Cost‐effectiveness of carbon ion radiation therapy for locally recurrent rectal cancer

Abstract

The aim of this study was to evaluate the cost‐effectiveness of carbon ion radiotherapy compared with conventional multimodality therapy in the treatment of patients with locally recurrent rectal cancer. Direct costs for diagnosis, recurrent treatment, follow‐up, visits, supportive therapy, complications, and admission were computed for each individual using a sample of 25 patients presenting with local recurrent rectal cancer at the National Institute of Radiological Science (NIRS) and Gunma University Hospital (GUH). Patients received only radical surgery for primary rectal adenocarcinoma and had isolated unresectable pelvic recurrence. Fourteen and 11 patients receiving treatment for the local recurrence between 2003 and 2005 were followed retrospectively at NIRS and GUH, respectively. Treatment was carried out with carbon ion radiotherapy (CIRT) alone at NIRS, while multimodality therapy including three‐dimensional conformal radiotherapy, chemotherapy, and hyperthermia was performed at GUH. The 2‐year overall survival rate was 85% and 55% for CIRT and multimodality treatment, respectively. The mean cost was ¥4 803 946 for the CIRT group and ¥4 611 100 for the multimodality treatment group. The incremental cost‐effectiveness ratio for CIRT was ¥6428 per 1% increase in survival. The median duration of total hospitalization was 37 days for CIRT and 66 days for the multimodality treatment group. In conclusion, by calculating all direct costs, CIRT was found to be a potential cost effective treatment modality as compared to multimodality treatment for locally recurrent rectal cancer. (Cancer Sci 2010)

Colorectal cancer is the fourth most common cancer worldwide and accounted for about 1 million new cases in 2002. In a low‐risk population, colon and rectal cancer rates are generally of the same magnitude.^{( 1 )} In 2002, 34 889 and 41 000 cases of rectal cancer were registered in the UK and USA, respectively.^{( 2 )} In Japan, where rectal cancer comprises 14.6% of all lethal cancers, 31 990 cases were reported and it is predicted that cases will increase to 51 206 by 2020, with a 2.91% annual growth of newly diagnosed cases.^{( 3 )} After radical surgery for primary rectal cancer, the incidence of local recurrence is up to 33%. Although surgery is the mainstay of treatment for locally recurrent rectal cancer (LRRC), 70% of the patients die within 5 years following its diagnosis. Unfortunately, as a result of pelvic wall involvement, the local recurrence is often unresectable, which generally leads to a poorer outcome than resectable lesions.^{( 4 )}

Due to the high recurrence rate and the high annual growth rate, the treatment strategy for LRRC is expected to become a major burden for health care systems. In developed countries, cancer‐related costs and public medical expenditures are increasing steadily owing to both increases in life expectancy and improved diagnostic and treatment options. For instance, preliminary data from the UK showed that spending on cancer treatment increased by 52% from 1990–1991 to 2000–2001, while total health spending increased by 12%.^{( 5 )} Total health costs were announced by the Japanese Ministry of Health, Labour and Welfare as amounting to roughly ¥21.87 trillion in 1995, rising to approximately ¥24.4 trillion in 2001 and 8.5% and 9.02%, respectively, were cancer‐related.^{( 6 )} Moreover, in the USA, the cost of colorectal cancer treatment alone represents 13.1% of total national expenditure on cancer treatment.^{( 5 )}

Recently published data from the National Institute of Radiological Science (NIRS) in Chiba, Japan, showed that carbon ion radiotherapy (CIRT) for LRRC has 3‐ and 5‐year survival rates of 60% and 42.8%, respectively, and that it could be a promising alternative treatment modality next to surgery.^{( 7 )} However, although the increased development of advanced technologies such as CIRT usually results in higher health care expenses,^{( 8 )} cost‐effectiveness of CIRT is rarely discussed. To date, only one cost‐effectiveness study of CIRT has recently been published based on 10 patients with skull base chordoma. Although this published study showed a cost‐effectiveness ratio of carbon ion of €2539 per 1% increase in survival, the study suffered from large uncertainty because direct costs were only estimated by a standard reimbursement system.^{( 9 )} In the present study, actual direct costs for diagnosis, treatment, follow‐up, supportive therapy, complications, and admission were retrospectively analyzed in 25 patients treated with CIRT at NIRS or multimodality therapy at Gunma University Hospital (GUH), Japan.

Materials and Methods

Inclusion criteria.  Between 2003 and 2005, medical records of all patients with unresectable recurrent tumors in the pelvis after radical surgery alone for primary rectal adenocarcinoma and no distant metastasis at the time of recurrence at NIRS and GUH, were studied. Locally recurrent rectal cancer (LRRC) without distance metastasis was confirmed by computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) findings. Patients with recurrence in the colon were not included in the study due to the fact that the involvement of the colon could probably allow for reduced radiation doses to be applied. Furthermore, patients with another primary tumor, and infection at the tumor site and digestive tract adjacent to the clinical target volume, were excluded. The location, stage, and surgery of primary rectal cancer were considered in the inclusion criteria. These strict inclusion criteria, which allowed only 25 patients to be recruited in the study, were chosen to guarantee that the patients treated at GUH would have been equally suited for CIRT (Table 1). The period between 2003 and 2005 was selected because in 2003 a lump‐sum payment system based on diagnosis procedure combinations (DPC) was introduced in 82 Japanese university hospitals including GUH.

Table 1.

 Patients’ characteristics

	Multimodality treatment (n = 11)	Carbon ion beam RT (n = 14)
Number of patients
Male	8	13
Female	3	1
Age
Mean	59	66
Median	60	65
Primary tumor site
Rectal ampulla	9	13
Rectosigmoid junction	2	1
Primary tumor operation
Abdominoperineal excision	4	7
Low anterior resection	6	6
High anterior resection	1	0
Hartmann’s resection	0	1
Primary tumor stage (UICC/6th)
I	1	1
IIa	3	3
IIIa	4	5
IIIb	3	5
Interval between primary surgery and recurrence/month
Median	30	35
Mean	32	34
Treatment for recurrence
Radiation	11	14
Chemotherapy	11	0
Hyperthermia	11	0
Additional treatment
Secondary surgery	3	0
Total dose/Gy of radiation
Mean	51.5	73.4
Median	50.0	73.6
Range	50–58	70.4–73.6
Radiation treatment duration (days)
Median	35	29
Mean	34	28
Range	25–45	25–30

RT, radiotherapy; UICC/6th, International Union Against Cancer tumor‐node‐metastasis (TNM) classification, sixth edition.

Diagnosis procedure combination (DPC).  Diagnosis procedure combination (DPC) payment in brief contains two parts, prospective and fee‐for‐service payment. Prospective payment, approximately corresponding to the total payments for admission, is the sum of hospitalization, 38.9%; injections, 11.0%; laboratory tests, 10.4%; diagnostic imaging, 6.6%; medication, 2.9%; procedures priced less than 1000 points (1 point = ¥10), 1.9%.

Fee‐for‐service payment, corresponding to the payment for the doctor’s fee and covering the remaining 28.3% of the fee, is the sum of surgery and its material costs, 18.2%; and additional services and treatments (procedures priced at 1000 points or higher, cardiac catheterization, endoscopy, radiotherapy, rehabilitation, etc.), 10.1%.^{( 10 )}

Fee‐for‐service payment depends on the national health insurance fee schedule. Prospective payment is paid per diem with a three‐level step down based on the average length of stay for each diagnosis group. Furthermore, the prospective payment is adjusted by hospital coefficient, securing the previous year’s payment in each hospital.^{( 10} , ^{11 )}

Conventional treatment at GUH.  All patients were treated by multimodality treatment including three‐dimensional conformal radiotherapy (3D‐CRT), chemotherapy, and hyperthermia, which is a standard treatment for unresectable LRRC at GUH. External beam radiation therapy at a total dose of 50 Gy (n = 9) or 58 Gy (n = 2) was delivered to the whole pelvis. The radiation treatments consisted of 25–29 fractions of 2.0 Gy, delivered 5 days a week with a Lineac of 10 MV. Chemotherapy consisted of 5‐fluorouracil (5‐FU) (250 mg/m² per day) and leucovorin (LV) (25 mg/m² per day) administered by continuous infusion during the night for 5 days a week in the second and fourth weeks of radiation therapy. Hyperthermia (mean, 40.4°C) once a week during the radiation therapy for 1 h was performed with radiofrequency devices (Thermotron‐RF 8; Yamamoto Vinita, Osaka, Japan).^{( 12 )} Consequently, all patients at GUH received chemo‐thermo‐radiation therapy as indicated by the standard treatment protocol. After being treated with chemo‐thermo‐radiation therapy, local resection for tumors was performed for three patients according to the treatment protocol at GUH. Therefore, only three patients received local resection for the recurrent tumors at GUH (two abdminoperineal resection and one stapled lower anterior resection).

Carbon ion radiotherapy at NIRS.  The patients were treated with carbon ion radiotherapy alone which is the standard treatment for LRRC at NIRS. A total radiation dose of 73.6 Gy (n = 13) or 70.4 Gy (n = 1) in 16 fractions over 4 weeks was delivered to the tumors.

Treatment cost of recurrence.  All patients in both treatment arms had undergone primary surgery alone, but calculation of the primary cost of the rectal cancer treatment is out of the scope of the present study. In order to assess the direct cost of recurrence; hospitalization (including in the intensive care unit), radiation therapy, chemotherapy, hyperthermia, surgical treatment, medical laboratory and imagining investigations, visits, follow‐up, medications, supportive therapy (physical, nutritional, and medical), and consequential costs (medical reports, images copies, and health education) were thoroughly calculated using the medical records.

However, indirect costs and costs of intangibles could not be evaluated in the current retrospective study. The indirect costs are lost resources, due illness effects on sick people, and their support system, such as lost production, days off work, sickness pay, invalidity, or premature death. Intangible costs are the psychological aspects of disease as pain and suffering.^{( 13 )} Therefore, since the present study is retrospective, only the direct cost of 2 years of follow‐up from the time of recurrence was computed individually for each patient; afterwards an average cost of for patients in each group was calculated. The mean cost for each treatment group CIRT (A) and for multimodality treatment (B) was calculated. Subsequently, the incremental cost‐effective ratio (ICER) which is expressed as the additional treatment costs of the new technique weighted by gain in outcome was analyzed.

The ICER can be based either on the gain in local control rates (ICER in terms of disease‐free survival) which can be used as a measure of disease‐free survival or on the overall survival rates (ICER per 1% increase in survival). Therefore, the 5‐year overall survival rate and 5‐year local control rate from literature review were analyzed for both groups using the calculated mean costs for CIRT (A) and multimodality treatment (B). Re‐recurrence cost was also estimated by multiplying the mean costs of CIRT (A) or multimodality treatment (B) by their re‐recurrence probability in each group.

It is worth mentioning that the multimodality treatment cost at GUH refers to real total costs paid by both the National Health Insurance System of Japan and the patient, while it refers to the real total costs paid by patient alone in case of carbon ion treatment since CIRT is still not covered by the National Health Insurance System.^{( 14 )}

Results

After initiation of local recurrence treatment, the 2‐year overall survival rate was 85% for CIRT and 55% for multimodality treatment, as shown by Kaplan–Meier curve (Fig. 1). According to the hazard ratio, the risk of dying in the multimodality treatment group was 1.4 of that in the carbon ion group. The 2‐year local control rate was 100% in patients treated with CIRT at NIRS, while the local control rate could not be evaluated due to incomplete documentation of exact date of distant metastasis at GUH. However, all cost details related to the metastasis were well documented. The absolute values of the direct cost of recurrence for all patients in both groups are summarized in Table 2.

Figure 1.

 Two‐year overall survival curve for the carbon ion radiotherapy (RT) and conventional multimodality treatment groups for locally recurrent rectal cancer.

Table 2.

 Days of hospitalization and absolute total cost for each patient treated with carbon ion radiotherapy and multimodality treatment

Carbon ion radiotherapy			Multimodality treatment
Patient	Days of admission	Overall treatment cost/¥	Patient	Days of admission	Overall treatment cost/¥
1	37	3 975 810	1	186	8 218 177
2	44	4 371 820	2	123	8 137 957
3	79	4 730 760	3	76	2 768 777
4	36	4 397 980	4	80	3 337 060
5	36	5 388 630	5	61	4 443 295
6	37	4 121 600	6	44	7 058 167
7	47	4 326 490	7	66	3 780 787
8	116	7 646 510	8	75	5 284 419
9	33	3 976 610	9	38	1 801 837
10	32	4 059 100	10	51	1 843 487
11	36	4 945 020	11	64	4 048 137
12	70	5 786 900
13	51	5 33 8210
14	35	4 189 800

The ICER for CIRT based on the calculated survival rate was ¥6428 per 1% increase in survival. The percentage of mean cost showed that 65% of the cost in the carbon ion group belonged to the carbon ion beams cost, which was almost seven times more than the photon radiation cost at GUH. On the other hand, the cost of prospective payment of DPC at GUH represented 74% of the total cost (Table 3). The median hospitalization duration was 66 days for the multimodality treatment group and 37 days for the CIRT group. Additionally, by using 5‐year survival and 5‐year local control rates from literature review (Table 4), the mean estimated re‐recurrence cost was ¥1 706 107 and ¥936 770 for multimodality treatment and CIRT, respectively. The average ICER for CIRT in terms of disease‐free survival was ¥13 454/year of disease‐free survival, while the average ICER due to CIRT per 1% increase in survival rate was ¥13 221. Given the age of the patients in the analysis (60 years), a remaining lifespan of at least 20 years could be estimated (Table 1); the ICER in terms of additional life year was ¥4397/year. Although all patients in both groups tolerated and completed their treatment courses, grade 3 toxicities were observed (Table 5). In brief, a grade 3 early toxicity (gastrointestinal tract) developed in three patients (27%) treated with multimodality treatment. In contrast, no severe toxicity was observed in the CIRT group and 93% of the patients developed only grade 1 early toxicity (skin). No severe late toxicity was detected and no urinary or hematological toxicities were recorded in any group.

Table 3.

 Mean of direct costs for both groups and percentage

	Carbon ion RT		Multimodality treatment
	Mean cost (¥)	Percentage (%)	Mean cost (¥)	Percentage (%)
Hospitalization cost (including DPC)	1 038 885	21.6	3 394 066	74.0
Food	66 154	01.4	114 795	02.5
Laboratory investigations	79 510	01.7	86 110	01.9
Imaging investigations	266 238	05.5	191 366	04.2
Radiotherapy	3 140 000	65.4	444 273	09.6
Chemotherapy	0	00.0	125 666	02.7
Hyperthermia	0	00.0	19 495	00.4
Surgery	0	00.0	24 384	00.5
Medication	57 435	01.2	186 584	04.0
Visit fee	14 028	00.3	13 063	00.3
Health education	48 297	01.0	11 298	00.2
Reports and image copies	93 399	01.9	0	0.00
Total (mean) (¥)	4 803 946		4 611 100

DPC, diagnosis procedure combinations; RT, radiotherapy.

Table 4.

 Overview of total costs of therapy for different local control and survival rates for locally recurrent rectal cancer

Treatment modality	Author	Year	No. of cases	5‐year survival (%)	5‐year local re‐recurrence (%)	Estimated cost of re‐recurrence (¥)	ICER (¥) in terms of disease‐free survival	ICER (¥) per 1% increase in survival
Multimodality	Willet et al. (30)	1991	30	27	38	1 752 218	10 424	12 205
	Bussierses et al. (31)	1996	73	31	29	1 337 219	20 300	16 343
	Valentini et al. (32)	1999	47	22	31	1 429 441	16 769	9271
	Wiig et al. (33)	2000	107	30	50	2 305 550	6323	15 066
Mean			64	27.5	37	1 706 107	13 454	13 221
Carbon ion	Tsujii et al. (7)	2008	90	42.8	19.5	936 770

ICER, incremental cost‐effective ratio.

Table 5.

 Acute and late toxicity by NCI‐CTC and RTOG/EORTC

	Carbon ion radiotherapy		Multimodality treatment
	Acute (NCI‐CTC)	Late (RTOG/EORTC)	Acute (NCI‐CTC)	Late (RTOG/EORTC)
Skin
Grade 0	0	4	0	0
Grade 1	13	10	0	0
Grade 2	1	0	0	0
Grade 3	0	0	0	0
Gastrointestinal
Grade 0	0	0	5	8
Grade 1	0	0	2	1
Grade 2	0	0	1	2
Grade 3	0	0	3	0

NCI‐CTC, National Cancer Institute – Common Toxicity Criteria, version 2; RTOG/EORTC, Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer.

Discussion

Carbon ion beams allow uniquely precise delivery of a high dose to the target volume, while sparing the surrounding normal tissue. Carbon ion beams deliver a large mean energy per unit length of their trajectory in the body (linear energy transfer, LET). In contrast to neutron beams whose LET remains uniform at any depth, the LET of carbon ion beams increases steadily from the point of entrance into the body with increasing depth, reaching a maximum in the peak region (Bragg peak). The ratio of the Bragg peak dose to the dose at the entrance region is larger for carbon ions than for protons. Carbon ion beams might therefore be used effectively in the treatment of cancers resistant to conventional radiation.^{( 14} , ^{15 )}

At present, carbon ion radiotherapy is available at three facilities: two hospital‐based facilities in Japan (Chiba and Hyogo), and the Heidelberg Ion Therapy facility in Germany.

Although little cost information is available, carbon ion facilities are anticipated to be costly. The proton/carbon ion facility in Hyogo, Japan, which opened in 2001, was estimated to cost ¥28 billion (approximately $US253 million).^{( 16 )} Even though this expenditure may suggest a significant cost issue, a cost‐benefit analysis by Nakagawa et al. showed that good financial balance can be achieved as 600 patients are treated annually with a CIRT cost of ¥3.14 million per patient. They analyzed carbon ion facilities in Hyogo and NIRS and the estimated lifespan of the accelerator, building, and equipment was 20, 30 and 6 years respectively. The total depreciation cost, which includes the accelerator, building, equipment, and operating costs as well as maintenance fee, was ¥1.826 billion per year.^{( 17 )} However, both models were installed over a decade ago and were not dedicated for CIRT alone but also for proton radiotherapy (Hyogo) and for research purposes (NIRS). Therefore, commercial vendors are currently offering fixed and compacted CIRT facilities that are expected to be less costly. For instance, a compact carbon ion beam accelerator was installed in 2008 at Gunma University, Japan.^{( 18 )} The facility size and construction costs of the Gunma University accelerator were about one‐third of those at NIRS.^{( 19 )} With such reduction in size and cost, spread of CIRT seems feasible. Germany has already had a second facility in operation since 2009 and two others are expected in 2010 and 2012.^{( 20} , ^{21 )} Italy,^{( 21 )} the USA,^{( 22 )} and Austria^{( 23 )} are anticipating their first facilities in 2010, 2013, and 2014 respectively. France is expecting to open two facilities, one in 2012 and another in 2014.^{( 21 )} Generally, about 20 CIRT centers are anticipated over the next decade.^{( 20 )} However, in respect to these centers, questions about the cost‐effectiveness of carbon ion radiotherapy compared to conventional treatment modalities remain unanswered.

The current average estimated cost of proton therapy is €25 000 and the cost ratio between proton treatment and intensity modulated photon irradiation is approximately 2.4.^{( 24 )} Based on the French ETOILE project, the cost of carbon ion treatment per patient varied widely from €12 000 to €28 000 as a result of variation in fraction number and session duration.^{( 25 )} However, our analysis showed that CIRT alone, which is paid per treatment not per fraction, could be a cost‐effective treatment modality for certain tumors that are typically treated by the multimodality approach including three‐dimensional conformal radiotherapy, such as LRRC. This cost effectiveness is related to costs of hospitalization and treatment‐related morbidity which generally was found to be much lower in cases where CIRT was used.^{( 26 )} Our findings also showed significantly less days of admission (Table 2) and less toxicity (Table 5) for CIRT than multimodality treatment. Compared to conventional radiotherapy, the superior physical property of CIRT allowing high‐precision delivery to the target volume, while sparing the surrounding normal tissue,^{( 7} , ¹⁴ , ^{26 )} explains the low rate of gastrointestinal tract (GIT) toxicity in the CIRT group in our study (Table 5).

In fact, when treating LRRC, photon radiotherapy alone has not been shown to achieve significant survival benefit.^{( 27} , ^{28 )} For this reason, the combination of conventional radiotherapy and chemotherapy is usually employed either for symptomatic or resectability improvement.^{( 29 )} Despite the use of multimodality therapy, 5‐year survival rates of patients with LRRC remain 22–31% and local control rates 50–71%.^{( 30} , ³¹ , ³² , ^{33 )} On the other hand, CIRT alone has an overall survival rate of 42.8% and local control rate of 81% at 5 years.^{( 7 )} By analyzing these 5‐year survival rates and local control rates based on our calculated mean cost of ¥4 803 946 for CIRT and ¥4 611 110 for multimodality treatment, CIRT seems a cost‐effective treatment modality for LRRC (Table 4). In addition, the wide range of cost and high cost at GUH (Table 2) was mainly a consequence of differences in survival (Fig. 1) and variation in days of admission (Table 2) that could be linked to severity of treatment complications (Table 5). For example, the absolute total costs for patients #1 and #2 in the multimodality treatment group were higher than the other patients in the same group (about ¥8 million) due to their long days of admission (Table 2) including admission to the intensive care unit. The same applies to patient #8 in the CIRT group (Table 2). On the other hand, patients #9 and #10 in the multimodality treatment group had a cost of about ¥1.8 million (Table 2) because they had the least survival among the group and died within the first year (Fig. 1).

The present study included all direct costs for 2 years of follow‐up from the time of recurrence. Although CIRT yielded better outcomes, there was insignificant difference between the mean costs of both treatment modalities. The calculated ICER in terms of gain in overall survival probability due to carbon ion radiotherapy is ¥6428 per 1% increase in survival.

The limitations of this study are that it is retrospective and that it could not include all indirect costs, such as loss of economic productivity during and after the treatment as well as the cost of intangibles. However, the duration of radiation therapy and length of hospital stay related to the complications and toxicity, are both in favor of CIRT and may provide some clues regarding indirect costs. Additionally, in the current 2‐year follow up study, the local control rate could not be evaluated due to improper documentation of exact date of distant metastasis at GUH. However, due to the latter limitation and a probability of falling survival rates beyond the 2 years, we additionally analyzed data in the literature representing both treatment modalities, but with longer follow‐up (5‐year survival and control rates) and larger sample sizes (Table 4).

In conclusion, our analysis provides some evidence that CIRT could be cost‐effective in the treatment of LRRC. To the best of our knowledge, this is the first cost‐effectiveness study of carbon ion beam radiotherapy including all direct costs. However, it is also necessary to take into account the indirect costs, which means that future prospective studies are needed. Yet, to perform a prospective cost‐effectiveness study before implementing a new technology still raises ethical concerns.^{( 34} , ³⁵ , ^{36 )} In general, there is a lack of information concerning the cost‐effectiveness of other cancers that are effectively treated by CIRT such as bone and soft tissue, lung, liver, prostate, and head and neck cancers.^{( 7 )} Additionally, there is little data available about the relative cost‐effectiveness of CIRT compared with proton radiotherapy. These may represent important areas for future research.

Abbreviations

RT

radiotherapy

UICC/6th

International Union Against Cancer tumor‐node‐metastasis (TNM) classification, sixth edition

DPC

diagnosis procedure combinations

RT

radiotherapy

ICER

incremental cost‐effective ratio

NCI‐CTC

National Cancer Institute – Common Toxicity Criteria, version 2

RTOG/EORTC

Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer