Randomised trial of proton vs. carbon ion radiation therapy in patients with chordoma of the skull base,clinical phase III study HIT-1-Study

Background  

Chordomas of the skull base are relative rare lesions of the bones. Surgical resection is the primary treatment standard, though complete resection is nearly impossible due to close proximity to critical and hence also dose limiting organs for radiation therapy. Level of recurrence after surgery alone is comparatively high, so adjuvant radiation therapy is very important for the improvement of local control rates. Proton therapy is the gold standard in the treatment of skull base chordomas. However, high-LET beams such as carbon ions theoretically offer biologic advantages by enhanced biologic effectiveness in slow-growing tumors.     

Emerging role of proton beam radiation therapy for chordoma and chondrosarcoma of the skull base

Chordomas and chondrosarcomas of the skull base are rare, indolent tumors with a natural history of locally invading their surroundings. Safe, maximal resection is the mainstay of treatment, followed by adjuvant radiation therapy. Even with multimodality therapy, local recurrence remains the most common failure pattern, translating to an adverse overall survival. Compared with other forms of radiation therapy, proton beam therapy has been used to increase the dose delivered to the tumor while elegantly sparing dosing to adjacent critical normal structures.     

Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience

PURPOSE: To assess the clinical results of spot scanning proton beam radiation therapy (PT) in the treatment of skull base chordomas and low-grade chondrosarcomas (CS). METHODS AND MATERIALS: Between October 1998 and October 2003, 29 patients (median age, 39 years) with chordomas (n = 18) and CS (n = 11) were treated at the Paul Scherrer Institut (PSI) with protons using the main 510-MeV cyclotron. Tumor conformal application of proton beams was realized by spot scanning technology. The median chordoma and CS dose was 74 and 68 cobalt Gy equivalent, respectively (cobalt Gy equivalent = proton Gy x 1.1). Median gross tumor volumes (GTV) were 16.4 mL (range, 1.8-48.1 mL) and 15.2 mL (range, 2.3-57.3 mL) for chordoma and CS, respectively. Late toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v3.0) grading system. The median follow-up time was 29 months (range, 6-68 months). RESULTS: Actuarial 3-year local control rates were 87.5% and 100% for chordoma and CS, respectively. We observed one surgical pathway and one marginal failure in patients with chordomas. No regional failure or distant metastasis was observed. At 3 years, actuarial PFS and OS for the entire cohort was 90% and 93.8%, respectively. Actuarial 3-year complication-free survival was 82.2%. Radiation-induced pituitary dysfunction was observed in 4 (14%) patients (CTCAE Grade 2). No patient presented with post-PT brainstem or optic pathways necrosis or dysfunction. In univariate analysis, age < or =40 years at the time of PT affected favorably on PFS (p = 0.09). CONCLUSION: Spot-scanning PT offers high tumor control rates of skull base chordoma and CS. These results compare favorably to other combined proton-photon or carbon ion irradiation series. Observed toxicity was acceptable. Younger age (< or =40 years) was a favorable prognostic factor of PFS. These preliminary results are encouraging but should be confirmed during a longer follow-up.     

On the cost-effectiveness of Carbon ion radiation therapy for skull base chordoma.

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 cost-effectiveness 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 cost-effective 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.     

A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy

PURPOSE: The quality of life (QOL) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy (RT). We assessed the effect of prophylactic d-threo-methylphenidate HCl (d-MPH), a central nervous system (CNS) stimulant on QOL and cognitive function in patients undergoing RT. METHODS AND MATERIALS: Sixty-eight patients with primary or metastatic brain tumors were randomly assigned to receive d-MPH or placebo. The starting dose of d-MPH was 5 mg twice daily (b.i.d.) and was escalated by 5 mg b.i.d. to a maximum of 15 mg b.i.d. The placebo was administered as one pill b.i.d. escalating three pills b.i.d. The primary outcome was fatigue. Patients were assessed at baseline, the end of radiation therapy, and 4, 8, and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue (FACIT-F) subscales, as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam. RESULTS: The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm (p = 0.61). At 8 weeks after the completion of brain RT, there was no difference in fatigue between patient groups. The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm (p = 0.64). Secondary outcomes were not different between the two treatment arms. CONCLUSIONS: Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL.     

质子碳离子笔形束扫描技术治疗头颈部脊索瘤与软骨肉瘤的初步结果

目的 采用质子碳离子笔形束扫描技术治疗头颈部脊索瘤软骨肉瘤患者的不良反应和近期疗效。方法 2014-2016年共收治61例接受质子重离子治疗作为首程放疗的头颈部脊索瘤及软骨肉瘤患者,其中脊索瘤45例,软骨肉瘤16例;男39例,女22例;中位年龄38岁(14~70岁),中位肿瘤最大直径4.1 cm (0~8.6 cm)。肿瘤原发部位以枕骨斜坡及颈椎为主。结果 单纯质子治疗8例,质子+碳离子治疗21例,单纯碳离子治疗32例,所有患者均顺利完成治疗。患者中位随访时间21个月(7~47个月)。未见3-4级急性不良反应,晚期不良反应仅1例放射性颞叶损伤。2年无进展生存率91%,2年总生存率100%。结论 质子重离子治疗脊索瘤软骨肉瘤取得了较好的短期疗效,长期疗效及不良反应仍需要进一步随访。     

重离子（12 C6＋）治疗恶性黑色素瘤的临床研究现状

恶性黑色素瘤（ malignant melanoma,MM）是一种恶性程度高、迁徙能力强的皮肤肿瘤。其发病率在全球范围呈现上升趋势,正日益威胁着人类的生命健康。放射治疗在不能手术切除的恶性黑色素瘤中起着重要作用,然而MM细胞对低LET射线（ x、γ）具有显著的抗拒性限制了常规射线放疗在MM中的应用。重离子由于其特有的物理学特性和生物学优势,使其在肿瘤治疗领域展现出良好的应用前景。本文就重离子在MM中的应用做一综述。     

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS).MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m² 24-h intravenous (i.v.) infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m² i.v. q3wk, or doxorubicin 60 mg/m² i.v. plus ifosfamide (range, 6–9 g/m²) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point.ResultsOne hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; hazard ratio = 0.86, p = 0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm.ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.     

3-D comparative study of proton vs. x-ray radiation therapy for rectal cancer.

To assess the usefulness of proton beams for treatment of patients with rectal cancer, we have performed comparative 3D treatment planning for proton beam and x-ray beam therapy. Three common x-ray techniques (AP-PA, 3-field, and 4-field box), a proton beam only plan, and a proton boost plan were compared. The plan which would have been treated without the aid of the 3D planning system was also simulated. Dose distributions were analyzed and dose-volume histograms computed for the target volumes and critical normal tissues. Analyses of these plans demonstrate that the proton beam techniques reduce the volume of small bowel irradiated. This may allow higher doses to be delivered to the tumor, with a probable increase in local control, or a reduction in normal tissue complications probability. All the plans developed with the 3D planning system treated significantly less bowel than the one planned without it.     

A phase III randomized study of misonidazole plus radiation vs. radiation alone for cervix cancer

BACKGROUND AND PURPOSE: A randomized-controlled study of radical radiotherapy for cervical cancer with or without the hypoxic sensitizer, misonidazole was conducted from 1981 to 1984 to investigate its therapeutic benefit. PATIENTS AND METHODS: Seventy-three patients were accrued from the Princess Margaret Hospital, and St John Regional Cancer Centre and randomized to either misonidazole (MISO, n = 39) or placebo (P, n = 34) in addition to radiotherapy. MISO was given orally each day 4 h prior to external beam radiation treatment (45Gy to midplane in 20 daily fractions) at a dose of 0.45 g/m(2), as well as during intra-uterine brachytherapy (40Gy). RESULTS: The 10-year overall survival (OS) for the entire group was 46%, and the disease-free survival (DFS) was 39%. The 10-year OS for patients in the MISO arm was 45%, compared to 49% for the P arm (P = 0.89). The corresponding DFS figures were 36 and 43%, respectively, (P = 0.6). Ten patients (14%) developed severe late complications (grade 3 or 4). The 10-year serious late complication rate was 14% for MISO and 12% for P (P = 0.51). CONCLUSIONS: Misonidazole failed to improve the outcome of patients with cervix cancer treated with radiotherapy.     

A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumors

Glial tumors with oligodendroglial components are considered chemo-responsive. Forty newly diagnosed patients (11 anaplastic oligodendrogliomas [OD] and 29 anaplastic oligoastrocytomas [OA]) were enrolled into this multicenter, open-label, single-arm Phase II trial of first-line temozolomide (200 mg/m² on days 1–5 every 4 weeks for 6 cycles). The primary endpoint was 6-month progression-free survival (PFS) with response rate (RR), median PFS, and median overall survival (OS) as secondary endpoints. Of 39 evaluable patients at the 6-month time point (median follow-up, 34 months), 6-month PFS was 77% (95% confidence interval [CI], 74.5%–79.3%). There were 15 complete responses (CRs, 38%), 6 partial responses (PRs, 15%), and 9 disease stabilization (23%). The median PFS was 21 months (95% CI, 3–39 months), and the median OS was 43 months (95% CI, 20–66 months). Chromosome 1p/19q codeletions were seen in 47% (18 of 38) of the patients, and O-6-methylguanine-DNA-methyltransferase (MGMT) methylation was seen in 48% (10 of 21) of the patients. All patients with OD showed MGMT methylation and most (71%) had chromosome 1p/19q codeletions. Conversely, fewer patients with OA showed MGMT methylation (23%) or had chromosome 1p/19q codeletions (31%). The presence of either 1p/19q codeletion or MGMT methylation was associated with increased RR at 6 months but not with improved PFS or OS. Only 18% of the patients (7 of 40) experienced treatment-related grade 3/4 toxicities. This regimen was active and well tolerated. These data add to the growing body of data showing that primary chemotherapy may be an acceptable alternative to radiotherapy for patients with gliomas containing oligodendroglial histology.     

Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial

Background:

The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. Results of the feasibility study on the first 100 enrolled patients are presented.

Methods:

Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC).

Results:

Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%).

Conclusions:

The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients.     

Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer

Background:

This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer.

Methods:

Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day⁻¹ based on body surface area (BSA), orally, days 1–28, every 6 weeks) or SOX (S-1 80/100/120 mg day⁻¹ based on BSA, orally, days 1–14, plus oxaliplatin 100 mg m⁻², intravenously, day 1, every 3 weeks). The primary end point was PFS.

Results:

Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65–1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79–1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%).

Conclusions:

Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.     

Bleomycin and radiation therapy in squamous cell carcinoma of the upper aero-digestive tract: a phase III clinical trial

A group of 222 consecutive patients admitted with squamous cell carcinoma of the upper aero-digestive tract were studied in a prospectively randomized and stratified clinical trial. One-half of the patients received bleomycin injected intramuscularly 1 hour before the radiation treatment daily for 5 days a week; the other half received radiation therapy without the added chemotherapy. The total dose of radiation in both groups was about the same, and was given with curative intent even to the patients with advanced tumors who constituted the majority in both groups. Interstitial radiation as boost therapy or surgery was added in patients with residual tumor if the lesions were considered operable and the patient's condition would allow surgery. The addition of bleomycin did not increase the combined local and regional tumor control rates nor did it improve the survival, but did significantly increase the morbidity and the complication rate.     

Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer.

BACKGROUND: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC) in phase II studies, alone or in combination. Its moderate toxicity profile is well tolerated in elderly patients. PATIENTS AND METHODS: Patients with metastatic prostate cancer, progressive after primary hormonal therapy, were randomised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks, and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression. Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy (HT) for all their patients. Randomisation was stratified by centre. Further chemotherapy was allowed after progression. The primary end point was progression-free survival (PFS). The final analysis was performed on a total of 414 patients. Reported results were all based on intention-to-treat analyses. All progressions and responses were reviewed by an independent panel. RESULTS: PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm, according to the statistical hypothesis of the protocol (P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10%). The 6-month PFS rates were 33.2% versus 22.8%, and the median durations of PFS were 3.7 versus 2.8 months. In the multivariate Cox analysis, which included age, Karnofsky performance status (PS), haemoglobin, alkaline phosphatase at study entry and number of prior hormonal treatments, the P value was decreased to 0.005. The prostate-specific antigen (PSA) response rate (> or =50% decline sustained for at least 6 weeks) was significantly higher for VRL plus HT compared with HT (30.1% versus 19.2%; P=0.01). Clinical benefit, defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks, and at least stable assessment in the other two, was also more frequently observed in patients who received VRL plus HT versus HT alone (30.6% and 19.2%; P=0.008). There was no statistical difference in overall survival. Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression, compared with 28% of patients in the VRL-based arm. Aminoglutethimide did not seem to result in better efficacy for either arm. VRL plus HT was well tolerated, with a median administered relative dose intensity of 90%; grade 4 neutropenia occurred in 6.5% of patients and non-haematological toxicity was rare. CONCLUSIONS: The combination of VRL and hydrocortisone compared with hydrocortisone alone resulted in improved clinical benefit, PFS and PSA response rate. This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids. There was no gain in survival; however, the combination is well tolerated in this elderly group of patients, who often present cardiac co-morbidities, and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer.     

Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer.

PURPOSE: This multicenter trial investigated whether daily pretreatment with amifostine (A) could reduce the incidence of acute and late lung toxicity and esophagitis without affecting antitumor efficacy of radiation in advanced lung cancer. PATIENTS AND METHODS: Radiotherapy (XRT) patients (n = 146) received a daily fraction of 2 Gy/5 days/week to a total of 55-60 Gy +/- amifostine 340 mg/m(2) administered daily 15 min before irradiation. Acute and late toxicities were graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer system. RESULTS: Ninety-seven patients were evaluated 2 months post-XRT for the incidence of pneumonitis; 43% (23/53) of patients in the XRT arm and 9% (4/44) in the A + XRT arm experienced > or = Grade 2 pneumonitis (p < 0.001) [corrected]. Forty-nine percent (26/53) of patients in the XRT arm and 16% (7/44) in the A+XRT arm demonstrated changes representative of > or = Grade 2 lung damage (p < 0.001). At 6 months, fibrosis was present in 53% (19/36) receiving XRT vs. 28% (9/32) receiving A+XRT (p < 0.05). Incidence of esophagitis > or = Grade 2 during Week 4 was 42% (31/73) in the XRT arm vs. 4% (3/73) in the A+XRT arm (p < 0.001). Among 97 patients evaluable for response 2 months after XRT, complete or partial response was present in 76% (40/53) of patients in the XRT arm and 75% (33/44) in the A+XRT arm (p = 1.0). CONCLUSION: Amifostine reduces the incidence of pneumonitis, lung fibrosis, and esophagitis in radiotherapy patients with lung cancer without compromising antitumor efficacy.     

A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 × 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m⁻² day⁻¹ × 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3–752/4–433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3–399/4–228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment.     

Importance of precise positioning for proton beam therapy in the base of skull and cervical spine.

Using proton beam therapy, high doses have been delivered to chordomas and chondrosarcomas of the base of skull and cervical spine. Dose inhomogeneity to the tumors has been accepted in order to maintain normal tissue tolerances, and detailed attention to patient immobilization and to precise positioning has minimized the margins necessary to ensure these dose constraints. This study examined the contribution of precise positioning to the better dose localization achieved in these treatments. Three patients whose tumors represented different anatomic geometries were studied. Treatment plans were developed which treated as much of the tumor as possible to 74 Cobalt-Gray-Equivalent (CGE) while maintaining the central brain stem and central spinal cord at less than or equal to 48 CGE, the surface of the brain stem, surface of the spinal cord, and optic structures at less than or equal to 60 CGE, and the temporal lobes at less than or equal to 5% likelihood of complication using a biophysical model of normal tissue complication probability. Two positioning accuracies were assumed: 3 mm and 10 mm. Both proton beam plans and 10 MV X ray beam plans were developed with these assumptions and dose constraints. In all cases with the same positioning uncertainties, the proton beam plans delivered more dose to a larger percentage of the tumor volume and the estimated tumor control probability was higher than with the X ray plans. However, without precise positioning both the proton plans and the X ray plans deteriorated, with a 12% to 25% decrease in estimated tumor control probability. In all but one case, the difference between protons with good positioning and poor positioning was greater than the difference between protons and X rays, both with good positioning. Hence in treating these tumors, which are in close proximity to critical normal tissues, attention to immobilization and precise positioning is essential. With good positioning, proton beam therapy permits higher doses to significantly more of the tumor in these sites than do X rays.