Localized hyperthermia and radiation in cancer therapy

Clinical researches in hyperthermia have recently expanded rapidly with the increase in our knowledge of the biological effects of heat on experimental systems. This article provides background information on the biological rationale and current status of technologies concerning thermometry and heating equipment for the application of hyperthermia to human cancer treatment. Much data has been accumulated recently in hyperthermia treatment with and without radiation to superficial tumours which are refractory to conventional treatments. In this paper the treatment results published recently have been surveyed. The complete responses of tumours treated by heat alone are in the range of 15 per cent as opposed to approximately 60 per cent for the combination of heat plus radiation. Clinical results so far published have demonstrated that local control is consistently better in the lesions treated with radiation plus heat than with radiation alone. The morbidity related to heat therapy is within tolerable limits. Several articles on the clinical results of deep-seated tumours treated by hyperthermia are reviewed. Problems to be solved in the application of heat to cancer therapy are discussed.     

Molecular type and maximal metastasis diameter influence risk of axillary recurrence in breast cancer patients after positive sentinel lymph node biopsy

BackgroundBreast cancer patients with positive sentinel lymph node biopsy (SLNB) may be spared axillary lymph node dissection (ALND) in favour of irradiation. The aim of the study was to estimate local control probability in the axilla (axLCP).Materials and methodsWe identified 1832 invasive breast cancer patients who had undergone SLNB at our centre. We measured maximal metastasis diameter (SLDmax) in the sentinel lymph nodes and lymph node metastasis volume (VALN) from ALND in 246 patients with one or two positive SLNs. We calculated axLCP after irradiation and systemic treatment for different molecular types.ResultsVALN values are higher for high grade tumours and larger metastases in SLNs (> 5 mm). It is smaller in luminal A tumours. axLCP is high, nearly 100%, in all molecular types in radiation sensitive tumours (SF2 Gy = 0.45), except luminal B. Expected axLCP is relatively low (67%) in luminal B radiation sensitive tumours with no chemotherapy and nearly 100% with chemotherapy.ConclusionVALN values differ among molecular tumour types. They depend on SLNDmax and tumour grade. New prognostic factors are needed for selected luminal B breast cancer patients (i.e. high grade tumours, large metastases in SLNs) after positive SLNB intended to be spared ALND and chemotherapy.     

Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer

Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.     

Hyperthermia in cervical cancer – current status

BackgroundThis article reviews the salient features of recent results of clinical studies. It puts a special emphasis on technical aspects, mechanisms of action together with radiotherapy and chemotherapy and points out areas for additional investigation.AimTo present the current state of knowledge on hyperthermia (HT) and to highlight its role in the treatment of cervical cancer.Materials and methodsThe literature on the clinical use of combined hyperthermia for cervical cancer was analyzed. Clinical outcomes together with the technical aspects and the role of HT were also evaluated.ResultsClinically randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in the treatment of cervical cancer without significant acute or late morbidities. The technological advances have led to an effective and safer treatment delivery, thermal treatment planning, thermal dose monitoring and online adaptive temperature modulation.ConclusionsDue to rapid development over the last decade of hyperthermia systems and new studies at the basic science and clinical level, the perception of hyperthermia as a part of multimodality treatment in cervical cancer has been changed. However, there is still a need for multicentre randomized clinical trials.     

Clinical Effects of Whole-body Hyperthermia in Advanced Malignancy

Fifty-one patients in the terminal stages of cancer have been treated with whole-body hyperthermia either alone (38 cases) or in combination with chemotherapy (13 cases). Altogether 227 treatment sessions were held averaging four hours each. The most sensitive tumours were those of the gastrointestinal tract and sarcomas. Breast and genitourinary tumours did not respond, and lung tumours and melanomas were only partially responsive. Major complications were remarkably few.     

The effects of some physical factors on the production of hyperthermia by ultrasound in neoplastic tissues

Summary A one-dimensional and a three-dimensional computer model have been built in order to study the importance of blood flow and ultrasonic absorption in tissues during local hyperthermia. The decreased blood flow in the interior of certain tumours and possibly the increased ultrasonic absorption of the malignant tissue in some cases may cause selectively higher temperatures inside the tumours though the heat input is the same as in the surrounding tissues. Also, the vasodilation of blood vessels in normal tissues as a response to heat causes a therapeutically useful temperature difference. These blood flow differences can lead to enhanced effects during sonication to produce hyperthermia in the tumour. The inhomogenity of blood flow in the tumour causes a non-uniform temperature distribution leaving the well-perfused cells in the advancing front at a much lower temperature than the cells in the necrotic centre. Thus, the combination of local hyperthermia with radio-and chemotherapy seems to offer the most attractive means of destroying malignant tissue.     

热疗联合奥沙利铂对SW480细胞增殖和凋亡的影响

目的:观察奥沙利铂联合热疗对人结肠癌细胞SW480增殖及凋亡的影响,确定联合用药的效果,为临床方案提供参考。方法:采用MTT(四唑盐)法检测热疗、奥沙利铂及联合用药对细胞增殖的影响;瑞士吉姆萨染色法观察细胞形态;流式细胞仪检测细胞凋亡和周期;Western blot检测Bax、Bcl-2以及Caspase8蛋白表达量变化;q PCR检测Bax、Bcl-2以及Caspase8 m RNA的积累。结果:热疗联合奥沙利铂可以显著抑制细胞增殖,与对照组相比,热疗组、化疗组、联合组细胞凋亡率分别为16.2%、20.5%和36.1%,具有显著性差异(P0.01);细胞学形态中,热疗组细胞发生皱缩,化疗组细胞膜破裂;化疗将细胞阻滞在G2/M期,热疗和联合组将细胞阻滞S期;Western blot和qPCR显示Bax/Bcl-2比值上升,Caspase8表达量增加,联合组三种蛋白的表达量均与对照组具有显著性差异(P0.01)。结论:热疗联合奥沙利铂可以显著促进细胞凋亡,提高治疗效果,为结肠癌的治疗提供参考。     

Evaluation of the effect of hyperthermia and electron radiation on prostate cancer stem cells

The aim of this study was to investigate the effect of hyperthermia, 6 MeV electron radiation and combination of these treatments on cancer cell line DU145 in both monolayer culture and spheroids enriched for prostate cancer stem cells (CSCs). Flowcytometric analysis of the expression of molecular markers CD133⁺/CD44⁺ was carried out to determine the prostate CSCs in cell line DU145 grown as spheroids in serum-free medium. Following monolayer and spheroid culture, DU145 cells were treated with different doses of hyperthermia, electron beam and combination of them. The survival and self-renewing of the cells were evaluated by colony formation assay (CFA) and spheroid formation assay (SFA). Flowcytometry results indicated that the percentage of CD133⁺/CD44⁺ cells in spheroid culture was 13.9-fold higher than in the monolayer culture. The SFA showed significant difference between monolayer and spheroid culture for radiation treatment (6 Gy) and hyperthermia (60 and 90 min). The CFA showed significantly enhanced radiosensitivity in DU145 cells grown as monolayer as compared to spheroids, but no effect of hyperthermia. In contrast, for the combination of radiation and hyperthermia the results of CFA and SFA showed a reduced survival fraction in both cultures, with larger effects in monolayer than in spheroid culture. Thus, hyperthermia may be a promising approach in prostate cancer treatment that enhances the cytotoxic effect of electron radiation. Furthermore, determination and characterization of radioresistance and thermoresistance of CSCs in the prostate tumor is the key to develop more efficient therapeutic strategies.     

Preoperative treatment of rectal cancer with radiation, chemotherapy and hyperthermia: analysis of treatment efficacy and heat-shock response

Preoperative treatment of locally advanced rectal cancer with radiation, chemotherapy and hyperthermia is analyzed with regard to heat-shock response. In 23 patients with locally advanced rectal cancer (uT3/uT4), hyperthermia was administered in combination with radiotherapy and chemotherapy. In parallel, the effect of the treatment on levels of the heat-shock proteins HSP27 and inducible HSP70 in tumors and surrounding tissues was investigated by Western blotting. The patients' sera were also examined for autoantibodies against HSPs. HSP27 and inducible HSP70 were detected in most rectal tumors and surrounding tissues before and after treatment. HSP27 and inducible HSP70 levels had changed in 10 tumors after treatment. However, prior to treatment, there existed an unexpected diversity in HSP levels in the tumors and surrounding tissue. Hyperthermia doses in cumulative minutes for which 90% of the tumor is above the reference temperature (cum min T90 > or = 15 min) led to increased survival and response compared to that of a control group of patients treated without or with low-dose hyperthermia (cum min T90 < 15 min). However, there was no correlation to different expression of the HSPs. Hyperthermia as used in this setting does not lead to any sustained expression of HSPs in either the tumor or the surrounding tissue.     

Microcalorimetric study of the metabolism of U-937 cells undergoing apoptosis induced by the combined treatment of hyperthermia and chemotherapy

Hyperthermia is a useful adjunct in cancer therapy, as it can increase the effectiveness and decrease the toxicity of currently available cancer treatments such as chemotherapy and radiation. In this study we determined the power-time curves of U-937 cell line treated by the combination of hyperthermia and Carmofur by using an LKB 2277 Bioactivity Monitor. The maximal thermal power and the heat production were used to evaluate the antitumor effect. Our results show that the combined treatment of hyperthermia and Carmofur had a synergistic antitumor effect, which is consistent with the apoptosis ratio obtained by TUNEL assay. The results also indicate that the metabolic activity of apoptotic cells is lower than that of normal cells. Thus microcalorimetry is a powerful tool in fields of hyperthermia.     

NF-κB targeting for overcoming tumor resistance and normal tissues toxicity

Radiotherapy and chemotherapy are two famous modalities in tumor-targeted therapy that lead to systemic and local toxicities for normal tissues. Moreover, several studies have confirmed that exposure of the tumor to radiation or chemotherapy drugs stimulate some signaling pathways in the tumor microenvironment (TME), leading to resistance of cancer cells to apoptosis, as well as promoting angiogenesis and tumor growth. Nuclear factor kappa B (NF-κB) plays a central role in the regulation of inflammatory responses in both normal tissues and tumors via the release of several cytokines, regulation of prostaglandins, reduction/oxidation (redox) reactions, angiogenesis, and cell death. Upregulation of NF-κB in normal tissues causes an appearance of inflammatory reactions and oxidative stress, whereas it regulates angiogenesis and suppresses apoptosis, leading to resistance to subsequent doses of radiation or chemotherapy. Selective inhibition of NF-κB in experimental studies has shown promising results for tumor sensitization via apoptosis induction, inhibition of angiogenesis, and increasing delay of tumor growth. The use of some agents for NF-κB inhibition has been shown to alleviate radiation/chemotherapy toxicities in normal cells/ tissues. In this current review, we explained the pivotal role of NF-κB in both normal tissue toxicity and tumor resistance. We also discussed the promising strategies for overcoming these problems with regard to chemotherapy and radiotherapy.     

Intraoperative radiation therapy in uterine cervical cancer: A review

Locally advanced uterine cervical cancer continues to present a high number of pelvic relapses. Intraoperative radiation therapy (IORT) allows a precise therapeutic intensification in the surgical area in cases in which removal of the tumour recurrence is feasible. At the same time, IORT excludes the radiosensitive organs from the field of irradiation. While the first gynecological IORT took place in 1905, procedures have been limited over the years and the series are retrospective, including few patients. At the same, time recurrences are located at different pelvic areas. Both heterogeneity and the long recruiting time make it difficult to correctly interpret the published results. Despite this, we have reviewed the most relevant publications. Some institutions indicated IORT as a boost on the surgical bed of the excised tumor recurrence. In others, IORT permits an extra radiation dose after radical surgery of the primary tumor, usually in stage IIB. Most studies conclude that the addition of IORT increases the local control but probably with little impact on survival. On the other hand, there is a controversy in the indication of IORT in surgically resectable primary tumours. No clear advantage over the usual scheme of chemoradiation and brachytherapy has been detected. Randomized studies that allow a breakthrough in the conclusions are highly unlikely to be performed in this area.     

Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer

Successful treatment of cancer patients with a combination of monoclonal antibodies (mAb) and chemotherapeutic drugs has spawned various other forms of additional combination therapies, including vaccines or adoptive lymphocyte transfer combined with chemotherapeutics. These therapies were effective against established tumors in animal models and showed promising results in initial clinical trials in cancer patients, awaiting testing in larger randomized controlled studies. Although combination between immunotherapy and chemotherapy has long been viewed as incompatible as chemotherapy, especially in high doses meant to increase anti-tumor efficacy, has induced immunosuppression, various mechanisms may explain the reported synergistic effects of the two types of therapies. Thus direct effects of chemotherapy on tumor or host environment, such as induction of tumor cell death, elimination of regulatory T cells, and/or enhancement of tumor cell sensitivity to lysis by CTL may account for enhancement of immunotherapy by chemotherapy. Furthermore, induction of lymphopenia by chemotherapy has increased the efficacy of adoptive lymphocyte transfer in cancer patients. On the other hand, immunotherapy may directly modulate the tumor’s sensitivity to chemotherapy. Thus, anti-tumor mAb can increase the sensitivity of tumor cells to chemotherapeutic drugs and patients treated first with immunotherapy followed by chemotherapy showed higher clinical response rates than patients that had received chemotherapy alone. In conclusion, combination of active specific immunotherapy or adoptive mAb or lymphocyte immunotherapy with chemotherapy has great potential for the treatment of cancer patients which needs to be confirmed in larger controlled and randomized Phase III trials.     

Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer

Although approved for the treatment of pancreatic cancer, the chemotherapeutic agent ifosfamide is not an effective therapy for this type of tumour. Ifosfamide must be activated by cytochrome P450 (P450) enzymes in the liver, initially to a short lived intermediate and then to toxic metabolites that are subsequently distributed by the circulatory system. Particularly for pancreatic cancer, this liver-mediated conversion results in relatively high systemic toxicities and poor therapeutic concentrations at the liver-distant site of the tumour. Activation of ifosfamide at the site of the tumour may allow lower doses to be used, while increasing the therapeutic index due to the resultant active concentrations generated locally. A cell-based therapy has been conceived where encapsulated, 293-derived cells genetically modified to overexpress a cytochrome P450 enzyme, are implanted near solid tumours. The cells are encapsulated in polymers of cellulose sulphate in order to provide a means of immunoprotection in vivo as well as to physically constrain them to the vicinity of the tumour. A major advantage of this strategy is that it allows one standard cell line to be applied to all patients and this approach can be extended to the treatment of other tumour types. After proof of principle studies in animal models, a phase I/II clinical trial was initiated in patients with stage III/IV nonresectable pancreatic cancer. Encapsulated cells were angiographically placed into the tumour vasculature of 14 patients and followed by systemic low dose ifosfamide treatment. Angiographic delivery of encapsulated cells proved feasible in all but one patient, and was well tolerated with no capsule or ifosfamide treatment-related adverse events. Four of the treated patients showed tumour regressions after capsule delivery and ifosfamide treatment in computer-tomography scans. The other 10 patients showed no further tumour growth (i.e. stable disease) during 20 weeks observation period. The median life expectancy of the patient collective was extended two fold as compared to age and status matched historical controls, with a 3-fold improvement in one year survival being attained. Evidence for a clinical benefit of the treatment was also obtained on the basis of standard parameters for quality of life. This approach has been evaluated by the European Medicines Evaluation Agency (EMEA) and orphan drug status has been granted. A pivotal clinical trial is now being planned with the help of the EMEA. Taken together, the data from this clinical trial suggest that encapsulated cytochrome P450-expressing cells combined with chemotherapy may be useful for the local treatment of a number of solid tumours and support the performance of further clinical studies of this new treatment.     

The response of mouse intestine to combined hyperthermia and radiation: the contribution of direct thermal damage in assessment of the thermal enhancement ratio

The thermal enhancement of X-ray damage to mouse jejunum has been assessed when heating was achieved by immersion of an exteriorized loop of intestine in Krebs-Ringer solution. The results have been compared with those previously obtained following heating in situ. The primary effect of 1 hour of mild hyperthermia was to reduce the should of the crypt survival curve obtained following X-rays given alone. Thermal enhancement ratio (TER) values increased with increasing temperature, up to 42.3 degrees C, and were within the range reported for other normal tissues. However, when hyperthermia itself caused crypt loss and the contribution of hyperthermal killing to the overall tissue response was taken into account, there was little enhancement of radiation damage. There was no evidence of a large increase in TER at high temperatures, as is seen in some tumours and has been reported by Merino, Peters, Mason and Withers (1978) for intestine. It is possible that very high TER values which have previously been reported mainly reflect the heat-alone component of damage. Some of the implications of these results are discussed in relation to the combination of heat and radiation in therapy.     

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site.     

胆道系统恶性肿瘤的内科治疗新进展

胆道系统恶性肿瘤是一种发病率低、预后差的肿瘤,包括胆管癌、胆囊癌及壶腹部癌.在西方国家胆道系统恶性肿瘤大约占胃肠道肿瘤的4％,东南亚发病率相对较高.在我国,胆道系统恶性肿瘤的发病率并没有明确数字,约占消化道肿瘤的第6位.胆系肿瘤生存率低,预后差,至今尚无有效的化疗方案.目前,关于进展期胆系肿瘤化疗的Ⅱ、Ⅲ期临床试验研究以逐渐开展,化疗方案以吉西他滨为主,单药或联合铂类等药物,得到了明显提高的有效率及生存期.本文就目前胆系肿瘤化疗方面新的进展及成果做综述.     

Inhibition of breast cancer cell growth by the combination of clofarabine and sulforaphane involves epigenetically mediated CDKN2A upregulation

Many antineoplastic nucleoside analogue-based combinatorial strategies focused on remodelling aberrant DNA methylation patterns have been developed. The number of studies demonstrate high efficacy of bioactive phytochemicals in support of conventional chemotherapy. Our recent discoveries of the epigenetic effects of clofarabine (2′-deoxyadenosine analogue, antileukaemic drug) and clofarabine-based combinations with dietary bioactive compounds in breast cancer cells led us to look for more DNA methylation targets of these cancer-preventive agents. In the present study, using methylation-sensitive restriction analysis (MSRA) and qPCR, we showed that clofarabine in combination with sulforaphane, a phytochemical from cruciferous vegetables, significantly reactivates DNA methylation-silenced CDKN2A tumour suppressor and inhibits cancer cell growth at a non-invasive breast cancer stage.