Amin Makar

Surgery for borderline tumor of the ovary.

The five-year survival for women with Stage I borderline tumors is about 95% to 97%, but because of late recurrence the 10-year survival is only 70% to 95%. The five-year survival for Stage II-III patients is 65% to 87%. A more correct staging procedure, classification of true serous implants, and agreement on how the presence of gelatinous ascites in mucinous tumors contributes to cancer stage might change the distribution of stage and survival data by stage for women with borderline tumors in the future. Independent prognostic factors for patients with borderline tumors without residual tumor after primary surgery are: DNA ploidy, morphometry, International Federation of Gynecology and Obstetrics (FIGO) stage, histologic type, and age. Different types of surgery and chemotherapy were not independent prognostic factors. Questions which should be addressed include the following: 1) Have patients with borderline tumors been over treated in general, and how should these patients be treated? 2) In which group of patients is fertility-sparing surgery advisable? 3) Do patients with borderline tumors benefit from adjuvant treatment? And 4) How is the high-risk patient defined?

Polymorphisms in nonhomologous end‐joining genes associated with breast cancer risk and chromosomal radiosensitivity

As enhanced chromosomal radiosensitivity (CRS) results from non‐ or misrepaired double strand breaks (DSBs) and is a hallmark for breast cancer and single nucleotide polymorphisms (SNPs) in DSB repair genes, such as non homologous end‐joining (NHEJ) genes, could be involved in CRS and genetic predisposition to breast cancer. In this study, we investigated the association of five SNPs in three different NHEJ genes with breast cancer in a population‐based case‐control setting. The total patient population composed of a selected group of patients with a family history of the disease and an unselected group, consisting mainly of sporadic cases. SNP analysis showed that the c.2099‐2408G>A SNP (XRCC6) has a significant, positive odds ratio (OR) of 2.81 (95% confidence interval (CI): 1.30–6.05) for the heterozygous (He) and homozygous variant (HV) genotypes in the selected patient group. For the c.‐1310 C>G SNP (XRCC5) a significant OR of 1.85 (95%CI: 1.01–3.41) was found for the He genotype in the unselected patient group. On the contrary, the HV genotype of c.1781G>T (XRCC5) displays a significant, negative OR of 0.43 (95%CI: 0.18–0.99) in the total patient population. The He+HV genotypes of the c.2099‐2408G>A SNP (XRCC6) also showed high and significant ORs in the group of “radiosensitive,” familial breast cancer patients. In conclusion, our results provide preliminary evidence that the variant allele of c.‐1310C>G (XRCC5) and c.2099‐2408G>A (XRCC6) are risk alleles for breast cancer as well as CRS. The HV genotype of c.1781G>T (XRCC5) on the contrary, seems to protect against breast cancer and ionizing radiation induced micronuclei.

Intensity-Modulated Arc Therapy with Simultaneous Integrated Boost in the Treatment of Primary Irresectable Cervical Cancer

Purpose:To report on the planning procedure, quality control, and clinical implementation of intensity-modulated arc therapy (IMAT) delivering a simultaneous integrated boost (SIB) in patients with primary irresectable cervix carcinoma.Patients and Methods:Six patients underwent PET-CT (positron emission tomography-computed tomography) and MRI (magnetic resonance imaging) before treatment planning. Prescription (25 fractions) was(1) a median dose (D50) of 62, 58 and 56 Gy to the primary tumor (GTV_cervix), primary clinical target volume (CTV_cervix) and its planning target volume (PTV_cervix), respectively;(2) a D50 of 60 Gy to the PET-positive lymph nodes (GTV_nodes);(3) a minimal dose (D98) of 45 Gy to the planning target volume of the elective lymph nodes (PTV_nodes).IMAT plans were generated using an anatomy-based exclusion tool with the aid of weight and leaf position optimization. The dosimetric delivery of IMAT was validated preclinically using radiochromic film dosimetry.Results:Five to nine arcs were needed to create valid IMAT plans. Dose constraints on D50 were not met in two patients (both GTV_cervix: 1 Gy and 3 Gy less). D98 for PTV_nodes was not met in three patients (1 Gy each). Film dosimetry showed excellent gamma evaluation. There were no treatment interruptions.Conclusion:IMAT allows delivering an SIB to the macroscopic tumor without compromising the dose to the elective lymph nodes or the organs at risk. The clinical implementation is feasible.Ziel:Evaluation einer intensitätsmodulierten Rotationsbestrahlung (IMAT) mit Applikation eines simultanen integrierten Boosts (SIB) zur primären Behandlung des fortgeschrittenen Zervixkarzinoms.Patienten und Methodik:Sechs Patientinnen mit einem fortgeschrittenen Zervixkarzinom wurden einer MRT- (Magnetresonanztomographie) und PET-CT-basierten (Positronenemissionstomographie-Computertomographie) Bestrahlungsplanung für eine IMAT unterzogen und bestrahlt. Das Dosis-Zeit-Muster wurde, bezogen auf die entsprechenden Zielvolumina für 25 Fraktionen, wie folgt festgelegt:1. Eine mediane Dosis (D50) von 62 Gy, 58 Gy und 56 Gy wurde für das makroskopische Zervixkarzinom (GTV), das klinische Zielvolumen (CTV) und das Planungszielvolumen (PTV) verschrieben.2. Eine mediane Dosis von 60 Gy wurde für die PET-positiven regionären Lymphknoten festgelegt.3. Elektiv zu bestrahlende regionäre Lymphknoten sollten eine minimale Dosis (D98) von 45 Gy erhalten.Die IMAT-Pläne wurden mit Hilfe eines anatomiebasierten Ausschlussalgorithmus durch Optimierung und Wichtung von Leafpositionen erzeugt. Die präklinische Dosimetrie erfolgte mittels Filmdosimetrie.Ergebnisse:Insgesamt fünf bis neun Rotationsfelder waren zur Erzeugung geeigneter IMAT-Pläne erforderlich. Bei zwei Patientinnen war die angestrebte Dosis für das makroskopische Zervixkarzinom (GTV) 1 Gy und 3 Gy zu niedrig. In drei Fällen wurde die minimale Dosis (D98) an den elektiv zu behandelnden Lymphknoten um je 1 Gy unterschritten. Die Daten der Filmdosimetrie zeigten eine ausgezeichnete Gammabewertung. Die Bestrahlung konnte in allen Fällen ohne Unterbrechung appliziert werden.Schlussfolgerung:Die klinische Umsetzung der IMAT mit SIB des Zervixkarzinoms ist ohne Dosiskompromisse an elektiven Lymphknotenstationen und Risikoorganen möglich.

Fertility preservation in gynecologic cancer

Subject. Management of patients with gynecologic cancer can now often be tailored to the extent of the disease and preservation of child‐bearing ability and/or sexual function may be possible for certain women with early invasive disease.

Probiotics enhance the clearance of human papillomavirus-related cervical lesions: a prospective controlled pilot study

Probiotics have been proposed for a number of urogenital infectious conditions. In this study, we examine a possible effect on human papillomavirus (HPV)-related precancerous lesions in cervical cytology. We conducted a prospective controlled pilot study, in which 54 women with an HPV+low-grade squamous intraepithelial lesion diagnosis in their PAP smear were followed for 6 months. The intervention group consumed a daily probiotic drink during the study period; the control group received no treatment, according to common care policy. Outcome measures were the control PAP smear and HPV status after 6 months. Probiotic users had a twice as high chance of clearance of cytological abnormalities (60 vs. 31%, P=0.05). HPV was cleared in 19% of control patients versus 29% of probiotic users (P=0.41). This exploratory pilot study suggests that the probiotic studied promotes the clearance of HPV-related cytological abnormalities. If confirmed, this would represent an entirely new option to manage cervical cancer precursors.

Epidemiological and Economic Impact of Human Papillomavirus Vaccines

Background: Despite screening, cervical cancer (CC) remains a serious health care problem. Because human papillomavirus (HPV) is the necessary cause of CC, the development of 2 new vaccines can have a tremendous impact on CC and other HPV-related conditions. In this systematic review, the epidemiological and economic impacts of HPV are evaluated. Methods: A literature search was conducted through MEDLINE, Web of Science, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature. Articles were selected based on inclusion and exclusion criteria. Economic evaluations were submitted to a quality assessment. Results: Sixteen articles were selected to review the epidemiological impact of HPV vaccines, and 11 were selected to review the economic impact. The studies were very heterogeneous because of different assumptions. Nevertheless, a substantial reduction in CC is reported consistently and a (smaller) reduction in precancerous lesions and HPV prevalence. Cost-effectiveness ratios are also very diverse and dependent on the assumptions made. An HPV vaccine can be profitable if duration of vaccine-related immunity is high, efficacy is high, price is low, screening is reduced, administration is before sexual activity, discount rate is not too high, or if there is herd immunity. Conclusions: Human papillomavirus vaccines have the potential to reduce CC by at least approximately half of its current incidence, and this might be cost-effective if there is high efficacy with a long-lasting immunity.

Postoperative Intensity-Modulated Arc Therapy for Cervical and Endometrial Cancer: A Prospective Report on Toxicity

PURPOSE To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). METHODS AND MATERIALS Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m(2), weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. RESULTS Regarding acute toxicity (n = 65), Grade 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of EC patients experienced Grade 2 fatigue and skin toxicity, respectively. Adding cisplatin led to an increase in Grade >2 nausea (57% vs. 9%; p = 0.01), Grade 2 nocturia (24% vs. 4%; p = 0.03), Grade ≥ 2 hematologic toxicity (38% vs. nil, p = 0.003), Grade ≥ 2 leukopenia (33% vs. nil, p = 0.009), and a strong trend toward more fatigue (14% vs. 2%; p = 0.05). Para-aortic lymph node irradiation led to an increase of Grade 2 nocturia (31% vs. 4%, p = 0.008) and a strong trend toward more Grade >2 nausea (44% vs. 18%; p = 0.052). Regarding late toxicity (n = 45), no Grade 3 or 4 late toxicity occurred. Grade 2 gastrointestinal toxicity, genitourinary toxicity, and fatigue occurred in 4%, 9%, and 1% of patients. Neither concomitant cisplatin nor PALN irradiation increased late toxicity rates. CONCLUSIONS Postoperative IMAT for EC or CC is associated with low acute and late toxicity. Concomitant chemotherapy and PALN irradiation influences acute but not late toxicity.

Sentinel node procedures in gynecologic cancers: an overview

The aim of this study was to assess the value of sentinel lymph node procedures in gynecologic cancers. A systematic literature overview, using the PubMed database, was performed. In early stage vulvar, endometrial and cervical cancer, lymph node status is the most important prognostic factor. Lymphadenectomy, performed for adequate staging, is associated with high morbidity rates. Sentinel node procedures hold the promise of adequate staging with less treatment‐related morbidity. Sentinel lymph node procedures in patients with early‐stage vulvar cancer are associated with low recurrence rates, excellent survival, lower morbidity and shorter hospital stay compared to classical inguinal dissection. Therefore, these procedures should be the standard of care in early‐stage unilateral vulvar cancer. Reports on sentinel lymph node procedures in endometrial and cervical cancer are ambiguous. The procedures in these cancers are reported in small studies only. Detection rates vary depending on the used injection sites and the used tracers. Bilateral detection rates are low and are not mentioned by default. Large controlled multi‐institutional studies are necessary to evaluate the validity and the prognostic significance of the sentinel lymph node procedures in endometrial and cervical cancer.

Whole Abdominopelvic Radiotherapy Using Intensity-Modulated Arc Therapy in the Palliative Treatment of Chemotherapy-Resistant Ovarian Cancer With Bulky Peritoneal Disease: A Single-Institution Experience

PURPOSE To retrospectively review our experience with whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy in the palliative treatment of chemotherapy-resistant ovarian cancer with bulky peritoneal disease. METHODS AND MATERIALS Between April 2002 and April 2008, 13 patients were treated with WAPRT using intensity-modulated arc therapy. We prescribed a dose of 33 Gy to be delivered in 22 fractions of 1.5 Gy to the abdomen and pelvis. All patients had International Federation of Gynecology and Obstetrics Stage III or IV ovarian cancer at the initial diagnosis. At referral, the median age was 61 years, and the patients had been heavily pretreated with surgery and chemotherapy. All patients had symptoms from their disease, including gastrointestinal obstruction or subobstruction in 6, minor gastrointestinal symptoms in 2, pain in 4, ascites in 1, and vaginal bleeding in 2. A complete symptom or biochemical response required complete resolution of the patients symptoms or cancer antigen-125 level. A partial response required ≥50% resolution of these parameters. The actuarial survival was calculated from the start of radiotherapy. RESULTS The median overall survival was 21 weeks, with a 6-month overall survival rate of 45%. The 9 patients who completed treatment obtained a complete symptom response, except for ascites (partial response). The median and mean response duration (all symptoms grouped) was 24 and 37 weeks, respectively. Of the 6 patients presenting with obstruction or subobstruction, 4 obtained a complete symptom response (median duration, 16 weeks). CONCLUSION WAPRT delivered using intensity-modulated arc therapy offers important palliation in the case of peritoneal metastatic ovarian cancer. WAPRT resolved intestinal obstruction for a substantial period.

Completion surgery after intensity-modulated arc therapy in the treatment of locally advanced cervical cancer: feasibility, surgical outcome, and oncologic results.

Introduction Since the addition of chemotherapy to radiotherapy, the survival rates of locally advanced cervical cancer (LACC) have improved but are still disappointing. Therefore, the idea of surgery after chemoradiation in case of LACC or bulky disease was adopted. One of the concerns regarding surgery following chemoradiotherapy is surgery-related morbidity. Aim The objectives of this study were to investigate the feasibility of surgery after advanced radiotherapy techniques such as intensity-modulated arc therapy (IMAT) and to describe the morbidity. Methods This was a prospective study of primary inoperable LACC patients primary treated with IMAT, in most cases combined with weekly cisplatin. Then the resectability was reevaluated. If resectable patients were treated with Wertheim type 2 surgery ± pelvic lymphadenectomy (on positron emission tomography–computed tomography indication). If tumor is not resectable, patients were treated with brachytherapy. Results Since 2006, 41 consecutive patients were included. After neoadjuvant IMAT, 34 were considered resectable and underwent surgery, whereas 7 proceeded with brachytherapy. The operative mortality rate was nil. There were no major perioperative complications. No ureter, bladder, or bowel injuries occurred. No postoperative urinary/digestive fistulae or stenoses were noted. Eleven patients had postoperatively urinary retention problems. At the time of discharge, 5 patients still needed self-catheterization. All problems resolved within 3 months. In 4 cases, we saw significant lymphoceles. In all patients intended to treat, overall survival and disease-free survival at 3 years were 63% and 74%. In the Wertheim group, overall survival and disease-free survival at 3 years were 81% and 91%. Conclusions Completing surgery after chemoradiation therapy (with IMAT) for LACC or bulky disease is feasible, and complication rates are comparable with those of primary surgery for cervical cancer.