Human papillomavirus status in advanced cervical cancer: predictive and prognostic significance for curative radiation treatment.

Human papillomavirus (HPV) infection plays a major role in oncogenesis of squamous cell carcinoma of the cervix. This study was performed to investigate if HPV status and E2 gene integrity are prognostic parameters for clinical outcome and predictive for radiation response. Forty women with locally advanced cervical cancer treated with curative radiotherapy were analyzed for HPV infection and E2 gene integrity by multiplex polymerase chain reaction. Statistical analyses were performed for overall survival, disease-free survival (DFS), local progression-free survival, and treatment response (clinical complete remission). Twenty-eight (70%) of 40 carcinomas were HPV positive. The only significant factor for a better overall survival, DFS, and local progression-free survival was HPV positivity (P < 0.02, P= 0.02, and P < 0.05, log-rank, respectively). HPV-positive tumors had a significantly better clinical complete remission (67% vs 33%, P= 0.04, Fisher's exact test). An intact E2 gene region showed a trend for a better DFS (P= 0.1, log-rank). This study reveals HPV as an independent prognostic parameter for outcome and radiation response. Integration of the virus genome into host cell DNA might be a molecular target to determine the treatment response of HPV-positive cancers.

Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy.

Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, beta3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of beta3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of beta3-integrin. The impact of immunoreactivity for beta3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. beta3-integrin was expressed in 61% (50 of 82) of the patients. Kaplan-Meier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with beta3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. beta3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.

Introduction of a novel dose saving acquisition mode for the PortalVision aS500 EPID to facilitate on-line patient setup verification.

In external beam radiotherapy, electronic portal imaging becomes more and more an indispensable tool for the verification of the patient setup. For the safe clinical introduction of high dose conformal radiotherapy like intensity modulated radiation therapy, on-line patient setup verification is a prerequisite to ensure that the planned dosimetric coverage of the tumor volume is actually realized in the patient. Since the direction of setup fields often deviates from the direction of the treatment beams, extra dose is delivered to the patient during the acquisition of these portal images which may reach clinical relevance. The aim of this work was to develop a new acquisition mode for the PortalVision aS500 electronic portal imaging device from Varian Medical Systems that allows one to take portal images with reduced dose while keeping good image quality. The new acquisition mode, called RadMode, selectively enables and disables beam pulses during image acquisition allowing one to stop wasting valuable dose during the initial acquisition of "reset frames." Images of excellent quality can be taken with 1 MU only. This low dose per image facilitates daily setup verification with considerably reduced extra dose.

[Results of strontium-yttrium-90 for pterygia]. / Résultat de la thérapie au strontium-yttrium-90 des ptérygions.

MATERIAL AND METHODS: [corrected] In the Institute of Radio-Oncology in Lucerne we reviewed the records of 75 patients with 97 pterygia in a retrospective study. All patients had the same number of fractions (4), the same single fraction dose (1250cGy) and the same total dose (5000cGy). The operation technique used was the bare sclera technique. Patients were treated following three different concepts. The first group was treated prior to the operation, 1 fraction weekly, at least 2 months before operation. The second group was treated postoperatively, also one fraction weekly, immediately after operation. The third group received 2 fractions prior to and 2 fractions following operation. RESULTS: We observed only 2 out of 97 (2%) recurrences in the second group. Because of their clinically inactive behavior these two cases required no further treatment. Three patients showed teleangiectasia as a moderate reaction. As a severe complication we observed one ulcus corneae, which was successfully treated with a lamellar keratoplasty, for a complication rate of 1%. CONCLUSION: Beta irradiation has proved to prevent pterygium recurrence. Severe late complications after excision and B-irradiation may partly be caused by other factors than irradiation alone. But it seems unequivocal that there is a relation with the high single-dose procedure of more than 2200cGy or re-irradiation. Fractionation must therefore be used.

Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma.

BACKGROUND: Epidemiologic evidence points to a connection between viral infection by the human papillomavirus (HPV) and a subgroup of squamous cell carcinoma of the oropharynx. To assess the impact of HPV infection on the response of these tumors toward radiotherapy, the authors retrospectively determined the presence of the virus and the integrity of the viral E2 gene in tumors of patients who have undergone curative irradiation. METHODS: Paraffin embedded biopsies from 99 patients were analyzed for HPV infection and E2 gene integrity by multiplex PCR. The experimental findings were correlated with clinical characteristics, known risk factors, and treatment outcome. RESULTS: Fourteen of 99 tumors were HPV positive (11 HPV16, 1 HPV33, 1 HPV35, and 1 HPV45). Human papillomavirus positivity was closely linked to female gender (odds ratio [OR], 5.75; P = 0.004), age older than 56 years (OR, 7.42; P = 0.012), nonsmokers (OR, 21.33; P = 0.00001), and alcohol abstainers (OR, 5.35; P = 0.012). There was an inverse association with p53 nuclear immunoreactivity (OR, 0.06; P = 0.008). The Kaplan-Meier survival estimates showed a better local control (P = 0.050, log-rank) and a better overall survival (P = 0.046, log-rank) for patients with HPV positive tumors. In the multivariate analysis, HPV positivity remained to be associated with a lower risk of local failure (risk ratio [RR], 0.31; P = 0.048). Four of 11 HPV16 positive tumors had a disrupted E2 gene. Only tumors with a disrupted E2 gene manifested local treatment failure. CONCLUSIONS: Human papillomavirus positivity designates a specific subgroup of oropharyngeal squamous cell carcinomas of the oropharynx that arise preferentially among individuals with no consumption of tobacco and alcohol and that have a favorable outcome attributable to an increased sensitivity toward radiotherapy.

Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer.

Hypoxia has long been recognized as detrimental to the successful treatment of malignant tumors with ionizing radiation. Because hypoxia-inducible factor (HIF)-1alpha plays an essential role in oxygen homeostasis in vitro, we explored the predictive potential of this factor in a cohort of 98 patients with squamous cell cancer of the oropharynx, who were treated by curative radiation therapy. Ninety-four % of the primary tumors showed overexpression of HIF-1alpha, relative to the surrounding tissue, as determined by immunohistochemistry. The degree of HIF-1alpha immunoreactivity correlated inversely with both the rate of complete remission of the primary tumor (odds ratio, 0.33; P = 0.03) and lymph node metastases (odds ratio, 0.34; P = 0.02) as well as with local failure-free survival (risk ratio, 2.15; P = 0.006), disease-free survival (risk ratio, 2.01; P = 0.008), and overall survival (risk ratio, 2.17; P = 0.002). The multivariate analysis revealed the predictive power of HIF-1alpha to be independent of other covariables. We conclude that HIF-1alpha is overexpressed in the vast majority of patients with squamous cell cancer of the oropharynx and that the degree of expression has predictive and prognostic significance in individuals undergoing curative radiation therapy.

Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation.

The activation of cytoplasmic signal transduction pathways by a number of growth factors and their tyrosine-kinase receptors, including hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met, exerts an inhibitory influence on apoptosis induced by ionizing radiation in vitro. The clinical relevance of the aforementioned ligand-receptor pair, of Bcl-xL, which is targeted by HGF/SF/c-met signaling, and of Bcl-2, was assessed by evaluating their predictive and prognostic impact in a cohort of 97 patients with radically irradiated squamous cell cancers of the oropharynx. Immunohistochemical expression of c-met and Bcl-xL was correlated with decreased rates of complete remission of the primary tumor in both the univariate (c-met: P = 0.01; Bcl-xL: P = 0.001) and multivariate analyses. Expression of c-met was, moreover, a significant and independent predictor of impaired local failure-free survival (P = 0.003), disease-free survival (P = 0.003) and overall survival (p = 0.001). Bcl-2 expression was, on the other hand, associated with a favorable outcome, in terms of both local failure-free survival (P = 0.01) and overall survival (P = 0.001). In accordance with in vitro data, c-met and Bcl-xL appear to be involved in the resistance of oropharyngeal cancers to ionizing radiation, and may therefore represent attractive targets for radiosensitization.

[Percutaneous radiotherapy--indications for and differentiation from surgical treatment of metastases]. / Perkutane Radiotherapie-indikatorische Abgrenzung zur chirurgischen Metastasen-behandlung.

One third up to half of the patients treated by the radiation oncologist are referred for palliative radiation therapy because of distant metastases, mostly for painful bone or symptomatic brain metastases. As malignant cells are often disseminating long before diagnosis and therapy of the primary tumor, solitary metastases occur very seldom. A single and good resectable brain metastasis is a well-known indication for surgical intervention, especially at infratentorial location. In spherical metastases below a size of 3 cm stereotaxic radio-surgery can be alternatively considered, especially at paramedian location. Bone metastases need more often a surgical therapy, e.g. an impending or already happened fracture of long hollow bones, or radio-resistent tumors of hands and feet. Surgical therapy of metastatic vertebrae are often demanding enormous efforts and skills. Indications for surgery are osteolytical metastases with potential static problems, highly advanced destruction and most of all symptoms of spinal cord compression. The radiation oncologist is well advised to make sure of the surgeon's partnership in regard to the treatment of metastases.

Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx.

PURPOSE: To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. MATERIALS AND METHODS: 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of x200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. RESULTS: Increasing IMD (range, 54-282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0. 0001; IMD categorical: 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). CONCLUSION: IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.

Carcinoma of the oropharynx: local failure as the decisive parameter for distant metastases and survival.

OBJECTIVE: How important and predictive are clinical parameters and locoregional failure after radical radiotherapy of oropharyngeal carcinomas for the probability of the occurrence of distant metastases? PATIENTS AND METHODS: From 1 August 1990 to 1 October 1998, 139 patients with carcinomas of the oropharynx were treated in a prospective study by radical radiotherapy and evaluated in regard to the clinical parameters reflex-otalgia, predominant structure of tumor growth, T-category, presence of involved lymph nodes, and smoking and drinking habits. Twenty-nine patients received a concomitant chemotherapy. Twenty-five out of 139 patients had a planned neck dissection after completion of radiotherapy. Ten patients received a salvage operation. RESULTS: The median follow up time was 24 months (range, 4 to 74). Two- and 5-year overall survival rates according to Kaplan Meier were 56.1 and 49.6%. The tumors were controlled in 77/139 patients (55%). The therapy failed in 62/139 patients (45%). Both groups, 62 patients with locoregional therapy failure and 77 patients with locoregionally control led tumors, were comparable in regard to performance status (Karnofsky index), age, gender, TNM-categories, histological differentiation, drinking habits, pretherapeutic diagnostics, total dose (Gy), and number of simultaneous chemotherapy cycles. Locoregional tumor control was significantly determined by the parameters reflex-otalgia (p < 0.0078), predominant growth pattern (p < 0.012), T-category (p < 0.03), and smoking (p < 0.0285). The median survival time of patients with locoregional failure is 17 months. At this moment 81% of locoregionally controlled patients are still alive. In 14/62 patients (23%) with locoregional failure, distant metastases were detectable against 4/77 (5%) of locally controlled patients, p < 0.0026. Probability of local control and distant metastases, predominantly pulmonary, reached a plateau after 24 months. CONCLUSIONS: Locoregional tumor control, determined by several clinical parameters, is an important parameter for the probability of the development of distant metastases. Failure of local therapy is caused by the biologic aggressiveness of the tumor.

Long-term evolution of renal function in patients with ovarian cancer after whole abdominal irradiation with or without preceding cisplatin.

BACKGROUND: The upper limit of the natural decline in creatinine clearance is 1 ml/min/year. To define the loss of renal function, we started a long-term assessment of patients with ovarian cancer treated by whole abdominal irradiation (WAI) with preceding cisplatin chemotherapy (CDDP) and second-look laparotomy (SLL). PATIENTS AND METHODS: We analyzed the creatinine clearance over time of 56 patients treated from 1982 to 1988 for ovarian cancer. Thirty-one of 56 patients had received WAI after their initial surgery, and 25 of 56 patients had undergone CDDP therapy followed by SLL, and then WAI after their initial surgery. Median follow-up was 99 months (7-156). Twenty of 56 patients accepted our invitation for additional assessment of tubular function, nine of the 31 patients without CDDP therapy and SLL, and 11 of the 25 patients with CDDP followed by SLL and WAI. Ten of twenty patients had received four to six cycles CDDP, 80 mg/m2/cycle, and one patient nine cycles. The median total dose for each kidney was 1450 cGy (480-1690). RESULTS: The mean creatinine clearance decreased from 84 ml/min to 66 ml/min. Seventy-six percent of the 25 patients who had undergone CDDP therapy, SLL and WAI had declines of more than 1 ml/min/year, 64% of these patients of more than 2 ml/min/year. For the 31 patients who had received WAI after their initial surgery, the corresponding numbers were 71% and 55%, respectively. The tubular function of the 20 patients who had undergone the additional investigations was not impaired. CONCLUSION: The decline in renal function after WAI is more pronounced than in healthy subjects. The treatment with cisplatin and SLL prior to WAI does not seem to contribute to this loss of kidney function.

Lymphadenectomy in high risk endometrial carcinoma stage I and II: no more morbidity and no need for external pelvic radiation.

The objectives of this retrospective study were to analyze the morbidity of surgical staging and to evaluate the omission of external radiotherapy in high-risk patients with stage I and II endometrial carcinoma when the lymph nodes were negative. From 1988 to 1996, 63 of 117 patients underwent a pelvic and periaortic lymphadenectomy. The decision to perform lymphadenectomy was influenced by patient general health. Patients with lymphadenectomy had a better physical status (P < 0.0001). Lymphadenectomy increased mean operative time (P < 0.0001) and blood loss (P < 0.01), but there was no increase in postoperative complications. At a median follow-up of 54 months, there was one cuff recurrence in 56 patients. Nineteen high-risk patients without external pelvic radiation had the same disease-free survival rate as 37 low-risk patients (P = 0.1). In the group without lymphadenectomy, the disease-free survival for 18 high-risk patients and 32 low-risk patients was similar (P = 0.21). Surgical staging in properly selected patients does not increase postoperative complications and brachytherapy without external radiotherapy is associated with excellent disease-free survival when the lymph nodes are negative.

[Breast carcinoma--breast preservation as a therapeutic principle]. / Mammakarzinom--Brusterhaltung als therapeutisches Prinzip.

Today there is no justification for a groundless mastectomy instead a breast conserving treatment for an invasive carcinoma of the breast. There is no oncologically based argument against breast conserving treatment in case of a resectable breast cancer. The literature concerning this subject has been able to demonstrate in many randomized, controlled studies that a mastectomy is not superior compared to a conserving treatment in terms of recurrence and survival. The engagement for conserving treatment does not exclude indications for reconstruction surgery and mastectomy, but it is essential that the advising physician knows the scientific data and that patients are informed accordingly.

[Radiotherapy of rectal carcinoma]. / Strahlentherapie beim Rektumkarzinom.

Approximately 2% of the Swiss population will develop rectal carcinoma during their lifetime. Most important prognostic factors are TNM category and quality of the surgical procedure. In advanced rectal carcinoma postoperative combined radio-chemotherapy reduces the rate of local recurrence by at least 50 percent and leads to a survival benefit of ca. 10-20%. However, preoperative radiotherapy (+/- chemotherapy) should be the treatment of choice as an adjunct to surgery, especially in cases of deep seated or fixed carcinomas. Intraoperative RT represents a promising modality in situations where a histologically complete excision of the tumor seems impossible.

[Target volume and indications of radiotherapy in breast carcinoma]. / Zielvolumen und Indikation der Strahlentherapie des Mammakarzinoms.

Breast-conserving surgery is now commonly used to treat breast cancer. While mastectomy has been the traditional treatment for ductal carcinoma in situ, it is felt to be excessive in most cases. A great effort has been made to identify pathobiological characteristics of DCIS that can be used to identify patients best suited for wide local excision vs. wide local excision and breast irradiation. Mastectomy and conservative surgery plus irradiation offer a similar outcome in patients with early stage invasive breast cancer. Radiotherapy has not been shown to improve survival but is able to reduce significantly the rate of local recurrence, which is regarded as a very undesirable outcome. There is still controversy concerning the necessity of irradiation of the breast in all patients. Analysis of predictors of outcome cannot identify a subgroup of patients with a very low risk for local breast recurrence who might not require radiation therapy. In premenopausal, node-positive breast cancer patients XRT has a beneficial effect not only on locoregional but also on systemic recurrences. Radiotherapy has to be integrated for a pre- or postoperative consolidation in new treatment concepts for locally advanced breast cancer which use primary chemotherapy and immediate or subsequent breast radiation. Radiation of internal mammary chain and supraclavicular fossa after conservative surgery does not lead to an increase in clinically important skin or pulmonary complications. Its role is being evaluated in current multicentre studies.

[Predictive significance of reflex otalgia in local radical radiotherapy of oropharyngeal carcinomas]. / Prädiktive Bedeutung der Reflexotalgie in der lokal radikalen Radiotherapie von Oropharynxkarzinomen.

BACKGROUND: Patients with carcinomas of the upper aero-digestive tract often suffer from ear pain as a tumor associated syndrome. This prospective study examines the predictive and prognostic value of this symptom. PATIENTS AND METHODS: Ninety-six consecutive patients who completed a locally radiotherapy of a carcinoma of the oropharynx were prospectively evaluated and followed. Forty-nine out of 96 patients stated the symptom, either spontaneously or after questioning. The 2 groups showed no difference regarding TNM-classification, histology and total dose. Overall survival, local control and disease specific survival were calculated according to Kaplan-Meier and compared by the log-rank test. RESULTS: A clinically complete remission was obtained in significantly fewer patients with reflex-otalgia as compared to patients without reflex-otalgia, 61.2% versus 89.3%, p < 0.002. Local control of patients with reflex-otalgia was significantly less with 49%, mean follow-up 564 days, in comparison to local control in patients without reflex-otalgia, mean follow-up 613 days, p = 0.01. Disease specific survival was significantly worse for patients with reflex-otalgia, p < 0.012. The probability of local control of T1/T2 tumors with reflex-otalgia was similar to T3/T4 tumors without reflex-otalgia. Local control for all tumor categories combined is 74% for patients without reflex-otalgia versus 49% for patients with reflex-otalgia. CONCLUSION: In our patients, reflex-otalgia is a new and statistically significant parameter for the probability of local control and disease specific survival.

No predictive value of the micronucleus assay for patients with severe acute reaction of normal tissue after radiotherapy.

In approximately 5% of cancer patients undergoing radiotherapy, this treatment has to be interrupted because of an acute reaction of normal tissues. To test the possibility of predicting this type of reaction, the micronucleus assay was used to determine radiosensitivities of peripheral blood lymphocytes of 15 patients with severe acute reaction of normal tissue, 15 patients without this reaction and 15 healthy donors. Whole-blood cultures were irradiated with X-rays (4 Gy, 1.08 Gy/min) and treated with cytochalasin B. The micronuclei scores observed in irradiated cells were corrected for the scores in unirradiated cells. Intra-individual and interindividual variations in micronuclei scores were analysed in samples from healthy donors, and highly significant interindividual differences were found (P < 0.001). Scores of cells not irradiated in vitro were higher for cancer patients before radiotherapy than for healthy donors (P < 0.001), and those for cancer patients after radiotherapy were higher than for patients before radiotherapy (P < 0.001). Average micronuclei scores induced by in vitro irradiation were significantly higher in samples from cancer patients compared with those from healthy donors (P < 0.01). Moreover, all subgroups of cancer patients included individuals with very high levels of micronuclei after in vitro irradiation. There was, however, no relationship between the micronuclei scores and the occurrence of severe acute reactions in normal tissues.