Phase I/II trial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma

Background:After deifnitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present signiifcant challenges for locally recur-rent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recur-rent NPC. However, only patients with small-volume tumors can beneift from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radio-resistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an increased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were pre-viously treated for NPC with a deifnitive dose of IMXT. The short-term response rates at 3–6months were also accept-able. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemo-therapy to CIRT can beneift locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the beneifts of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results. Methods and design:The maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concur-rent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 GyE (2.5 GyE×21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Effcacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%. Conclusions:Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate effcacy but causes potentially severe toxicities. Improved outcomes in terms of effcacy and toxicity proifle are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemo-therapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.     

Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy

DNA damage of exposed tumour tissue leading to cell death is one of the detrimental effects of ionising radiation that is exploited, with beneficial consequences, for radiotherapy. The pattern of the discrete energy depositions during passage of the ionising track of radiation defines the spatial distribution of lesions induced in DNA with a fraction of the DNA damage sites containing clusters of lesions, formed over a few nanometres, against a background of endogenously induced individual lesions. These clustered DNA damage sites, which may be considered as a signature of ionising radiation, underlie the deleterious biological consequences of ionising radiation. The concepts developed rely in part on the fact that ionising radiation creates significant levels of clustered DNA damage, including complex double-strand breaks (DSB), to kill tumour cells as clustered damage sites are difficult to repair. This reduced repairability of clustered DNA damage using specific repair pathways is exploitable in radiotherapy for the treatment of cancer. We discuss some potential strategies to enhance radiosensitivity by targeting the repair pathways of radiation-induced clustered damage and complex DNA DSB, through inhibition of specific proteins that are not required in the repair pathways for endogenous damage. The variety and severity of DNA damage from ionising radiation is also influenced by the tumour microenvironment, being especially sensitive to the oxygen status of the cells. For instance, nitric oxide is known to influence the types of damage induced by radiation under hypoxic conditions. A potential strategy based on bioreductive activation of pro-drugs to release nitric oxide is discussed as an approach to deliver nitric oxide to hypoxic tumours during radiotherapy. The ultimate aim of this review is to stimulate thinking on how knowledge of the complexity of radiation-induced DNA damage may contribute to the development of adjuncts to radiotherapy.     

III期非小细胞肺癌碳离子放疗与光子容积旋转调强放疗的剂量学对比研究

目的:比较碳离子二维放射治疗(two-dimensional carbon-ion radiotherapy,2D-CIRT)计划与光子容积调强放射治疗(volume modulated arc therapy,VMAT)计划在III期非小细胞肺癌中剂量学优劣,为临床碳离子治疗提供依据。方法:选取我中心13例III期非小细胞肺癌患者,使用相同的处方剂量及危及器官约束条件,分别在Ciplan计划系统上设计2D-CIRT计划和Eclipse计划系统上设计VMAT计划,比较剂量-体积直方图,评价靶区剂量分布及危及器官受量。采用SPSS 22.0软件进行数据分析。结果:CIRT和VMAT计划肿瘤覆盖率均较好,PTV1的D98、D95、D50差异无统计学意义,两种计划的均匀性指数（homogeneity index,HI）相似（CIRT与VMAT:0.39 Gy与0.38 Gy,P＞0.05）。PTV2两种方案在D95、D98、D50、D2均有显著性差异,PTV2采用CIRT的HI也明显优于VMAT(CIRT vs VMAT:0.08 Gy vs 0.16 Gy,P=0.003)。与光子VMAT相比,CIRT计划中健侧肺的V5、V10、V20、V30、V40和Dmean明显降低。患侧肺中CIRT的V5低于VMAT（CIRT vs VMAT:53.00 Gy vs 64.41 Gy,P=0.003）,V10、V20、V30、V40、Dmean两种计划均无统计学差异;CIRT有较低的脊髓Dmax（CIRT vs VMAT:18.61 Gy vs 43.03 Gy,P=0.000）、食管Dmean（CIRT vs VMAT:16.25 Gy vs 20.38 Gy,P=0.031）和V50（CIRT vs VMAT:4.49 Gy vs 11.43 Gy,P=0.005）、骨V10和V30,以及气管和支气管树的V50。结论:与光子VMAT相比,2D-CIRT被动束流扫描技术在III期非小细胞肺癌治疗中显著降低了对危及器官的辐射剂量,对正常组织有更好的保护作用。     

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

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

Risks of brain tumour following treatment for cancer in childhood: Modification by genetic factors,radiotherapy and chemotherapy

A cohort of 4,400 persons treated for various cancers of childhood in France and the UK was followed up over an extended period to assess risks of subsequent brain tumour in relation to the radiotherapy and chemotherapy that the children received for their first cancer. Elevated risks of subsequent brain tumours were associated with first central nervous system (CNS) tumour (two-sided p =0.0002) and neurofibromatosis (two-sided p =0.001). There was also elevated brain tumour risk (two-sided p =0.003) associated with ionising radiation exposure, the risk being concentrated among benign and unspecified brain tumours. The radiation-related risk of benign and unspecified brain tumours was significantly higher than that of malignant brain tumours (two-sided p≤ 0.05); there was no significant change of malignant brain tumour risk with ionising radiation dose (two-sided p > 0.2). In general, there were no strong associations between alkylating agent dose and brain tumour risk. The only significant association between brain tumour risk and alkylating agent dose was in relation to compounds used (bleomycin, chloraminophen) that are thought not to deliver substantial doses to the brain; the statistical significance of the trend with dose depended on a single case, and thus must be considered a weak result. Int. J. Cancer 78:269–275, 1998. Published 1998 Wiley-Liss, Inc.     

Phase 1 trial of preoperative,short‐course carbon‐ion radiotherapy for patients with resectable pancreatic cancer

BACKGROUND:

The authors evaluated the tolerance and efficacy of carbon‐ion radiotherapy (CIRT) as a short‐course, preoperative treatment and determined the recommended dose needed to reduce the risk of postoperative local recurrence without excess injury to normal tissue.

METHODS:

Patients radiographically defined with potentially resectable pancreatic cancer were eligible. A preoperative, short‐course, dose‐escalation study was performed with fixed 8 fractions in 2 weeks. The dose of irradiation was increased by 5% increments from 30 grays equivalents (GyE) to 36.8 GyE. Surgery was to be performed 2 to 4 weeks after the completion of CIRT.

RESULTS:

The study enrolled 26 patients. At the time of restaging after CIRT, disease progression with distant metastasis or refusal ruled out 5 patients from surgery. Twenty‐one of 26 patients (81%) patients underwent surgery. The pattern of initial disease progression was distant metastasis in 17 patients (65%) and regional recurrence in 2 patients (8%). No patients experienced local recurrence. The 5‐year survival rates for all 26 patients and for those who underwent surgery were 42% and 52%, respectively.

CONCLUSIONS:

Preoperative, short‐course CIRT followed by surgery is feasible and tolerable without unacceptable morbidity. Cancer 2013. © 2012 American Cancer Society.     

Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer

Surgical resection is the standard treatment for stage I non-small cell lung cancer (NSCLC). However, elderly patients with NSCLC often suffer from other conditions, such as chronic obstructive pulmonary disease (COPD) or cardiovascular disease, and are not suitable candidates for surgery. Different modalities to treat stage I NSCLC have been developed, such as stereotactic radiotherapy (SRT), proton beam radiotherapy and carbon ion radiotherapy (CIRT). Between April 1999 and November 2003, we treated 129 patients with stage I NSCLC using CIRT. In this study, we focused on 28 patients aged 80 years and older who underwent CIRT, and analyzed the effectiveness of CIRT in treating their lung cancer and the impact on their activity of daily life (ADL). The 5-year local control rate for these patients was 95.8%, and the 5-year overall survival rate was 30.7%, but there were no patients who started home oxygen therapy or had decreased ADL. Our data demonstrate that CIRT was effective in treating elderly patients with stage I NSCLC.     

Carbon ion radiotherapy with pencil beam scanning for hepatocellular carcinoma: Long-term outcomes from a phase I trial

This study evaluates the feasibility of the pencil beam scanning technique of carbon ion radiotherapy (CIRT) in the setting of hepatocellular carcinoma (HCC) and establishes the maximum tolerated dose (MTD) calculated by the Local Effect Model version I (LEM-I) with a dose escalation plan. The escalated relative biological effectiveness-weighted dose levels included 55, 60, 65, and 70 Gy in 10 fractions. Active motion management techniques were employed, and several measures were applied to mitigate the interplay effect induced by a moving target. CIRT was planned with the LEM-I-based treatment planning system and delivered by raster scanning. Offline PET/CT imaging was used to verify the beam range. Offline adaptive replanning was performed whenever required. Twenty-three patients with a median tumor size of 4.3 cm (range, 1.7–8.5 cm) were enrolled in the present study. The median follow-up time was 56.1 months (range, 5.7–74.4 months). No dose limiting toxicity was observed until 70 Gy, and MTD had not been reached. No patients experienced radiation-induced liver disease within 6 months after the completion of CIRT. The overall survival rates at 1, 3, and 5 years were 91.3%, 81.9%, and 67.1% after CIRT, respectively. The local progression-free survival and progression-free survival rates at 1, 3 and 5 years were 100%, 94.4%, and 94.4% and 73.6%, 59.2%, and 37.0%, respectively. The raster scanning technique could be used to treat HCC. However, caution should be exercised to mitigate the interplay effect. CIRT up to 70 Gy in 10 fractions over 2 weeks was safe and effective for HCC.     

Single fraction carbon ion radiotherapy for colorectal cancer liver metastasis: A dose escalation study

Prognosis is usually grim for those with liver metastasis from colorectal cancer (CRC) who cannot receive resection. Radiation therapy can be an option for those unsuitable for resection, with carbon ion radiotherapy (CIRT) being more effective and less toxic than X‐ray due to its physio‐biological characteristics. The objective of this study is to identify the optimal dose of single fraction CIRT for colorectal cancer liver metastasis. Thirty‐one patients with liver metastasis from CRC were enrolled in the present study. Twenty‐nine patients received a single‐fraction CIRT, escalating the dose from 36 Gy (RBE) in 5% to 10% increments until unacceptable incidence of dose‐limiting toxicity was observed. Dose‐limiting toxicity was defined as grade ≥3 acute toxicity attributed to radiotherapy. The prescribed doses were as follows: 36 Gy (RBE) (3 cases), 40 Gy (2 cases), 44 Gy (4 cases), 46 Gy (6 cases), 48 Gy (3 cases), 53 Gy (8 cases) and 58 Gy (3 cases). Dose‐limiting toxicity was not observed, but late grade 3 liver toxicity due to biliary obstruction was observed in 2 patients at 53 Gy (RBE). Both cases had lesions close to the hepatic portal region, and, therefore, the dose was escalated to 58 Gy (RBE), limited to peripheral lesions. The 3‐year actuarial overall survival rate of all 29 patients was 78%, and the median survival time was 65 months. Local control improved significantly at ≥53 Gy (RBE), with a 3‐year actuarial local control rate of 82%, compared to 28% in lower doses. Treatment for CRC liver metastasis with single‐fraction CIRT appeared to be safe up to 58 Gy (RBE) as long as the central hepatic portal region was avoided.     

Intensity modulated radiotherapy (IMRT) in bilateral retinoblastoma

Background

External beam radiotherapy (EBRT) for retinoblastoma has traditionally been done with conventional radiotherapy techniques which resulted high doses to the surrounding normal tissues.

Case report

A 20 month-old girl with group D bilateral retinoblastoma underwent intensity modulated radiotherapy (IMRT) to both eyes after failing chemoreduction and focal therapies including cryotherapy and transpupillary thermotherapy. In this report, we discuss the use of IMRT as a method for reducing doses to adjacent normal tissues while delivering therapeutic doses to the tumour tissues compared with 3-dimensional conformal radiotherapy (3DCRT). At one year follow-up, the patient remained free of any obvious radiation complications.

Conclusions

Image guided IMRT provides better dose distribution than 3DCRT in retinoblastoma eyes, delivering the therapeutic dose to the tumours and minimizing adjacent tissue damage.     

Programming of radiotherapy in the treatment of non-small-cell lung cancer--a way to advance care

Radical radiotherapy, the mainstay of treatment for early inoperable non-small-cell lung cancer, is most commonly given in daily fractions, Monday to Friday, to a total dose of 60-70 Gy over 6-8 weeks. Since the 1980s, novel fractionation schedules have been explored with the aim of improving local tumour control and survival without increasing late morbidity. There have been two main approaches. In hyperfractionated radiotherapy the dose per fraction is reduced and the total dose increased to give improved tumour control without increased late morbidity. Hyperfractionation schedules, with more than one fraction per day have been successfully evaluated, but so far significant benefit has not been achieved when compared with conventional radiotherapy plus chemotherapy. In accelerated radiotherapy the overall duration of radiotherapy is reduced to overcome repopulation of tumour cells during the course of treatment. In all the different regimens of accelerated radiotherapy a common feature is giving two or more fractions on some or all treatment days and, in some cases, a lower dose per fraction is also incorporated. CHART (continuous hyperfractionated accelerated radiotherapy) is the most novel and accelerated schedule tested, and a randomised controlled trial showed a significant survival advantage from CHART compared with conventional radiotherapy. Changes in the fractionation of radiotherapy must be combined with other approaches such as neoadjuvant and concomitant chemotherapy, hypoxic-cell modifiers, and conformal radiotherapy, so that care of patients with non-small-cell lung cancer can be further advanced.     

Clinical evidence of particle beam therapy (carbon)

Carbon ion radiotherapy (CIRT) is unique as it possesses well-localized and superior-depth dose distribution in addition to less repairable radiobiological effects. The use of CIRT for various diseases has been explored as clinical trials at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Since 1994, when the first clinical study of cancer therapy with carbon ion beams was started, about 50 clinical studies have been completed safely and effectively. These studies revealed that intractable cancers such as inoperable bone and soft-tissue sarcomas can be cured safely in a shorter overall treatment time, as can cancers in the head, neck, lung, liver, prostate, and postoperative pelvic recurrence of rectal cancer. The number of patients receiving CIRT has reached 6,000, and the therapy was approved as a highly advanced medical technology in 2003. Based on these experiences, we embarked on the research and development of new-generation beam delivery facilities such as a 3D scanning method with a pencil beam and a compact rotating gantry. Clinical research using pencil-beam scanning has been in operation since May 2011.     

Clinical and Practical Considerations for the Use of Intensity-modulated Radiotherapy and Image Guidance in Neuro-oncology

Intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy offer significant opportunities to improve outcomes for our patients, although they are not yet as widely used as they might be. IMRT allows better target coverage and lower organ at risk doses than conformal therapy. It also allows inhomogeneous dose plans to be developed, where these can provide benefit, either to dose escalate the tumour or reduce dose to adjacent or overlapping organs at risk. Image guidance adds precision and the possibility of careful reduction in planning target volume margins. The technologies can be valuable both for patients with highly malignant tumours, such as glioblastoma, and those with less malignant or benign tumours. In glioblastoma, temozolomide chemotherapy and surgical developments have improved survival, and developments in radiotherapy techniques should also be used to optimise outcome. Target volume delineation, including calculation of the planning target volume margin is critical. Clear definitions of the gross tumour and clinical target volumes are essential, following established guidelines. Normal tissue volume delineation is also essential for IMRT. The planning organ at risk volume has become a valuable tool to manipulate dose away from organs at risk to avoid toxicities. This is distinct from ‘optimising volumes’ used to drive the computer optimiser during planning. Hard data on central nervous system (CNS) normal tissue tolerance is surprisingly slight, reflecting the clinical imperative to avoid serious complications in neurological tissues. The effect of chemotherapy on radiotherapy tolerance in the CNS remains obscure, and more needs to be done to develop the knowledge base. IMRT provides better conformation of the high dose treatment to the shape of the target, and reduces the dose to normal tissue structures. Image guidance improves the accuracy of dose delivery, which is particularly important where steep dose gradients are present. These technologies should be regarded as the state-of-the-art for our CNS patients.     

Microtubule stabilising agents and ionising radiation: Multiple exploitable mechanisms for combined treatment

Combined radiochemotherapy treatment modalities are in use for many indications and therefore of high interest. Even though a combined modality in clinical use is often driven by pragmatic aspects, mechanistic preclinical-based concepts of interaction are of importance in order to translate and implement an optimal combination and scheduling of two modalities into the clinics. The use of microtubule stabilising agents is a promising strategy for anti-cancer therapy as a part of combined treatment modality with ionising radiation. Traditionally, microtubule targeting agents are classified as cytotoxic chemotherapeutics and are mostly used in a maximally tolerated dose regimen. Apart from direct cytotoxicity and similar to mechanisms of molecular targeting agents, microtubule stabilising agents interfere with multiple cellular processes, which can be exploited as part of combined treatment modalities. Recent preclinical investigations on the combination of ionising radiation and microtubule stabilising agents reveal new mechanistic interactions on the cellular and tumour level and elucidate the supra-additive tumour response observed particularly in vivo. The major focus on the mechanism of interaction was primarily based on radiosensitisation due to cell cycle arrest in the most radiosensitive G2/M-phase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we summarise and allocate additive and synergistic effects induced by the combined treatment of clinically relevant microtubule stabilising agents and ionising radiation along a described radiobiological framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionising radiation.     

Feasibility of carbon ion radiotherapy for locally advanced sinonasal adenocarcinoma

Background and purposeTo evaluate the safety and efficacy of carbon ion radiotherapy (CIRT) for locally advanced sinonasal adenocarcinoma.Material and methodsTwenty-two patients with sinonasal adenocarcinoma were treated with CIRT. CIRT was the primary treatment for 16 patients. Four patients received CIRT for local recurrence after surgery and two for residual tumour after surgery or chemotherapy. At the start of CIRT, 1 patient had T-classification (T) 2 disease, 2 had T3 disease, 5 had T4a disease, and 14 had T4b disease. Fourteen patients were treated with 57.6 Gy equivalent (GyE)/16 fractions, and 8, with 64.0 GyE/16 fractions.ResultsThe median follow-up period was 43 months for all patients. The 3-year local control and loco-regional control rates for all patients were 76.9% (95% confidence interval [CI] = 56.7–97.1%) and 61.3% (95% CI = 38.5–84.1%), respectively. The 3-year overall survival and disease-specific survival rates were 59.1% (95% CI = 38.6–79.6%) and 65.6% (95% CI = 44.9–86.3%), respectively. Acute reactions of grade 3 of the skin and mucosa were observed in 2 and 4 patients, respectively. Late reactions included lateral visual loss (5 patients), mucosal ulceration (1 patient), and brain necrosis with clinical symptoms (1 patient). In the 5 patients who developed visual loss, the optic nerve was close to the tumour.ConclusionsCIRT was effective and generally safe for locally advanced sinonasal adenocarcinoma.     

Efficacy of carbon-ion radiotherapy and high-dose chemotherapy for patients with unresectable Ewing’s sarcoma family of tumors

Background

Treatment for unresectable Ewing’s sarcoma family of tumors (ESFT) is a formidable challenge because of its high tendency for local and distant failure. Recently, carbon-ion radiotherapy (CIRT) has been applied to unresectable bone and soft tissue sarcoma. Additionally, high-dose chemotherapy (HDC) with stem cell rescue has been used to improve the survival of patients with relapsed ESFT. Here we report our experience with CIRT and HDC in the treatment of unresectable ESFT.

Methods

Five unresectable ESFT patients including 4 who underwent CIRT and HDC and one who underwent CIRT from 1999?2009 were retrospectively studied. After neoadjuvant chemotherapy, CIRT was conducted at the National Institute of Radiological Sciences in Chiba as local therapy. Consecutively, we employed HDC including busulfan, melphalan, and thiotepa with stem cell rescue.

Results

Two patients showed tumor shrinkage after CIRT, including 1 patient who achieved partial response. No severe acute toxicity related to CIRT was observed. Local failure was observed in only 1 patient at 22 months after CIRT. Four patients conducted HDC with stem cell rescue after CIRT and 1 patient suffered from veno-occlusive disease just after HDC. Distant failure was observed in 3 patients after completion of the treatment.

Conclusions

CIRT and HDC for unresectable ESFT patients show favorable local control, with unsatisfactory results for distant control.     

Retrospective analysis of the response of tumours in patients treated with a combination of radiotherapy and hyperthermia

One hundred and twelve patients with various carcinomas were treated on 112 fields with radiotherapy and hyperthermia, using non-invasive techniques. Radiotherapy dose ranged from 13-70 Gy (except for one patient receiving hyperthermia alone) with a mean of 28.6 Gy. The combined treatment was primarily aimed at giving palliation; 79 per cent of the patients had received previous irradiation on the same area. Hyperthermia was given twice weekly following radiotherapy. From the temperature data collected, 12 different parameters expressing the hyperthermia 'dose' were derived. The various parameters for both treatment modalities, i.e. radiotherapy and hyperthermia, and some of the tumour parameters were statistically evaluated with respect to their influence on tumour response. The overall response rate was 87 per cent including 33 per cent complete response. The complete response rate increased with increasing radiotherapy total dose, i.e. from 23 per cent (14-25 Gy) and 38 per cent (28-36 Gy) to 60 per cent (greater than 38 Gy). A positive correlation between the tumour temperature parameter representative of the coldest spot in the tumour, and the level of response was found. Achievement of complete response appeared also to be determined to a considerable extent by radiotherapy total dose as well as tumour volume. The correlation between response level and the minimum hyperthermia dose parameters persisted, however, after correction for the influence of tumour volume and radiotherapy total dose. These results support the opinion that higher tumour response rates can be achieved by increasing the hyperthermia treatment level at the coldest spot in the tumour.     

Recombinant mistletoe lectin induces p53-independent apoptosis in tumour cells and cooperates with ionising radiation

Mistletoe extracts are used as alternative cancer treatment in addition to standard chemotherapy and radiation treatment and have an immunostimulatory and pain-relieving effect. A direct antitumour effect of mistletoe extracts against tumour cells of lymphoid origin has been linked to the D-galactoside-specific mistletoe lectin I. In this study, we investigated the cellular effect of bacterially expressed, recombinant mistletoe lectin alone or in combination with ionising radiation in a genetically defined p53-wild-type and p53-deficient E1A/ras-transformed murine tumour cells system. Downregulation of the proliferative activity and cell killing by recombinant mistletoe lectin occurred in a clear dose response (0.1-1 ng ml(-1)). Induction of apoptosis was p53-independent, but apoptosis-associated factor-1-dependent. Cellular treatment with lectin in combination with ionising radiation resulted in both p53-wild-type and p53-deficient tumour cells in an at least additive, antiproliferative effect and enhanced activation of caspase-3. Combined treatment with ionising radiation and lectin revealed a similar cytotoxic effect in human, p53-mutated adenocarcinoma cells. Thus, recombinant mistletoe lectin alone and in combination with ionising radiation bypasses often prevalent apoptotic deficiencies in treatment-resistant tumour cells.     

Cancer‐specific mortality of high‐risk prostate cancer after carbon‐ion radiotherapy plus long‐term androgen deprivation therapy

The treatment outcomes of patients with high‐risk localized prostate cancer (PC) after carbon‐ion radiotherapy (CIRT) combined with long‐term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC‐specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed‐dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high‐risk or very‐high‐risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow‐up time was 88.4 months, and the 5‐/10‐year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9–10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10‐year PCSM rates of patients having all three (n = 16), two (n = 74) or one of these risk factors (n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10‐year follow‐up (10‐year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (P <0.001). CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high‐risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high‐risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high‐risk PC patients treated with CIRT.