Therapeutic effect of recombinant human epidermal growth factor (rhEGF) on mucositis in patients undergoing radiotherapy,with or without chemotherapy,for head and neck cancer

BACKGROUND:

We evaluated the efficacy of topically applied human recombinant epidermal growth factor (rhEGF) for the treatment of oral mucositis induced by radiotherapy (RT), with or without chemotherapy, in patients with head and neck cancer.

METHODS:

Patients receiving definitive chemoradiotherapy, definitive RT, or postoperative RT to the oral cavity or oropharynx were recruited from 6 institutions and enrolled in a randomized, double‐blind, placebo‐controlled phase 2 trial. Patients were assigned to a placebo group or to 1 of 3 EGF‐treatment groups (10, 50, or 100 μg/mL doses, delivered in a spray, twice daily). The grade of mucositis was evaluated using the Radiation Therapy Oncology Group (RTOG) scoring criteria. Responders to EGF were defined as having an RTOG grade of 2 or lower at the fourth‐ or fifth‐week examinations during RT, but an enduring RTOG grade 2 for 2 weeks was an exception.

RESULTS:

Of the 113 patients included in the study, 28 received placebo and 29 received EGF at 10 μg/mL, 29 at 50 μg/mL, and 27 at 100 μg/mL. EGF significantly reduced the incidence of severe oral mucositis at the primary endpoint (a 64% response was observed with 50 μg/mL EGF vs a 37% response in the control group; P = .0246).

CONCLUSIONS:

The EGF oral spray may have potential benefit for oral mucositis in patients undergoing RT for head and neck cancer. Phase 3 studies are ongoing to confirm these results. Cancer 2009. © 2009 American Cancer Society.     

Elevated plasma levels of transforming growth factor-beta 1 (TGF-beta 1) in patients with advanced breast cancer: association with disease progression

We examined the association between an elevated plasma TGF-beta 1 level and the disease progression of advanced breast cancer (BC) patients (n = 44). TGF-beta 1 levels were detected by an enzyme-linked immunosorbent assay (ELISA). Platelet carryover and in vitro platelet activation in our plasma samples was assessed and found to be insignificant. Plasma TGF-beta 1 values were significantly elevated (P < 0.05) in stage IIIB/IV patients (median value: 2.40 ng/ml, range: 0.13-8.48 ng/ml, n = 44) compared with healthy donors (median value: 1.30 ng/ml, range: 0.41-4.93 ng/ml, n = 36). Although pronounced in metastatic patients, especially those who had been newly diagnosed, TGF-beta 1 elevation was independent of tumour mass, site of distant metastases, histopathological type, steroid receptor (SR) content and age of the BC patients. Follow-up of 6 patients indicated a relationship between the plasma TGF-beta 1 and the patient's response. This suggests that TGF-beta 1, may be a promising prognostic marker for breast cancer patients with advanced disease. Confirmatory large-scale studies are needed, particularly given the overlap of values between our different subgroups analysed.     

High serum transforming growth factor beta 1 (TGFB1) level predicts better survival in breast cancer

The transforming growth factor beta 1 (TGFB1) is a regulatory cytokine with both tumor suppressor and tumor-promoting effects in breast cancer (BC) cell lines and tissue. Data about level of circulating TGFB1 and its prognostic significance in BC patients is conflicting. The objective of this study is to determine the clinical significance of the serum TGFB1 levels in BC patients. We enrolled 96 female patients with histopathologically diagnosed BC who did not receive chemotherapy (CT) or radiotherapy. Serum TGFB1 levels were measured by ELISA method and compared with 30 healthy controls. The mean serum TGFB1 level of BC patients was significantly higher than controls (0.08 vs. 0.04 ng/ml, p?<?0.001). There was no significant difference according to known disease-related clinicopathological or laboratory parameters. Serum TGFB1 level had a significant impact on overall survival in both univariate (p?=?0.01) and multivariate analysis (p?=?0.013). Serum TGFB1 level is elevated in BC patients and has a favorable prognostic value. However, it has no predictive role on CT response.     

Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis

Transforming growth factor beta (TGF-beta) type-II receptor mutations have been reported in several epithelial-type human malignancies. To elucidate the role of TGF-beta RII in lung cancer progression, we prepared gene-modified clones of the human lung cancer cell line NCI-H23. NCI-H23, a human non-small-cell lung adenocarcinoma cell line which has a frameshift mutation in, and reduced expression of, the TGF-beta type-II receptor (TGF-beta RII), exhibits resistance to growth inhibition by TGF-beta(1) in vitro. Transfection of NCI-H23 with a retroviral vector expressing wild-type TGF-beta RII restored the responsiveness of cells to exogenous TGF-beta(1) with reduced cell proliferation. Immunocytochemical analysis demonstrated nuclear translocation of Smad3 after TGF-beta(1) treatment in RII-restored NCI-H23 cells. Underphosphorylation of the retinoblastoma protein accompanying p21 up-regulation was observed after TGF-beta(1) treatment of NCI-H23-RII cells. Receptor restoration also changed the levels of VEGF mRNA induced by TGF-beta(1). However, impairment of TGF-beta signalling did not alter microvessel formation in vivo in transplanted tumours. Instead, in vivo tumorigenesis experiments revealed a remarkable difference in the number and sizes of the tumours derived from NCI-H23-RII cells and dominant negative NCI-H23-dnRII cells (P < 0.01). Collectively, these observations suggest that impairment of TGF-beta signal transduction contributes significantly to tumour progression, mainly by cell proliferation rather than by modulation of angiogenesis in human NCI-H23 lung carcinoma cells.     

Insulin-like factor of growth (IGFI), insulin-like growth factor binding protein 3 (IGFBP3) and transforming growth factor beta1 (TGF-beta1) in patients with locally-advanced and metastatic cancer of prostate

The paper deals with a study of growth factors in blood serum from patients with locally-advanced and metastatic cancer of prostate prior to treatment. Twelve months after diagnosis was made, the data were compared with the initial indices. Immunoenzymatic assay was used in combination with the existing standard procedures of examination of cancer patients. Data were compared with clinico-morphological and serologic evidence on tumor process using medico-biological statistics.     

Synchronous radiotherapy and chemotherapy with cisplatin in the management of locally advanced or recurrent head and neck cancer.

A synergism between cisplatin and radiotherapy has been demonstrated in in vitro and in vivo studies. To improve the locoregional control of disease and the survival rate in patients affected by locally advanced or recurrent squamous cell carcinoma of the head and neck, we planned a Phase II study of concurrent radiotherapy, 2 Gy for 5 days every week for a total dose of 60-70 Gy with cisplatin 80 mg/m2 every 21 days for 2 or 3 doses (on days 1, 21, 42). Fifty-one patients were entered in the study; 48 were evaluable for response and toxicity; 18 (37.5%) had untreated Stage III disease; 25 (52%) had Stage IV disease; 5 (10.5%) had recurrent disease. The complete response rate in Stage III-IV patients was 63% (27 of 43) with 95% confidence limits from 48 to 77% (+/- 14.5%). In the group of five patients with recurrent disease, only one (20%) achieved a complete response. In patients with Stage III-IV disease, a significantly higher complete response rate was observed for those younger than 58.5 years (p = 0.05). The overall estimated 1- and 2-year survival was 59% and 37%, respectively, and a significantly better survival was observed in complete responders compared to partial responses or patients with stable disease (p = 0.037). Disease-free survival was 46% and 36% at 1 and 2 years, respectively. Distant failure occurred only in 12.5% of the patients. Overall, the treatment was well tolerated, and only three patients refused to complete the planned therapy. Gastrointestinal and hematological toxicity were the most common side effects. Data from present trial were compared with that of 50 patients with comparable characteristics treated with radiotherapy alone from 1985 to 1987 as a historical control. The complete response rate, the disease-free survival, and the overall survival appear to be better in the patients treated with chemoradiotherapy. It was concluded that the combination of chemoradiotherapy in patients with Stage III-IV head and neck squamous cell carcinoma is an effective and safe treatment with an apparent better locoregional control than radiotherapy alone. Survival results need to be evaluated in a Phase III randomized trial.     

Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy.

PURPOSE: Elevated local and circulating levels of transforming growth factor beta(1) (TGF-beta(1)) have been associated with prostate cancer invasion and metastasis. We tested the hypothesis that preoperative plasma TGF-beta(1) levels would independently predict cancer stage and prognosis in patients who undergo radical prostatectomy. PATIENTS AND METHODS: The study group consisted of 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer (median follow-up, 53.8 months). Preoperative plasma levels of TGF-beta(1) were measured and correlated with pathologic parameters and clinical outcomes. TGF-beta(1) levels also were measured in 44 healthy men without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 men with prostate cancer metastatic to bone. RESULTS: Plasma TGF-beta(1) levels in patients with lymph node metastases (14.2 +/- 2.6 ng/mL) and bone metastases (15.5 +/- 2.4 ng/mL) were higher than those in radical prostatectomy patients (5.2 +/- 1.3 ng/mL) and healthy subjects (4.5 +/- 1.2 ng/mL) (P <.001). In a preoperative analysis, preoperative plasma TGF-beta(1) level and biopsy Gleason sum both were predictors of organ-confined disease (P =.006 and P =.006, respectively) and PSA progression (P <.001 and P =.021, respectively). In a postoperative multivariate analysis, preoperative plasma TGF-beta(1) level, pathologic Gleason sum, and surgical margin status were predictors of PSA progression (P =.020,P =.020, and P =.022, respectively). In patients who progressed, preoperative plasma TGF-beta(1) levels were higher in those with presumed distant compared with local-only failure (P =.019). CONCLUSION: Plasma TGF-beta(1) levels are markedly elevated in men with prostate cancer metastatic to regional lymph nodes and bone. In men without clinical or pathologic evidence of metastases, the preoperative plasma TGF-beta(1) level is a strong predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.     

Plasma levels of vascular endothelial growth factor during and after radiotherapy in combination with celecoxib in patients with advanced head and neck cancer

Celebrex and radiotherapy in advanced head and neck cancer. This phase I dose-escalation study seeks to determine the phase II recommended dose of cyclooxygenase type 2 (COX-2) inhibitor in patients with locally advanced squamous cell head and neck (H&N) cancer, treated with accelerated radiotherapy. Anti-vasculogenic effect of this treatment on serum vascular endothelial growth factor (VEGF) is examined. Patients were irradiated with curative intent (72Gy in 6weeks). Celecoxib was administered throughout the radiotherapy course. Serum VEGF level were tested during radiotherapy and in follow-up. Tumor specimens were stained to quantify the COX-2 expression. Thirty-two patients completed the treatment. The dose of celecoxib was escalated (200, 400 and 800mg bid, then de-escalated to 600mg bid). The acute toxicity related to the treatment in the first and second cohort did not reach grade III; in the third cohort three patients had grade III radiation toxicity and one had celecoxib-related toxicity. In the last fourth cohort the toxicity was acceptable. Significant VEGF level drop (p=0.011) was found between radiation day 1 and post-treatment visit. Significant decrease (p=0.022) of the VEGF level was shown in patients with high COX-2 expression in the tumor. Phase II recommended dose of celecoxib combined with accelerated radiotherapy in advanced H&N cancer was 600mg bid. A significant decrease of the post-treatment serum VEGF level compared to the initial level was noticed only in patients with high COX-2 expression in tumors.     

肺癌患者放疗前后血液TGF-β1变化与淋巴细胞亚群变化趋势相关性分析

目的 研究肺癌患者放疗后血浆TGF-β₁变化与肺癌近期疗关系,分析其与外周血淋巴细胞亚群变化趋势相关性。方法 前瞻性收集2014—2016年在我院39例肺癌患者疗前、疗中及疗后血液标本,采用酶联免疫吸附试验测定血浆中TGF-β₁表达水平,同时检测对应时间点患者外周血中淋巴细胞亚群变化,动态监测二者变化趋势。放疗结束后1个月复查胸部CT等,评价肿瘤近期疗效,根据RECIST标准分为治疗有效和无效。结果 放疗后血浆TGF-β₁水平降低患者近期疗效较好(P<0.05)。放疗开始后2、4周及放疗结束时血浆TGF-β₁和疗前相比变化水平与相同时间点的CD₄(+) T淋巴细胞(r=-0.581、-0.516、-0.648,P<0.001)、CD₈(+) T淋巴细胞(r=0.558、0.545、0.626,P<0.001),以及CD₄(+)/CD₈(+)值(r=-0.615、-0.648、-0.598,P<0.001)变化水平显著相关。结论 肺癌患者放疗后TGF-β₁水平下降者近期疗效较好,其具体机制可能与机体抗肿瘤免疫有关。     

晚期肺癌支气管动脉内灌注化疗合并放疗的疗效

Forty-two patients with Stage III and IV advanced lung cancer received bronchial arterial infusion of Cyclophosphamide or Mitomycin in combination with Adriamycin and Cisplatin (CAP or MAP). Twenty-six patients were given radiotherapy too. Histologically, 16 had squamous cell carcinoma, 11 adenocarcinoma, 3 small cell anaplastic carcinoma and 1 un-classified cancer. Eleven were diagnosed by bronchial arterial radiography. The short-term results showed that complete response rate (CR) was 53.8% and partial response rate (PR) 38.5% in patients treated with combined chemotherapy and radiotherapy whereas in those treated with infusion chemotherapy, CR and PR were 0% and 81.3% respectively.     

Combination chemotherapy with cis-diammine-di-chloro-platinum (II) and bleomycin in advanced head and neck cancer

Combination chemotherapy of cis-diammine dichloro platinum (II) (CDDP) and bleomycin was given to 10 patients with advanced squamous cell carcinoma of the head and neck. Nine patients had received prior radical radiotherapy, 2 had major ablative surgical procedures, and one had been previously treated with chemotherapy. Responses were as follows (duration in months): 2 CRs (4,6+), 2 PRs (1.5,1.5), and 2 minors. Vomiting related to CDDP was observed in 5 patients, nephrotoxicity and hypocalcemia in one patient were also observed.     

Postoperative radiotherapy in locally advanced head and neck cancer

This retrospective study was conducted on 255 consecutive patients with locally advanced squamous-cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx, treated at the Radiotherapy Department of Pordenone General Hospital between January 1975 and December 1985. All patients underwent radical surgery followed, after an interval ranging from 10 days to 2.9 months, by radiotherapy given either through a 6 MeV linear accelerator or a cobalt-60 unit. Field extension and dose delivered were comparable in relation to stage and involvement of the surgical resection margins. The aims of the study were to evaluate the survival rate and to analyze the clinical parameters which can influence the disease-free survival. The adjusted overall 5-year survival rate was 71%; stage, performance status at diagnosis, and site of the primary tumor were significant factors in determining patient prognosis, whereas infiltration of resection margins was not significant in determining loco-regional control of disease. Seventy-five patients relapsed and 67 died of cancer-related diseases whereas death in 52 patients was not related to the head and neck cancer. The combined modality treatment consisting of surgery followed by radiotherapy was well tolerated and proved to be effective in the treatment of locally advanced head and neck tumors.     

Two- vs three-drug combination chemotherapy in advanced or recurrent head and neck cancer

Head and neck squamous cancer is a major concern in India. The proportion of advanced cases is significantly high, and these patients have dismal survival prospects despite aggressive therapy. Often surgical resection and/or radiotherapy are not feasible in these patients. Hence, we decided to explore the option of neoadjuvant chemotherapy using effective agents like ifosfamide and paclitaxel in combination with cisplatin in these patients. A total of 361 patients were evaluable at the end of study. Of these, 207 had received ifosfamide and cisplatin and 154 had received taxanes (paclitaxel or docetaxel) in addition to ifosfamide and cisplatin. The ifosfamide-cisplatin group had an overall response rate of 66.67% (CR, 16.42%; PR, 50.24%) and the median duration of response was 5.5 mo; whereas the group in which taxanes were added, showed an overall response rate of 73.37% (CR, 7.79%; PR, 65.58%) with a median duration of response of 10 mo. The toxicity in both the groups was acceptable and there was no mortality. We conclude that taxane-based combinations have a significant activity in advanced head and neck squamous cancer and warrant further studies.     

Future chemotherapy and radiotherapy options in head and neck cancer

Chemoradiation is a standard approach to advanced unresectable head and neck cancer, although the optimum combination regimen remains controversial. However, in the past few years, chemoradiation has been successfully extended from the treatment of unresectable disease to the postsurgical therapy of high-risk patients and its value as an organ preservation procedure is under evaluation. More recently, molecular-targeted therapies have emerged, which interfere with mechanisms of chemo- and radioresistance, and preliminary data are promising. Their use in the combined treatment of head and neck cancer will hopefully further improve the value of chemoradiation in the clinical setting.     

Concurrent cisplatin and radiotherapy in advanced head and neck cancer

Management of Head and Neck Cancers poses a challenge inspite of several advances because of poor success in terms of response rate, survival and reduced morbidity of the patients. In the present study 30 untreated histologically proven cases of head and neck cancers were subjected to weekly radiotherapy with adjuvant chemotherapy (cisplatin 30 mg/m² intravenously). This study group was compared with a group of 30 patients who were given only radiotherapy. Results have shown that combination of chemotherapy with radiotherapy gives a significantly better results in tumour as well as nodal response with minimal toxicities.     

Increased risk of stroke in young head and neck cancer patients treated with radiotherapy or chemotherapy

Background

Chemo-radiotherapy-induced carotid stenosis and cerebrovascular events in head and neck cancer patients can cause severe disability and death. We aimed to estimate the risk of stroke in such patients over a six-year follow-up period.

Patients and methods

The study cohort consisted of head and neck cancer patients (n = 10,172). Cox proportional hazard model was used to compare the stroke-free survival rate between the patients treated with radiotherapy or chemotherapy, surgery alone, and surgery with adjuvant therapy after adjusting for possible confounding factors.

Results

At the end of follow-up, 384 patients had strokes: 126 (4.3%) from the surgery alone group, 167 (3.8%) from the radiotherapy or chemotherapy group, and 91 (3.2%) from the surgery with adjuvant therapy (P = 0.222). Head and neck cancer patients aged less than 55 years treated with radiotherapy or chemotherapy conferred a 1.8-fold higher risk for stroke (95% CI, 1.22–2.56; P = 0.003) after adjusting for patient characteristics, co-morbidities, geographic region, urbanization level, and socio-economic status. There was no statistical difference in stroke risk between different treatment modalities in head and neck cancer patients aged 55 years and more.

Conclusions

Young head and neck cancer patients treated with radiotherapy or chemotherapy have higher risks for stroke. Different treatment strategies should be considered in such patients.     

Transforming growth factor beta 1 (TGF-beta 1) expression in proliferating thyroid disease

In order to clarify some of the molecular mechanisms involved in the pathogenesis of thyroid proliferating diseases we have investigated the role of TGF-beta in thyroid carcinoma, adenoma and multinodular goiter. TGF-beta 1 expression studies were carried out in surgically removed thyroid tissue isolated from 15 patients affected by multinodular goiter, 4 patients affected by papillary carcinoma and 4 patients affected by follicular adenoma. TGF-beta 1 gene expression, evaluated by Northern analysis, dramatically increased in malignant proliferating thyroid disease and decreased drasticly in multinodular goiter patients with respect to normal thyroid. Immunocytochemical analysis demonstrated that TGF-beta 1 is produced by an autocrine mechanism in the carcinoma and in the benign thyroid disease (multinodular goiter), whereas TGF-beta seems to be produced in adenoma tissues in both an autocrine and a paracrine fashion. This feature further supports the hypothesis that TGF-beta may contribute to regulation of thyrocyte growth and differentiation.