Conclusion: Current results support the thesis that Carbon ion RT, although more expensive, is at least as costeffective as advanced photon therapies for these patients. Ion RT, however, offers substantial benefits for the patients such as improved control rates and less severe side effects. c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 83 (2007) 133–138.
Keywords: Radiation therapy; Carbon ion; Skull base; Cost-effectiveness
The total number of newly diagnosed tumors in Germany is increasing by 3–4% per year [1]. Due to the expected further increase of the expectancy of life and better diagnostic possibilities in the industrialized countries, this trend is expected to continue. The increasing costs for tumor therapies will therefore soon become a major burden for the health care systems. In the US, the NCI (National Cancer Institute) estimated the total treatment costs for cancer patients to amount to 18 billion US $ in 1985 and 41 billion US $ in 1995. These numbers do not include any indirect costs, which were estimated to be around 100 billion US $ for 1995. In view of these facts, the introduction of new cost intense therapy modalities is discussed very critically. It has even been stated that technology has been the primary driver of the increase in healthcare costs in the last 50 years [18]. Concerning new methods in cancer therapy, even the allegation has been made that ‘‘The distinctions between evidence-based medicine and if-it’s-reimbursable-we’lldo-it medicine have been lost’’ [7]. Before new expensive therapy modalities can be introduced into clinical practice, it is therefore important, to demonstrate not only the effectiveness of the therapy,
but to assess also the cost-effectiveness of the modality in comparison with conventional methods. In this article an attempt is made to analyze the costeffectiveness of Carbon ion radiotherapy (RT) using currently available data for the largest clinical trial performed in Germany. The German pilot project on Carbon ion radiotherapy is carried out by the University Hospital of Heidelberg, Department of Radiation Oncology, in cooperation with the Department of Medical Physics at the German Cancer Research Center (DKFZ, Heidelberg) and the Gesellschaft fu ¨r Schwerionenforschung (GSI) in Darmstadt.
Materials and methods Heavy ion radiotherapy Within the last two decades particle therapy with protons and Carbon ions has gained increasing interest worldwide. The primary rationale for RT with heavy charged particles is the sharp increase of dose in a well defined depth (Bragg peak) and the rapid dose fall-off beyond that maximum. The ratio of Bragg peak dose vs. dose in the entrance region is larger for Carbon ions than for
0167-8140/$ - see front matter c 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2007.03.010
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On the cost-effectiveness of Carbon ion radiation therapy
protons. Due to their larger mass, angular and energy straggling can be neglected with the use of Carbon ions as compared to protons. Carbon ions therefore offer an improved dose conformation as compared to photon and proton RT with better sparing of normal tissue structures close to the target. In addition, Carbon ions exhibit a strong increase of the linear energy transfer (LET) in the Bragg peak as compared to the entrance region. The radiobiological advantage of high LET radiation in tumor therapy is well known from neutron therapy. Unlike in radiotherapy with neutron beams, in Carbon ion radiotherapy the high LET region can also be conformed to the tumor. First clinical experiences with heavy ions (mainly Helium and Neon) have been made between 1977 and 1992 at the Lawrence Berkeley Laboratory [2,3]. Currently, Carbon ion RT is available at 3 facilities: two hospital based facilities in Japan (HIMAC/Chiba and HIBMC/Hyogo) and a physics research facility at GSI (Darmstadt, Germany). There is, however, an increasing interest in ion radiotherapy especially in Europe, where new facilities are being built in Heidelberg (Germany) and Pavia (Italy) or are in an advanced planning phase like in Wiener Neustadt (Austria), Lyon and Caen (France), Marburg and Kiel (Germany) [16]. The clinical experience with Carbon ions is still limited. At HIMAC, about 2400 patients have been treated within a series of clinical trials mainly for patients with tumors of the lung, liver, prostate, head and neck as well as for bone and soft tissue sarcoma patients since 1994. At the German facility, more than 330 patients have been treated since 1997 using a spot-scanning technique, the majority with chordoma and chondrosarcoma located at the base of skull, cervical spine and sacrum [11]. A smaller group of patients with adenoid-cystic carcinoma was treated with a combination of conventional and Carbon ion RT [14]. In these studies the observed radiation induced side effects after Carbon ion therapy were generally less pronounced as compared to conventional or even proton therapy. For skull base tumors, acute radiation induced effects (mainly mucositis) of grade 3 CTC were observed only in very few patients. The rate of late toxicity (temporal lobe injury) was reduced by about a factor of 2 as compared to proton RT [12,13]. The dose sparing potential of a scanned ion beam in RT is of special importance for patients with recurrent tumors that already received a course of RT. Using the spot-scanning beam delivery technique the dose can be confined to the target even if only a single field of ions is used. Commonly only two fields are used for the treatment of a skull base tumor, but in some cases treatments with even a single field are possible. The amount of involved normal tissue can therefore be reduced to a minimum.
Estimate of treatment costs The cost analysis was performed for patients with chordoma at the base of skull, which is the largest group of patients treated with Carbon ions in Germany. In total 96 patients with this indication have been treated with Carbon ions in Germany. In order to assess the cost-effectiveness of
Carbon ion radiotherapy, the primary treatment costs1 for conventional and Carbon ion RT were evaluated first. In a second step, the costs resulting from the treatment of recurrent tumors after primary treatment were assessed. In order to calculate the costs for the treatment of recurrent tumors, a sample of ten patients presenting at the DKFZ with recurrent chordoma at the base of skull was selected randomly and the medical records were analyzed. The overall costs of RT with photons and ions were calculated by adding the reimbursement for the primary treatment and the mean reimbursement for the treatment of a patient with a recurrent chordoma, weighted by the probability of recurrence.
Primary treatment costs According to common therapy standards, the primary treatment of patients with chordoma of the base of skull was assumed to be a combination of a neurosurgical resection of the tumor followed by a definitive radiation therapy [4]. In order to assess the treatment costs, only the major cost drivers were taken into account: surgical treatment, hospitalization and radiation therapy. Further costs for diagnostic investigations (biopsy, pathological examinations, imaging), supportive therapy (e.g. analgesics) or consequential costs (nursing, diagnostic follow-up, rehabilitation costs) were disregarded. The reason for doing so is twofold: first, only the medical records of the treatment performed in our institutions were available with all requested details, whereas treatments performed at other institutions were documented, however, not all details were at our disposal; second, the costs, especially for rehabilitation, may be substantial. A great difference between these costs for either RT modality is, however, not expected. Furthermore, as ion RT leads to a reduction of side effects, this cost factor will probably be smaller for ion therapy. The costs taken into account are only direct treatment related costs. All indirect costs (like e.g. loss of economic productivity during and after treatment, costs for treatments of late effects induced by radiation) were neglected. These indirect costs may be substantial and may be very different for the various modalities (as discussed below) but they could not be evaluated for the patients in this study. Neurosurgical resection of a tumor at the base of skull is a very demanding surgery that leads to a strong strain for the patient and requires long hospitalization. An inquiry at the department for neurosurgery at the Heidelberg University hospital resulted in an average reimbursement for a neurosurgical intervention at the base of skull of approximately 11 000 € (status June 2004). According to the same inquiry, the mean duration of the hospitalization following the surgical intervention is 3 weeks. The standard reimbursement paid by the assurance 1
The term treatment cost does not always refer to the real costs of the treatment. In the case of conventional RT or neurosurgical treatment this term refers to the reimbursement paid by the insurance companies. In the case of heavy ion RT, this value refers to an estimate of the real costs, taking into account all connected costs.
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companies for a single day of hospitalization in a university hospital is 600 €. The additional mean reimbursement for the hospitalization therefore amounts to 12 600 €. This number is probably too low, since it is neglected that after such a resection, patients often need intensive care for several days, which is considerably more expensive. Rehabilitation treatment of the patients is only necessary in cases where neurosurgical deficits appear after treatment. Since again these data were not available, the rehabilitation costs were also omitted. The reimbursement for conventional radiotherapy with photons was estimated according to the common scale of charges and fees defined within the German health care system. For a full course of high precision radiotherapy a maximum fee of approximately 3500 € can be charged. This includes the fees for the irradiation (2300 €) as well as fees for three-dimensional computer-based treatment planning, including CT and MR imaging (1200 €). Very similar figures were found in the literature for Belgium [8] and various European countries [9]. Carbon ion radiotherapy in Germany is currently reimbursed as a standard treatment only for a few indications after individual consent has been obtained from the patient’s health insurance. The reimbursement for a full course of Carbon ion irradiation of 20 fractions (as performed for the patients treated for skull base tumors) is 20 000 €. For the new clinical ion facility in Heidelberg a reimbursement of 19 500 € was agreed upon with the insurance companies. This is consistent with estimated costs of around 1000 € per fraction, as calculated within the proposal written for the clinical particle therapy facility in Heidelberg [6]. Again these figures are very similar to estimates performed for the Italian [9], French and Austrian projects [10].
Costs for recurrent tumors In order to estimate the mean costs for patients treated with recurrent chordoma, the medical records of 10 chordoma patients, presenting at the DKFZ with recurrences, were analyzed. The available medical records only covered the treatment given at DKFZ in detail; other treatments and procedures performed were documented (including any prior diagnoses, information on nursing or rehabilitation), however, were commonly not performed at our institution and therefore not all required details for the present analysis were readily available. In order to calculate the overall treatment costs, the costs for repeated surgery, hospitalization and repeated radiotherapy were added according to the medical records. In doing so the treatment costs were taken as specified above. This number was calculated for each patient individually. All patients in the investigated group received conventional RT with photons, before the tumor recurred. The treatment of the recurrent tumors mainly was performed using repeated surgical approaches, while a second course of conventional RT was performed only for a single patient using a restricted target volume and dose in order not to exceed the radiation tolerances of the normal tissues. The majority of patients (6/10), however, were consequently treated with the more expensive Carbon ion RT for the
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recurrent tumor, which was possible due to the high degree of dose conformation achievable with the spot-scanning technique. One of the patients could even be treated with a third course of RT. The treatment of recurrent tumors with Carbon ions was performed using single or two fields. The prescribed doses were limited by the radiation tolerances of the pre-irradiated normal tissues. From these overall individual costs, the cost for the primary treatment (neurosurgery plus conventional RT) is subtracted in order to obtain the additional costs for the treatment of the recurrencies. The cost for treatment of patients with recurrent tumors was averaged over all patients to obtain the mean cost for the treatment in the case of a recurrence. Without such a correction, the mean treatment costs for recurrent tumors would be exaggerated. In order not to overestimate the costs for these patients, the above correction was applied, in such a way, that only the reduced costs were taken into account that would result from conventional therapy, rather than the costs from Carbon ion RT.
Analysis of the cost-effectiveness Given the above numbers, the total treatment costs resulting from various scenarios with different outcomes of RT can be analyzed. To do so, the costs for the primary treatment and the mean cost for the treatment of a patient with a recurrent chordoma, weighted by the probability of recurrence, were added. If the local control (LC) rate is assumed to be the probability for a cure of the patient, then the quantity (1-LC) is an estimate for the probability of recurrent tumor. The resulting total treatment costs are then valid for a population of patients similar to the one presented in Table 2. The control rate for chordoma patients after conventional radiotherapy has been shown to be between 23% and 38% [15]. Best results with photons have been achieved using high precision stereotactically guided fractionated RT providing a local control rate of 50% [4]. In contrast to this, the 5-year local control rates for the treatment of chordoma patients with Carbon ion RT which have recently been analyzed [12] are at 70%. In addition to the best achievable control rates for conventional RT and ion RT (50% and 70%, respectively) and in order to study the effect of the local control rate on the cost-effectiveness, the calculations were also performed using a local control rate of 35% (assuming conventional RT) and 60% (assuming Carbon ion RT). Carbon ion RT has the potential of reducing further the overall number of fractions as is demonstrated by the results of the HIMAC facility [17]. Therefore, a second scenario (B) was introduced, where the overall treatment costs for Carbon ions were reduced by 20% equivalent to a moderate reduction of the total number of fractions to 16.
Results Costs for primary treatments and treatment of recurrent tumors The cost for the primary treatment as given in the text is summarized in Table 1. The resulting overall costs for the
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Table 1 Primary cost drivers and composition of treatment costs for the primary treatment of a patient with a skull base chordoma as described in the text Treatment
Treatment costs in €
Conventional photon RT Carbon ion RT Neurosurgical resection
Treatment planning Treatment delivery Planning + delivery Surgery Hospitalization
Total costs for conv. RT Total costs for ion RT
1200 2300 20 000 11 000 12 600 27 100 43 600
primary treatment using conventional photon RT and Carbon ion RT are 27 100 € and 43 600 €, respectively. The individual treatment costs for each patient and overall costs as calculated from the data in the medical records are summarized in Table 2. The mean overall cost for the treatment of a patient in this collective amounted to 121 770 €. If the individual cost for the primary treatment (neurosurgery plus conventional RT) is subtracted, the remaining mean cost for treatment in the case of recurrences amounts to 94 670 €. If the costs for patients receiving Carbon ion therapy were corrected, the mean costs for the treatment of recurrences thus amounted to 81 470 €.
Cost-effectiveness The overall treatment costs resulting from the sum of the costs for the primary treatment and the costs for the treatment of recurrent tumors, weighted with the probability of recurrence have been calculated for various scenarios. The results of the overall costs using local control rates for RT of 35%, 50%, 60%, and 70% are presented in column (A) of Table 3. The presented data only depend on the local control rate and treatment modality used to achieve them. It has to be stressed that the calculations for 35% and 50% local control were performed assuming conventional RT, while for the results at 60% and 70% local control, Carbon RT was assumed to be the primary RT modality. This affects only the primary treatment costs, as the costs for recurrent tumors are independent, due to the correction explained above.
The results for the second scenario (B), with the reduced number of fractions (16 instead of 20) and a 20% reduction of the overall costs, are given in column (B) of Table 3. As compared to results of standard conventional RT not using conformal stereotactic techniques, it is obvious that Carbon ion RT is certainly more cost-effective and yields much better local control. Looking at the best achievable results with conventional RT, the break-even point for Carbon RT applied in 20 fractions is reached at a control rate of 70.3%, where the saving of costs for recurrent tumors compensates for the more expensive ion RT. If the number of fractions can be reduced to 16 the costs of the primary treatment including carbon ion RT are 39 600 and this break-even is reached already at a control rate of 65.3%. The cost-effectiveness ratio (CER) is expressed as the additional treatment costs of the new technique weighed by gain in outcome. The CER can be based either on the gain in local control, which can be used as a measure of disease free survival, or on the overall survival rates. Taking the mean local control rates of 50% and 70% (for 5 years) for conventional and ion RT, the CER in terms of disease free survival is 16 500 €/year of disease free survival. The reported overall survival rates for precision RT using photons are 82% (at 5 years) [4] and 88.5% after Carbon RT [15]. The CER therefore is 2539 € per 1% increase in survival rate. Given the mean age of the patients in the analysis (47 years), a remaining lifespan of at least 33 years can be expected. In terms of additional life years the CER becomes 7692 €/year.
Discussion Skull base chordoma are tumors, where a complete surgical resection is rarely possible due to the anatomical structures in close vicinity including brain stem, optic system as well as bony structures. The standard for the primary treatment is therefore a combination of surgery and RT, which is a very common situation in tumor therapy. The major cost driver in the primary therapy consequently is surgery and not RT. Due to this fact, the primary therapy including ion RT is only roughly a factor of 2 more expensive than conventional RT, although ion RT is roughly 6.5 times more expensive than conventional RT.
Table 2 Treatments and costs for the health care of 10 patients presenting with recurrent chordoma of the skull base at the DKFZ in 2002/2003 Patient 1 2 3 4 5 6 7 8 9 10
No. of surgeries
Days of hospitalization
No. of RT treatments
Overall treatment costs
4 5 4 7 4 3 4 3 2 4
84 105 124 147 144 74 84 68 63 84
1 1 2 3 2 1 2 2 1 2
114 400 € 138 000 € 125 400 € 208 700 € 153 900 € 97 400 € 101 400 € 97 300 € 79 800 € 101 400 €
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Table 3 Overview of total costs of therapy for different local control rates of Carbon ion RT and different cost scenarios (A: current costs, B: reduced costs for Carbon RT) 5-Year local control rate
35% 50% 60% 70%
(conv. RT) (conv. RT) (Carbon RT) (Carbon RT)
Cost of primary therapy in €
27 100 27 100 43 600 43 600
Furthermore, since recurrent tumors are a rather common phenomenon in patients with skull base chordoma, the cost for the treatment of recurrent tumors is roughly 3 times higher than the cost for the primary treatment (based on conventional RT). It is certainly a common feature for tumors that are difficult to control, that the overall treatment costs are dominated by the costs for the treatment of the recurrent tumors. Any improvement in the local control rate therefore has a potential to decrease this large fraction of the overall treatment costs. The calculated CER in terms of gain in overall survival probability due to Carbon ion RT is 2539 € per 1% increase. If not only the primary treatment costs but also the costs for treatment of recurrent tumors are taken into account, carbon RT is not more expensive than conventional RT, but yields considerably better outcome. The analysis therefore shows clearly that Carbon ion RT is more cost-effective than a conventional RT treatment for chordoma patients. The analysis, however, suffers from large uncertainties in the cost estimates, which are mainly due to a lack of patient specific data and a lack of transparency in the system of charges and fees in the German health care system. Since realistic treatment costs for conventional RT or neurosurgical treatments are not accessible, the costs were assumed to be given by the standard reimbursement for these treatments (see also footnote 2). Any additional cost factor which is independent from the RT modality (like e.g. rehabilitation) would further increase the non-RT related costs and lead to an even higher cost-effectiveness of ion RT. If as an example, additional costs of 3000 € were assumed as additional costs after each neurosurgical treatment, the mean costs for recurrent tumors would increase by 12 000 € (for a mean of 4 surgeries) and the overall treatment costs for conventional RT would increase by 9000 € towards 76 835 € (at 50% local control), while for carbon RT the increase would be 6600 € towards 74 641 € (70% local control). Concerning additional costs, which are RT-related, it can be assumed that these costs are even lower for ion RT as compared to photon RT. For example, treatment related morbidity is generally much lower in the case of ion RT as compared to conventional RT (see e.g. [13,12]). Consequently the cost for additional supportive therapy and medication is lower. The lower iatrogenic morbidity together with an overall shortened therapy (20 fractions instead of 40 fractions) and the fact that ion RT can be administered on an outpatient basis lead to a significant reduction of the loss of economic productivity. In the group of patients being treated with Carbon ion RT there have been several patients that were working regularly even during the course
Cost of recurrencies in €
52 956 40 735 32 588 24 441
Total costs in € Scenario A
Scenario B
80 056 67 835 76 188 68 041
— — 72 188 64 041
of RT. The reason for this may be found in the low grade (and sometimes the absence) of even mild side effects like alopecia or skin erythema in these patients. It should also be pointed out that the reimbursement for high precision conventional RT is fixed at a rather low level by German governmental regulations, while for ion RT the true costs were estimated. For the US it was estimated [5] that the cost of a high precision conventional RT is around 10 000 €. The current reimbursement for a modern precision RT with photons (like stereotactically guided RT or IMRT) in Germany is probably not covering the true costs. Moreover, there is still a potential for ion RT to be even more cost-effective, if the number of fractions can be reduced further, as has been done quite successfully at the Japanese facility HIMAC for a number of tumors [17]. Another aspect that is not included in the cost analysis is the fact that an increased local control and reduced side effects of the treatment are of course invaluable benefits for the patient, which cannot easily be evaluated in terms of costs.
Conclusions In view of the numerous hospital based ion facilities which are currently planned or are already under construction, the question about cost-effectiveness of ion RT inevitably appears. Our analysis provides some evidence that ion RT can be more cost-effective in the treatment of some tumors, which are typically treated by a combination of surgery and RT and for which a clear increase of the control rates can be shown, when ion RT is used. In order to identify other more common tumor entities, for which ion RT can be used with increased cost-effectiveness, it is very important to perform clinical studies on the clinical effectiveness of ion beams as compared to photon RT. In addition it is also necessary to improve the accuracy of the calculated direct and indirect treatment costs. This can only be achieved, however, if realistic treatment costs become available and if the health care system becomes generally more transparent. * Corresponding author. Oliver Ja ¨kel DKFZ, Abt. Medizinische Physik in der Strahlentherapie (E040), 69120 Heidelberg, INF 280, Germany. E-mail address: [email protected] Received 10 October 2006; received in revised form 8 March 2007; accepted 19 March 2007; Available online 8 May 2007
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