Microcystic elongated and fragmented (MELF) pattern of invasion: Molecular features and prognostic significance in the PORTEC-1 and -2 trials.

OBJECTIVE: Microcystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of MELF invasion was uncertain due to conflicting data, and it had not yet appropriately been studied in the context of the molecular EC classification. We aimed to determine the relation of MELF invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early-stage low/intermediate risk EC. METHODS: Single whole tumor slides of 979 (85.8%) out of 1141 (high)intermediate-risk EC of women who participated in the PORTEC-1/-2 trials were available for review. Clinicopathological and molecular features were compared between MELF invasion positive and negative cases. Time-to-event analyses were done by Kaplan-Meier method, log-rank tests and Cox' proportional hazards models. RESULTS: MELF invasion was found in 128 (13.1%) cases, and associated with grade 1-2 histology, deep myometrial invasion and substantial lymph-vascular space invasion (LVSI). 85.6% of MELF invasion positive tumors were no-specific-molecular-profile (NSMP) EC. NSMP EC with MELF invasion were CTNNB1 wild type in 92.2% and KRAS mutated in 24.4% of cases. Risk of recurrence was lower for MELF invasion positive as compared to MELF invasion negative cases (4.9% vs. 12.7%, p = 0.026). However, MELF invasion had no independent impact on risk of recurrence (HR 0.65, p = 0.30) after correction for clinicopathological and molecular factors. CONCLUSIONS: MELF invasion has no independent impact on risk of recurrence in early-stage EC, and is frequently observed in low-grade NSMP tumors. Routine assessment of MELF invasion has no clinical implications and is not recommended.

The role of multimodal adjuvant therapy for FIGO I-II carcinosarcoma of the uterus: a systematic review.

The uterine carcinosarcoma (UCS) is a rare entity with poor prognosis. Treatment of FIGO I-II UCS usually consists of surgery with or without adjuvant treatment. Due to the high metastatic potential, aggressive combined modality adjuvant treatment approaches, consisting of chemo- and radiotherapy, have been of interest. Our systematic review aims to compare survival, disease control and toxicity profiles in patients receiving adjuvant chemoradiation to other adjuvant strategies (e.g.observation, chemotherapy or radiotherapy). A total of ten studies were included for a combined cohort size of 6520 patients. Generally, the studies showed a trend towards improved disease control and survival in patients undergoing adjuvant multimodal treatment, although statistical significance was often not reached. Selection bias and non-randomized treatment allocation pose serious challenges to extrapolate these outcomes to clinical practice. We recommend additional prospective research on the role of adjuvant chemoradiation in FIGO I-II UCS.

Brachytherapy treatment verification using gamma radiation from the internal treatment source combined with an imaging panel-a phantom study.

Brachytherapy has an excellent clinical outcome for different treatment sites. However,in vivotreatment verification is not performed in the majority of hospitals due to the lack of proper monitoring systems. This study investigates the use of an imaging panel (IP) and the photons emitted by a high dose rate (HDR)192Ir source to track source motion and obtain some information related to the patient anatomy. The feasibility of this approach was studied by monitoring the treatment delivery to a 3D printed phantom that mimicks a prostate patient. A 3D printed phantom was designed with a template for needle insertion, a cavity ('rectum') to insert an ultrasound probe, and lateral cavities used to place tissue-equivalent materials. CT images were acquired to create HDR192Ir treatment plans with a range of dwell times, interdwell distances and needle arrangements. Treatment delivery was verified with an IP placed at several positions around the phantom using radiopaque markers on the outer surface to register acquired IP images with the planning CT. All dwell positions were identified using acquisition times ≤0.11 s (frame rates ≥ 9 fps). Interdwell distances and dwell positions (in relation to the IP) were verified with accuracy better than 0.1 cm. Radiopaque markers were visible in the acquired images and could be used for registration with CT images. Uncertainties for image registration (IP and planning CT) between 0.1 and 0.4 cm. The IP is sensitive to tissue-mimicking insert composition and showed phantom boundaries that could be used to improve treatment verification. The IP provided sufficient time and spatial resolution for real-time source tracking and allows for the registration of the planning CT and IP images. The results obtained in this study indicate that several treatment errors could be detected including swapped catheters, incorrect dwell times and dwell positions.

Brachytherapy quality assurance in the PORTEC-4a trial for molecular-integrated risk profile guided adjuvant treatment of endometrial cancer.

OBJECTIVE: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence. METHODS: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist. RESULTS: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length. CONCLUSIONS: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes.

Decision Support Systems in Prostate Cancer Treatment: An Overview.

BACKGROUND: A multifactorial decision support system (mDSS) is a tool designed to improve the clinical decision-making process, while using clinical inputs for an individual patient to generate case-specific advice. The study provides an overview of the literature to analyze current available mDSS focused on prostate cancer (PCa), in order to better understand the availability of decision support tools as well as where the current literature is lacking. METHODS: We performed a MEDLINE literature search in July 2018. We divided the included studies into different sections: diagnostic, which aids in detection or staging of PCa; treatment, supporting the decision between treatment modalities; and patient, which focusses on informing the patient. We manually screened and excluded studies that did not contain an mDSS concerning prostate cancer and study proposals. RESULTS: Our search resulted in twelve diagnostic mDSS; six treatment mDSS; two patient mDSS; and eight papers that could improve mDSS. CONCLUSIONS: Diagnosis mDSS is well represented in the literature as well as treatment mDSS considering external-beam radiotherapy; however, there is a lack of mDSS for other treatment modalities. The development of patient decision aids is a new field of research, and few successes have been made for PCa patients. These tools can improve personalized medicine but need to overcome a number of difficulties to be successful and require more research.

The Effect of the Time Interval Between Radiation and Hyperthermia on Clinical Outcome in 400 Locally Advanced Cervical Carcinoma Patients.

Background: Addition of deep hyperthermia to radiotherapy results in improved local control (LC) and overall survival compared to radiotherapy alone in cervical carcinoma patients. Based on preclinical data, the time interval between radiotherapy, and hyperthermia is expected to influence treatment outcome. Clinical studies addressing the effect of time interval are sparse. The repercussions for clinical applications are substantial, as the time between radiotherapy and hyperthermia should be kept as short as possible. In this study, we therefore investigated the effect of the time interval between radiotherapy and hyperthermia on treatment outcome. Methods: We analyzed all primary cervical carcinoma patients treated between 1996 and 2016 with thermoradiotherapy at our institute. Data on patients, tumors and treatments were collected, including the thermal dose parameters TRISE and CEM43T90. Follow-up data on tumor status and survival as well as late toxicity were collected. Data was analyzed using Cox proportional hazards analysis and Kaplan Meier analysis. Results: 400 patients were included. Kaplan Meier and univariate Cox analysis showed no effect of the time interval (range 30-230 min) on any clinical outcome measure. Besides known prognostic factors, thermal dose parameters TRISE and CEM43T90 had a significant effect on LC. In multivariate analysis, the thermal dose parameter TRISE (HR 0.649; 95% CI 0.501-0.840) and the use of image guided brachytherapy (HR 0.432; 95% CI 0.214-0.972), but not the time interval, were significant predictors of LC and disease specific survival. Conclusions: The time interval between radiotherapy and hyperthermia, up to 4 h, has no effect on clinical outcome. These results are re-ensuring for our current practice of delivering hyperthermia within maximal 4 h after radiotherapy.

Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy.

BACKGROUND: PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis. METHODS: 427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis. RESULTS: Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors. CONCLUSION: Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial.

OBJECTIVE: The Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-4a trial is a randomized trial for women with high-intermediate risk endometrial cancer (EC), comparing individualized adjuvant treatment based on a molecular-integrated risk profile to standard adjuvant treatment; vaginal brachytherapy. To evaluate patient acceptability and pathology logistics of determining the risk profile, a pilot phase was included in the study. METHODS: PORTEC-4a is ongoing and the first 50 patients enrolled were included in the pilot phase. Primary endpoints of the pilot phase were patient acceptance, evaluated by analyzing the screening logs of the participating centers, and logistical feasibility of determination of the risk profile within 2 weeks, evaluated by analyzing the pathology database. RESULTS: In the first year, 145 eligible women were informed about the trial at 13 centers, of whom 50 (35%) provided informed consent. Patient accrual ranged from 0 to 57% per center. Most common reasons for not participating were: not willing to participate in any trial (43.2%) and not willing to risk receiving no adjuvant treatment (32.6%). Analysis of the pathology database showed an average time between randomization and determination of the molecular-integrated risk profile of 10.2 days (1-23 days). In 5 of the 32 patients (15.6%), pathology review took >2 weeks. CONCLUSIONS: The PORTEC-4a trial design was proven feasible with a satisfactory patient acceptance rate and an optimized workflow of the determination of the molecular-integrated risk profile. PORTEC-4a is the first randomized trial to investigate use of a molecular-integrated risk profile to determine adjuvant treatment in EC.

Positron emission tomography-magnetic resonance imaging (PET-MRI) for response assessment after radiation therapy of cervical carcinoma: a pilot study.

BACKGROUND: Advanced stage cervical cancer is primarily treated by radiotherapy. Local tumor control is a prerequisite for cure. Imaging after treatment is controversial. Positron emission tomography (PET) combined with computer tomography (PET-CT) shows great promise for detecting metastases. On the other hand, magnetic resonance imaging (MRI) is superior in depicting anatomical details. The combination of PET-MRI could result in more accurate evaluation of cervical cancer treatment outcome. The aim of this pilot study is to share our initial experience with PET-MRI in the evaluation of treatment response in cervical cancer after radiation treatment. METHODS: Ten patients with cervical carcinoma (FIGO ≥IB2) were prospectively evaluated. Eleven weeks (median; range 8-15 weeks) after radiation therapy, treatment response was evaluated by PET-MRI. The PET, MRI, and combined PET-MRI images were evaluated for the presence of local residual tumor and metastasis. Diagnostic performance was assessed by area under the receiver operator characteristic (ROC) curve for evaluation of local residual tumor. The readers were blinded for outcome data. Local residual disease, metastasis, diagnostic confidence, and change of opinion were scored on a 5-point Likert scale. The reference standard consisted of pathology and/or follow-up according to the clinical guidelines. RESULTS: Three out of ten patients had local residual abnormalities suggestive for tumor residue after radiation treatment. The availability of both PET and MRI resulted in an increase in diagnostic confidence in 80-90% of all patients. Change of opinion was observed in 70% and change of policy in 50%, especially in the group with residual tumor. The diagnostic accuracy increased significantly for the radiologist if PET-MRI was combined (AUC .54 versus .83). CONCLUSIONS: PET-MRI shows promise for evaluation of treatment response after radiation for cervical cancer, especially increasing diagnostic confidence, while potentially increasing diagnostic performance.

Dynamics of rectal balloon implant shrinkage in prostate VMAT : Influence on anorectal dose and late rectal complication risk.

PURPOSE: To assess the effect of a shrinking rectal balloon implant (RBI) on the anorectal dose and complication risk during the course of moderately hypofractionated prostate radiotherapy. METHODS: In 15 patients with localized prostate cancer, an RBI was implanted. A weekly kilovolt cone-beam computed tomography (CBCT) scan was acquired to measure the dynamics of RBI volume and prostate-rectum separation. The absolute anorectal volume encompassed by the 2 Gy equieffective 75 Gy isodose (V75Gy) was recalculated as well as the mean anorectal dose. The increase in estimated risk of grade 2-3 late rectal bleeding (LRB) between the start and end of treatment was predicted using nomograms. The observed acute and late toxicities were evaluated. RESULTS: A significant shrinkage of RBI volumes was observed, with an average volume of 70.4% of baseline at the end of the treatment. Although the prostate-rectum separation significantly decreased over time, it remained at least 1 cm. No significant increase in V75Gy of the anorectum was observed, except in one patient whose RBI had completely deflated in the third week of treatment. No correlation between mean anorectal dose and balloon deflation was found. The increase in predicted LRB risk was not significant, except in the one patient whose RBI completely deflated. The observed toxicities confirmed these findings. CONCLUSIONS: Despite significant decrease in RBI volume the high-dose rectal volume and the predicted LRB risk were unaffected due to a persistent spacing between the prostate and the anterior rectal wall.

Consecutive magnetic resonance imaging during brachytherapy for cervical carcinoma: predictive value of volume measurements with respect to persistent disease and prognosis.

BACKGROUND: Cervical cancer is associated with a high yearly mortality. The presence of persistent disease after radiotherapy is a significant predictor of patient survival. The aim of our study was to assess if tumor volume regression measured with MR imaging at the time of brachytherapy can discriminate between patients who eventually will achieve a complete response to radiotherapy from those who will not. The second objective was to evaluate whether tumor volume regression predicts overall treatment failure. METHODS: MRI was evaluated quantitatively in 35 patients; by means of tumor volumetry on T2-weighted MR images before treatment, at the first BCT application, and at the final BCT. The MR images were independently analyzed by two investigators. As a reference standard histopathologic confirmation of residual tumor and/or clinical exam during follow-up > 1 year were used. Area under the curve were compared, P-values <0.05 were considered significant. RESULTS: There was a good correlation between volume measurements made by the two observers. A residual tumor volume >9.4 cm(3) at final BCT and tumor volume regression < 77 % of the pre-treatment volume were significantly associated with local residual tumor after completion of therapy (p < 0.02) (AUC, 0.98-1.00). A volume >2.8 cm(3) at final BCT was associated with overall treatment failure (p < 0.03). CONCLUSION: Our study shows that volume analysis during BCT is a predictive tool for local tumor response and overall treatment outcome. The potential of local response assessment to identify patients at high risk of overall treatment failure is promising.

Treatment preferences and involvement in treatment decision making of patients with endometrial cancer and clinicians.

BACKGROUND: Vaginal brachytherapy (VBT) in high-intermediate-risk endometrial cancer (EC) provides a significant reduction in the risk of local cancer recurrence, but without survival benefit and with increased mucosal atrophy. Five-year local control is estimated to be similar for VBT and a watchful waiting policy (WWP), in which patients receive VBT combined with external radiation in case of a recurrence. Our aim was to assess treatment preferences of EC patients and clinicians regarding VBT and WWP, and to evaluate their preferred and perceived involvement in treatment decision making. METHODS: Interviews were held with 95 treated EC patients. The treatment trade-off method was used to assess the minimally desired benefit from VBT in local control. Patients' preferred and perceived involvement in decision making were assessed using a questionnaire. Seventy-seven clinicians completed a questionnaire assessing their minimally desired benefit and preferred involvement in decision making. RESULTS: Minimally desired benefit of VBT was significantly lower for patients than for clinicians (median=0 vs 8%, P<0.001), for irradiated than for non-irradiated patients (median=0 vs 6.5%, P<0.001), and for radiation oncologists than for gynaecologists (median=4 vs 13%, P<0.001). Substantial variation existed within the groups of patients and clinicians. Participants preferred the patient and clinician to share in the decision about VBT. However, irradiated patients indicated low perceived involvement in actual treatment decision making. CONCLUSIONS: We found variations between and within patients and clinicians in minimally desired benefit from VBT. However, the recurrence risk at which patients preferred VBT was low. Our results showed that patients consider active participation in decision making essential.

Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.

BACKGROUND: After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. METHODS: In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. FINDINGS: At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17-3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for VBT and 2.1% (0.8-5.8) for EBRT (HR 2.08, 0.71-6.09; p=0.17). 1.5% (0.5-4.5) versus 0.5% (0.1-3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32-29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1-13.4] vs 5.7% [3.3-9.9]; HR 1.32, 0.63-2.74; p=0.46). We recorded no differences in overall (84.8% [95% CI 79.3-90.3] vs 79.6% [71.2-88.0]; HR 1.17, 0.69-1.98; p=0.57) or disease-free survival (82.7% [76.9-88.6] vs 78.1% [69.7-86.5]; HR 1.09, 0.66-1.78; p=0.74). Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215] vs 53.8% [112/208]). INTERPRETATION: VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. FUNDING: Dutch Cancer Society.

Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model.

Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and nonmalignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To combine these requirements, we have developed a nonmyeloablative conditioning regimen, consisting of low-dose total body irradiation and cyclophosphamide-based chemotherapy. In a haploidentical F1 --> F1 mouse model, this nonmyeloablative transplantation protocol resulted in stable full donor chimerism, but also in the development of severe GVHD. Administration of keratinocyte growth factor (KGF) reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis, compared to saline-treated controls. KGF preserved plasma citrulline and tumor necrosis factor-alpha levels, both indicative for reduced injury to the gastrointestinal tract. This was confirmed by histological findings. At 6 months after transplantation, survival rates were significantly higher in KGF-treated animals as compared to phosphate buffered saline-treated controls. These results indicate that KGF preserves gut integrity and might therefore contribute substantially to reduction of lethal GVHD in (nonmyeloablative) haploidentical transplantation.

Citrulline: a potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy.

We noted a significant decline in the serum concentrations of citrulline of 32 haematopoietic stem cell transplant recipients following intensive myeloablative therapy during the first 3 weeks after transplantation when patients have oral mucositis, a markedly disturbed gut integrity (L/R ratio) and are most at risk of infection and other severe complications. Closer inspection of the citrulline concentrations of 12 patients confirmed that the decline did indeed correspond to the onset of oral mucositis and altered gut integrity. Since serum citrulline is a reliable biochemical marker of small bowel enterocyte mass in humans with villous-atrophy-associated diseases, it may prove a useful marker for intestinal mucosal damage induced by chemotherapy, allowing the relationship between gut mucosal damage and post-transplant complications including infections to be explored more readily.

Age-specific differences in treatment and survival of patients with cervical cancer in the southeast of The Netherlands, 1986-1996.

Age at diagnosis has been proven to be an important determinant of the choice of initial treatment for several sites of cancer. Elderly patients are more likely to receive no treatment or less intensive treatment modalities. This study analysed the influence of age on treatment choice and survival in patients diagnosed with cervical cancer. This population-based study used data on 1176 new cases of invasive cervical cancer diagnosed in the period of 1986-1996 from three regional cancer registries in the Netherlands. All available information on treatment and survival (on 1 January 1998) was recorded. Relative survival rates were calculated according to the Hakulinen method. Relative risks (RR) for excess mortality due to the diagnosis of cervical cancer were calculated with a regression model for relative survival rates. Only 5% of the patients aged 70 years and older (n=224) were diagnosed with stage IA disease, compared with 11 and 30% of the patients aged 50-69 years and 49 years and younger, respectively. Almost 50% of the 70+ patients with stage IB-IIA were treated with radiotherapy as a single treatment modality, whereas 64% of the patients aged < or =49 years were treated with surgery alone. In all age groups, treatment for advanced stage disease (stage > or =IIB) was radiotherapy alone. No treatment was given to 10% of the patients aged 70 years and older, 5% of those aged 50-69 years and 1% of those aged 49 years and younger. Five-year relative survival was 69% (95% Confidence Interval (CI): 66-72%) and differed significantly (P=0.001) with age (70+ years: 49%; 50-69 years 58%; < or =49 years: 81%). Multivariate analyses on a subset of patients showed that age was not an independent prognostic factor, whereas stage and treatment modality were very important prognostic factors. Although elderly cancer patients were sometimes treated differently from younger patients, this was in accordance with the guidelines. Relative survival rates differed significantly by age. The multivariate analyses on the subset of patients also revealed that excess mortality increased with age. However, when adjustment was made for stage and treatment, this difference disappeared. The influence of treatment on survival is likely to be due to the selection of patients based on other characteristics, such as tumour volume, comorbidity and performance status.

Point-counterpoint: what is the optimal trial design to test hyperthermia for carcinoma of the cervix? Point: addition of hyperthermia or cisplatin to radiotherapy for patients with cervical cancer; two promising combinations--no definite conclusions.

Randomized trials have shown that results of radiotherapy in patients with cervical cancer can be improved by combining the treatment with either cisplatin based chemotherapy, or hyperthermia. The studies on both the combination of radiotherapy with chemotherapy, and the combination on radiotherapy with hyperthermia, leave several important questions unanswered. At present, no definite conclusions can be drawn with regard to which combination results in the best therapeutic ratio. Therefore, on both ethical and scientific grounds, the next logical step would be to compare the two types of combined treatment to each other, and each combination with a treatment including all three modalities, in a randomized fashion.

The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial.

PURPOSE: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. METHODS AND MATERIALS: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French-Italian glossary. RESULTS: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1-4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3-4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1-2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06). CONCLUSION: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.

Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation?

Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma.

BACKGROUND: Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma. METHODS: Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints. FINDINGS: Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors. INTERPRETATION: Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.