Adjuvant Bestatin immunotherapy in patients with transitional cell carcinoma of the bladder

Summary The first clinical results of an ongoing, prospective trial to determine the value of adjuvant Bestatin immunotherapy in the management of bladder cancer are presented. Patients with nonmetastatic transitional cell carcinoma of the bladder, scheduled for fulldose local radiation therapy (64 Gy), were randomly allocated to adjuvant oral Bestatin treatment (30 mg daily for at least 1 year), starting at completion of irradiation, or no Bestatin. The longest follow-up period of the 151 evaluable patients is 6 years. The results have shown that the disease-free survival of the patients taking Bestatin is significantly improved compared to the controls (p=0.04). However, the overall survival of the patients was not affected by the Bestatin treatment. The beneficial effect of Bestatin seemed to be more marked among men than women. Furthermore, statistical analyses of the patient material according to T tumor categories suggested that compared to the controls, patients with less advanced disease (T1 and T2) benefitted more from Bestatin treatment than those with more advanced tumors (T3 and T4). The results of this ongoing trial thus show that patients with bladder cancer benefit from adjuvant Bestatin treatment in terms of disease-free survival.     

Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients

Background

although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up.

Methods

patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3–4/anyN, or anyT/N1–2; ECOG Performance Status 0–2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 ± 2 days after RT completion, adopting the total mesorectal excision technique.

Results

24 men and 23 women were enrolled; median age was 55 years (r.: 39–77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18–84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence.

Conclusion

bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT.

     

The effect of misonidazole as a hypoxic radiosensitizer at low dose

Using an automated low dose survival assay, the radiosensitizing effectiveness of misonidazole at low radiation dose (0-6 Gy) was measured in cultured mammalian cells. Also measured was its effectiveness at high doses of radiation (0-35 Gy) using the conventional survival assay. In both cases, several concentrations of the drug from 0 to 5 mM were used. The data at low doses were analyzed by a two-parameter mathematical equation with linear and quadratic dose terms, S = e-alpha D-beta D2, which proved to be a good fit to the experimental data at all misonidazole concentrations. It is shown that whereas the coefficient of the quadratic dose term, beta, increases significantly with increasing misonidazole concentration, the drug does not significantly affect the coefficient of the linear term, alpha. The enhancement ratio (ER) of misonidazole is shown to be decreased at lower doses. The clinical implications of this result are discussed.     

Sensitivity of SP cell line of melanoma B16 to low- and high-ionizing radiation

Cancer stem cells (CSC) found in multiple tumor types and cancer cell lines were shown to be more resistant to low-LET radiation in comparison to other cancer cells. Therefore, CSC are supposed to determine the long-term effect of cancer therapy. Research into the CSC sensitivity to high-LET radiation is of great interest because of the advances in hadron therapy. The aim of this investigation is to compare CSC and other cancer cell sensitivity to the low- (60Co gamma-rays) and high-LET (neutron) radiation. To identify CSC, we used the low cytometry-based side population (SP) technique based on the CSC capacity to produce the efflux of the vital dye Hoechst 33342. SP and non SP cells were sorted and exposed to gamma and neutron radiation at doses of 1-10 Gy and 0.1-4.7 Gy, correspondingly. We applied the colony-formation test to examine the SP and non SP survival rate after irradiation. It was shown that the sensitivity of SP to gamma-irradiation was lower than that of other cells: D0 average values (+/- SE) made up 2.3 +/- 0.3 Gy and 1.4 +/- 0.2 Gy, correspondingly (p = 0.047). The survival rate of SP and non SP did not differ after neutron irradiation. The values of relative biological effectiveness of neutron radiation relative to gamma-radiation at the D10 level were 2.6 for SP and 2.1 for other cells. The obtained results justify for the first time a high efficiency of application of neutrons in radiotherapy from the point of view of CSC elimination.     

Local application of dimethyl sulfoxide at different concentrations to the prevention of radiation-induced damages in patient with cancer of the cervix uteri

OBJECTIVE: to study the efficacy of dimethyl sulfoxide ((DMSO) at different concentrations in preventing radiation-induced rectal and urinary bladder damages in patients with cervix uteri cancer (CUC). MATERIAL AND METHODS: combined radiation therapy (RT) was performed in 807 patients with CUC. In the control group (n = 221), RT was made, without applying radio-modified agents. An hour prior to a session of intracavitary irradiation, 10% DMSO solution was instilled into the rectum and urinary bladder in 113 patients and applications of metronidazole (MN) dissolved in 100% DSMO were made in 473 patients. Teleradiotherapy was performed, by using megavolt irradiation sources in the conventional fractionation mode; the total focal dose (TFD) was increased up to 40-46 Gy. Intracavitary irradiation was carried out on "AGAT-V" and "AGAT-VU" devices once weekly; the single focal dose in point A was 7 Gy; TFD was 49-56 Gy. RESULTS: 10% DMSO instillations reduced the incidence of late radiation-induced damages to the rectum and urinary bladder. In the control group, the incidence of these conditions was 19.0 and 9.5%, respectively; with the use of 10% DMSO, that was 8.8 and 7.1%. Applications of MN dissolved in 100% DMSO reduced the incidence of late radiation-induced damages to 1.7%. CONCLUSION: Local application of DMSO is a method for preventing late radiation-induced damages to the rectum and urinary bladder in patients with CUC. When the concentration of DMSO is increased, its preventive effect increases.     

肝细胞癌根治性切除术后预后因素分析

目的:探讨影响肝细胞癌患者根治性术后预后相关因素。方法:回顾性分析2004年1月1日至2009年12月31日245例我院行根治性切除术的肝细胞癌患者,采用Kaplan-Meier法和Cox比例风险模型分析临床资料、手术过程、病理特征与预后的关系。结果:多因素分析结果显示术前AFP水平、术中出血量、TNM分期是影响无进展生存时间和总生存时间的独立风险因素。术前AFP水平越高、术中出血量越大、TNM分期越晚则患者无进展生存时间及总生存时间明显缩短。此外,患者出现肿瘤组织局部坏死、门静脉癌栓,则总生存时间明显缩短。结论:术前AFP水平、术中出血量、TNM分期是外科根治性切除术后肝细胞癌患者复发及死亡的相关因素,对于临床医师判断预后及延长术后生存时间具有重要的临床意义。     

A Re-Emerging Marker for Prognosis in Hepatocellular Carcinoma: The Add-Value of FISHing c-myc Gene for Early Relapse

Hepatocellular carcinoma is one leading cause of cancer-related death and surgical resection is still one of the major curative therapies. Recently, there has been a major effort to find mechanisms involved in carcinogenesis and early relapse. c-myc gene abnormality is found in hepatocarcinogenesis. Our aim was to analyze the role of c-myc as prognostic factor in terms of overall survival and disease-free survival and to investigate if c-myc may be an important target for therapy. We studied sixty-five hepatocellular carcinomas submitted to surgical resection with curative intent. Size, macro-microvascular invasion, necrosis, number of nodules, grading and serum alfa-fetoprotein level were registered for all cases. We evaluated the c-myc aberrations by using break-apart FISH probes. Probes specific for the centromeric part of chromosome 8 and for the locus specific c-myc gene (8q24) were used to assess disomy, gains of chromosomes (polysomy due to polyploidy) and amplification. c-myc gene amplification was scored as 8q24/CEP8 > 2. Statistical analysis for disease-free survival and overall survival were performed. At molecular level, c-myc was amplified in 19% of hepatocellular carcinoma, whereas showed gains in 55% and set wild in 26% of cases. The 1- and 3-year disease-free survival and overall survival for disomic, polysomic and amplified groups were significantly different (p=0.020 and p=.018 respectively). Multivariate analysis verified that the AFP and c-myc status (amplified vs. not amplified) were significant prognostic factors for overall patients survival. c-myc gene amplification is significantly correlated with disease-free survival and overall survival in patients with hepatocellular carcinoma after surgical resection and this model identifies patients with risk of early relapse (≤12 months). We suggest that c-myc assessment may be introduced in the clinical practice for improving prognostication (high and low risk of relapse) routinely and may have be proposed as biomarker of efficacy to anti-c-myc targeted drugs in clinical trials.     

Retreatment for prostate cancer with stereotactic body radiation therapy (SBRT): Feasible or foolhardy?

The most popular therapeutic option in the management of radio-recurrent prostatic carcinoma is represented by the androgen deprivation therapy, that however should be considered only palliative and hampered by potential adverse effects of testosterone suppression. Local therapies such as surgery, cryoablation or brachytherapy might be curative choices for patients in good conditions and with a long-life expectancy, but at cost of significant risk of failure and severe toxicity. The administration of stereotactic body radiation therapy (SBRT) in this setting have come about because of tremendous technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumor with reduced margins and high gradients outside the target, thereby reducing the volume of rectum which already received significant doses from primary radiotherapy. So far, very modest data are available to support its employment. Rationale, clinical experience, and challenges are herein reviewed and discussed.     

The role of radiation therapy for carcinoma of the lung

A large proportion of patients with carcinoma of the lung may benefit from the use of radiation therapy. Operable patients have not been shown to benefit from preoperative irradiation, but postoperative irradiation has improved survival in those found to have involvement of hilar or mediastinal lymph nodes. Radiation therapy is the only potentially curative treatment for patients who are inoperable, but do not have distant metastasis. Control of the local tumor is very dependent upon dose-fractionation-time relationships. Patients who are relatively asymptomatic, i.e., they have a high performance status, are curable if treated promptly with radiation therapy. Small cell carcinoma requires both radiation therapy and chemotherapy. The optimal method of combining the two modalities is yet to be determined, but prophylactic cranial irradiation is necessary to control microscopic metastases that are not affected by systemic chemotherapy, and thoracic irradiation is necessary to give the highest probability of control of the primary tumor. Prophylactic cranial irradiation has also been shown to reduce the frequency of brain metastasis in patients with squamous carcinoma, large cell carcinoma, and adenocarcinoma; it may become more important in these cell types when more effective chemotherapy is developed.     

Effects of dexamethasone on late radiation injury following partial-body and local organ exposures.

Dexamethasone was evaluated as a treatment for radiation-induced lung, kidney, liver, and spinal cord injuries in rats. One experimental group was partial-body-irradiated (22.5 Gy) with the head, femur, and exteriorized intestine shielded to prevent acute mortality. Other animals received local irradiation to the kidney (20 Gy), liver (25 Gy), or a 1-cm segment of cervical spinal cord (18 to 40 Gy). Following irradiation half of the animals in each radiation group were given drinking water containing 188 micrograms/liter of dexamethasone. Tests were done to assess kidney function (hematocrit, plasma urea nitrogen, ethylenediaminetetraacetic acid clearance), liver function (rose bengal clearance, plasma glutamic oxaloacetic acid transaminase), or spinal cord injury (paralysis). The effectiveness of dexamethasone in preventing radiation injury was tissue specific. Dexamethasone eliminated lethal pleural fluid accumulation after partial-body irradiation and delayed development of kidney dysfunction after local kidney irradiation. As a result, dexamethasone increased the median survival time from 63 to 150 days after partial-body irradiation and from 126 to 175 days after local kidney irradiation. After whole-liver irradiation, development of hepatic functional injury was retarded by dexamethasone treatment but without significantly changing survival time. Dexamethasone had no effect on spinal cord tolerance but significantly shortened the latent period between radiation and paralysis.     

膀胱及小肠受量对直肠癌术后放疗副反应的影响

目的:探讨直肠癌术后放疗患者膀胱平均受量及直肠受量对放射性膀胱炎及放射性肠炎的影响。方法:收集我院2005年7月至2010年12月收治的直肠癌根治术后给予放疗的患者130例,收集临床因素、病理因素、放疗因素资料,统计放疗后6个月内放射性肠炎、放射性膀胱炎发生情况。结果:放疗因素中,膀胱壁平均照射剂量对放射性肠炎及膀胱炎的发生有显著影响(P0.05),即膀胱壁剂量越高,副反应发生率越大;当膀胱壁平均剂量达到49.12 Gy时,放射性膀胱炎的发生率显著升高。小肠平均剂量控制在50 Gy以下,其值与放射性肠炎的发生无相关性。结论:直肠癌术后放疗患者膀胱壁平均受量控制在49.12 Gy以下,对减少放射性膀胱炎的发生率有意义。     

Treatment of stage III–IV nasopharyngeal carcinomas by external beam irradiation and local low doses of IL-2

The therapeutic effect of intratumoural application of Interleukin-2 (IL-2) was studied in patients with stage III–IV nasopharyngeal carcinoma (NPC) that received radiotherapy. Patients with stage III–IV NPC receiving a standard treatment of 7,000 cGy external beam irradiation have a mean disease-free survival of about 1.5 years. In this paper, we describe ten of these patients who were treated with additional peritumoural and intratumoural injections with 3×10⁴ U IL-2 on 5 days in weeks 2, 4, and 6 of the 7-weeks irradiation period. This combined treatment group was compared with a historical group of patients treated with standard irradiation alone. Local IL-2 therapy showed a marked clinical and statistical significant improvement of disease-free survival. After 5 years, 63% of the IL-2 treated patients were disease-free versus 8% of the control patients. These results suggest that the therapeutic results of radiotherapy can be significantly improved by combining it with local IL-2 treatment. To our knowledge, this is the first clinical report showing that local IL-2 therapy is effective against an infiltrative and locally metastasizing tumour in human patients.This study was presented as a poster at the Dutch Society for Immunology, December 2003, Noordwijkerhout, The Netherlands.     

Synchronous early primary adenocarcinoma of both rectum and gallbladder. Report of a case

Background

Synchronous early primary cancers are rare and in addition synchronous adenocarcinoma of both rectum and gallbladder is extremely rare.

Case report

We report an unusual case of synchronous early primary adenocarcinoma of rectum and gallbladder. The patient was a 72-year-old woman with complaints of bloody stools and constipation. An endoscopy revealed adenocarcinoma of the lower rectum. A through preoperative investigation showed also cholelithiasis. The patient underwent abdominoperineal resection and cholecystectomy. The histopathological diagnosis was well to middle differentiate adenocarcinoma of the gallbladder (T2, N0, M0; stage II) and middle differentiate adenocarcinoma of the rectum (T2, N0, M0; stage II).

Conclusion

For the cases of extracolonic primary cancer associated with colorectal primary carcinoma, Warren and Gates' diagnostic criteria are used. All patients with colorectal carcinoma, should undergo a throughout preoperative examination to exclude the possibility of synchronous early primary cancers.

     

The effect of radiotherapy on NKT cells in patients with advanced head and neck cancer

Background

Cancer immunotherapy with NKT cells is a potential new treatment strategy for advanced head and neck cancer. NKT cell therapy is promising due to its unique anti-tumor activity and higher degree of safety compared to current therapies. Radiotherapy is indispensable as a standard treatment for advanced head and neck cancer. To elucidate the possibility of using NKT cells as an adjuvant immunotherapy with radiotherapy, we examined the effect of radiotherapy on NKT cells in patients with head and neck cancer.

Methods

The number, IFN-γ production and proliferation capacity of NKT cells were analyzed before and after 50 Gy radiation therapy in 12 patients with stage IV head and neck squamous cell carcinoma. The cytotoxic activity of NKT cells was examined in vitro.

Results

The number of NKT cells in the blood varied widely between patients. After radiation therapy, the population of CD3 T cells decreased significantly, while the NKT cell population remained stable. The number of NKT cells was the same after radiation therapy as before. IFN-γ production from NKT cells collected just after radiotherapy was impaired after stimulation with exogenous ligand, but the proliferative responses of these NKT cells was enhanced in comparison to those collected before radiation therapy. Furthermore, the proliferated NKT cells displayed a significant level of anti-tumor activity.

Conclusion

NKT cells are relatively resistant to radiation and might therefore be suitable for adjuvant immunotherapy to eradicate remnant cancer cells in patients who have undergone radiation therapy.     

Stereotactic Body Radiation Therapy as an Alternative Treatment for Small Hepatocellular Carcinoma

Background

Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment.

Materials and Methods

A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT.

Results

The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients’ survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%).

Conclusions

SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.     

Estimation and reduction of the radiation dose to the fetus from external-beam radiotherapy

The appearance of a malignant disease during pregnancy is relatively rare. The use of external-beam radiation therapy is limited to non-pelvic tumors which are usually located above the diaphragm. However, supradiaphragmatic radiotherapy unavoidably exposes the fetus to secondary radiation due to head leakage, scatter from the machine and scatter produced inside the patient. This fetal exposure may be associated with an elevated risk for the development of deterministic harmful effects and/or carcinogenesis. The decision about the administration of radiotherapy in a pregnant patient is influenced by the fetal dose which must always be estimated before the patient’s treatment course. The methods employed for fetal dosimetry in external-beam radiotherapy are described in this review study. Direct dose measurements using thermoluminescent dosemeters or large ionization chambers placed on physical phantoms may be used. Monte Carlo simulations on computational phantoms may also provide accurate fetal dose calculations. The physical and/or computational phantoms need to simulate the full-scatter geometry of the pregnant patient. Typical fetal dose values attributable to radiation therapy for brain tumors, head and neck cancer, breast carcinoma and Hodgkin lymphoma at the first, second and third trimesters of gestation are presented. The effectiveness of different shielding devices for fetal dose reduction in radiotherapy is discussed. The effect of the dimensions and setup of the shielding material on the radiation dose received by the fetus is described. Moreover, practical methods for reducing the fetal dose by selecting the appropriate irradiation parameters are presented.     

Salvage I-125 brachytherapy for locally-recurrent prostate cancer after radiotherapy

PurposeRetrospective, single-institution analysis of clinical outcomes and treatment-related toxicity in patients treated with salvage I-125 low-dose rate (LDR) brachytherapy (BT) for locally-recurrent prostate cancer after radiotherapy.Materials and methodsBetween 2008 and 2018, 30 patients with biopsy-confirmed prostate cancer recurrence underwent salvage treatment with I-125 LDR-BT. Of these 30 patients, 14 were previously treated with primary external beam radiotherapy (EBRT; median dose, 73 Gy) and 16 with primary I-125 LDR-BT (145 Gy and 160 Gy in 14 and 2 cases, respectively). At seed implantation, the mean age was 75.8 years, with a median Gleason score of 7 and pre-salvage PSA of <10 ng/mL. Six patients received androgen deprivation therapy for six months after relapse diagnosis. The prescribed salvage I-125 BT dose to the gland was 120−130 Gy, with dose restrictions of Dmax <135% (urethra) and <100% (rectum). Toxicity was evaluated according to the CTCAE scale (v4.0).ResultsAt a median follow-up of 45 months, the biochemical recurrence-free survival rates at 1, 3 and 5 years were 86.7%, 56.7% and 53.3%, respectively. Overall survival at 5 years was 87%. On the multivariate analysis, two variables were significant predictors of recurrence: PSA at relapse and nadir PSA post-salvage. Grade 3 genitourinary toxicity was observed in 5 patients (radiation-induced cystitis in 3 cases and urethral stenosis in 2) and G3 gastrointestinal toxicity in 3 patients (rectal bleeding).ConclusionSalvage therapy with I-125 brachytherapy is a safe and effective treatment option for locally-recurrent prostate cancer in previously-irradiated patients. High pre-salvage PSA and post-salvage nadir PSA values were significantly associated with a worse disease control after salvage I-125 LDR-BT. In well-selected patients, I-125 LDR-BT is comparable to other salvage therapies in terms of disease control and toxicity. However, more research is needed to determine the optimal management of locally-recurrent prostate cancer.     

Equivalence of pulsed-dose-rate to low-dose-rate irradiation in tumor and normal cell lines

To determine whether different fractionation schemes could simulate low-dose-rate irradiation, ovarian cells of the carcinoma cell lines A2780s (radiosensitive) and A2780cp (radioresistant) and AG1522 normal human fibroblasts were irradiated in vitro using different fraction sizes and intervals between fractions with an overall average dose rate of 0.53 Gy/h. For the resistant cell line, the three fractionation schemes, 0.53 Gy given every hour, 1.1 Gy every 2 h, and 1.6 Gy every 3 h, were equivalent to low dose rate (0.53 Gy/h). Two larger fraction sizes, 2.1 Gy every 4 h and 3.2 Gy every 6 h, resulted in lower survival than that after low-dose-rate irradiation for the resistant cell line, suggesting incomplete repair of radiation damage due to the larger fraction sizes. The survival for the sensitive cell line was lower at small doses, but then it increased until it was equivalent to that after low-dose-rate irradiation for some fractionation schemes. The sensitive cell line showed equivalence only with the 1.6-Gy fraction every 3 h, although 0.53 Gy every 1 h and 1.1 Gy every 2 h showed equivalence at lower doses. This cell line also showed an adaptive response. The normal cell line showed a sensitization to the pulsed-dose-rate schemes compared to low-dose-rate irradiation. These data indicate that the response to pulsed-dose-rate irradiation is dependent on the cell line and that compared to the response to low-dose-rate irradiation, it shows some equivalence with the resistant carcinoma cell line, an adaptive response with the parental carcinoma cell line, and sensitization with the normal cells. Therefore, further evaluation is required before implementing pulsed-dose-rate irradiation in the clinic.