Management of nonfunctioning pituitary tumors: radiotherapy

External beam radiotherapy (RT) is an essential part of the management of intracranial tumors and has been used in treating pituitary adenomas for more than five decades. It has been demonstrated that conventional RT for postoperative residual or progressive nonfunctioning pituitary adenomas (NFAs) present an excellent long-term local tumor control, although its use has been limited because of the potential late toxicity related to radiation treatments. Recent advances in radiation techniques have led to more accurate treatments, rendering obsolete many commonly held views of the “old” radiotherapy. New techniques include intensity modulated radiotherapy, volumetric-modulated arc therapy, and stereotactic techniques, either stereotactic radiosurgery or fractionated stereotactic radiotherapy. New techniques allow the delivering of higher radiation doses to the target with rapid dose fall-off in the surrounding normal tissues, and potentially limiting the long term toxicity of radiation. In this review, we present a critical analysis of the most recent available literature on the use of radiation in patients with NFAs, focusing particularly on the efficacy and safety of radiation stereotactic techniques.     

Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy

In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.KEYWORDS : Low Doses Fractionated Radiation Therapy (LDFRT), hyper-radiation sensitivity (HRS), induced radiation resistance (IRR), hyperfractionation, chemopotentiation, stereotactic body radiation therapy (SBRT), stereotactic ablative radiosurgery (SARS), stereotactic ablative radiotherapy (SABR), stereotactic radiosurgery (SRS), spatially fractionated GRID radiotherapy (SFGRT), lattice     

Is there still a role for radiotherapy in acromegaly?

External radiotherapy (ideally 3-field radiotherapy with a daily fractional dose no higher than 1.8 Gy or conformal irradiation) has been used extensively in the treatment of acromegaly, and virtually all studies have documented a predictable but slow reduction in growth hormone (GH) excess, which is at its maximum in the first year after treatment (30-50%) and continues at an average rate of 10-15% thereafter in the long term. Therefore, achievement of 'safe' GH concentrations in an acceptable time interval after radiotherapy will be realized only in those patients who have lower GH concentrations prior to irradiation either as a result of mild disease or previous surgery. Recent studies have demonstrated the value of stereotactic radiotherapy (either as multiple arc X-irradiation or as 'gamma knife' therapy) in the post-surgical treatment of acromegaly or as salvage therapy for disease persisting after conventional external irradiation. The development of potent medical therapies for acromegaly (somatostatin analogues and the GH receptor antagonist) has called into question the role of radiotherapy in the treatment of this disease. However, even if the concept of primary, open-ended medical therapy for selected patients is accepted, reference to the success rates of surgery and response rates to somatostatin analogues indicates that approximately 10-20% of all patients with acromegaly will require consideration of radiotherapy for hormonal or tumour mass control. For these reasons, radiotherapy (both conventional external and stereotactic irradiation) continues to have a major role in controlling acromegaly in selected patients.     

Successful treatment of a T1 cancer of the pancreatic head with high dose rate brachytherapy and external radiotherapy

In this report, a unique case of a localized (T1N0M0) adenocarcinoma of the head of the pancreas is presented, which was successfully treated with interstitial high dose rate brachytherapy combined with percutan irradiation after biopsy. A total dose of 18 Gy was delivered with brachytherapy (6 Gy per fraction on three consecutive days) to the tumor via after-loading catheter. Brachytherapy was followed by external radiotherapy, delivering an additional dose of 46 Gy (18 MV-x) with four-field technique using conventional fractionation (2 Gy/day). Thirty-six months after completion of the treatment the patient is alive with no evidence of disease. The combination of interstitial high dose rate brachytherapy and external beam radiation therapy may be an effective tool to deliver curative dose without any significant sequelae in the treatment of operable pancreatic carcinoma, when the patient's condition contraindicates surgery.     

立体定向放射治疗常规外照射后复发非小细胞肺癌

目的研究三维适形放射治疗常规放射治疗后复发的非小细胞肺癌可行性,观察近期疗效及早期并发症的发生率。方法2001年10月~2003年10月,27例非小细胞肺癌放疗后复发病例,OUR--TPS三维治疗计划系统设计放射治疗计划,剂量体积直方图(DVH)评价和优化放射治疗计划,体部固定装置立体定向放射治疗。计划靶区为临床所见肿瘤区外放1.0~1.5cm,计划靶区体积(PTV)中位体积为302 cm3(78.9~514.2 cm3),计划照射剂量为42 G y,6~7G y/次,隔日照射。观察急性放射反应及近期疗效。结果27例患者均顺利完成治疗;27例患者的中位随访期为8个月(6~14个月),随访率为100%。初次放射治疗至再放射治疗的中位间隔时间为17个月(12~29个月),再放射治疗肿瘤中位剂量46 G y(42~48 G y)。近期疗效为完全缓解(CR)26%(7/27),部分缓解(PR)48%(13/27),无变化(NR)15.0%(4/27),进展(PD)11%(3/37),总有效率为74.0%(20/27)。根据RTOG分级,急性放射性食管炎发生率1~2级11%(3/27),急性放射性肺炎发生率1~2级15%(4/27);骨髓抑制发生率1~2级8.3%(7.4/27);心脏损伤发生率1~2级7.4%(2/27)。结论三维适形放射治疗放疗后复发的非小细胞肺癌有较好的近期疗效,早期放射反应较低,患者能耐受,晚期反应及远期疗效有待观察。     

Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas

CONTEXT: Radiation therapy is a potentially curative treatment for corticotroph adenomas refractory to surgery. Protons have an advantage over photons (x-rays) by depositing energy at the target with no exit dose, providing a lower dose to adjacent normal tissues. Until recently, proton stereotactic radiotherapy (PSR) was available at only two U.S. centers; use will increase as proton facilities are under development. OBJECTIVE: Our objective was to evaluate the efficacy and safety of PSR for persistent Cushing's disease (CD) and Nelson's syndrome (NS). DESIGN: This was a retrospective review of 38 patients (33 with CD and five with NS) treated between 1992 and 2005. PARTICIPANTS: All patients had transsphenoidal surgery without biochemical cure. Four had previous irradiation with photons. The patients with NS underwent bilateral adrenalectomy 29-228 months (median 40) before PSR. INTERVENTION: Single-fraction PSR was delivered at a median dose of 20 Cobalt Gray Equivalents (range 15-20) on 1 treatment day. MAIN OUTCOME MEASURES: Complete response (CR) was defined as sustained (> or =3 months) normalization of urinary free cortisol off medical therapy. CR in NS was based on normalization of plasma corticotropin. RESULTS: At a median follow-up of 62 months (range 20-136), CR was achieved in five patients (100%) with NS and 17 (52%) patients with CD. Among all patients with CR, median time to CR was 18 months (range 5-49). No secondary tumors were noted on follow-up magnetic resonance imaging scans, and there was no clinical evidence of optic nerve damage, seizure, or brain injury. There were 17 patients (52%) who developed new pituitary deficits. CONCLUSIONS: PSR is effective for patients with persistent corticotroph adenomas with low morbidity after a median follow-up of 62 months; longer follow-up is warranted for late radiation-related sequelae.     

重视肝癌的立体定向放射消融治疗

肝细胞癌(HCC)是最常见的原发性肝脏恶性肿瘤,手术切除及肝移植被认为是目前HCC可能的治愈方法,但仅30%～40%的患者能够受益。体部立体定向放射消融治疗(SABR)是近几年应用于体部恶性肿瘤治疗的一种新的精确放疗技术,以"少分次、大剂量"改变了传统的剂量分割模式,因其提高了体部恶性肿瘤的局部控制率、延长了总生存时间而受到重视。射波刀(CK)完成的SABR放疗技术具有高精度、无创伤的优点,可完成实时追踪照射(很好地解决了肿瘤的呼吸移动对治疗的影响),获得了理想的治疗有效率和局部无进展生存率、总生存率,同时3级以上放疗毒性反应发生率很低,是一种理想的治疗技术,为进一步提高HCC的临床疗效带来了新的希望。     

New trend of cardiac imaging--intravenous coronary arteriography by synchrotron radiation

Synchrotron radiation is a broadspectrum intense X-ray beam. Selected X-ray wavelength was obtained by Bragg reflex. That is a monochromatic beam, which has a high spatial resolution, and has a K-edge discontinuity in attenuation coefficient, which, by energy subtraction, contributes to improve time resolution. An attempt to apply this method to intravenous coronary arteriography was performed in 7 anesthetized dogs. The beam was obtained by synchrotron radiation from accumulation ring, was reflected by silicon crystal, and was detected by 7 inch image intensifier system. Two-dimensional real time images were recorded on video tape. Phantom experiment was also performed. In dogs, coronary arteries were clearly distinguished by synchrotron radiation, especially at real time by video system. Phantom experiment suggested that coronary arteries could be visualized even over the visualized left ventricle. In conclusion, synchrotron radiation using two-dimensional real time images is expected to be useful in intravenous coronary arteriography in man.     

Role of radiotherapy in the management of hepatocellular carcinoma:A systematic review

Many patients with hepatocellular carcinoma(HCC) present with advanced disease,not amenable to curative therapies such as surgery,transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization(TACE) and radiation therapy. Especially TACE,delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy,has given favorable results on local control and survival. Radiotherapy,as a therapeutic modality of internal radiation therapy with radioisotopes,has also achieved efficacious tumor control in advanced disease. On the contrary,the role of external beam radiotherapy for HCC has been limited in the past,due to the low tolerance of surrounding normal liver parenchyma. However,technological innovations in the field of radiotherapy treatment planning and delivery,have provided the means of delivering radical doses to the tumor,while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy,evaluated for efficacy and safety for HCC,report encouraging results. In this review,we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.     

Endovascular brachytherapy — Treatment planning and radiation protection

The risk of restenosis, main late effect limiting the success of percutaneous transluminal coronary artery angioplasty, can be reduced significantly by vascular radiotherapy, subsequent to PTCA. This discovery lead to the development of new irradiation techniques. Endovascular brachytherapy is the choice in treatment of coronary artery stenosis. Successful irradiation, however, requires precise treatment planning. This review addresses the physical possibilities and problems of intravascular brachytherapy planning, and the radiobiologically based definition of the target volume and of structures at risk. Recommendations for dose specification, recording and reporting are given. The criteria for selecting a vascular radiotherapy technique are discussed as well as the possibilities of dosimetric treatment planning and quality assurance based on precise plastic scintillator dosimetry and intravascular ultrasound. Radiation protection and safety must be reconsidered prior to the usage of therapeutic radiation sources in the catheter laboratory and for the decision about emergency plans. Finally, the design of clinical trials, the role of medical physicists, and the future of irradiation treatment of stenosis is discussed.     

Radiotherapy and radiosurgery for Cushing's disease

Patients with residual or recurrent Cushing's disease receive external beam radiotherapy (RT) with the aim of achieving long-term tumour control and normalization of elevated hormone levels. Treatment is given either as conventional radiotherapy using conformal techniques or as stereotactic radiotherapy, which is either used as fractionated treatment (SCRT) or as single fraction radiosurgery (SRS). We describe the technical aspects of treatment and report a systematic review of the published literature on the efficacy and toxicity of conventional RT, SCRT and SRS. There are no studies directly comparing the different radiation techniques and the reported results are inevitably of selected patients by investigators with interest in the treatment tested. Nevertheless the review of the published literature suggests better hormone and tumour control rates after fractionated irradiation compared to single fraction radiosurgery. Hypopituitarism represents the most commonly reported late complication of radiotherapy seen after all treatments. Although the incidence of other late effects is low, the risk of radiation injury to normal neural structures is higher with single fraction compared to fractionated treatment. Stereotactic techniques offer more localized irradiation compared with conventional radiotherapy, however longer follow-up is necessary to confirm the potential reduction of long-term radiation toxicity of fractionated SCRT compared to conventional RT. On the basis of the available literature, fractionated conventional and stereotactic radiotherapy offer effective treatment for Cushing's disease not controlled with surgery alone. The lower efficacy and higher toxicity of single fraction treatment suggest that SRS is not the appropriate therapy for the majority of patients with Cushing's disease.     

立体定向放射治疗Ⅰ期非小细胞肺癌临床分析

目的使用立体定向放射治疗52例Ⅰ期非小细胞肺癌的临床效果,并探讨使用淋巴引流区照射的价值。方法从1998年6月~2003年6月共有52例因医学原因或者拒绝手术Ⅰ期非小细胞肺癌患者接受了根治性立体定向放射治疗。所有患者均接受根治性立体定向放射治疗,治疗方案为边缘剂量6G y×7次和7G y×6次,以60%~90%的等剂量曲线包括靶区,每周4次,总疗程不超过2周,其中有23例患者同时接受淋巴引流区照射。结果中位随访期为20个月(范围:8~60个月);1、2、3年的局部控制率分别为88%,69%,63%;1、2、3年的生存率分别为73%,51%,34%;7G y×6次生存率和6G y×7次之间无显著性差异。接受与未接受淋巴引流区照射之局部控制率,生存率之间无显著差异。未出现严重早和晚反应放射毒副反应。结论立体定向放射治疗是治疗Ⅰ期非小细胞肺癌安全有效的治疗方法;它缩短治疗总时间,提高了肿瘤吸收剂量;不进行淋巴引流区照射不影响局部控制率和生存率。     

巨大原发性肝癌立体定向放射治疗计划设计

目的探讨巨大原发性肝癌γ射线立体定向放射治疗计划的设计。方法采用γ射线立体定向放射治疗37例巨大原发性肝癌患者,计划靶区体积（vptv）≥300cm^3,PTV周边照射总剂量为3200～3900cGy,分割处方剂量为300～350cGy,每日治疗,6次/周。PTV均由50%～55%等剂量线包绕,每一计划需14～22个等中心。靶区剂量均匀指数为1.60～1.72,无正常组织受照剂量超过相应的耐受剂量。结果本组总有效率（CR＋PR）为78.4%（29/37）,无变化（SD）8.1%,进展（PD）13.5%。主要反应为消化道反应,表现为上腹部不适,食欲下降。结论能设计出合格的巨大原发性肝癌的立体定向放射治疗计划,治疗计划所需等中心数多,靶区剂量不均匀。     

Irradiation causes acute and long-term spermatogonial depletion in cultured and xenotransplanted testicular tissue from juvenile nonhuman primates

Infertility is a serious late effect in childhood cancer survivors. Little is known about acute irradiation effects in immature primate testis. Radiation defects have previously only been studied in postpubertal primates. Here we use the juvenile rhesus monkey as a preclinical model. We expose fragments of testicular tissue to 0, 0.5, 1.0, and 4.0 Gy irradiation in vitro. We then maintain the fragments in organ culture for 24-48 h or xenograft the fragments into nude mice for 4 months. Histological endpoints were determined to explore the cellular responses to the irradiation. At the highest dose, irradiation provoked an acute depletion of A-spermatogonia and a rise of apoptotic germ and Sertoli cells in organ culture. A dose-dependent decrease in the number of seminiferous tubules containing type A dark and type A pale spermatogonia was observed in irradiated xenografts. The number of Sertoli-cell only tubules increased respectively. Outgrowth of grafts was affected by the 4-Gy dose. Our observations reveal that irradiation evoked an immediate and sustained depletion of A-spermatogonia. We conclude that spermatogonia in the juvenile primate testis are highly sensitive to irradiation and that spermatogonial depletion and cessation of proliferation is an acute response. In contrast to adult testes, where such damage is immediately visible, this damage in immature testes becomes apparent only when spermatogonial insufficiency leads to spermatogenic failure, and thus infertility, at the onset of puberty. Our methods are applicable to immature human testis and might serve as powerful tool to study irradiation toxicity in the juvenile human testis.     

Radiotherapy for esophageal cancer in Japan

Currently, surgery is the most popular treatment method for esophageal cancer. Radiation is not main treatment but only a supporting one. This situation is now changing because of chemoradiotherapy (CRT). In the 1980s, although most patients treated with radiotherapy were inoperable for extremely advanced or some medical reasons, treatment outcome of surgery was undoubtedly superior to that of radiotherapy. Low-dose rate radiotherapy has many biological benefits. We tried low-dose rate telecobalt therapy (LDRT) as a boost to improve the outcome of radiotherapy for esophageal cancer. However, the LDRT did not improve survival. Since 1990s, studies have demonstrated the effectiveness of CRT using cisplatin and 5-fluorouracil. We made a prospective comparison of surgery and CRT with salvage surgery after recurrence for operable esophageal cancer. Five-year survival rates of 75 CRT patients and 76 surgery ones were 67.5 and 57.7 %, respectively. Twenty-eight patients in the CRT group underwent salvage surgery and 14 survived. Thirty-nine patients in the CRT group (52 %) survived, preserving their esophagus and their QOL was excellent. CRT with salvage surgery should be offered to all operable patients. After CRT, some patients complained severe radiation pneumonitis and myocardial disease. Radiation field should be as small as possible, including the low-dose area. Dose distribution of proton and heavy particle therapies is superior to ordinary radiotherapy. In future, particle beam therapy alone or in combination with photon beam therapy will become widespread as a radiotherapy method during CRT for esophageal cancer.     

New administration modalities for radiotherapy in lung cancer

Much progress has been made in recent years in administration modalities for radiotherapy for lung cancer. Exposure time to external irradiation was the first parameter to be modified: hyperfractionated radiotherapy, hyperfractionated accelerated radiotherapy with or without concomitant irradiation, synchronous or asynchronous protocols, split course radiotherapy. Radiosensitizing agents have also been the subject of much research: radiosensitization of hypoxic cells, modifiers of the biological response, concomitant radiochemotherapy. The main drugs used are 5-fluorouracil, platinum salts, etoposide, hydroxyurea, taxanes, topotecan, vinorelbin, and gemcitabine. Outcome with these combinations is discussed, both for non-small-cell and small-cell lung cancer. 3D conformational radiotherapy can enable increased dosing in the tumoral target while better preserving healthy tissues. High dose endoluminal brachytherapy is used particularly as a palliative treatment for bronchial obstructions or as curative treatment for weakly infiltrative small endoluminal tumors.     

The role of radiation therapy in the treatment of cancer of the prostate

The review of the literature assessing the value of external radiotherapy in treatment of patients with prostatic cancer is presented. Radiotherapy appears to be the curative treatment since about 55% of 10 years symptoms free survival rate can be achieved in stages A and B and 35% in stage C. The results of radiotherapy in cancer limited to prostate are equal to those obtained with radical prostatectomy. Postoperative irradiation seems to improve survival in patients treated with incomplete surgery. The value of elective irradiation of the pelvic and periaortic lymph nodes has not been established. The impact of TURP on survival is discussed. The factors influencing local control and complications rates like: Treatment volume, dose levels and treatment techniques are analyzed. Several experimental approaches in radiotherapy of prostatic cancer are presented.     

原发性巨大肝癌与小肝癌立体定向放射治疗计划比较

目的比较原发性巨大肝癌与小肝癌立体定向放射治疗计划的设计。方法采用γ射线立体定向放射治疗原发性肝癌患者：A组43例患者,计划靶区体积（vptv）均≥300cm3;B组28例患者,31个vptv均≤100cm3。设计不同的立体定向放射治疗计划。结果 A组PTV均由50%～55%等剂量线包绕,PTV周边照射总剂量3200～3900cGy,分割处方剂量300～350cGy,每一计划需14～22个射野,靶区剂量均匀指数1.60～1.72;B组PTV均由70%～90%等剂量线包绕,PTV周边照射总剂量4000～5400cGy,分割处方剂量400～600cGy,每一计划至多需3个射野,靶区剂量均匀指数1.06～1.43。两组计划无正常组织受照剂量超过相应的耐受剂量。结论设计出合格的原发性巨大肝癌与小肝癌的立体定向放射治疗计划是可能的,然而,原发性巨大肝癌治疗计划所需射野数明显多于小肝癌治疗计划,小肝癌立体定向放射治疗计划靶区剂量均匀性优于巨大肝癌。     

Liver tissue tolerance for irradiation: experimental and clinical investigations

Radiation treatment of the liver for malignant disease has gained renewed interest due to newly developed treatment modalities. Still limited specific knowledge is available concerning liver damage following irradiation. Inconsistencies between reported animal experimental studies are largely due to differences in irradiation techniques and to varying observation periods. Following the introduction of Megavoltage irradiation and the development of more sophisticated irradiation techniques, clinical reports concerning more reliable studies became available. The reaction of the liver to irradiation depends specifically on parameters as type of irradiation, dose, dose rate, fractionation schedule, and irradiated volume. Also the use of cytotoxic agents and liver surgery are of importance for the ultimate therapeutic result. Radiation hepatitis in humans may develop following high-dose liver irradiation resulting in clinical and histopathological disorders resembling a veno-occlusive disease-like syndrome. These disorders may either totally or partially recover or be progressive in time resulting in hepatic failure. It is concluded that depending on the variables mentioned, ionizing radiation up to 35 Gy to the human liver, given to a limited volume, can be applied without major liver function disturbances.