Intensity-modulated arc therapy with cisplatin as neo-adjuvant treatment for primary irresectable cervical cancer. Toxicity, tumour response and outcome.

PURPOSE: The goal of this work was to evaluate the feasibility and outcome of intensity-modulated arc therapy ± cisplatin (IMAT ± C) followed by hysterectomy for locally advanced cervical cancer. PATIENTS AND METHODS: A total of 30 patients were included in the study. The primary tumour and PET-positive lymph node(s) received a simultaneous integrated boost. Four weeks after IMAT ± C treatment, response was evaluated. Resection consisted of hysterectomy with or without lymphadenectomy. Tumour response, acute and late radiation toxicity, postoperative morbidity and outcome were evaluated. RESULTS: All hysterectomy specimens were macroscopically tumour-free with negative resection margins; pathological complete response was 40%. In 2 patients, one resected lymph node was positive. There was no excess in postoperative morbidity. Apart from two grade 3 hematologic toxicities, no grade 3 or 4 acute radiation toxicity was observed. No grade 3, 1 grade 4 (4%) intestinal, and 4 grade 3 (14%) urinary late toxicities were observed. The 2-year local and regional control rates were 96% and 100%, respectively. The 2-year distant control rate was 92%. Actuarial 2-year progression free survival rate was 89%. Actuarial 1- and 2-year overall survival rates were 96% and 91%, while 3-year overall survival was 84%. CONCLUSION: Surgery after IMAT ± C is feasible with low postoperative morbidity and radiation toxicity. Local, regional, distant control and survival rates are promising.

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G(2) assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (P<0.001). Using the 90th percentile of the G(2) scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P=0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (

Intraoperative high-dose-rate brachytherapy (IBT) for locally unresectable intraabdominal malignancy.

PURPOSE: Intraoperative high-dose-rate brachytherapy (IBT) has been successfully used in locally advanced unresectable intraabdominal malignancy. We retrospectively evaluated the safety, feasibility, and general outcome of IBT following cytoreductive surgery. PATIENTS AND METHODS: After radical resection, the target area to be treated by IBT was determined jointly by the surgeon and the radiation oncologist. A silicon template was used to position parallel hollow catheters spaced 1 cm apart against the area of interest. IBT doses were prescribed at 1 cm depth from the template surface and calculated using standard plans. Radiation was administered in a dedicated shielded room. RESULTS: Between August 2001 and February 2006, 10 patients (colorectal cancer n = 6, cervix cancer n = 1, extramedullar plasmocytoma n = 1, liposarcoma n = 1 and sacrococcygeal teratocarcinoma n = 1) were treated. The mean delivered IBT dose was 8 Gy (range 7.5-20). No postoperative mortality was seen, while major complications developed in one (10%) patient with a rectovaginal fistula and intraabdominal abscess. Five of the six colorectal cancer patients developed local recurrence while 3 also developed distant metastases. The mean disease-free and overall survival in this group was 8.5 months (range 4-15) and 25.5 months (range 10-48) respectively. Palliation of symptoms was observed in 89 % of cases. CONCLUSION: IBT combined with debulking surgery is feasible and can be safely performed. While cure is rarely achieved, IBT offers the potential to prolong local control and survival in locally unresectable intraabdominal cancer. Therefore, IBT can be considered as a valuable adjuvant in the therapeutic and palliative armamentarium in these selected patients.

An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer.

The objective of this study was to evaluate the problems with miction, defecation, and sexuality after a radical hysterectomy with or without adjuvant radiotherapy for the treatment of cervical cancer stage I-IIA. This study included an observational longitudinal study of self-reported bladder, defecation, and sexual problems with a baseline score. Ninety-four women were included in the study. An age-matched control group consisted of 224 women. The patients showed significantly more negative effects on sexual function compared with both the controls and their situation before the treatment throughout 24 months of follow-up. The problems included less lubrication, a narrow and short vagina, senseless areas around the labia, dyspareunia, and sexual dissatisfaction. Up to 12 months after the treatment, the patients complained significantly more of little or no urge to urinate and diarrhea as compared with the controls. Adjuvant radiotherapy did not increase the risk of bladder dysfunction, colorectal motility disorders, and sexual functions. We conclude that a radical hysterectomy for the treatment of early-stage cervical carcinoma is associated with adverse effects mainly on sexual functioning.

Phase II study of the combination of pegylated liposomal doxorubicin and topotecan in platinum-resistant ovarian cancer.

The combination of liposomal doxorubicin and topotecan was evaluated in a phase II study in patients with platinum-resistant ovarian cancer. Twenty-seven patients received liposomal doxorubicin (30 mg/m(2)) infused at day 1, followed by topotecan (1 mg/m(2)) infusion daily for 5 days. Cycles were repeated every 21 days. This combination regimen showed an overall response rate of 28%. Median time to progression was 30 weeks, with a median overall survival of 40 weeks. Grade 3/4 neutropenia was shown in 70% of patients and grade 3/4 thrombopenia in 41% of patients. Neutropenic fever was reported in 11% of patients. After reviewing the first 12 patients, the internal review board decided to administer topotecan at a dose of 0.75 mg/m(2) and liposomal doxorubicin at 40 mg/m(2) for the remainder of the study. However, this adjustment did not lead to reduction in bone marrow toxicity nor to an improvement in dose intensity. Palmar-plantar erythrodysesthesia and mucositis were more reported in the second cohort but usually mild. The combination of liposomal doxorubicin and topotecan demonstrates favorable response data in platinum-resistant ovarian cancer. However, substantial bone marrow toxicity limits further clinical use.

Microsatellite polymorphisms in DNA repair genes XRCC1, XRCC3 and XRCC5 in patients with gynecological tumors: association with late clinical radiosensitivity and cancer incidence.

This study investigates the association of microsatellite polymorphisms in XRCC1, XRCC3 and XRCC5 with the development of late radiation-induced radiotherapy reactions and examines the correlation between these microsatellites and cancer incidence. Sixty-two women with cervical or endometrial cancer treated with radiotherapy were included in the study. According to the CTCAEv3.0 scale, 22 patients showed late adverse radiotherapy reactions (grade 2 or more). PCR on lymphocyte DNA followed by automated fragment analysis was performed to examine the number of tandem repeat units at each locus. No significant association was found between the repeat length at any of the microsatellites in XRCC1, XRCC3 or XRCC5 and the incidence of late radiotherapy complications. Since higher odds ratios (ORs) were found for the rare XRCC1 [AC]11 and [AC]21 repeats (OR = 2.65, P = 0.325 and OR = 8.67, P = 0.093, respectively), the possible involvement of these small and large repeats in clinical radiosensitivity cannot be completely ruled out. When specific numbers of repeats were examined, no significant correlation was found between the microsatellite repeat length in XRCC1 and XRCC5 and cancer incidence. A weak correlation between XRCC3 [AC]16 homozygotes and cancer incidence was found (OR = 2.56, P = 0.055). A large-scale multicenter study of cancer patients with a high number of radiosensitive individuals is needed to clarify the value of rare polymorphic microsatellite repeats in XRCC1 and XRCC3 as a biomarker of clinical radiosensitivity or increased cancer risk.

Pelvic exenteration as treatment of recurrent or advanced gynecologic and urologic cancer.

Pelvic exenteration is used as therapeutic option for advanced or recurrent cancer in the pelvis. We determined the complications of and the survival after pelvic exenteration. The study was performed as a retrospective cohort (n = 62) study from January 1, 1989, until January 1, 2000. Descriptive statistics were used. Survival was estimated according to the Kaplan-Meier life table. The operative mortality was 1.6%. Seventy-five percent of the patients had postoperative complications of which ileus and urinary tract infection were the most common. Late complications occurred in 83% of the patients. Recurrent disease was observed in 38% of the women, whereas 50% had died on January 1, 2000. Five-years disease-free and overall survival were 42% (confidence interval [CI] +/- 14%) and 46% (CI +/- 14%), respectively. Elderly patients (> 70 years old) do not experience more complications. Despite considerable morbidity, pelvic exenteration is a therapeutic option for survival, even for patients of 70 years and older.

Quality of life after pelvic exenteration.

OBJECTIVES: Pelvic exenteration, for gynecological and urological cancer, is an extensive and mutilating procedure. The 5-year survival rate is fairly good (40-60%), but little is known about the long-term quality of life. METHODS: In this retrospective cohort study, the quality of life was assessed using the EORTC QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires. RESULTS: Healthy females and those who underwent pelvic exenteration for a gynecological or urological malignancy reported comparable levels of emotional functioning and general quality of life. More physical, sexual, and social problems were, however, noted after exenteration. Younger patients and patients who underwent total pelvic exenteration had the most difficulty in adapting to daily life, disease, and treatment. They also had a worse body image, and the influence of the operation on their sex life was greater compared to other patient groups of this study. CONCLUSION: Despite the immense effect of pelvic exenteration on physical, sexual, and social functioning, women who underwent this procedure reported similar levels of emotional functioning and general quality of life compared to healthy women. Adaptation and the mechanism of response shift presumably play an important role.

Overall major histocompatibility complex class I expression is not downregulated in cervix cancer, as detected by immunoelectron microscopy.

Downregulation of major histocompatibility complex (MHC) class I molecules in cervix cancer has been proposed as a mechanism for cancer cells to escape immunodetection. By means of light microscopic immunohistochemistry, it has been shown that in 20-70% of cervix cancers MHC class I is downregulated. We have reinvestigated this phenomenon by quantitative immunogold analysis of MHC class I labeling on the plasma membrane of cervix epithelial cells in ten human squamous cancers and ten normal human cervices. We have not found a statistically significant difference in MHC class I expression between normal and cancer cells. The difference with published light microscopic data probably reflects the higher morphologic resolution and quantifiable immunoreactivity of the immunoelectron microscopy.

The value of abdominal CT scans in decision-making during chemotherapy in ovarian cancer.

OBJECTIVE: During chemotherapy of ovarian cancer many CT scans are performed to assess tumor response during treatment. The aim of this study was to determine the value of abdominal CT scan in the decision to continue chemotherapy or not, after the standard six cycles. METHODS: All ovarian cancer patients diagnosed between 1991 and 1997 were retrospectively included in the study. Clinical parameters, surgical results, diagnostic test results, and therapeutic strategies were collected from medical records. With logistic modeling those parameters were chosen that predicted best the chance of receiving additional chemotherapy. The chance of receiving further chemotherapy after six cycles based on these parameters was computed and compared to the chance based on CT scan results in addition to these parameters. Arbitrarily we defined a change of over 20% as meaningful. RESULTS: Eighteen of 50 included patients (36%) received over six cycles of chemotherapy; 29 patients (10%) were at low risk for receiving over six cycles, because they had an optimal debulking surgery and low levels of CA-125 at cycle six. The chance of receiving continued chemotherapy after taking into account positive tumor signs on CT-scan was 22%. This figure further increased to 33% if tumor presence was based on judgment of two CT scans. High-risk patients were patients with suboptimal debulking surgery or patients with an optimal debulking, but high CA-125 levels at cycle six (n = 21). Based on these parameters their chance of receiving additional chemotherapy was 71%, and after taking into account results of one or two CT-scans, the risks increased to 74% and 81%, respectively. CONCLUSION: CT scans are of no value in deciding the number of chemotherapy cycles in the initial treatment for ovarian cancer. They cost a lot of money, can add a lot of confusion, and offer no benefit over results of debulking surgery and CA-125 levels.

Pregnancy after EMA/CO for gestational trophoblastic disease: a report from The Netherlands.

OBJECTIVE: To investigate whether a desire for pregnancy changed after etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA/CO) treatment for gestational trophoblastic disease and whether the incidence of infertility and adverse pregnancy outcome differed from the general population. DESIGN: A cohort study was performed. Data were collected from hospital records and questionnaires. SETTING: The study was carried out in referral hospitals in The Netherlands. POPULATION: All women registered by the Dutch Working Party on Trophoblastic Disease and treated with EMA/CO were included. METHODS: A questionnaire was sent to all surviving patients treated with EMA/CO from 1986 until 1997. Women who underwent a hysterectomy were excluded from the study. MAIN OUTCOME MEASURE: Pregnancy outcome and pregnancy wish after chemotherapy. RESULTS: Fifty patients were treated with EMA/CO. In 86%, a complete remission was achieved. A questionnaire was sent to 33 patients. Response rate was 82% (27/33). After EMA/CO, 18 of the patients experienced a regular menstrual cycle. Three patients had an amenorrhoea. Fourteen patients had a pregnancy wish. Twelve patients conceived; 21 pregnancies occurred. Sixteen pregnancies were term deliveries. Two pregnancies ended in a miscarriage and two congenitally abnormal children were delivered prematurely. CONCLUSION: After EMA/CO, 86% of women with a pregnancy wish achieved pregnancy. However, women can be so anxious about a new pregnancy that they refrain from it. A causative relation between the two congenitally abnormal children and EMA/CO cannot be determined because of the small sample. The rate of miscarriages is not higher than in the general population. We can reassure patients that pregnancy after EMA/CO has a high probability of success and a favourable outcome. To diminish the fear of getting pregnant in some patients, psychosocial care should be considered in addition to medical care.

[Chronic radiation enteritis after irradiation of the lesser pelvis: surgical (im)possibilities]. / Chronische radiatie-enteritis na bestraling op het kleine bekken: chirurgische (on)mogelijkheden.

Three women aged 74, 59 and 36 years, had chronic complaints of abdominal pain, nausea, vomiting and diarrhoea, 1 to 8 years after radiotherapy for pelvic malignancies. Mechanical ileus due to fibrotic adhesions was found to be the cause; all three patients recovered after one or more operations. The prevalence of chronic radiation injury correlates with both radiation factors (volume) and patient characteristics. If possible, tumour recurrence needs to be excluded. Chronic intermittent ileus is the predominant symptom of chronic radiation injury. It often occurs within 2 years, but sometimes as long as 10 to 20 years after radiotherapy. Resection is warranted when short segments are affected. In other cases an intestinal bypass or stoma is the treatment of choice.

Update on the treatment of advanced cervical cancer.

In this review we discuss the most important issues concerning the treatment of advanced cervical cancer. Advances in the treatment of cervical cancer are made slowly, but recently the data from five important randomised studies gave rise to an important change in the standard treatment of this disease. For the new standard in advanced cervical cancer, it is clear that chemotherapy should be added to the radiation regimen for an optimal treatment. However, firm conclusions to which drugs or regimens cannot be drawn at this moment.

Preoperative selection of patients with low-stage endometrial cancer at high risk of pelvic lymph node metastases.

The goal of this study was to determine diagnostic accuracy of preoperative transvaginal sonography (TVS) to assess myometrial infiltration in patients with endometrial cancer and to determine the possibility of preoperatively selecting low-stage endometrial cancer patients at high risk of lymph node metastases. The depth of myometrial infiltration of endometrial cancer was assessed using TVS before or after curettage. Infiltration was classified as superficial if less than half of the myometrium was involved, otherwise it was classified as deep infiltration. Results were compared with the histology results of the definitive specimens. Patients were classified as high risk when they satisfied two of the following three criteria: 60 years of age or older; deep myometrial infiltration; and poorly differentiated or undifferentiated tumor. A total of 93 patients from 11 clinics were analyzed. The mean age was 66.1 years (SD +/- 11.4). The sonography and histology findings were in agreement in 69 of 93 patients. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), of "deep infiltration" by preoperative TVS were 79% (95% CI 0.65-0.93), 72% (95% CI 0.61-0.83), 61% (95% CI 0.46-0.75), and 86% (95% CI 0.76-0.96), respectively. Combining tumor grade and myometrial infiltration in the hysterectomy specimen and age, 30 of 81 patients were classified as high-risk patients. Sensitivity and PPV, specificity, and NPV for preoperative diagnosis of high risk were 80% (95% CI 0.65-0.94) and 88% (95% CI 0.79-0.97), respectively. Preoperative assessment of myometrial tumor infiltration using just TVS is only moderately reliable in endometrial cancer patients. If the results of TVS, however, are combined with the patient's age and the degree of tumor differentiation in curettings, it is possible to preoperatively select endometrial cancer patients with a high risk of pelvic lymph node metastases with sufficient reliability.

Dosimetry of 192Ir sources used for endovascular brachytherapy.

An in-phantom calibration technique for 192Ir sources used for endovascular brachytherapy is presented. Three different source lengths were investigated. The calibration was performed in a solid phantom using a Farmer-type ionization chamber at source to detector distances ranging from 1 cm to 5 cm. The dosimetry protocol for medium-energy x-rays extended with a volume-averaging correction factor was used to convert the chamber reading to dose to water. The air kerma strength of the sources was determined as well. EGS4 Monte Carlo calculations were performed to determine the depth dose distribution at distances ranging from 0.6 mm to 10 cm from the source centre. In this way we were able to convert the absolute dose rate at 1 cm distance to the reference point chosen at 2 mm distance. The Monte Carlo results were confirmed by radiochromic film measurements, performed with a double-exposure technique. The dwell times to deliver a dose of 14 Gy at the reference point were determined and compared with results given by the source supplier (CORDIS). They determined the dwell times from a Sievert integration technique based on the source activity. The results from both methods agreed to within 2% for the 12 sources that were evaluated. A Visual Basic routine that superimposes dose distributions, based on the Monte Carlo calculations and the in-phantom calibration, onto intravascular ultrasound images is presented. This routine can be used as an online treatment planning program.

Treatment of metastatic invasive moles in two husband-side sisters-in-law. Case reports and review of literature.

PURPOSE OF INVESTIGATION: The treatment of "high risk" persistent trophoblastic disease (PTD) consists of poly-chemotherapy. This policy probably will lead to overtreatment of some patients. Also, familiar molar pregnancies through the paternal line are unknown in the literature up till now. METHODS: We describe two cases of "high risk" PTD in two husband-side sisters-in-law, in which poly-chemotherapy was stopped after histology became available and showed invasive metastatic mole. CONCLUSION: It should be stressed that treatment decisions should be made based on the concept of "high" or "low" risk PTD, but if histology becomes available, chemotherapy might be less aggressive in cases of invasive mole. If invasive mole could be familiar through the paternal line remains unclear with the current knowledge of genetics in trophoblastic disease.

Monte Carlo calculations of dose distributions around 32P and 198Au stents for intravascular brachytherapy.

3D dose distributions are calculated for a 32P impregnated stent and a 198Au stent for intravascular brachytherapy with the EGS4 Monte Carlo simulation code. The stents were modeled as a combination of eight helicoidal struts. This allowed investigation of the effect of the stent geometry and the electron absorption in the strut material on the dose distributions. Absorbed dose to water was calculated at radial distances ranging from 50 microm to 5 mm from the stent surface. The dose distributions around the stents are compared to the dose distribution around an intravascular brachy-therapy 192Ir source, also calculated with the EGS4 Monte Carlo code. The dose profiles near the struts show hot spots. At 50 microm distance a peak to valley ratio of 3 for 32P and 6 for 198Au in the dose distribution is obtained. For both the isotopes the inhomogeneities decrease with distance and at a radial depth of 350 microm the effect becomes negligible. The calculations showed the importance of the effect of the absorption in the stent material as this leads to a dose decrease to 67% for the 198Au stent and to 77% for 32P near the stent at a distance of 2 mm from the stent axis. It is concluded that from the dosimetric point of view, the 198Au stent is inferior to the 32P stent and the 192Ir source. Application of the 198Au stent in clinical practice requires further investigation of the importance of the adventitia in the restenosis process, and the tolerance dose of the intima.

In vivo distribution and identification of 11C-activity after injection of [methyl-11C]thymidine in Wistar rats.

UNLABELLED: [Methyl-11C]thymidine and PET offer an in vivo, noninvasive quantitative approach for studying nucleoside uptake in cells on the condition the fraction of [methyl-11C]thymidine (in deoxyribonucleic acid [DNA] or as DNA precursors) versus the total accumulated activity is known. METHODS: In a group of normal (n = 6) and a group of tumor-bearing (n = 3) Wistar rats, the biodistribution of 11C-activity was studied dynamically. In a second group of rats (n = 6), the animals were killed at 20 min postinjection and the organs and tissues of interest (liver, heart, brain, duodenum and tumor) were measured for activity and then homogenized. 11C-activity in each fraction (cell debris, protein/ DNA-fraction, lipids and supernatant) was measured. The supernatant was analyzed by high-performance liquid chromatography (HPLC)-radiochromatography for identification of different 11C-labeled compounds. RESULTS: After venous injection, most of the 11C-activity was rapidly trapped in the liver and in fast-dividing tissue (e.g., duodenum); minor activity was located in the bladder, kidneys, heart and brain. HPLC separation showed that the 11C-activity of the liver tissue consisted of metabolites only. For the duodenum and tumor, at least 55% of the 11C-activity was precipitated in the protein/DNA-fraction and about 60% as DNA precursors (thymidine, 2'-deoxythymidine 5'-monophosphate and 2'-deoxythymidine 5'- triphosphate ) in the supernatant. CONCLUSION: Despite the in vivo metabolism, major 11C-activity in rapidly dividing tissue consists of [methyl-11C]thymidine incorporated in the DNA. Catabolism takes place mainly in the liver where the degradation products are stored. PET quantification data using [methyl-11C] thymidine can give information about thymidine incorporation in DNA and cell proliferation of tumors.