Number Of Tumor Sites Research Articles

Epidemiological Study of Metastatic Brain Tumors in Miyazaki Prefecture: A Regional 10-year Survey in Southern Japan.

Advances in cancer treatment have improved the survival of patients with cancer, with a concomitant increase in the proportion of patients with metastatic brain tumors (MBTs). In this study, we used cancer registries established in Japan after 2016 and available patient data by organ in order to conduct an accurate epidemiological study. To the best of our knowledge, this is the first study to report on the detailed epidemiological data on MBT at the prefectural level in Japan using the Miyazaki Brain Tumor Database and Miyazaki Cancer Registry. This study included 425 new cases of MBTs diagnosed in Miyazaki Prefecture from 2007 to 2016. As per our findings, the most frequent primary tumor in Miyazaki Prefecture was found to be in the lung (49.4%), followed by colon/rectum/anus (9.4%) and breast (8.5%). Among patients with MBTs, 59.1% were males, a number closely similar to that of Japan, as shown in the Japanese Brain Tumor Registry (55.5%). The median age at diagnosis was 68 and 63 years in Miyazaki Prefecture and Japan, respectively. Although more patients were symptomatic in Miyazaki Prefecture than in Japan (88.5% vs. 15.5%), fewer patients opted for surgery (33.6% vs. 61.9%), probably because of their advanced age at diagnosis. As per the findings of this study, the annual incidence rate of new MBTs (i.e., ratio of the number of new cancer registrations to that of new MBT patients in Miyazaki Prefecture) was at 0.41%. The number of tumor sites in MBTs was independent of the total number of cancers per organ. Considering the expansion of cancer registries worldwide, including those on brain tumors, further epidemiological analysis of MBTs is deemed warranted.

Abstract 6474: Stress-related sick leave and subsequent cancer risk: A Swedish national register study of 516 678 cancer cases

Abstract Background: Despite previous studies investigating psychological stress in relation to cancer risk, no consensus has been reached as to whether stress is a modifiable risk factor for cancer. This study aims to investigate whether sick leave due to psychological stress can affect the risk of developing cancer. Method: This is a matched case-control study using Swedish nation-wide register data (study period 2005-2018). The main exposure is stress-related sick leave defined as registered sick leave due to psychological stress with the diagnosis codes of F43 (International Classification of Diseases codes: ICD) and its subclassifications and hereafter referred to as stress leave. For each primary cancer case (except non-melanoma skin cancer), up to five cancer-free controls were matched based on sex, age and county. Conditional logistic regression, conditioned on matching factors and adjusting for socioeconomic factors, was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). For subgroup analyses by specific tumor sites, Bonferroni-corrected significance level of 0.002 (alpha value divided by the number of tumor sites = 0.05/24) was also applied. Results: The study comprised 516 678 cancer cases and 2 357 433 matched controls. Stress leave of any duration, was associated with a modestly increased risk of cancer, with the highest risk observed for 1-30 days of leave, vs no leave during follow-up (adjusted OR 1.05, 95% CI 1.02-1.09). In subgroup analyses by tumor sites, stress leave was associated with an increased risk of prostate cancer (adjusted OR for >90 days vs no stress leave 1.10, 95% CI 1.01-1.20) and cervix cancer (adjusted OR>90 days vs no leave 1.11, 95% CI 1.05-1.17). For lung cancer, an inverse risk relationship was found (adjusted OR>90 days vs no leave 0.88, 95% CI 0.77-0.99). For other tumor sites, associations were generally null or had wide confidence intervals. After applying a Bonferroni-corrected significance level, the association was still significant for cervical cancer. Further examination by sex, specific types of psychological stress and cancer groups based on established etiology (tobacco use, obesity, alcohol consumption and gastric hyperacidity) showed a clear exposure-response trend in men and pronounced associations for exhaustion disorder (ICD code: F43.8A) and tobacco-related cancers. In a post-hoc analysis, the association for other HPV-related cancers was similar to that for cervical cancer but not statistically significant. Conclusion: In this register study covering the entire Swedish population, we found that stress-related sick leave was associated with modestly higher risk of cancer, particularly the risk of cervical cancer. Potential higher risk of prostate cancer and lower risk of lung cancer were observed, though these associations were not statistically significant after controlling for multiple testing. Citation Format: Sai San Moon Lu, Jenny Hadrévi, Lisbeth Slunga Järvholm, Florentin Späth, Richard Palmqvist, Tommy Olsson, Sophia Harlid, Bethany van Guelpen. Stress-related sick leave and subsequent cancer risk: A Swedish national register study of 516 678 cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6474.

Cryotherapy’s impact on quality of life in inoperable esophageal cancer.

260 Background: dysphagia (dys) palliation in non-operable esophageal cancer (EC) continues to be a challenge. While chemotherapy and radiation help with dys, many patients require endoscopic interventions during their illness. Self-expanding metal stents have been the mainstay of endoscopic interventions but have a significant risk of severe adverse events and prevent the patient from being able to lie flat without severe reflux. Cryotherapy (cryo) is an emerging technique that can be used while the patient is receiving systemic therapy (ST). Previous retrospective studies showed improvement in dys with a favorable adverse event profile but did not report on quality of life (QOL) or reflux symptoms in patients receiving ST. Prospective studies have shown modest improvement in dys and QOL in patients not receiving ST. This prospective study reports the outcomes of cryo including dys, QOL, reflux symptoms and adverse events (AE) in patients receiving ST. Methods: A prospective multicenter cohort study of 35 adult inoperable EC patients undergoing cryo from Sep 2017 to Aug 2021. QoL was assessed using a modified EORTC QLQ-OES18 questionnaire (score 18 to 72, higher scores indicating worse QoL) while dys was measured using a 4-point Likert scale (0, no Dys; 1, Dys to solids; 2, Dys to semi-solids; 3, Dys to liquids; 4, Dys to saliva) at the start of cyro and 1-2 weeks post cryo. Paired t-test was used to evaluate changes in QoL and Dys between pre- and post-cryo. Results: There were 29 males and 6 females (30 stage IV and 5 stage III at diagnosis). Among 35 patients, a total of 104 cryo procedures were performed, with a mean of 3 per patient. The median number of tumor sites treated per cryo was 2 while the median number of cryo cycles delivered per tumor site was 3. The median total freeze time per tumor site was 60 seconds. The mean QoL score improved significantly from 31.8 pre-cryo to 28.2 with one cryo session (improvement of 3.6 points; p < 0.001). The mean dysphagia score improved significantly from 1.42 to 1.05 per cryo session (improvement of 0.37 points; p = 0.002). The mean After a mean of 3 cryo sessions, QoL score improved significantly from 35.9 pre-cryo to 29.8 post-cryo (improvement of 6 points; p = 0.001) and the mean dysphagia score improved significantly from 1.97 pre-cryo to 1.25 post-cryo (improvement of 0.72 points; p = 0.004). 86.5% of patient were able to sleep lying flat without heartburn or regurgitation. 6 patients received another intervention (1 stenting, 3 radiation and 2 dilation) for Dys palliation. 8 patients underwent feeding tube placement. Cryotherapy related grade 3 or higher adverse events occurred after 3 cryo sessions. Conclusions: Cryotherapy for palliation in non operable esophageal cancer improved dysphagia and quality of life without causing reflux and had a favorable adverse event profile with most patients not needing another intervention for dysphagia palliation.

Organ-Specific Therapeutic Effect of Paclitaxel and Carboplatin Chemotherapy After Platinum-Based Chemotherapy and Pembrolizumab for Metastatic Urothelial Carcinoma.

BackgroundTo evaluate the organ-specific therapeutic effect of paclitaxel and carboplatin (TC) chemotherapy in patients who failed platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma (UC).Patients and MethodsWe retrospectively reviewed the data of patients with metastatic UC who had received TC chemotherapy after the failure of platinum-based chemotherapy and pembrolizumab. The RECIST 1.1 criteria were used to assess the objective response to pembrolizumab and TC chemotherapy at tumor sites.ResultsWe analyzed 8 patients (male, n=5; female, n=3; median age, 65 years old). All patients except one had visceral metastasis. The median overall survival for TC was 10.9 months (95% confidence interval, 1.0‑12.7 months), and the objective response rate was 25.0% (partial response [PR]: 2 cases). The metastatic organs were the lymph nodes in 5 cases (number of tumor sites: 8), lung in 4 cases (number of tumor sites: 12), liver in 3 cases (number of tumor sites: 14), bone in 3 cases (number of tumor sites: 12), and primary lesion in 3 cases (number of tumor sites: 3). There were no cases of a complete response or progressive disease in any metastatic organs due to TC chemotherapy. A PR was seen in 2 cases of lymph node metastasis (40.0%), 2 cases of lung metastasis (50.0%), and 2 cases of liver metastasis (66.7%). All 3 cases of bone metastasis showed stable disease, as did all 3 cases of primary lesion. Improvement in the therapeutic effect of TC chemotherapy compared with pembrolizumab was observed in 2 cases (40.0%) of lymph node metastasis, 2 cases (50.0%) of lung metastasis, and 1 case (33.3%) of liver metastasis.ConclusionLymph node, lung, and liver metastases may respond to TC chemotherapy, even if exacerbated with pembrolizumab after platinum-based chemotherapy in metastatic UC.

CEA response at four weeks as an early predictor for outcomes in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line cetuximab-based chemotherapy: A STEP-analysis in the JACCRO CC-05/06 trials.

543 Background: We have reported that carcinoembryonic antigen (CEA) response correlated with clinical outcomes of 1st-line cet-based therapy (Target Oncol 2017). Early tumor shrinkage (ETS) is considered to be an on-treatment biomarker for outcomes of chemotherapy; however, clinical biomarkers to predict outcomes earlier are warranted. Methods: This study included 69 pts who were assessable for CEA at baseline and 4 wks, and with observed survival time from 2 phase II trials of 1st-line therapy for KRAS exon2 wild-type mCRC; JACCRO CC-05 of cet plus FOLFOX (UMIN000004197) and CC-06 of cet plus SOX (UMIN000007022). We investigated the influence of baseline age, gender, PS, primary tumor sidedness (PTS), number of tumor sites, as well as the CEA decrease at 4 wks to the patient’s OS and PFS. Results: PTS and the CEA decrease at 4 wks were found to be important predictors to OS and PFS. Baseline CEA and CEA decrease at 4 wks were median of 31.0 (range, 1.0-20920.0) and median of 35% (range, -259%-97%), respectively. The STEP-analysis indicated that CEA response was most significantly associated with OS when a cut-off value of 50% for CEA-responder (HR 0.49, log-rank test p = 0.03). Median OS in responders (n = 25) and non-responders (n = 44) were 36.2 m and 21.5 m, respectively. When the same cut-off value was used, median PFS in responders and non-responders were 11.6 m and 6.5 m, respectively (HR 0.64, log-rank test p = 0.08). In addition, a multivariate Cox Proportional-Hazards Model with both PTS and CEA response as risk factors showed that PTS correlated with both OS and PFS. In pts with left-sided tumors, non-responders (n = 33) had shorter OS and PFS compared to responders (n = 23). In the above 2-covariate Cox proportional hazard model, adjusted HR for CEA 50% decrease is 0.55, p = 0.1; adjusted HR for PTS is 2.66, p = 0.008. Conclusions: Our analysis suggests 50% CEA decrease at 4 wks as an early on-treatment biomarker for 1st-line cet-based therapy in mCRC. It may potentially predict outcomes earlier compared to ETS. Also, CEA response at 4 wks may differentiate pts who receive more benefit from cet treatment in left-sided tumors. Clinical trial information: UMIN000004197 and UMIN000007022.

Targeting ncRNAs in the 3q26.2 amplicon.

Targeting ncRNAs in the 3q26.2 amplicon.

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Analysis of prognostic factors for 60-day mortality: Evaluation of a randomized phase III trial investigating FUFIRI versus mIROX as first-line treatment of metastatic colorectal cancer (mCRC).

3554 Background: Mortality rates in published irinotecan-based randomized trials range between 1.7% and 5.0%. Prognostic factors for death within the first 60 days of treatment in mCRC studies have not been published yet. The purpose of this analysis was to evaluate clinical, histopathological and lab-report data associated with PFS and OS as published by Koehne et al. (Annals of Oncology 13: 308, 2002) and to identify prognostic factors of 60-day mortality in pts receiving first-line therapy of mCRC. Methods: Data from a randomized phase III study comparing FUFIRI vs. mIROX in 479 pts were evaluated. According to Koehne et al. we analyzed: Platelets, alkaline phosphatase (AP), white blood cell count (WBC), haemoglobin, number of tumor sites, LDH, CEA, CA 19-9 and several other baseline parameters. Prognostic factors were estimated via uni- and multivariate logistic regression analysis. Apart from Karnofsky performance status (KPS), none of these factors were part of the in- or exclusion-criteria in the FIRE trial. Results: The total 60-day mortality rate was 5.0% (24/479). 60- day mortality was observed in 5.5% (13/238) of pts in the FUFIRI-arm and in 4.6% (11/241) in the mIROX-arm (p = 0.680). Mortality was qualified as disease-related in 71% (17 pts) and treatment-related in 29% (7 pts) (p = 0.695). Univariate analysis showed KPS, LDH, AP and WBC as prognostic factors for death within first 60 days of treatment. In multivariate analysis, only high LDH-levels (p = 0.010) and an elevated WBC (p = 0.006) remained as significant, independent prognostic factors. Low KPS showed a strong trend, but failed to reach statistical significance (p = 0.057) as did AP and the number of metastatic sites. Conclusions: In this study, 71% of early deaths were disease-related, while only 29% were possibly related to study medication. Independent prognostic factors for death within the first 60 days of treatment were LDH and WBC. KPS showed a strong trend in multivariate analysis. Future trials may consider LDH and WBC for definition of exclusion criteria. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis

VEGF and Bcl-2 interact via MAPKs signaling pathway in the response to hypoxia in neuroblastoma.

Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites, which suggests a positive correlation between tumor hypoxia and increased metastatic efficiency. Evidence shows that vascular endothelial growth factor (VEGF) stimulates angiogenesis in tumor growth and mediates neuroprotection to prevent an apoptotic cell death. Human neuroblastoma cells (CHP126) were exposed to moderate hypoxia for different time spans to explore the molecular stress responses. Apoptotic features as an increase of Bax/Bcl-2 ratio and activation of caspase 3 were observed at early period of exposure time, but these effects were reversed with the extension of hypoxic treatment. Hypoxia also activated MAPKs signaling pathways in a time-relative manner, which were involved in the regulation of hypoxia-related resistance of CHP126 cells. Meanwhile, VEGF and its receptor KDR were found to interact with MAPKs signaling pathways except the effect of hypoxia. Furthermore, rhVEGF(165) was utilized to discern that VEGF increased Bcl-2 and procaspase 3 expressions, contributing to a synergistic relationship of an angiogenic response with Bcl-2 in hypoxia via a cross talk, while the activation of ERK MAPK is important for both productions. These altered signals may be critical to predict a poor outcome; therefore, our knowledge provides new insight into apoptosis and angiogenesis control of tumor cells and suggests a strategy based on the blockade of hypoxia-induced VEGF signaling under hypoxia in neuroblastoma.

ASTRO Presidential Address “Sculpting the Landscape of Radiation Oncology”

It has been exciting and gratifying to work in the field of radiation oncology as significant advances have been made through coordinated intraand inter-disciplinary research activities. Three decades of intensive studies on how to rationally fractionate radiotherapy or to combine radiation with chemotherapy have changed the standard-of-care for many cancers. Progress in high-precision radiotherapy with superior topographic tumor targeting have begun to yield benefit in a number of tumor sites in terms of improving tumor control and reducing some toxicity. Further investigations are ongoing to assess its full potential in a variety of tumors. Better understanding of molecular processes underlying neoplastic transformation-progression and those governing cellular radiation responses prompted the development of strategies for selective enhancement of tumor response by modulating specific signaling pathways. For example, coordinated laboratory-clinical studies led to the demonstration that a short course of biologically targeted therapy with cetuximab (antibody against the epidermal growth factor receptor) combined with radiotherapy improved the local-regional control and survival rates in patients with locally advanced head and neck carcinoma without increasing radiation-induced side effects. Validation of this concept has inspired further methodical testing of many classes of novel agents.

Survey of cetuximab activity in irinotecan-refractory metastatic colorectal cancer patients

13533 Background: The BOND study demonstrated Cetuximab (Cx) activity in irinotecan-refractory metastatic colorectal cancer (IRMCCR) patients (pts). Cx was approved in Europe early 2004 for this population. The aim of this study was to survey its efficacy in a unselected population of IRMCCR treated in 4 french academic centers. Methods: Data of all IRMCCR pts who had received Cx with or without irinotecan regimen between Jan 2004 and Sept 2005 were included in this survey. Exhaustivity of treated pts was established based on pharmacy registry. Primary end-point was time to tumor progression (TTP). Secondary end-points were overall survival (OS) and tumor response (RECIST). Results: Characteristics of the 76 included IRMCCR pts were : male/female : 44/32; median age 59.5 yrs (range 23 - 79); performance status : 0–1 (59 pts) and 2–3 (17); median number of tumor sites : 2 (1 - 5). The median number of chemotherapy regimens preceeding first Cx administration was 3 (range 1 to 5). At least one local treatment of the metastases (surgical resection and/or radiofrequency ablation) was a part of the strategy before Cx for 39 pts (51.3%). EGFR status was positive in 72 pts and negative in 4. Cx was administered : alone in 4 pts, combined with FOLFIRI in 4 and with irinotecan alone in 68 (89%). 10 pts received only one infusion Cx (early clinical progression : 6; patient decision : 2; early death : 2). Median number of Cx infusions was 10 (range 1 to 60). Median TTP (intent-to-treat) was 3.3 months [IC95% : 2.2–4.6]. Median OS since first-line chemotherapy and first Cx administration were 33.6 months [IC95% : 27.7–41.1] and 7.6 months [IC95% : 5.6–9.5], respectively. Tumor response (full population) was complete response 1.3%, partial response 19.7% (overall response 21%), stable disease 25% (disease control : 46%), progression 37% and not evaluable 17%. Conclusions: This therapeutic survey in a unselected population of IRMCCR are in accordance with the results of the BOND study for TTP, OS and tumor response. (supported by ADEBIOPHARM ER48). [Table: see text]

Is the hypoxia-inducible factor pathway important in gastric cancer?

Tumour hypoxia is well recognised in oncology to be a key factor resulting in treatment resistance and poor prognosis. Hypoxia leads to the expression of a number of gene products that are involved in tumour progression, invasion and metastasis formation. The most important of these proteins is thought to be hypoxia-inducible factor-1α (HIF-1α), which appears to be a master regulator of the cellular response to hypoxia. HIF-1α expression is associated with a poor prognosis and treatment response in a number of tumour sites. There is some evidence that the HIF-1α pathway might be involved in gastric carcinogenesis. Studies have shown reactive oxygen species from Helicobacter pylori, associated with the development of gastric cancer, stabilise HIF-1α. Non-steroidal anti-inflammatory drugs, shown to reduce the risk of gastric cancer, can decrease HIF-1α expression. Although a large study correlating HIF-1α expression with prognosis is lacking in gastric cancer, the immunohistochemical expression of HIF-1α target genes ( Glut-1, VEGF, CA9, iNOS) is associated with a poor prognosis. In addition, the targeted inhibition of HIF-1α has been shown to inhibit the growth of gastric tumours in animals. Increased understanding of the importance of hypoxia and the HIF-1α pathways may therefore hold the key to prevention strategies, improved selection of patients for adjuvant therapy and new treatments for the disease.

Intensity-modulated radiation therapy for the treatment of pediatric cancer patients

Intensity-modulated radiation therapy (IMRT) is a novel form of radiotherapy, which has the potential to reduce the amount of radiation unintentionally delivered to normal tissues while maintaining a high radiation dose to the tumor in comparison with standard radiation techniques. In adults, this technology has been implemented in a number of tumor sites, but in children it has been little used. This article will review the current studies in which IMRT has been used in children. It will also discuss possible future applications for IMRT, and anticipated problems with its use.

Prognostic analysis of early lymphocyte recovery in patients with advanced breast cancer receiving high-dose chemotherapy with an autologous hematopoietic progenitor cell transplant.

The purpose of this study was to evaluate the prognostic effect of early posttransplant lymphocyte recovery in patients with advanced breast cancer receiving high-dose chemotherapy with autologous hematopoietic progenitor cell transplantation. We analyzed the effect of the absolute lymphocyte count on day +15 posttransplant on freedom from relapse and overall survival in patients with high-risk primary breast cancer or metastatic breast cancer, enrolled between 1990 and 2001 in prospective high-dose chemotherapy trials, using a uniform regimen of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea. Four hundred and seventy-six patients (264 high-risk primary breast cancer and 212 metastatic breast cancer patients) were evaluated at median follow-up of 8 years (range, 1.5-11 years). The disease-free survival and overall survival rates in the high-risk primary breast cancer group were 67% and 70%, respectively. Patients with metastatic breast cancer patients had 21.8% disease-free survival and 31.5% overall survival rates. Day +15 absolute lymphocyte count correlated with freedom from relapse (P = 0.007) and overall survival (P = 0.04) in the metastatic breast cancer group, but not in the high-risk primary breast cancer group (P = 0.5 and 0.8, respectively). The prognostic effect of absolute lymphocyte count in metastatic breast cancer was restricted to those patients receiving unmanipulated peripheral blood progenitor cells (P = 0.04). In contrast, absolute lymphocyte count had no significant effect in those metastatic breast cancer patients receiving bone marrow or a CD34-selected product. In multivariate analyses, the prognostic effect of day +15 absolute lymphocyte count in metastatic breast cancer was independent of other predictors, such as disease status, pre-high-dose chemotherapy treatment, number of tumor sites, or HER2. Early lymphocyte recovery is an independent outcome predictor in metastatic breast cancer patients receiving high-dose chemotherapy and an autologous peripheral blood progenitor cell transplant. These observations suggest that immune strategies targeting minimal posttransplant residual disease may prove worthwhile.

Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis.

Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites. Both clinical and experimental studies have suggested a positive correlation between tumor hypoxia and increased metastatic efficiency; however, the mechanisms are not understood. In this study, the mechanisms of hypoxia-enhanced metastasis have been investigated in murine KHT fibrosarcoma and SCC VII cells. We have observed that hypoxia-pretreated KHT-C cells have a higher survival rate than control KHT-C cells after being arrested in mouse lungs. cDNA microarray analysis revealed many hypoxia-regulated genes, most of which have been reported to be involved in cell survival and growth. Among these genes, we have confirmed the up-regulation of Mdm2 by hypoxia and have demonstrated that this up-regulation is p53 independent. The up-regulation of Mdm2 by hypoxia is associated with decreased p53 protein and inhibition of the transactivation of p53 downstream proapoptotic genes. Overexpression of Mdm2 or suppression of p53 by transient transfection increased metastatic efficiency in KHT-C cells. These data suggest that hypoxia can increase tumor cell metastatic efficiency by rendering the tumor cells less sensitive to stress-induced cell death, e.g., through modifying the levels of Mdm2 and p53.

How to overcome (and exploit) tumor hypoxia for targeted gene therapy.

Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), and exploiting this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

Clinical determinants of survival in patients with 5-fluorouracil- based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients

BackgroundPatients with metastatic colorectal cancer are usually offered systemic chemotherapy as palliative treatment. A multivariate analysis was performed in order to identify predictors and their constellation that allow a valid prediction of the outcome in patients treated with 5-fluorouracil (5-FU)-based therapy. Patients and methodsA total of 3825 patients treated with 5-FU within 19 prospective randomised and three phase II trials were separated into learning (n = 2549) and validation (n = 1276) samples. Data were analysed by tree analysis using the recursive partition and amalgamation method (RECPAM). A predictor could only enter the RECPAM analysis if the number of patients with missing values was <33.3% within a node, and the minimal node size was set to 50 patients. Twenty-three potential predictors were grouped into subsets of laboratory variables (11 parameters), tumour-related variables (seven parameters) and clinical variables (five parameters). In the first step, tree analysis was performed separately for each predictor subset. The selected prognostic parameters of the resulting partial models (the ‘winners’) were entered into the general model. The classification rule from the data of the learning set was applied to the independent validation set. ResultsWinners of the subgroup analysis for laboratory variables were: platelets ≥400 × 109/l, alkaline phosphatase ≥300 U/l, white blood cell (WBC) count ≥10 × 109/l and haemoglobin <11 × 109/l, and all predicted a worse outcome. Negative predictors within the subgroup of tumour parameters were: number of tumour sites more than one or more than two, presence of liver metastases or peritoneal carcinomatosis, which predicted a worse outcome. Furthermore, presence of lung metastases, a primary rectal cancer and presence of lymph node metastases all predicted a better outcome in the multivariate setting. Among the clinical parameters only performance status of ECOG 0 or 1 predicted better outcome. In the final regression tree, three risk groups could be identified: low risk group (n = 1111) with a median survival of 15 months for patients with ECOG 0/1 and only one tumour site; intermediate risk group (n = 904) with a median survival of 10.7 months for patients with ECOG 0/1 and more than one tumour site and alkaline phosphatase <300 U/l or patients with ECOG >1, WBC count <10 × 109/l and only one tumour site; high risk group (n = 534) with a median survival of 6.1 months for patients with ECOG 0/1 and more than one tumour site and alkaline phosphatase of ≥300 U/l or patients with ECOG >1 and more than one tumour site or WBC count >10 × 109/l. The median survival times for the good, intermediate and high risk groups in the validation sample were 14.7, 10.5 and 6.4 months, respectively. ConclusionsPatients can be divided into at least three risk groups depending on the four baseline clinical parameters: performance status, WBC count, alkaline phosphatase and number of metastatic sites. Any molecular or biological marker should be validated against these clinical parameters and decisions for more or less intensive treatments may be studied separately in these three risk groups. Also, clinical trials should be stratified according to the three risk groups.

Prognostic Model for Relapse After High-Dose Chemotherapy With Autologous Stem-Cell Transplantation for Stage IV Oligometastatic Breast Cancer

PURPOSE: To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer. PATIENTS AND METHODS: Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions. RESULTS: Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 an...

Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer.

To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer. Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions. Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 and the axillary nodal ratio were independent predictors of OS. The following prognostic categories for RFS were established (RFS rate, median RFS): good risk, no factors (77%, 80 months); intermediate risk, one factor (41%, 28 months); and poor risk, both factors (10%, 10 months). Long-term results in patients with oligometastatic breast cancer are encouraging but need validation in prospective randomized studies. HER-2 expression, number of sites, and primary nodal ratio are independent outcome predictors. Confirmation of these observations in this selected population would imply the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit.

Hyperthermia-regulated immunogene therapy

One of the key milestones that must be reached before gene therapy becomes feasible for clinical cancer treatment is to be able to regulate therapeutic gene expression. This is true for most current cancer gene therapy approaches, since the majority of therapeutic genes are toxic to both tumour and normal tissues. Among the wide array of strategies available for regulating gene expression, hyperthermia represents a unique approach. Hyperthermic regulation of gene therapy is feasible because of the widely conserved heat shock response, which allows therapeutic gene expression to be elevated to thousands of fold higher than background when temperature reaches 3-5°C over physiological temperature (37°C). In addition, because of the long history of experimental research on the use of hyperthermia as an approach for cancer therapy, it is now quite feasible to apply hyperthermia to a number of tumour sites and to achieve temperatures that are sufficient to induce a heat shock response. This review will attempt to discuss the current status of hyperthermia-regulated gene therapy, with special emphasis on hyperthermia-regulated immunogene therapy.