© 2005 Foundation for Promotion of Cancer Research
Radiotherapy for Uterine Cervical Cancer: Results of the 1995–1997 Patterns of Care Process Survey in Japan
1 Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, 2 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 3 Department of Radiation Oncology, Chiba University Graduate School of Medicine, Chiba, 4 Department of Radiation Oncology, Aichi Cancer Center, Nagoya, 5 Department of Radiology, Nagano National Hospital, Nagano, 6 Department of Radiology, Tokyo Women's Medical University, Tokyo, 7 Department of Medical Physics and Engineering and 8 Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
For reprints and all correspondence: Takafumi Toita, Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa, 903-0215 Japan. E-mail: b983255{at}med.u-ryukyu.ac.jp
Received November 29, 2004; accepted January 19, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The aim of this study is to establish Japanese national practice patterns for uterine cervical cancer patients who received radiotherapy without surgery.
Methods: The Japanese Patterns of Care Study (JPCS) conducted a national survey of 73 institutions using two-stage cluster sampling, and collected specific information on 591 patients with uterine cervical cancer treated by radiotherapy without planned surgery between 1995 and 1997.
Results: The median age of the patients was 70 years. Karnofsky performance status (KPS) was 
90 for 37%. Most patients (95%) had histology of squamous cell carcinoma. Ten percent were stage I, 29% stage II, 48% stage III and 13% stage IVA. Photon beams of 10–14 MV were the most used for external beam radiotherapy (EBRT). The beam energy utilized varied significantly by institution strata. Midline block was used in 
70% of institutions. Intracavitary brachytherapy (ICBT) was performed in 77%. Institution strata correlated significantly with the ICBT application. The majority of patients (89%) were treated with high-dose-rate (HDR) ICBT. The median single point A dose of HDR-ICBT was 600 cGy. The median summated point A dose from EBRT and HDR-ICBT was 5800 cGy (range: 1196–8600). The median overall treatment time including ICBT was 49 days. Twenty-four percent of the patients received chemotherapy. Concurrent chemoradiation was performed in 5%.
Conclusions: The JPCS established the Japanese national practice patterns of care for uterine cervical cancer patients treated with radiotherapy without planned surgery between 1995 and 1997. This survey demonstrated that the institutional strata significantly affected several practice patterns.
Key Words: cervical neoplasms • radiotherapy • Patterns of Care Study
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Radiotherapy has long played an important role in the treatment of uterine cervical cancer. The method has developed with the advance of technology and a large amount of clinical experience. Hence, cervical cancer has become one of the diseases in which patterns of radiotherapy practice are well standardized.
The Patterns of Care Study (PCS) has established the national average of process of care for several malignancies including cervical cancer in the USA (1). The Japanese Patterns of Care Study (JPCS) conducted the first nationwide survey for uterine cervical cancer from 1996 to 1997. The first JPCS survey demonstrated the practice patterns for cervical cancer patients treated with radiotherapy between 1992 and 1994 in Japan (2).
In September 1998, the JPCS started the second national survey of patients with uterine cervical cancer treated with radiotherapy during 1995–1997. Although its institution stratification and patient eligibility were almost the same as the first survey, the data format was newly developed. The national practice patterns of post-operative radiotherapy during 1995–1997 have already been published elsewhere (3). The purpose of this study is to establish national patterns of practice for uterine cervical cancer patients who received radiation therapy without planned surgical treatments during the period 1995–1997. The influence of institutional stratification on process of care was also analyzed.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The JPCS conducted a national survey of patients with uterine cervical cancer treated with radiotherapy during 1995–1997. The survey was performed from September 1998 to March 2001. The JPCS developed an original data format for patients with uterine cervical cancer with reference to the fifth PCS format of the American College of Radiology (ACR). Seventy-three out of 556 institutions were selected for the survey by using a stratified two-staged cluster sampling method. The data collection method consisted of two steps of random sampling. Prior to the random sampling, all the institutions were classified into four groups. The criteria for stratification of the institutions have been described elsewhere (2,3). Briefly, institutional stratification of JPCS was as follows: A1, academic institutions treating
300 patients a year; A2, academic institutions treating <300 patients a year; B1, non-academic institutions treating 120 patients a year; and B2, non-academic institutions treating <120 patients a year. Academic institutions include cancer center hospitals and university hospitals. Non-academic institutions consist of other facilities such as national, prefectural, municipal and private hospitals. The first step was to randomly select institutions from each group. The second step was to randomly select eligible patients from each of the sampled institutions. To be eligible for this study, patients had to meet several criteria: carcinoma, treated from 1995 to 1997, without distant metastases, without prior or concurrent malignancies, without gross para-aortic lymph node metastases and no previous pelvic radiotherapy. The JPCS surveyors consisted of 20 radiation oncologists from 10 academic institutions. One radiation oncologist visited and surveyed the data by reviewing patients' charts for each of the institutions. Data collection included patient characteristics (e.g. patient history, age, performance status, laboratory data, pathology, staging), extent of work-up for lymph node status, details of treatment (e.g. radiotherapy, chemotherapy, surgery) and treatment outcomes. The JPCS collected clinical data on 1065 patients with uterine cervical cancer who were treated with radiotherapy. In this study, 591 patients treated by radiotherapy without planned surgery were analyzed. These include 207 patients from A1 institutions, 145 patients from A2 institutions, 179 patients from B1 institutions and 60 patients from B2 institutions.
Statistical significance was tested by the 
2 test. Cases with unknown values were included, but cases with missing values were not included in calculations of percentage and significance.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENTS AND TUMOR CHARACTERISTICS (TABLE 1)
Data on height and weight were collected in 384 (65%) and 429 (73%) patients, respectively. The median height was 150 cm (range 119–168) whilst the median weight was 50 kg (range 26–97). Age data were collected for all 591 patients. Seventy-four patients (13%) were younger than 50 years, and 194 patients (33%) were older than 74 years. Patients over 74 years were frequently seen in A2 (37%) and B2 (50%) compared with in A1 (28%) and B1 (29%) institutions. The Karnofsky performance status (KPS) was 90–100 in 37%, and was <80 in 23%. The KPS distribution varied significantly by the institution strata (P = 0.002). Although approximately half of the patients in the A1 stratum had a favorable KPS (90–100), this was only the case for 20% of B2 institutions. Data on the pre-treatment hemoglobin value were obtained for 489 cases (83%). There was a significant difference in hemoglobin value among the groups of institutions (P < 0.0001). Patients of A1 and B1 institutions had higher hemoglobin values than those of A2 and B2 institutions. Most patients (95%) had histology of squamous cell carcinoma. No significant difference in histology was observed among each stratum. Patients with stage III were seen most frequently. Information of hydronephrosis/non-functioning kidney was noted for 267 of 280 stage III patients (95%), and 72 of 75 stage IVA patients (96%). Sixty patients (22%) with stage III and 41 patients (57%) with stage IVA had hydronephrosis/non-functioning kidney. Institutional strata did not significantly affect this distribution.
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For the assessment of pelvic nodal status, lymphangiography (four out of 495 patients; 1%) and surgical exploration (17 out of 505 patients; 3%) were rarely performed. Data on the nodal status were recorded using computed tomography (CT) in 369 out of 547 patients (67%) and magnetic resonance imaging (MRI) in 320 out of 540 patients (59%). However, data with an ‘unknown’ value were frequent for these items (CT, 146; MRI, 128). There was no significant difference among each institutional stratum for these variables on pelvic nodal evaluation.
TREATMENT
Only 12 (2%) of 519 patients for whom information was available entered an investigational protocol.
External beam radiotherapy
Treatment parameters of external beam radiotherapy (EBRT) according to the stratified institutions are listed in Table 2. Photon beams of 10–14 MV were the most popular category used for EBRT. Beam energies utilized varied significantly by institution strata (P < 0.0001). A beam energy of 10 MV was used for 93% in A1, 68% in A2, 55% in B1 and 18% in B2. For most patients, EBRT was given in daily fraction doses of 1.8 or 2.0 Gy. Treatment volume included only the pelvic region for almost all patients. Extended field prophylactic radiotherapy including the para-aortic region was rarely performed. The majority of the patients were treated with anterior and posterior opposed fields. The four-box technique was rarely used. Approximately 70% of the patients had a midline block (MLB) for a portion of their treatment course. Use of an MLB varied significantly among each stratum (P < 0.0001). An MLB was used more frequently in A1 compared with other strata.
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Brachytherapy
Only one patient (B2 institution) was treated with interstitial brachytherapy. Table 3 shows details of intracavitary brachytherapy (ICBT). ICBT was performed for approximately three-quarters of patients. Institution strata correlated significantly with the application of ICBT. ICBT was administered to 85% of patients in A1, 78% in A2, 75% in B1 and 53% in B2 (P < 0.0001). Performance of ICBT correlated well with the use of an MLB for EBRT. However, a discrepancy was observed between these two in A2 institutions. Further analysis of MLB utilization for patients treated with ICBT revealed that the MLB utilization rate was lower in A2 (74%) than other strata (A1, 93%; B1, 92%; B2, 88%). Use of ICBT according to the FIGO stage was noted for 584 patients. Forty-three patients with stage I received ICBT (75%), 144 patients with stage II (85%), 220 patients with stage III (79%) and 42 patients with stage IVA (55%). The majority of patients were treated with high-dose-rate (HDR) ICBT. Low-dose-rate (LDR) was used slightly more frequently in A1 institutions (14%) compared with other strata (2–7%). The most popular radionuclide used for brachytherapy sources was cobalt-60 (Co-60), followed by iridium-192 (Ir-192). Ir-192 was used more frequently in A1 institutions than in A2 and B1. Adequate sedation was rarely performed at the time of ICBT applicator insertion. Over half of the patients were treated without any sedation. Patients in B1 institutions tended to be treated more with sedation than other institution strata. The most frequently used method was the use of non-steriodal anti-inflammatory drugs (NSAIDs) delivered orally or rectally in all strata. ICBT was done using various methods. A combination of tandem and ovoid applicator was most frequently used regardless of institution strata.
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Radiation dose and treatment duration
For the following analyses regarding dose of ICBT, 361 patients (HDR, 327 patients; LDR, 34 patients) treated with a combination of tandem and vaginal applicator or tandem only were analyzed. Total dosage of radiotherapy in 327 patients treated with HDR-ICBT according to the institution strata is shown in Table 4. The median single point A dose of ICBT was 600 cGy for HDR, and 1412 cGy for LDR. The most frequent category of single dose of HDR-ICBT was 600–699 cGy, followed by 500–599 and 700–799 cGy. A single dose
800 cGy was rarely applied. Single dose HDR-ICBT use was significantly lower in A2 than those of other strata.
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The median total dose of EBRT delivered to the central pelvis (point A) and the lateral pelvis (point B) was 3220 and 5000 cGy, respectively. The median total dose of ICBT at point A was 2400 cGy for HDR and 2850 cGy for LDR. Consequently, the median summated point A dose from EBRT and ICBT was 5800 cGy (range 1196–8820) for HDR, and 6974 cGy (range 4464–9160) for LDR.
Table 5 shows the total radiotherapy doses in patients treated with HDR-ICBT according to the FIGO stage. FIGO stage significantly affected the EBRT doses to the central pelvis (point A). In contrast, total point A dose from HDR-ICBT was not affected by stage. The cumulative point A dose of EBRT and HDR-ICBT increased significantly with increasing FIGO stage. The total dose to the lateral pelvis (point B) from EBRT also varied significantly by FIGO stage, although those median values were almost the same. Some patients with stage III/IV received a total point B dose of >6000 cGy.
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Overall treatment time (OTT) could be calculated for all 591 patients. The median OTT including ICBT was 49 days. OTT exceeded 8 weeks (56 days) in 193 patients (33%), and 10 weeks (70 days) in 59 patients (10%). There was no significant variance in OTT by either institutional strata or FIGO stage. An unplanned treatment break occurred in 56 out of 565 patients (10%). Patients whose treatment period included consecutive national holidays (e.g. holidays from April 29 to May 5, the year end's and the New year's holidays) had significantly longer OTT (P = 0.023). The median OTT was 58 days for patients with these national holidays during their treatment period (n = 140), and 48 days for those without (n = 451). Sixty-eight out of 193 patients (35%) with OTT >8 weeks were those whose treatment period included the consecutive national holidays.
Chemotherapy
Data on chemotherapy application were collected for 574 patients (97%). One hundred and forty patients (24%) received chemotherapy. Use of chemotherapy significantly varied according to FIGO stage (P = 0.001). Chemotherapy was administered in eight patients (15%) in stage I, 22 patients (13%) in stage II, 87 patients (32%) in stage III and 21 patients (28%) in stage IVA.
Neoadjuvant chemotherapy (NAC) prior to radiotherapy was given in 81 of 574 patients (14%). Twenty-eight of 574 patients (5%) were treated with concurrent chemoradiation. The most frequently used agent for concurrent chemoradiation was bleomycin/pepleomycin, and it was followed by oral 5-fluorouracil. No patients received cisplatin concurrently with radiotherapy.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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This study demonstrated the national practice patterns for cervical cancer patients treated with radiotherapy without planned surgery between 1995 and 1997 in Japan. Several significant variances in the process according to the stratification of institutions were also observed.
Status of patient background, such as age and KPS, were unfavorable compared with the JPCS data of post-operative radiotherapy for the same period (3). This tendency was also observed when compared with the US PCS (4,5). This might imply that radiotherapy without surgery was mainly given to patients with unfavorable general conditions in Japan. This was also suggested by the distribution ratio of stage I/II patients. Whereas the ratio in the US PCS was 70% (5,6), it was only 39% in this study. Many investigators demonstrated that definitive radiotherapy brought equivalent outcomes to radical surgery in respectable stage I/II disease (7). Furthermore, a randomized trial clearly confirmed this hypothesis in 1997 (8). The present study identified that patient backgrounds varied by institutional strata. In addition to the factors mentioned above, the hemoglobin value was found to affect the outcome. Several investigators indicated that the pre-treatment hemoglobin value was one of the important prognostic indicators for uterine cervical cancer patients treated with radiotherapy (9). Patients in A1 institutions tended to be favorable for these patient-related factors. This was consistent with the previous JPCS survey (2). This suggested that patients with definitive status tended to be treated at large academic institutions, when radical radiotherapy was attempted. Concerning histology, most patients (95%) had squamous cell carcinoma. The breakdown in histology was different from that of the JPCS data of post-operative radiotherapy (3) and the US PCS (1996–1999) (6). Squamous cell carcinoma was found in 83% of patients in both the JPCS post-operative radiotherapy data and the US PCS (3,6). This might reflect the majority opinion of Japanese gynecological oncologists, i.e. radiotherapy is less effective for cervical adenocarcinoma despite some encouraging treatment results of radical radiotherapy (10,11).
As mentioned above, >60% of the patients were stage III/IV in this survey. The distribution ratio was higher than that of the US PCS (5,6). However, this observation should be interpreted with caution. The incidence of hydronephrosis/non-functioning kidney (23%) in stage III patients demonstrated in this study was lower than that of the US PCS (41%) (5). This suggested that some type of overstaging migration existed in Japan. Eifel has stressed the importance of accurate staging closely adhering to the FIGO notes and rules (12,13). Besides the FIGO stage, we consider that tumor size assessment using MRI could be one of the effective means to evaluate and compare tumor status among different institutions and countries. Although MRI is not permitted to be used in the FIGO staging system, its usefulness in measuring cervical tumor diameter has been demonstrated in several studies (14,15). In evaluation of lymph node status, the present study showed that CT was most commonly used. The same observation was made in the US PCS (5,6). However, lymphangiography and surgical exploration were rarely performed in this survey, although certain numbers of patient were evaluated with these examinations in the USA (5,6). Pre-treatment studies should be investigated further in the next survey using a revised data format.
Several interesting findings were demonstrated regarding methods of EBRT. The most common category of beam energies was 10–14 MV. A beam energy of 15 MV was used in <10% of patients. Concerning beam arrangement, the majority of the patients were treated with AP–PA opposite portals. The four-field technique was rarely applied. These treatment parameters are quite different from those demonstrated in the US PCS. In the US PCS survey, a beam energy of 15 MV was most frequently used, and 80% of patients were treated with the four-field technique (5). One might claim that the process of EBRT observed in the JPCS is inappropriate to achieve proper dose distribution. However, we consider that the physique of patients, such as antero-posterior (AP) separation, should be taken into account to evaluate the appropriateness of EBRT. While we did not directly collect the data of AP separation, height and weight of the patients were documented in this study. Median height and weight demonstrated in this series should be quite a lot smaller than those of the US patients. We consider that simple beam arrangement using medium beam energy might be sufficient for the majority of Japanese patients. However, this survey also revealed that 20–30% of the patients of A2 and B2 institutions were treated with linear accelerators of <6 MV or Co-60 machines. When only these insufficient beams can be used, we consider that the four-box field technique should be applied, even for small patients. Although RTOG79-20 has demonstrated the therapeutic value of extended field radiotherapy (16), it had not penetrated into clinical practice during the surveyed period. This was also shown in the 1992–1994 US PCS survey (5). An MLB was used in 70% of the patients during a part of their treatment course of EBRT. The rate was higher than that of the US PCS (5). A difference in the beam arrangements mentioned above might be one of the reasons. It is difficult to add the MLB for the four-field technique. The present study showed that facility type significantly affected the use of the MLB. We speculate that this closely relates to the application of ICBT.
The US PCS has demonstrated that the use of ICBT significantly improved survival and reduced local failures over EBRT alone (17,18). Nevertheless, the utilization rate of ICBT was lower than expected in the present study. The utilization varied significantly according to the types of institution. We consider that this relates to the problems of institutional infrastructure of radiotherapy in Japan (19). Inoue revealed that brachytherapy equipment and the number of staff were insufficient especially in small non-academic institutions in Japan (19). This survey demonstrated that most patients were treated with HDR-ICBT in all institutional strata. In contrast, the latest US PCS survey (1996–1999) showed that only 12% of the patients were treated with HDR-ICBT (6). We consider that this is one of the most remarkable differences between the USA and Japan. Concerning brachytherapy sources, Co-60 was mostly used, followed by Ir-192. Ir-192 was used more frequently in A1 institutions compared with other strata. In 2002, a quality assurance committee of the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) recommended that old HDR machines with Co-60 sources should be replaced with the new type of HDR machines (20). In consequence, the use of Ir-192 sources would be increasing. It is important to note that ICBT applicator insertion was performed without any sedation for about half of the patients. Furthermore, the methods are deemed to be almost insufficient even for sedated patients, such as those receiving orally or rectally administrated NSAIDs. The American Brachytherapy Society (ABS) recommended routine conscious sedation for HDR-ICBT applicator insertions whenever possible (21). The fraction size of HDR-ICBT was within 800 cGy for almost all patients in this survey. This met the recommendation of the ABS and the Gynecologic Oncology Group (GOG) (21,22). The ABS proposed some other technical issues concerning HDR insertion, such as a method of normal tissue displacement, and dose specification (21). These issues should be monitored in detail to assess the quality of ICBT in the next JPCS survey.
We found that there was an obvious difference in total radiation dose of EBRT and HDR-ICBT between the USA and Japan. Although simple dose summation of EBRT and HDR-ICBT is not appropriate, the median total point A dose was 7480 cGy in the US PCS (5) and 5800 cGy in this JPCS series. We consider that this is also one of the remarkable differences in the treatment process between the two countries. This discrepancy was also observed in previously published clinical studies (23–26). We think that it may be closely related to the difference in standard treatment schedules in both countries. A Japanese guideline of radiotherapy has been established for the treatment of uterine cervical cancer by the Japan Society of Obstetrics and Gynecology (JSOG) and the Japan Radiological Society (JRS) in 1987. Its English version came out in 1999 (27). Total doses of EBRT and HDR-ICBT used for patients in this survey were almost the same as the recommended schedules in the guideline. We consider that the majority of patients in this survey were treated in accordance with the guideline. In contrast, the ABS recommended doses are higher than those of the Japanese guideline (21). We consider that there are no conclusive clinical data regarding the optimum radiotherapy schedule for uterine cervical cancer. The outcome analysis using PCS data could be one of the measures to solve this problem.
Several investigators indicated that prolonged OTT reduced the pelvic control rate for patients with uterine cervical cancer (28,29). The ABS recommended that the OTT should be kept within 8 weeks (21). The median OTT of this study (49 days) was shorter than that of the US PCS (63 days) (5). However, the OTT exceeded 8 weeks for >30% of the patients in this JPCS series. Further effort should be made to shorten the OTT. The present analysis revealed that consecutive national holidays had a negative influence on the OTT. We consider this to be one of the important problems to be solved.
Approximately one-quarter of the patient received chemotherapy in this survey. Although several randomized clinical trials (RCTs) had failed to demonstrate any positive prognostic value of NAC prior to radiotherapy in the early 1990s (30), this study showed that not a small number of patients were treated with NAC. This indicated that the negative results had not yet penetrated into clinical practice during this period in Japan. On the other hand, concurrent chemoradiotherapy was applied to only 5% of the patients. In 1999, several RCTs demonstrated the survival benefit of concurrent chemoradiotherapy compared with radiotherapy alone (31). We consider that the increasing application of concurrent chemoradiotherapy will be observed in the next JPCS survey.
In conclusion, the JPCS established the national practice patterns of care for uterine cervical cancer patients treated with radiotherapy without planned surgery between 1995 and 1997 within Japan. This survey demonstrated that the institutional strata significantly affected several practice patterns. Some practice patterns were remarkably different from those established by the US PCS. Further improvements in pre-treatment evaluation including staging, and the method of EBRT and ICBT are necessary.
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Acknowledgments |
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We thank all the radiation oncologists and staff at participating facilities for their support and cooperation. This work was supported by Grants-in-Aid for Cancer Research (Grant Nos. 10-17, and 14-6) from the Ministry of Health, Labor and Welfare in Japan, the Japan Society for the Promotion of Sciences (JSPS), and Japanese Foundation of Aging & Health (JFAH). This paper was presented in part at the 43rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), San Francisco, CA, November 2001, and at the 1st USA/Japan PCS Workshop, San Francisco, CA, November 2001.
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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  T. Teshima and Japanese PCS Working Group Patterns of Care Study in Japan Jpn. J. Clin. Oncol., September 1, 2005; 35(9): 497 - 506. [Abstract] [Full Text] [PDF]
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