Elisabeth Pras

Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer

Randomised studies in locally advanced cervical cancer patients showed that cisplatin should be given concurrently with radiotherapy, because of a better long-term survival compared to radiotherapy alone. This increases the relevance of treatment related toxicity. This review summarises the acute and long-term toxicity of radiotherapy given with or without chemotherapy for cervical cancer. Acute toxicity (all grades) of radiotherapy is reported in 61% of the patients in the rectosigmoid, in 27% as urological, in 27% as skin and in 20% as gynaecological toxicity. Moderate and severe morbidity consists of 5% to 7% gastrointestinal and 1% to 4% genitourinary toxicity. Adding chemotherapy to radiotherapy increases acute haematological toxicity to 5% to 37% of the patients and nausea and vomiting in 12% to 14%. Late effects of radiotherapy include gastrointestinal, urological, female reproductive tract, skeletal and vascular toxicity, secondary malignancies and quality of life issues. For at least 20 years after treatment, new side effects may develop. Gastrointestinal toxicity usually occurs in the first 2 years after treatment in about 10% of the patients. The incidence of moderate and severe urological toxicity can increase up to 10% and rises over time. Gynaecological toxicity usually occurs shortly after treatment while skeletal and vascular toxicity can occur years to decades later. Thus far, no increase in late toxicity has been observed after the addition of cisplatin to radiotherapy. Finally, methods to prevent or decrease late toxicity and therapeutical options are discussed. However, most randomised studies still have a limited follow-up period.

Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for Endometrial Carcinoma

PURPOSE To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. PATIENTS AND METHODS The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. RESULTS 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). CONCLUSIONS The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.

Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer

Purpose: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients. Experimental Design: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays. Results: EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014). Conclusions: EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials. (Clin Cancer Res 2009;15(23):7389–97)

MLH1 and MSH2 protein expression as a pre‐screening marker in hereditary and non‐hereditary endometrial hyperplasia and cancer

The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non‐polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (II) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non‐malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin‐embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI‐low and 12 MSI‐high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC‐related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Immunohistochemical pre‐screening of the MLH1 and MSH2 proteins in endometrial hyperplasia or cancer can thus be helpful in HNPCC families. Frequent loss of MLH1 or MSH2 protein in endometrial hyperplasia indicates that this loss is an early event in endometrial carcinogenesis.

Prognostic Cell Biological Markers in Cervical Cancer Patients Primarily Treated With (Chemo)radiation: A Systematic Review

The aim of this study was to systematically review the prognostic and predictive significance of cell biological markers in cervical cancer patients primarily treated with (chemo)radiation. A PubMed, Embase, and Cochrane literature search was performed. Studies describing a relation between a cell biological marker and survival in ≥50 cervical cancer patients primarily treated with (chemo)radiation were selected. Study quality was assessed, and studies with a quality score of 4 or lower were excluded. Cell biological markers were clustered on biological function, and the prognostic and predictive significance of these markers was described. In total, 42 studies concerning 82 cell biological markers were included in this systematic review. In addition to cyclooxygenase-2 (COX-2) and serum squamous cell carcinoma antigen (SCC-ag) levels, markers associated with poor prognosis were involved in epidermal growth factor receptor (EGFR) signaling (EGFR and C-erbB-2) and in angiogenesis and hypoxia (carbonic anhydrase 9 and hypoxia-inducible factor-1α). Epidermal growth factor receptor and C-erbB-2 were also associated with poor response to (chemo)radiation. In conclusion, EGFR signaling is associated with poor prognosis and response to therapy in cervical cancer patients primarily treated with (chemo)radiation, whereas markers involved in angiogenesis and hypoxia, COX-2, and serum SCC-ag levels are associated with a poor prognosis. Therefore, targeting these pathways in combination with chemoradiation may improve survival in advanced-stage cervical cancer patients.

Current concepts about testicular cancer

In the past 20 years, testicular cancer, which occurs in the young, has become a curable malignancy; 90% of the patients treated will achieve long-term survival. However, there is a significant morbidity associated with the management of the disease process. The literature was reviewed concerning the current treatment strategies and prognosis, as well as the long-term sequelae of the various diagnostic and therapeutic procedures. Surveillance has become a key element in the management of patients with a primary (stage I) testicular non-seminoma. Although approximately 25% of these patients will relapse, 100% survival can be achieved with cisplatin in combination with etoposide and bleomycin (BEP). Patients with a disseminated non-seminoma are usually treated with 4 courses of BEP; an 80% survival rate can be achieved. The long-term effects of chemotherapy include Raynauds phenomenon, acral paraesthesia, hyperlipidaemia, nephrotoxicity, infertility and hormonal disturbances. Retroperitoneal lymph node dissection or resection of residual disease following chemotherapy are associated with a low mortality and morbidity rate, ejaculatory dysfunction excepted. However, with specific modifications in technique (e.g. nerve-sparing) antegrade ejaculation can be preserved in the majority of patients. Radiotherapy is used in stage I and II seminoma. With the conventional dose of 25–30 Gy to the retroperitoneal and ipsilateral iliac lymph nodes, temporary dysfunction of the germ and Leydig cells of the remaining testis may occur by scatter radiation. Patients with advanced seminoma are treated with cisplatin-based chemotherapy. To date, testicular cancer patients can receive appropriate curative treatment with acceptable acute toxicity, depending on the therapy given. The detrimental effects of late toxicities require careful study and follow-up. However, little attention is paid currently to quality of life aspects, in particular the impact of the disease and its treatment on general well-being, including sexual function.

Serum squamous cell carcinoma antigen and CYFRA 21-1 in cervical cancer treatment

PURPOSE To analyze whether serum squamous cell carcinoma (SCC) antigen and cytokeratin-19 fragments (CYFRA) levels can assist in selecting patients with locally advanced cervical cancer who will benefit from combined treatment or additive surgery. METHODS AND MATERIALS Of 114 patients with cervical cancer Stage IB-IV, the first 39 patients received radiotherapy, the following 75 patients received identical radiotherapy plus concomitant chemotherapy (3 cycles of carboplatin and 5-fluorouracil). SCC antigen and CYFRA 21-1 serum levels were measured before treatment, after therapy, and during follow-up. Baseline tumor markers were related to tumor stage and size and clinical outcome. RESULTS Before treatment, SCC antigen was elevated (>1.9 microg/L) in 60% and CYFRA 21-1 (>2.2 microg/L) in 46% of patients. For all patients, disease-free survival (DFS) was better after combined treatment (67% vs. 43%, p < 0.0005). For patients with elevated baseline SCC antigen, DFS was better after combination therapy (67% vs. 27%, p = 0.001) which resulted more frequently in a normal SCC antigen (93% vs. 65%, p = 0.004). In contrast, in those with a normal baseline CYFRA 21-1, combined therapy resulted in a better DFS (p = 0.04). Patients who achieved a normal SCC antigen or CYFRA 21-1 after treatment had a better DFS (respectively 63 vs. 17% and 64 vs. 30%). Elevated SCC antigen posttreatment indicated residual tumor in 11/12 patients (92%), elevated CYFRA 21-1 in 7/10 patients (70%). Forty-seven patients had a tumor recurrence. At recurrence, SCC antigen was raised in 70% and CYFRA 21-1 in 69%. CONCLUSIONS In patients with an elevated pretreatment SCC antigen, SCC antigen normalized more frequently with combined treatment and those patients had a better DFS. Elevated SCC antigen or CYFRA 21-1 levels after treatment completion indicated residual tumor in respectively 92% and 70%. The presence of elevated posttreatment levels of SCC antigen or CYFRA 21-1 indicates the need for additional salvage surgery. SCC antigen proved to be superior to CYFRA 21-1 in predicting DFS and disease recurrence.

THE CLINICAL VALUE OF SQUAMOUS CELL CARCINOMA ANTIGEN IN CANCER OF THE UTERINE CERVIX

A review is given of the clinical use and interpretation of serum tumor marker levels during the treatment of patients with cancer of the uterine cervix. Pretreatment serum squamous cell carcinoma (SCC) antigen provides a new prognostic factor in early stage squamous cell carcinoma of the uterine cervix. Elevated serum values of SCC antigen at the time of diagnosis of stage IB and IIA cervical cancer indicate a 3 × increased risk of tumor recurrence, independent of tumor diameter, grade or the presence of lymph node metastases. High pretreatment SCC antigen levels could therefore be used to select ‘high-risk’ patients for adjuvant therapy. Measurement of the serum SCC antigen levels provides a means of monitoring the effect of therapy. During the postoperative follow-up of patients with localized cancer of the uterine cervix the measurement of SCC antigen can lead to the early detection of recurrent disease when curative therapy is still an option. The profile of serum SCC antigen parallels the response to radiotherapy and provides a way of evaluating the effectiveness of chemotherapy. Serial measurements after surgery and during radio- and chemotherapy demonstrate that SCC antigen is a more sensitive marker for recognizing tumor progression or recurrence than CYFRA-21.1, TPS or CEA. When following up patients with a pure adenocarcinoma of the cervix measurements of serum CA 125 and CEA are preferred over SCC antigen measurements.

Radiation-Induced Sarcoma: A Challenge for the Surgeon

BackgroundTreatment of radiation-induced sarcoma (RIS) remains an unsolved problem. To provide more insight into the disease process, its characteristics, outcome, and potential outcome determinants were defined.MethodsFrom 1978 to 2003, 27 patients—20 females (74%) and 7 males (26%) with a median age 44 years (range, 1–73 years) at the time of diagnosis of the primary tumor—developed an RIS after a median interval of 8 years (range, 3–41 years). The histology of the RIS was 10 (37%) undifferentiated high-grade pleomorphic sarcomas, 7 (26%) angiosarcomas, 6 (22%) fibrosarcomas, 2 (7%) osteosarcomas, 1 (4%) pleomorphic rhabdomyosarcoma, and 1 (4%) pleomorphic leiomyosarcoma. Surgical resection was performed in 21 patients: 13 (62%) R0 (microscopically radical), 4 (19%) R1 (microscopically irradical), 2 (9.5%) R2 (macroscopically irradical), and 2 (9.5%) RX (unknown radicality). Six (22%) patients underwent no resection.ResultsThe 5-year disease-free and overall survival rates were 27% and 30%, respectively. The local failure rate after R0 resection was 54%. The distant failure rate for the entire group was 41%. Patients with an R0 resection had a significantly better survival rate (P < .05) than patients with an R1, R2, or no resection.ConclusionsRISs are aggressive malignancies with a high tendency for local recurrence and distant metastases. Previously applied treatment often hampers adequate resection. Therefore, radical surgical resection is the only chance to improve disease-free and overall survival, but it may also have a palliative role. Still, the overall prognosis remains poor.

Isolated limb perfusion with tumor necrosis factor α and melphalan for locally advanced soft tissue sarcoma : The value of adjuvant radiotherapy

BackgroundThe aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor α and melphalan followed by limb-saving surgery.MethodsFrom 1991 to 2003, 73 patients (median age, 54 years; range, 14–80 years) underwent 77 ILPs, followed by resection in 68 patients (93%). Radiotherapy was administered in case of marginally or microscopically positive resection margins. Local recurrences were scored and calculated according to the Kaplan-Meier method and log-rank test.ResultsAfter residual tumor mass resection, 58% received radiotherapy (external beam radiotherapy [EBRT]+ group), and 42% did not (EBRT− group). The median follow-up was 28 months (range, 2–159 months). A significantly better local control rate was observed in the EBRT+ compared with the EBRT− group (P < .0001). When only R0 resections in patients without metastasis were considered, the significance remained between groups (P = .0003). In the EBRT− group, an R1 or R2 resection resulted in earlier relapse of local disease compared with R0 resections (P = .0475).ConclusionsAdjuvant EBRT reduces the risk for local recurrence after delayed resection in soft tissue sarcoma patients treated with ILP and tumor necrosis factor and is indicated when resection margins are close or microscopically positive. It also seems beneficial after an R0 resection.