Advanced-technology radiation therapy for bone sarcomas.

BACKGROUND: Bone sarcomas are rare primary tumors. Radiation therapy (RT) can be useful in securing local control in cases where negative surgical margins cannot be obtained or where tumors are not resected. Recent technical advances in RT offer the opportunity to deliver radiation to these tumors with higher precision, thus allowing higher doses to the tumor target with lower doses to critical normal tissues, which can improve local tumor control and/or reduce treatment-related morbidity. METHODS: The authors conducted a survey of recent technical developments that have been applied to the RT for bone sarcomas. RESULTS: RT techniques that show promise include intensity-modulated photon radiation therapy, 3-D conformal proton RT, intensity-modulated proton RT, heavy charged-particle RT, intraoperative RT, and brachytherapy. All of these techniques permit the delivery of higher radiation doses to the target and less dose to normal tissue than had been possible with conventional 3-D conformal radiation techniques. Protons deliver substantially less dose to normal tissues than photons. CONCLUSIONS: Data from clinical studies using these advanced radiation techniques suggest that they can improve the therapeutic ratio (the ratio of local control efficacy to the risk of complications). This is expected to improve the treatment outcome for these challenging tumors.     

Update on radiation therapy in prostate cancer

Higher doses of radiation result in improved clinical control of prostate cancer,and the recent advances in prostate cancer radiotherapy are designed to escalate dose while minimizing toxicity. To achieve this goal, tighter treatment margins are needed, which require more accurate delineation of the prostate target and normal tissue at the time of treatment planning and before actual daily treatments. Modem radiation therapy techniques can deposit conformal dose virtually anywhere in the body; however, this precise therapy is of no value if it is not accurately hitting the target. Whether dose escalation is achieved by external beam techniques (eg, IMRT, protons) or brachytherapy, these ba-sic planning and delivery considerations are essentially the same. Future directions in prostate radiation therapy will use even higher radiation doses,alternative fractionation patterns, intraprostatic targets (eg, prostate tumor seen on MRI), and improved patient selection regarding which patients will benefit the most from these advanced techniques.     

Radiation therapy for lung cancer

Radiation therapy is one of the most important modalities for the treatment of lung cancer. Current progress of radiation therapy in cooperation with the development of physics and biology is remarkable. The techniques of three-dimensional treatment planning and three-dimensional conformal radiotherapy (3D-CRT) have facilitated the use of higher radiation doses. Patients with early-stage non-small cell lung cancer (NSCLC) are candidates for curative surgical resection. However, the number of elderly patients has been increasing, and these patients often have medical contraindications that prevent curative surgery. Recently, several clinical trials on stereotactic body radiotherapy (SBRT) using the 3D-CRT technique for solitary lung tumors have been reported. The local control rate for stage I disease is more than 90%, and survival rates are promising. Now a prospective multi-institutional trial is ongoing to determine whether this modality can become a standard treatment for inoperable patients or an alternative to lobetectomy. For locally advanced NSCLC, unfortunately, recent studies have demonstrated that conventional therapies may have reached a therapeutic plateau. Now several radiation dose escalation studies utilizing conventional fractionation and 3D-CRT techniques are ongoing. The strategies of almost all of these trials are to eliminate elective nodal irradiation and deliver a higher dose of radiation to gross tumor volume while sparing normal tissues. Preliminary experience has resulted in promising survival, but should be developed to integrate into the combined treatment to completely control both local disease and other microscopically involved lesions. The combination of novel chemotherapeutic agents and molecular targeting therapies with radiation therapy is being investigated. Development of molecular imaging techniques is expected to facilitate more selective dose escalation in tumors.     

国际淋巴瘤放射治疗协作组(ILROG)现代放射治疗靶区勾画及剂量指南——HL

放疗是HL最有效的LC治疗手段和重要的治疗组成部分。这些指南用来指导现代综合治疗条件下放疗在HL中的应用。结合现代影像的三维治疗计划和先进的治疗技术,能减少照射体积和照射剂量。最初使用的EF和IF技术,是基于淋巴结站的大体积治疗方式,目前已被仅以最初可检测到的淋巴结(和结外侵犯)范围为基础的有限的照射野所取代。这种照射技术基于增强CT、PET-CT、MRI或结合运用。ICRU定义了GTV、CTV、ITV和PTV概念。更新的治疗技术包括IMRT、呼吸门控、IGRT和4D图像应用,可以显著降低正常组织损伤风险且同时可达到对原发肿瘤控制的主要目的。能够获得理想治疗前影像患者,可以采用高度适形的受累淋巴结放疗(INRT)。受累部位放疗(ISRT)这个新概念作为标准的适形治疗方式被提出,通常在最佳的影像不可获得的情况下使用。越来越多证据表明过去应用的放疗剂量在综合治疗时代比疾病控制所需剂量高。现有数据支持在早期HL中应用INRT和更低放疗剂量。尽管INRT的应用尚未在正式的研究中得到验证,其应用比ISRT更加保守谨慎,原因为欠理想的影像信息和合适的靶区设计以达到可靠的肿瘤LC。目前使用更小照射野治疗的目标是减少治疗体积和剂量,同时维持治疗有效性并使急性和晚期并发症最小化。这篇综述是ILROG督导委员会关于HL放疗现代治疗手段的共识,概括了对HL在可以达到有效LC的同时减少治疗体积的新概念,即ISRT。     

The role of radiotherapy in the treatment of liver metastases

Radiotherapy has historically played a minor role in the treatment of patients with unresectable liver metastases from colorectal cancer and other malignancies. This can be attributed chiefly to the low tolerance of the whole liver to radiation. High-precision radiotherapy planning techniques have allowed much higher doses of radiation to be delivered safely to focal liver metastases, while sparing most of the normal liver. When combined with hepatic arterial fluorodeoxyuridine, high-dose focal liver radiotherapy is associated with excellent response rates, local control, and survival in patients with unresectable liver metastases from colorectal cancer. Radiotherapy, with and without concurrent systemic chemotherapy, has also been used with encouraging outcomes for patients with liver metastases from colorectal cancer and other cancers. There appears to be a radiation dose response for liver metastases; tumors treated with doses of 70 Gy or greater are likelier to have durable local control. Advancements in tumor imaging, in radiotherapy techniques that will allow the safe delivery of higher doses of radiation, and in novel tumor radiation sensitizers and normal tissue radioprotectors should substantially improve the outcome of patients with unresectable liver metastases treated with radiotherapy.     

Stereotactic body radiotherapy (SBRT)

The techniques of three-dimensional conformal radiotherapy (3 D-CRT) and patient immobilization have recently been developed, enabling us to focus high doses on the target with relatively less irradiation of normal tissues. In radiotherapy for solitary lung tumors, the local control may be safely improved by delivering a higher dose at only the target volume using these techniques. Recently, several clinical studies on stereotactic body radiotherapy (SRT) using the 3 D-CRT technique for solitary lung tumors have been reported. The single dose used is 10-15 Gy, and the total sessions are three to five. The local control rate is more than 90% and complication rates are very low. Therefore, this treatment is a promising new non-invasive treatment for early stage lung cancer. A multi-institutional clinical study, JCOG 0403, in now underway.     

Intraoperative radiation therapy

The modern use of intraoperative radiation therapy (IORT) was initiated by the studies of Abe and colleagues at the University of Kyoto. This work stimulated significant laboratory and clinical investigation into the use of IORT throughout Japan, Europe, and the United States. Because of this experience, single high doses of irradiation can be safely delivered to a tumor volume in appropriate clinical situations. Most importantly, this high dose of additional radiation treatment yields improved local control of selected tumors. Treatment programs of external beam radiation therapy, surgical resection, and IORT for patients with locally advanced primary and recurrent rectal carcinoma and retroperitoneal sarcoma have yielded excellent local control and higher survival rates. The future of IORT will be in the successful integration of this therapy into multimodality treatment programs of chemotherapy, external beam irradiation, and surgery for locally advanced malignancies. Received: August 20, 2001     

Radiation therapy for patients with locally advanced pancreatic cancer: Evolving techniques and treatment strategies

Despite ongoing efforts, patients with locally advanced pancreatic cancer (LAPC) continue to have a dismal prognosis. Such tumors are unresectable, and optimal treatment with chemotherapy and/or radiation therapy is still not established. While chemotherapy is conventionally aimed at preventing metastatic spread of disease, radiation therapy acts locally, improving local control which can potentially improve overall survival and most importantly quality of life. Here, we aim to review the primary literature assessing the role of diverse radiation therapy strategies for patients with LAPC.Many radiation regimens can be considered, and no standard treatment has demonstrated a clear improvement in clinical outcomes. We advise that the modality of choice be dependent on the availability of equipment, the dose and fractionation of treatment, as well as the dose received by normal tissue. Moreover, a candid discussion with the patient concerning treatment goals is equally as essential. Three notable strategies for LAPC are intensity-modulated radiation therapy, volumetric modulated arc therapy, and proton. These radiation modalities tend to have improved dose distribution to the target volumes, while minimizing the radiation dose to surrounding normal tissues. Stereotactic body radiation therapy can also be considered in LAPC patients in cases where the tumor does not invade the duodenum or other neighboring structures. Because of the high doses delivered by stereotactic body radiation therapy, proper respiratory and tumor motion management should be implemented to reduce collateral radiation dosing. Despite improved clinical outcomes with modern radiation modalities, evolving techniques, and more accurate planning, future studies remain essential to elucidate the optimal role for radiation therapy among patients with LAPC.     

Conformal chemoradiation for primary and metastatic liver malignancies

Historically, radiation therapy has played a minor role in the management of patients with unresectable primary hepatobiliary malignancies and liver metastases from colorectal cancer. This can be attributed chiefly to the low tolerance of the whole liver to radiation. Three-dimensional radiation planning techniques have allowed much higher doses of radiation to be delivered to focal liver tumors, while sparing the majority of the normal liver. When combined with fluorodeoxyuridine (FUdR), high-dose focal liver radiation is associated with excellent response rates, local control, and survival in patients with large unresectable tumors. There appears to be a radiation dose response for intrahepatic malignancies. Advancements in tumor imaging, radiation techniques that can safely deliver higher doses of radiation, novel tumor radiation sensitizers, and normal-tissue radioprotectors should substantially improve the outcome of patients with unresectable intrahepatic malignancies treated with chemoradiation.     

Trends in radiation therapy for the treatment of metastatic and oligometastatic disease in 2010

The role of radiation therapy in metastatic disease has evolved from palliative to potentially curative intent for selected oligometastases using highly conformal radiation techniques, including extracranial stereotactic body radiotherapy (SBRT) in the last decade. SBRT has a potential to use small numbers of large doses aiming at achieving high rates of local control while preserving the quality of life even in highly pretreated patients. A wide range of techniques, doses, and dose fractionation schedules can be found. However, the 2-year local control is around 80% for lung metastases with corresponding 2-year survival of 50%, and a 5% rate of grade III or higher radiation toxicities. The 2-year local control varies between 57 and 92% for liver metastases and radiation-induced liver disease is exceptional provided that 700 cm3 of healthy liver are irradiated to less than 15 Gy in three fractions or more. Stereotactic radiation is also particularly interesting for spinal, and cranial metastases and reirradiations. Also, it has come into focus that associations of chemotherapy or targeted therapies and radiation may be used for optimized treatment of limited metastatic disease and that irradiation of the primary tumor may be recommended in the context of metastatic disease. It also appears that the definition of target volumes for palliative radiation therapy and scores to assess for life expectancy-based need for irradiation should be improved.     

Advances in treatment techniques: arc-based and other intensity modulated therapies

Treatment planning and radiation delivery techniques have advanced significantly during the past 2 decades. The development of the multileaf collimator has changed the scope of radiotherapy. The dynamic conformal arc technique emerged from traditional cone-based conformal arc therapies, which aim to improve target dose uniformity and reduce normal tissue doses. With dynamic conformal arc, the multileaf collimator aperture is shaped dynamically to conform to the target. With the advent of intensity-modulated radiotherapy (IMRT), the concept of arc therapy in combination with IMRT has enabled better-quality dose distributions and more efficient delivery. Helical tomotherapy has been developed to treat targets sequentially by modulating the beam intensity in each "slice" of the patient. Helical tomotherapy offers improved dose distributions for complicated treatments, such as whole-body radiation. Intensity-modulated arc therapy has been studied to modulate fluences in a cone beam rather than fan beam geometry to improve delivery efficiency. This article reviews arc-based IMRT, intensity-modulated arc therapy, and helical tomotherapy techniques. We compare the dosimetric results reported in the literature for each technique in various treatment sites. We also review the application of these techniques in specialized clinical procedures including total marrow irradiation, simultaneous treatment of multiple brain metastases, dose painting, simultaneous integrated boost, and stereotactic radiosurgery.     

Small Cell Lung Cancer: The Influence of Dose and Treatment Volume on Outcome

The treatment of small cell lung cancer is clearly enhanced by the addition of radiation therapy. Survival increases modestly while local thoracic failure as first site of progression is reduced from approximately 60% when chemotherapy alone is used to 30% after combined modality therapy. The variables of radiation dose and treatment volume seem to be important in the successful management of this disease. Local chest control appears to increase as doses are escalated from low levels (25 Gy) to moderate levels (45 to 50 Gy(. With about one third of patients experiencing local chest progression, one can speculate that higher radiation doses might be of value. However, at this time there is no proof that increased dose or dose intensity bears out this promise. Indeed, increasing dose intensity of radiotherapy, eg, twice-daily treatment, increases esophagitis, perhaps reduces local failure, but has not improved overall survival. Using larger total doses or altered fraction schemes must still be considered to be under investigation. To increase dose in a safe manner, reduction in the volume covered by radiation portals will likely need to take place. Modern trials suggest that prophylactic treatment of the radiographically or clinically negative contralateral hilum and/or supraclavicular nodal regions may not be necessary for survival or local control. Importantly, reducing treatment volumes may permit increasing doses without exceding normal tissue tolerance. Also, reduced volumes pave the way for further clinical trials that improve radiation dose delivery by better target definition and more conformal therapy.     

The impact of three-dimensional radiation on the treatment of non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) patients with locally advanced unresectable disease have a grim prognosis. Radiotherapeutic strategies are necessary to improve the permanent eradication of thoracic disease. The poor results achieved with conventional external beam radiation therapy reflect in part, the inadequacy of such therapy in achieving its primary objective of achieving local control. The impact of three-dimensional conformal radiation therapy (3-DCRT) on local disease eradication and its potential role in improving survival is assessed. DESIGN: This review addresses aspects of the software and hardware technology of 3-DCRT, the clinical and technical aspects of target volume definition, the use of 3-DCRT to predict radiation pneumonitis, strategies for dose escalation in NSCLC, and analyses the clinical results to date. RESULTS: Initially investigators compared the best treatment techniques devised with conventional planning techniques to those devised with 3-DCRT. These analyses showed that 3-DCRT had the potential to deliver high dose radiation (>70 Gy) with minimal underdosing and with a concomitant relative sparing of normal tissues. This technical demonstration of enhanced therapeutic ratio is the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Software and hardware developments continue to develop and have the potential to solve evolving clinical issues. Dose-volume-histograms have been used to accurately quantify lung dose and derived parameters have the potential to predict the risk of pneumonitis for individual patients before treatment. Initial clinical results have been promising and strategies for further dose escalation are emerging. CONCLUSION: Preliminary experience has resulted in promising survival following three-dimensional conformal radiation therapy alone for locally advanced NSCLC. More follow-up and experience will determine late toxicity, maximum dose, and efficacy of dose escalation with three-dimensional conformal radiation therapy. Strategies should be developed to integrate this modality into the combined treatment of locally advanced non-small cell lung cancer.     

Technological advances in radiotherapy for the treatment of localised prostate cancer

There is good evidence that radiation dose escalation in localised prostate cancer is associated with increased cell kill. The traditional two-dimensional (2D) technique of treatment planning and delivery is limited by normal tissue toxicity, such that the dose that can be safely delivered to the prostate by external beam radiotherapy is 65-70 Gy. Several technological advances over the last 20 years have enhanced the precision of external beam radiotherapy (EBRT), and have resulted in improved outcomes. The three-dimensional conformal radiotherapy (3D-CRT) approach reduces the dose-limiting late side-effect of proctitis and has allowed for dose escalation to the whole prostate to 78 Gy. More recently, intensity modulated radiotherapy (IMRT), an advanced form of conformal therapy, has resulted in reduced rectal toxicity when using doses greater than 80 Gy. In addition, IMRT can potentially escalate the dose to specific parts of the prostate where there are resistant subpopulations of tumour clonogens, or can be used to extend the high-dose region to pelvic lymph nodes. The addition of androgen deprivation to conventional radiotherapy has an impact on survival and local control. Initial hormone therapy causes cytoreduction of the prostate cancer allowing for a reduction in radiotherapy volume as well as an additive effect on cell kill. Long-term adjuvant androgen deprivation has been shown to improve overall survival in more advanced tumours. Prostate brachytherapy is now a recognised treatment for those with low-risk disease. It achieves similar long-term outcome to other treatment modalities. Brachytherapy can be used as monotherapy for localised disease, or as boost treatment following conventional EBRT for locally advanced disease. New techniques are available to improve the precision of both target definition and treatment verification. This so-called image-guided radiotherapy will help to enhance the accuracy of dose delivery by correcting both for inter-fraction positional variation and for intra-fraction movement of the prostate in real-time and will allow for tighter tumour margins and avoidance of normal tissues, thereby enhancing the safety of treatment.     

Advances in External Beam Radiation Therapy and Brachytherapy for Cervical Cancer

The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent chemotherapy followed by a brachytherapy boost. Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy. Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy, may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and future directions.     

State-of-the-art lung cancer radiation therapy

External-beam radiotherapy, often combined with chemotherapy, is the treatment of choice for locally advanced inoperable lung cancer. Locoregional control and disease-free survival, however, are limited with the current clinically applied treatment strategies. An important factor is the inability to deliver sufficiently high dose levels, mainly caused by the fact that the limited geometrical accuracy impedes further dose escalation owing to risk of complications. Higher conformality of the planned dose distributions and higher levels of accuracy in radiotherapy delivery reduces the amount of normal tissues irradiated, such that the tumor and pathologic lymph nodes can be safely irradiated to higher doses. In this review we describe recent developments in imaging, treatment planning and treatment delivery that have the potential to increase the efficacy of lung cancer radiation therapy. Respiratory-correlated imaging techniques eliminate respiratory-induced artifacts and produces 4D scans representing the patient’s anatomy (CT) and biology (18-fludeoxyglucose [¹⁸FDG]-PET) over the respiratory cycle. Moreover, ¹⁸FDG-PET scans provide information on the heterogeneous tumor characteristics. Intensity-modulated radiotherapy planning techniques produce highly conformal dose distributions tailored to the patient-specific respiratory motion patterns and, possibly, tumor characteristics. Image-guided radiotherapy utilizes repetitive imaging in the treatment room to measure and correct tumor misalignments. Finally, adaptive radiotherapy monitors the patient over the course of treatment and allows for adaptive treatment-plan modifications to individualize the treatment to the observed patient-specific changes. These techniques thus allow the delivery of higher doses of irradiation that yield a greater probability of complete response, higher tumor control and better survival in irradiated lung cancer patients.     

Radiation-therapy of malignant gliomas

On the surgery of glioblastoma multiforme, most cases are beyond the scope for desirable removal of tumors. The restriction of the surgical treatment has inevitably required postoperative radiation therapy. Although patients treated with postoperative radiation therapy showed significantly extended survival rates as compared to those receiving surgical resection alone, the glioblastoma recurred within a 2cm margin of the primary site in more than 90% of the patients and conventional external radiation therapy with a doses of 50-60 Gy did not result in local cure. However, it was reported that survivals extended in proportion to target absorbed doses and suggested that a higher localized radiation dose would improve the poor prognosis of these tumors. In order to obtain a local cure of glioblastoma, the first step of therapy should be an intensive local treatment. Intraoperative radiation therapy (IOR) and brachytherapy using high activity iodine-125 or iridium-192 become a logical local treatment for sterilizing the remaining malignant remnants by a high target absorbed dose without damaging surrounding brain tissues. IOR for 19 patients with glioblastoma resulted in a 2-year survival rate of 61.4%. Brachytherapy has shown excellent local effects for recurrent tumors.     

Optimization of physical dose distributions with hadron beams: comparing photon IMRT with IMPT

Intensity modulated radiotherapy with high enery photons (IMRT) and with charged particles (IMPT) refer to the most advanced development in conformal radiation therapy. Their general aim is to increase local tumor control rates while keeping the radiation induced complications below desired thresholds. IMRT is currently widely introduced in clinical practice. However, the more complicated IMPT is still under development. Especially, spot- scanning techniques integrated in rotating gantries that can deliver proton or light ion-beams to a radiation target from any direction will be available in the near future. We describe the basic concepts of intensity modulated particle therapy (IMPT). Starting from the potential advantages of hadron therapy inverse treatment planning strategies are discussed for various dose delivery techniques of IMPT. Of special interest are the techniques of distal edge tracking (DET) and 3D-scanning. After the introduction of these concepts a study of comparative inverse treatment planning is presented. The study aims to identify the potential advantages of achievable physical dose distributions with proton and carbon beams, if different dose delivery techniques are employed. Moreover, a comparison to standard photon IMRT is performed. The results of the study are summarized as: i) IMRT with photon beams is a strong competitor to intensity modulated radiotherapy with charged particles. The most obvious benefit observed for charged particles is the reduction of medium and low doses in organs at risk. ii) The 3D-scanning technique could not improve the dosimetric results achieved with DET, although 10-15 times more beam spots were employed for 3D-scanning than for DET. However, concerns may arise about the application of DET, if positioning errors of the patient or organ movements have to be accounted for. iii) Replacing protons with carbon ions leads to further improvements of the physical dose distributions. However, the additional degree of improvement due to carbon ions is modest. The main clinical potential of heavy ion beams is probably related to their radiobiological properties.     

Dose-escalated 3D conformal radiotherapy in prostate cancer

3D conformal radiotherapy involves the delivery of radiation to a defined 3D tumor volume while minimizing doses to adjacent critical tissues. The use of sophisticated imaging tools and advanced treatment planning software have allowed for better target definition enabling the oncologist to conform or shape radiation volume more closely around the target while minimizing dose to the rectum and bladder. 3D conformal radiotherapy has resulted in dramatic reductions in acute and late toxicity of radiation treatment in prostate cancer. It has also allowed for safe escalation of radiation dose with improved tumor control compared with conventional dose radiotherapy. Long-term tumor control rates with 3D conformal radiotherapy are comparable with results using radical prostatectomy.