Search

OBJECTIVE: To evaluate recurrence patterns and overall survival in patients treated with adju- vant radiation after surgical staging for Stage II endometrial carcinoma. Secondary goals include identification of prognostic factors for recurrence and toxicity assessment. METHODS/MATERIALS: The medical records of 41 patients treated with adjuvant radiotherapy at Washington University School of Medicine after surgical staging for endometrial cancer (total abdominal hysterectomy and bilateral salpingo-oophorectomy, peritoneal cytology, lymph node dissection) were reviewed. Nineteen were treated with a combination of external beam radiotherapy and vaginal brachytherapy (VB), and 22 patients were treated with postoperative VB alone. Median followup for all patients was 41 months. RESULTS: Median patient age was 59 years (range, 42e87 years). All tumors were of endome- trioid histology. There were 20 Grade 1 tumors, 13 Grade 2 tumors, and 8 Grade 3 tumors. For all patients, the 5-year overall survival was 69.8%, and the 5-year recurrence-free survival was 89.0%. There was no statistically significant difference in overall survival (p 5 0.510) or freedom from vaginal (p 5 0.840), distant (p 5 0.133), or any recurrence (p 5 0.275) with respect to modality of treatment (external beam radiotherapy and VB vs. VB alone). There were no pelvic lymph node recurrences. In the univariate analysis, there were no risk factors influencing overall survival or re- currences. One patient experienced a toxicity requiring hospital admission. She was treated with pelvic external beam radiation plus brachytherapy. CONCLUSIONS: VB alone results in excellent local control for patients with Stage II endome- trial cancer after surgical staging. Long-term toxicities are rare and more common in the group of patients who were treated with pelvic external beam plus brachytherapy. 2015 American Brachy

Purpose To evaluate outpatient-based high-dose-rate (HDR) interstitial brachytherapy (ISBT) in the treatment of gynecologic malignancies. Methods and Materials Between December 2006 and July 2012, 50 patients were treated with twice-daily outpatient-based HDR iridium-192 ISBT at our institution. Thirty-two patients had vaginal cancers, 13 vulvar, 3 urethral, and 2 cervical cancers. The most common histologies were squamous cell carcinoma (58%) and endometrioid adenocarcinoma (26%). Twenty-six patients were treated with definitive radiation therapy with or without platinum-based chemotherapy, 16 were treated for recurrent disease, 5 were treated in the postoperative setting, and 3 were treated palliatively. Forty patients received external beam radiation therapy before ISBT. Results Median followup was 13.7 months. Median interstitial dose was 18 Gy in 2.25 Gy twice-daily fractions prescribed to the implant volume. Median external beam dose was 50.4 Gy in 1.8 Gy daily fractions prescribed to the primary disease site. Eight patients (16%) were seen in the emergency room or were admitted to the hospital during treatment. Six patients (17%) experienced significant complications after treatment (3 ulcerations at the primary site, 1 vaginal necrosis, 1 vaginal abscess, and 1 patient with urinary obstruction). Larger volume encompassing 100% of the prescribed dose was correlated with significant complications on multivariate analysis ( p = 0.039). Actuarial local control at 1 year was 72%, with univariate analysis demonstrating worse local control for nonendometrioid adenocarcinoma compared with squamous cell carcinoma (20% vs. 84%, p = 0.044). Conclusions Outpatient-based HDR ISBT is feasible and safe, with toxicity and local control rates consistent with historical outcomes.

Background PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability. Experimental Design Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233*) were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206) with or without the glucose analogue 2-deoxyglucose (2-DG). Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay. Results Activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) and MK-2206 (30 µM-49%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment. Conclusions The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.

Curative Radiation Therapy for Locally Advanced Cervical Cancer: Brachytherapy Is NOT Optional Kari Tanderup, PhD,*,y Patricia J. Eifel, MD,z Catheryn M. Yashar, MD,x Richard Potter, MD,k and Perry W. Grigsby, MD* *Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; yDepartment of Oncology, Aarhus University Hospital, Aarhus, Denmark; zDepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; xDepartment of Radiation Oncology, University of California, San Diego, La Jolla, California; and kDepartment of Radiotherapy and Oncology, Comprehensive Cancer Center and Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna, Austria

Purpose: The purpose of this study was to evaluate the late toxicity and efficacy of twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. Patients and Methods: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and lumbar para-aortic lymph nodes (simultaneously) at 4–6-h intervals, 5 days per week. The total external radiation doses were 24–48 Gy to the whole pelvis, 12–36 Gy parametrial boost, and 48 Gy to the lumbar para-aortic region with an additional boost to a total dose 54–58 Gy to the positive para-aortic lymph node(s). One or two intracavitary implants were performed to deliver a minimum total dose of 85 Gy to point A. Cisplatin (75 mg/m 2 ; Days 1, 22, and 43) and 5-fluorouracil (1,000 mg/m 2 /24 h × 4 consecutive days, beginning on Days 1, 22, and 43) were given for two or three cycles. Results: Thirty patients with clinical Stages I–IV carcinoma of the cervix with biopsy-proven para-aortic lymph node metastases were enrolled in this study. Hyperfractionated external irradiation was completed in 87% (26 of 30). Brachytherapy was given in two implants to 47% (14 of 30) and in one implant to 33% (10 of 30); 13% (4 of 30) did not receive brachytherapy, 1 patient had three implants, and 1 had five high-dose-rate implants. Radiotherapy was completed per protocol in 70%. Three cycles of chemotherapy were given to 23% (7 of 30); 73% (22 of 30) received two cycles, and 1 patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Acute toxicity from radiotherapy was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. Late toxicity was Grade 1 in 10%, Grade 2 in 17%, Grade 3 in 7%, and Grade 4 in 17%. Grade 5 toxicity occurred in 1 patient during the course of therapy, but none had a late Grade 5 toxicity. The median follow-up time for the 7 patients alive at the time of last follow-up was 57 months. The overall survival estimates were 46% at 2 years and 29% at 4 years. The probability of local-regional failure was 40% at 1 year and 50% at 2 and 3 years. The probability of disease failure at any site was 46% at 1 year, 60% at 2 years, and 63% at 3 years. Conclusion: The results suggest that twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (17%, 5 of 29) of Grade 4 late toxicity. One patient died of acute complications of therapy. The survival estimates seem no better than standard fractionation irradiation without chemotherapy.

Purpose: To demonstrate that high-dimensional voxel-to-voxel transformations, derived from continuum mechanics models of the underlying pelvic tissues, can be used to register computed tomography (CT) serial examinations into a single anatomic frame of reference for cumulative dose calculations. Methods and Materials: Three patients with locally advanced cervix cancer were treated with CT-compatible intracavitary (ICT) applicators. Each patient underwent five volumetric CT examinations: before initiating treatment, and immediately before and after the first and second ICT insertions, respectively. Each serial examination was rigidly registered to the patient’s first ICT examination by aligning the bony anatomy. Detailed nonrigid alignment for organs (or targets) of interest was subsequently achieved by deforming the CT exams as a viscous-fluid, described by the Navier-Stokes equation, until the coincidence with the corresponding targets on CT image was maximized. In cases where ICT insertion induced very large and topologically complex rearrangements of pelvic organs, e.g., extreme uterine canal reorientation following tandem insertion, a viscous-fluid-landmark transformation was used to produce an initial registration. Results: For all three patients, reasonable registrations for organs (or targets) of interest were achieved. Fluid-landmark initialization was required in 4 of the 11 registrations. Relative to the best rigid bony landmark alignment, the viscous-fluid registration resulted in average soft-tissue displacements from 2.8 to 28.1 mm, and improved organ coincidence from the range of 5.2% to 72.2% to the range of 90.6% to 100%. Compared to the viscous-fluid transformation, global registration of bony anatomy mismatched 5% or more of the contoured organ volumes by 15–25 mm. Conclusion: Pelvic soft-tissue structures undergo large deformations and displacements during the external-beam and multiple-ICT course of radiation therapy for locally advanced cervix cancer. These changes cannot be modeled by the conventional rigid landmark transformation method. In the current study, we found that the deformable anatomic template registration method, based on continuum-mechanics models of deformation, successfully described these large anatomic shape changes before and after ICT. These promising modeling results indicate that realistic registration of the cumulative dose distribution to the organs (or targets) of interest for radiation therapy of cervical cancers is achievable.

The emergent use of combined modality approach (chemotherapy and radiation therapy) for the treatment of patients with cervical cancer is associated with significant gastrointestinal and genitourinary toxicity. Intensity-modulated radiation therapy (IMRT) has the potential to deliver adequate dose to the target structures while sparing the normal organs and could also allow for dose escalation to grossly enlarged metastatic lymph node in pelvic or para-aortic area without increasing gastrointestinal/genitourinary complications. We conducted a dosimetric analysis to determine if IMRT can meet these objectives in the treatment of cervical cancer.Computed tomography scan studies of 10 patients with cervical cancer were retrieved and used as anatomic references for planning. Upon the completion of target and critical structure delineation, the imaging and contour data were transferred to both an IMRT planning system (Corvus, Nomos) and a three-dimensional planning system (Focus, CMS) on which IMRT as well as conventional planning with two- and four-field techniques were derived. Treatment planning was done on these two systems with uniform prescription, 45 Gy in 25 fractions to the uterus, the cervix, and the pelvic and para-aortic lymph nodes. Normalization was done to all IMRT plans to obtain a full coverage of the cervix with the 95% isodose curve. Dose-volume histograms were obtained for all the plans. A Student's t test was performed to compute the statistical significance.The volume of small bowel receiving the prescribed dose (45 Gy) with IMRT technique was as follows: four fields, 11.01 +/- 5.67%; seven fields, 15.05 +/- 6.76%; and nine fields, 13.56 +/- 5.30%. These were all significantly better than with two-field (35.58 +/- 13.84%) and four-field (34.24 +/- 17.82%) conventional techniques (p0.05). The fraction of rectal volume receiving a dose greater than the prescribed dose was as follows: four fields, 8.55 +/- 4.64%; seven fields, 6.37 +/- 5.19%; nine fields, 3.34 +/- 3.0%; in contrast to 84.01 +/- 18.37% with two-field and 46.37 +/- 24.97% with four-field conventional technique (p0.001). The fractional volume of bladder receiving the prescribed dose and higher was as follows: four fields, 30.29 +/- 4.64%; seven fields, 31.66 +/- 8.26%; and nine fields, 26.91 +/- 5.57%. It was significantly worse with the two-field (92.89 +/- 35.26%) and with the four-field (60.48 +/- 31.80%) techniques (p0.05).In this dosimetric study, we demonstrated that with similar target coverage, normal tissue sparing is superior with IMRT in the treatment of cervical cancer.

After the logic of evidence-based medicine, there are several conclusions to be reached from these recent prospective, randomized phase III clinical trials. Patients with stages IB2 and IIA cervical carcinoma, although technically manageable, should be treated with external pelvic irradiation and brachytherapy and weekly (cisplatin 40 mg/m2 x 6 wk), if it is suspected that the likelihood of positive lymph nodes or margins requiring adjuvant treatment after radical surgery would be significant. In those patients in whom the risks of either positive margins or lymph nodes are low, either radical surgery or radiation are equally efficacious options. A recent report that surveyed the Surveillance, Epidemiology, and End Results program database suggested that there may be a survival advantage for surgical intent-to-treat patients compared with the radiation intent-to-treat patients for tumors 4 cm or smaller in patients with stage IB and IIA cervical cancers. Certainly, toxicity criteria for these patients in terms of long-term problems need to be further examined. For those patients who undergo a radical hysterectomy and lymph node dissection, postoperative irradiation is indicated if high-risk factors such as large tumor size, lymph vascular space invasion, and deep stromal invasion are identified. Patients who are found to have positive lymph nodes, positive parametrial invasion, or positive margins at the time of hysterectomy should receive postoperative irradiation with chemotherapy. All other patients with more advanced clinical stages of cervical carcinoma should be treated with external pelvic irradiation, brachytherapy, and concurrent chemotherapy. Based on the results of the randomized studies, there appears to be no role for either hydroxyurea or fluorouracil. The chemotherapy agent of choice, at present, is cisplatin administered concurrently with irradiation at a dose of 40 mg/m2 weekly for 6 weeks. Concurrent chemotherapy should be avoided in patients with a poor performance status and other severe comorbidities, and these patients should be treated with irradiation alone. Further refinement of treatment for those patients who require combined chemo/radiation versus those with comorbidities such that combination chemotherapy is actually too toxic must be defined.

PURPOSE: The aim of this study was to compare the results of computed tomography (CT) and positron emission tomography (PET) with [18F]-fluoro-2-deoxy-d-glucose (FDG) for lymph node staging in patients with carcinoma of the cervix and to evaluate the relationship of the imaging findings to prognosis. PATIENTS AND METHODS: We retrospectively compared the results of CT lymph node staging and whole-body FDG-PET in 101 consecutive patients with carcinoma of the cervix. Patients were treated with standard irradiation and chemotherapy (as clinically indicated) and observed at 3-month intervals for a median of 15.4 months (range, 2.5 to 30 months). Progression-free survival was evaluated by the Kaplan-Meier method. RESULTS: CT demonstrated abnormally enlarged pelvic lymph nodes in 20 (20%) and para-aortic lymph nodes in seven (7%) of the 101 patients. PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67 (67%), in para-aortic lymph nodes in 21 (21%), and in supraclavicular lymph node in eight (8%). The 2-year progression-free survival, based solely on para-aortic lymph node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (P < .0001). A multivariate analysis demonstrated that the most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes as detected by PET imaging (P = .025). CONCLUSION: This study demonstrates that FDG-PET detects abnormal lymph node regions more often than does CT and that the findings on PET are a better predictor of survival than those of CT in patients with carcinoma of the cervix.

Purpose: To ( 1 ) measure radiation therapy costs for patients in randomized controlled clinical trials, ( 2 ) compare measured costs to modeling predictions, ( 3 ) examine cost distributions, and ( 4 ) assess feasibility of collecting economic data within a cooperative group. Methods: The Radiation Therapy Oncology Group conducted economic pilot studies for two Phase III studies that compared fractionation patterns. Expected quantities of Current Procedural Terminology (CPT) codes and relative value units (RVU) were modeled. Institutions retrospectively provided procedure codes, quantities, and components, which were converted to RVUs used for Medicare payments. Cases were included if the radiation therapy quality control review judged them to have been treated per protocol or with minor variation. Cases were excluded if economic quality review found incomplete economic data. Results: The median and mean RVUs were within the range predicted by the model for all arms of one study and above the predicted range for the other study. Conclusion: The model predicted resource use well for patients who completed treatment per protocol. Actual economic data can be collected for critical cost items. Some institutions experienced difficulty collecting retrospective data, and prospective collection of data is likely to allow wider participation in future Radiation Therapy Oncology Group economic studies.

The acute phase response is characterized by changes in the plasma concentrations of a number of liver-synthesized proteins, one of which is C-reactive protein (CRP). The existence of these changes in the plasma profile underlies the change in erythrocyte sedimentation rate (ESR). Acute phase response itself is an illness and may result from immunologic reactions and inflammatory processes. This study is designed to determine whether the CRP level and ESR increase during radiotherapy and whether their rise correlates with acute and late radiation morbidity.Between April 1997 and October 1998, 51 patients with the diagnosis of endometrium and cervical cancer were treated with surgery and postoperative radiotherapy. Median age at the time of radiotherapy was 52 (range, 26-73) years. Thirty patients received pelvic radiotherapy, and 21 patients were treated by pelvic-paraaortic irradiation. A total dose of 50.4 Gy to the pelvis and 45 Gy to the paraaortic field were delivered in conventional fraction. Erythrocyte sedimentation rates and CRP levels were studied before, during, and at the end of radiotherapy.The mean ESR measurements before and after radiotherapy were 40 (8-100) and 52 (10-120), and mean CRP levels were 1.4 (0.12-9.8) and 2.7 (0.12-32.2), respectively. The statistical analysis yielded significant rise in ESR and CRP levels at the end of radiotherapy (p0.001). The increase was more prominent in patients who were irradiated through pelvic-paraaortic field than in patients with pelvic radiation (p = 0.005 and 0.028 respectively).Acute phase response was present during radiotherapy. Radiotherapy should be considered as a cause of increase in CRP level and ESR especially in clinical conditions where acute phase response is important.

Clinical outcome of papillary thyroid carcinoma (PTC) in children differs significantly from that of adults. There is no clear explanation of this difference although previous studies have demonstrated a lower prevalence of the BRAF(V600E) mutation in PTC of children. However, data are limited due to the rarity of this diagnosis. BRAF(V600E) mutation prevalence and its relationship with outcome in pediatric PTC remain unclear.BRAF(V600E) mutational status was determined in 27 PTC patients less than 22 years of age using restriction fragment length polymorphism (RFLP) analysis. The relationship between BRAF(V600E) mutation status, patient and tumor characteristics as well as progression-free survival (PFS) were analyzed.BRAF(V600E) was present in 63% of patients and occurred more often in male patients versus females (P = 0.033). Presence of the mutation did not correlate with any difference in extent of disease at diagnosis, tumor size, capsular invasion, vascular invasion, soft tissue invasion, or margin status. At 10 years, PFS for BRAF(V600E) positive versus negative patients was 55.5% versus 70.0%, respectively (P = 0.48). Overall survival was 100% and median follow-up was 13.9 years.This study of pediatric PTC demonstrates that BRAF(V600E) mutations occur in children at a rate comparable to adults. We found a correlation of BRAF(V600E) with the male gender, but no evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that differences in disease course of PTC in children versus adults are not strongly dependent upon the presence of the BRAF(V600E) mutation.

Background. The purpose of this investigation was to evaluate the significance of race on the cancer-specific survival outcome of women treated with radiotherapy for advanced-stage cancer of the uterine cervix. Methods. Data from 922 women with cancer of the uterine cervix treated with radiotherapy were reviewed. Patients were treated at the Mallinckrodt Institute of Radiology from 1959 through 1993. There were 576 women with clinical Stage II cancer and 346 women with clinical Stage III cancer. All women were treated following standard medical care treatment policies according to the stage of their disease. Data were analyzed by race and known treatment-related prognostic factors. Overall and cancer-specific survivals were evaluated. Results. The 5-year cancer-specific survivals for clinical Stage II were 66 and 61% ( P = 0.56) for white and black women, respectively. The corresponding 5-year overall survivals were 60 and 51% ( P = 0.02). The 5-year cancer-specific survivals for clinical Stage III were 38 and 47% ( P = 0.34) for white and black women, respectively. The associated 5-year overall survivals were 32 and 40% ( P = 0.37). No differences in treatment-related factors were identified. Conclusions. In a cancer treatment system where black and white women with clinical Stage II and III cancer of the uterine cervix are all treated with radiotherapy alone, following standard treatment policies, no significant difference in cancer-specific survival outcome is shown. Multivariate analysis revealed that clinical stage and overall treatment time are significant variables affecting the control of tumor by radiotherapy. Overall survivals for the two racial groups are different and may be related to other non-cancer-related factors.

Grigsby PW. Radiation Therapy Oncology Group clinical trials for carcinoma of the cervix. The purpose of this paper is to review the primary data of the clinical trials performed by the Radiation Therapy Oncology Group (RTOG) for patients with carcinoma of the uterine cervix. The trials, their strengths, limitations, and the implications of the results are discussed. During the past 25 years there have been several clinical trials performed by the RTOG to test various hypotheses for improving local control and survival for patients with carcinoma of the uterine cervix. The major research themes that have been appraised are the use of hyperbaric oxygen, altered fractionation radiotherapy, hypoxic cell sensitization, chemo-sensitization, prophylactic paraaortic irradiation, and neutron radiotherapy. There are two general research themes. The initial RTOG trials for cervical cancer attempted to address the issues of tumor volume and hypoxic cells while the latter studies addressed these issues and the issue of micrometastatic disease. The phase III clinical trials performed by the RTOG have not demonstrated a local control or survival advantage in the experimental arm with the use of hyperbaric oxygen, split-course radiotherapy, hypoxic cell sensitization, or neutron radiotherapy. Acceptable toxicity and efficacy results were shown in phase II studies evaluating twice-daily irradiation and chemo-sensitization. The positive phase III trials were RTOG 79-20 which evaluated prophylactic paraaortic irradiation in patients with bulky stages IB, IIA, and IIB disease, and RTOG 90-01 which evaluated concurrent chemotherapy. Results of more recent clinical trials are pending their completion.

The purpose of this analysis was to evaluate the prognostic significance of cervical tumor size in patients with Stages Ib and IIa carcinoma of the cervix treated with preoperative irradiation and radical or conservative hysterectomy.This study is a retrospective analysis of 177 patients. One hundred forty-one patients had Stage Ib and 36 patients had Stage IIa carcinoma of the cervix. All patients were treated with preoperative irradiation and surgery. Radiation therapy consisted of external pelvic irradiation and intracavitary brachytherapy; total doses ranged from 30 to 60 Gy to the pelvic sidewall and 60 to 70 Gy to point A. Surgery consisting of radical hysterectomy and lymph node dissection or a conservative hysterectomy and lymph node dissection was performed 4 to 6 weeks after completion of irradiation.The 5-year progression-free survivals were 80% for Stage Ib and 63% for Stage IIa (p = 0.03). The 5-year cumulative pelvic failure rates for Stage Ib were 16% for tumors3 cm and 9% for tumors3 cm (p = 0.90). The 5-year cumulative pelvic failure rates for Stage IIa were 22% for tumors3 cm and 22% for tumors3 cm (p = 0.75). The corresponding cumulative distant metastasis failure rates at 5 years for Stage Ib were 21% for tumors3 cm and 21% for tumors3 cm (p = 0.60). For patients with Stage IIa disease, the 5-year cumulative distant metastasis rates were 33% for tumors3 cm and 36% for tumors3 cm (p = 0.70). A multivariate analysis was performed to evaluate prognostic factors for the endpoint of progression-free survival. The variables that were analyzed were patient age, tumor histology, tumor size, clinical stage, point A and pelvic lymph node irradiation dose, and cervical tumor status and pelvic lymph node status at the time of hysterectomy. The variables that were found to be of independent significance for progression-free survival by multivariate analysis were pelvic lymph node irradiation dose (p0.001), pelvic lymph node status at the time of hysterectomy (p = 0.01), and clinical stage (p = 0.02). Cervical tumor size at the time of diagnosis and the presence of tumor cells in the cervix in the hysterectomy specimen was not an independent prognostic factor by multivariate analysis. The overall severe complication rate was 11% for all patients.For this population of patients treated with preoperative irradiation and surgery, pelvic lymph node status at the time of hysterectomy and the preoperative irradiation dose to the pelvic lymph nodes are independent predictors of progression-free survival and the development of distant metastasis. The pretreatment cervical tumor size is of less importance for predicting progression-free survival and the development of distant metastasis but clinical stage is an important prognostic variable. These results are in contrast with those of surgery or irradiation alone, in which primary tumor size is a critical prognostic factor for all outcome parameters.

Objective: This report evaluates prognostic and technical factors affecting outcome of patients with primary carcinoma of the vagina treated with definitive radiation therapy. Methods and Materials: A retrospective analysis was performed on records of 212 patients with histologically confirmed carcinoma of the vagina treated with irradiation. Results: Tumor stage was the most significant prognostic factor; actuarial 10-year disease-free survival was 94% for Stage 0 (20 patients), 80% for Stage I (59 patients), 55% for Stage IIA (63 patients), 35% for Stage IIB (34 patients), 38% for Stage III (20 patients), and 0% for Stage IV (15 patients). All in situ lesions except one were controlled with intracavitary therapy. Of the patients with Stage I disease, 86% showed no evidence of vaginal or pelvic recurrence; most of them received interstitial or intracavitary therapy or both, and the addition of external-beam irradiation did not significantly increase survival or tumor control. In Stage IIA (paravaginal extension) and IIB (parametrial involvement) 66% and 56% of the tumors, respectively, were controlled with a combination of brachytherapy and external-beam irradiation; 13 of 20 (65%) Stage III tumors were controlled in the pelvis. Four patients with Stage IV disease (27%) had no recurrence in the pelvis. The total incidence of distant metastases was 13% in Stage I, 30% in Stage IIA, 52% in Stage IIB, 50% in Stage III, and 47% in Stage IV. The dose of irradiation delivered to the primary tumor or the parametrial extension was of relative importance in achieving successful results. In patients with Stage I disease, brachytherapy alone achieved the same local tumor control (80–100%) as in patients receiving external pelvic irradiation (78–100%) as well. In Stage II and III there was a trend toward better tumor control (57–80%) with combined external irradiation and brachytherapy than with the latter alone (33–50%) ( p = 0.42). The incidence of grade 2–3 complications (12%) correlated with the stage of the tumor and type of treatment given. Conclusion: Radiation therapy is an effective treatment for patients with vaginal carcinoma, particularly Stage I. More effective irradiation techniques, including optimization of dose distribution combining external irradiation and interstitial brachytherapy in tumors beyond Stage I, are necessary to enhance locoregional tumor control. The high incidence of distant metastases emphasizes the need for earlier diagnosis and effective systemic cytotoxic agents to improve survival in these patients.

We performed fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) in 23 women with carcinoma of the uterine cervix to determine sites of metastatic disease. PET results were compared with those of computed tomography (CT) or lymphangiography. Increased FDG uptake was seen in the primary tumor in 10 of 11 patients with newly diagnosed disease. Additional sites of FDG uptake were identified in pelvic lymph nodes in 8, in extrapelvic lymph nodes in 5, and at distant metastatic sites in 3. In 12 patients with suspected recurrent disease, FDG uptake was present in 11; the presence of tumor was confirmed by CT in 10 and by biopsy in 9. For both patient groups, FDG-PET demonstrated more sites of tumor metastasis than did conventional imaging studies. Our results suggest that FDG-PET is a sensitive method for detecting regional and distant metastasis in patients with cervical carcinoma and has the potential to replace conventional imaging studies and allow more rational treatment planning.

BACKGROUND The purpose of this study was to evaluate the utility of surveillance with annual whole-body iodine-131 (131I) scintigraphy for patients with recurrent thyroid carcinoma. METHODS The records of patients with thyroid carcinoma were reviewed. The 76 patients included in this study had undergone thyroidectomy and postoperative 131I therapy, and had at least 1 negative whole-body 131I scintigraphy 1 year after 131I therapy. There were 59 females and 17 males (age range, 12–74 years). Surgery consisted of a total thyroidectomy for 84% of patients and a subtotal thyroidectomy for 16%. 131I was administered within 1 month of thyroidectomy and annually thereafter until complete ablation of remaining thyroid tissue occurred. Annual follow-up diagnostic whole-body 131I scintigraphy was performed at Years 1 and 2, and then every 3–5 years. Some patients also had scintigraphy performed in Years 3, 4, and 5. RESULTS Patients received 1–4 annual administrations of 131I (median, 1). The administered activity per treatment was 30–211 mCi, and the total activity administered that was necessary to achieve complete ablation of functioning thyroid tissue ranged from 30 to 514 mCi (median, 100 mCi). The relapse free survival at both 5 and 10 years was 88%. By definition, all of these patients had a negative 131I scintigraphy at 1 year after their last therapeutic 131I administration. Seven patients had a positive 131I scintigraphy 1 year after the first negative scintigraphy. Two other patients had positive 131I images after 2 consecutive negative annual 131I scintigraphic studies. The predictive value for relapse free survival of 1 negative diagnostic 131I study of these patients was 91% (± 0.02), and for 2 consecutive annual negative 131I studies the value was 97% (± 0.02); these results were significantly different (P = 0.0197). A stepwise logistic regression analysis was performed in an effort to identify risk factors for disease recurrence after complete ablation. None of the variables assessed—age, gender, tumor histology, tumor size, vascular invasion, capsular invasion, surgical margin status, or lymph node status—was predictive of recurrence after complete ablation. CONCLUSIONS A single negative 131I scintigraphic study after complete ablation has a lower predictive value for relapse free survival than do two consecutive annual negative studies. Annual 131I imaging is recommended for surveillance until 2 consecutive annual negative studies are obtained, after which repeat imaging at 3–5 years appears to be satisfactory. Cancer 1999;85:945–51. © 1999 American Cancer Society.

Purpose: This report reviews the increasing role of radiation therapy in the management of patients with histologically confirmed vulvar carcinoma, based on a retrospective analysis of 68 patients with primary disease (2 in situ and 66 invasive) and 18 patients with recurrent tumor treated with irradiation alone or combined with surgery. Methods and Materials: Of the patients with primary tumors, 14 were treated with wide local excision plus irradiation, 19 received irradiation alone after biopsy, 24 were treated with radical vulvectomy followed by irradiation to the operative fields and inguinal–femoral/pelvic lymph nodes, and 11 received postoperative irradiation after partial or simple vulvectomy. The 18 patients with recurrent tumors were treated with irradiation alone. Indications and techniques of irradiation are discussed in detail. Results: In patients treated with biopsy/local excision and irradiation, local tumor control was 92% to 100% in Stages T1-3N0, 40% in similar stages with N1-3, and 27% in recurrent tumors. In patients treated with partial/radical vulvectomy and irradiation, primary tumor control was 90% in patients with T1-3 tumors and any nodal stage, 33% in patients with any T stage and N3 lymph nodes, and 66% with recurrent tumors. The actuarial 5-year disease-free survival rates were 87% for T1N0, 62% for T2-3N0, 30% for T1-3N1 disease, and 11% for patients with recurrent tumors; there were no long-term survivors with T4 or N2-3 tumors. Four of 18 patients (22%) treated for postvulvectomy recurrent disease remain disease-free after local tumor excision and irradiation. In patients with T1-2 tumors treated with biopsy/wide tumor excision and irradiation with doses under 50 Gy, local tumor control was 75% (3 of 4), in contrast to 100% (13 of 13) with 50.1 to 65 Gy. In patients with T3-4 tumors treated with local wide excision and irradiation, tumor control was 0% with doses below 50 Gy (3 patients) and 63% (7 of 11) with 50.1 to 65 Gy. In patients with T1-2 tumors treated with partial/radical vulvectomy and irradiation, local tumor control was 83% (14 of 17), regardless of dose level, and in T3-4 tumors, it was 62% (5 of 8) with 50 to 60 Gy and 80% (8 of 10) with doses higher than 60 Gy. The differences are not statistically significant. There was no significant dose response for tumor control in the inguinal–femoral lymph nodes; doses of 50 Gy were adequate for elective treatment of nonpalpable lymph nodes, and 60 to 70 Gy controlled tumor growth in 75% to 80% of patients with N2-3 nodes when administered postoperatively after partial or radical lymph node dissection. Significant treatment morbidity included one rectovaginal fistula, one case of proctitis, one rectal stricture, four bone/skin necroses, four vaginal necroses, and one groin abscess. Conclusions: Irradiation is playing a greater role in the management of patients with carcinoma of the vulva; combined with wide local tumor excision or used alone in T1-2 tumors, it is an alternative treatment to radical vulvectomy, with significantly less morbidity. Postradical vulvectomy irradiation in locally advanced tumors improves tumor control at the primary site and the regional lymphatics in comparison with reports of surgery alone.

Objective The purpose of this article is to objectively evaluate the merits of surgery and radiotherapy in the treatment of women with early stage carcinoma of the uterine cervix. Design Retrospective review of the literature. Results Surgery and radiotherapy are both utilized in the treatment of women with carcinoma of the uterine cervix. Either surgery or radiotherapy can be used in the treatment of patients with early stage disease (carcinoma in situ, stages Ia to IIa). However, moderate controversy surrounds the issue of standard therapy for women with stages Ib and IIa cervical cancer. There is no evidence that both treatments should be utilized together for that group. Quality of life and survival outcomes are excellent for women with early stage cervical cancer treated with radiotherapy. Women with stages Ib2 and IIa disease should receive primary radiotherapy rather than surgery in order to avoid the possibility of also requiring postoperative irradiation and its associated costs and complications. The standard treatment for women with advanced stages (IIb, III, and IVa) of carcinoma of the uterine cervix is radiotherapy; surgical therapy is not utilized for these women. Adjuvant chemotherapy has not demonstrated a survival advantage and remains experimental. Conclusion Surgery and radiotherapy are utilized in the treatment of patients with carcinoma of the cervix. Selection criteria should be developed to guide individualized patient treatment.

Purpose: The purpose of this study was to evaluate the toxicity and efficacy of twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. Methods and Materials: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and para-aortics at 4- to 6-h intervals, 5 days per week. The total external radiation doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics with an additional boost to a total dose of 54 to 58 Gy to the known metastatic para-aortic site. One or two intracavitary applications were performed to deliver a total minimum dose of 85 Gy to point A. Cisplatin (75 mg/m 2 , days 1 and 22) and 5-FU (1000 mg/m 2 /24 h × 4 days; days 1 and 22) were given for two or three cycles. Results: Twenty-nine patients with clinical Stages I to IV carcinoma of the cervix with biopsy-proven para-aortic lymph nodes were enrolled in this study. Hyperfractionated external radiotherapy was completed in 86% (25 of 29). Brachytherapy was given in two applications to 48% (14 of 29), 31% (9 of 29) had one intracavitary application, 14% (4 of 29) had no brachytherapy, one had three applications, and one had five HDR applications. Radiotherapy was completed per protocol in 69%. Three courses of chemotherapy were given to 24% (7 of 29), 72% (21 of 29) received two courses, and one patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Radiotherapy toxicity was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. One Grade 5 toxicity occurred and the patient died from a myocardial infarction from chemotherapy and radiotherapy colitis during her course of therapy. The median follow-up time was 18.9 months. The overall survival estimates were 59% at 1 year and 47% at 2 years. The probability of local-regional failure was 38% at 1 year and 49% at 2 years. The probability of disease failure at any site was 45% at 1 year and 59% at 2 years. Conclusion: The results suggest that twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (31%, 9 of 29) of Grade 4 nonhematologic toxicity. One patient died from complications of therapy. Radiotherapy was completed per protocol in 69%. The survival estimates appear no better than standard fractionation radiotherapy without chemotherapy. Additional follow-up is necessary for long-term survival estimates.

There are two criteria for the diagnosis of Stage IIIB cervical cancer in the FIGO staging system: tumor fixation to the pelvic side wall and/or the presence of hydronephrosis due to tumor. However, we often encounter hydronephrosis without tumor fixed to the pelvic side wall or the level of ureteral obstruction not corresponding to the main tumor mass in the pelvis. The clinical implication of these phenomena remains unclear. We investigated the Stage IIIB population treated at the Mallinckrodt Institute of Radiology and hypothesized that, if hydronephrosis presents without tumor fixation to the pelvic side wall or if the level of ureteral obstruction is above the main pelvic tumor mass, it most likely resulted from external compression of ureter(s) by enlarged lymph nodes and, consequently, a worse outcome is expected.From 1959 to 1989, there were 297 patients with Stage IIIB cervical cancer who received definitive radiation therapy at the Mallinckrodt Institute of Radiology and were assessable for the presence of hydronephrosis and the level of ureteral obstruction. There were 281 patients who presented with tumor fixed to the pelvic side wall, and 62 of them were associated with concurrent hydronephrosis. An additional 16 patients presented with hydronephrosis without tumor fixation to the pelvic side wall. Among these 78 documented cases of hydronephrosis, the level of ureteral obstruction was above the true pelvis in 39 patients, and below the true pelvis in the other 39. Radiation therapy was individualized according to tumor extension and configuration; para-aortic lymph nodes were not routinely treated except in patients with clinical evidence of nodal metastasis.The progression-free survival (PFS) at 5 years was 35% in 62 patients with hydronephrosis and tumor fixed to the pelvic side wall vs. 43% in 213 patients with tumor fixed to the pelvic side wall only (p=0.12). However, PFS at 5 years decreased to 23% in 16 patients who presented with hydronephrosis without tumor fixation to the pelvic side wall (p0.001). When the level of ureteral obstruction was investigated, 5-year PFS was 39% vs. 22%, respectively, for the obstruction below vs. above the true pelvis (p=0.02). The majority of patients with ureteral obstruction above the true pelvis died of distant metastasis.The additional presence of hydronephrosis did not significantly worsen the PFS among Stage IIIB patients with tumor fixation to the pelvic side wall. However, hydronephrosis without tumor extending to the pelvic side wall or the level of ureteral obstruction above the true pelvis was associated with poor outcome due to a significant increase in distant failure. We propose that this population be separated from current Stage IIIB classification.

Purpose: Radiation therapy is the standard management for locally advanced cervical cancer, but it has not yielded fully satisfactory results; a relatively high incidence of local failure remains. Standard radiation therapy techniques combine external beam radiation and brachytherapy generating a homogeneously composite dose distribution covering the lateral parametria but may not be adequate in the uterosacral and perirectal areas due to the spatial arrangement of intracavitary system and the constraints of rectal tolerance. We hypothesize that these dosimetric characteristics might lead to a higher incidence of central/marginal failures when the uterosacral space is involved by locally advanced carcinoma of uterine cervix. Methods and Materials: Between January 1970 and December 1989, 343 patients with clinical Stage IIIB cervical cancer were treated at the Mallinckrodt Institute of Radiology with radiation therapy alone. We identified 83 patients with clinical evidence of tumor in the uterosacral region; the remaining 260 patients either did not have uterosacral involvement or were unspecified. The dose of external beam irradiation ranged from 18.02 to 33.20 Gy to the central pelvis and 48.22 to 59.40 Gy to the lateral parametrium. The average total dose, including brachytherapy contribution, to point A and the lateral pelvis was 80.30 to 86.46 Gy and 60.50 to 73.40 Gy, respectively. External beam dose to the lateral parametria was, on average, 10 Gy higher in patients with uterosacral involvement. Results: We categorized the patterns of pelvic failure into central/marginal (including medial parametrium) and lateral parametria. The cumulative incidence of central/marginal failure at 5 years was significantly higher in the group of patients with uterosacral involvement (36% compared with 21% for patients without uterosacral involvement or unspecified) (p = 0.002). Lateral parametrial failure was similar for patients with and without uterosacral involvement (39% and 38% at 5 years, respectively) (p = 0.42). The actuarial incidence of distant metastasis was identical in the two groups: 46% at 5 years. Multivariate analysis confirmed that uterosacral space involvement increased the risk of pelvic recurrence (p = 0.044) and was the most significant factor that influenced the central/marginal pelvic failure (p = 0.002). Conclusions: Uterosacral involvement by locally advanced carcinoma of the uterine cervix significantly increased overall pelvic failure and was the most significant prognosticator of central/marginal pelvic failure. This is the result of the spatial constraints of the standard intracavitary geometry that deliver inadequate dose posteriorly to encompass the uterosacral space. Plausible ways to compensate the underdose in the uterosacral space include increasing whole pelvis dose without compromising the intracavitary brachytherapy dose, using a supplemental interstitial implant or adding a posterior oblique external beam boost.

To perform a cost-utility analysis utilizing a cooperative group protocol and constrasting the results with the published quality adjusted survival.A cost-utility analysis was performed on Radiation Therapy Oncology Group (RTOG) protocol 83-02. The quality-adjusted survival has been published previously. Pretreatment tests and chemotherapy costs are not considered, as these were similar across all treatment arms. Payor costs are calculated from Federal Register data for Medicare Region IV. Global charges are used to calculate the professional and technical charges. Costs are measured in relative value units (RVUs) and are tabulated assuming equal treatment complexity for all treatment arms.The number of RVUs calculated for each arm were 48 Gy--166.65; 54.4 Gy--182.17; 64.8 Gy--232.53; 72.0 Gy--272.19; 76.8 Gy--287.11; and 81.6 Gy--302.63. The RVU/QALY for the50-year-old group were 48 Gy--119.03; 54.4 Gy--100.65; 64.8 Gy--104.78; 72.0 Gy--90.73; 76.8 Gy--193.99; and 81.6 Gy--165.37. The RVU/QALY for the50-year-old group were 48 Gy--198.39; 54.4 Gy--276.85; 64.8 Gy--426.57; 72.0 Gy--423.71; 76.8 Gy--703.70; and 81.6 Gy--519.10. Sensitivity analysis of one treatment plan, simulation, and set of blocks for the 48 Gy and 54.4 Gy arms decreased the RVU/QALY to 105.34 and 90.05, respectively.Our analyses shows the experimental arm with the lowest RVU/QALY is also the arm with the longest quality-adjusted survival. This arm had the most efficient use of resources in this protocol. Prospective collection of all pertinent cost data is required for comparison of one treatment against another. All cooperative group protocols should have prospective quality of life and economic endpoints to allow for comparison of the most cost efficient treatment method.

This article describes the potential role of chemotherapy combined with irradiation in the management of patients with locally advanced carcinoma of the uterine cervix. A review of a Medline literature search and preliminary data from a nonrandomized study comparing irradiation alone with irradiation plus chemotherapy (5-fluorouracil and cisplatin) in the management of patients with locally advanced carcinoma of the uterine cervix treated at Washington University between 1984 and 1992 are presented. Except for one report, there is currently no conclusive evidence that chemotherapy plus irradiation significantly improves tumor control or survival in these patients. Nevertheless, chemotherapy may have a potential role in managing carcinoma of the uterine cervix as an adjuvant to irradiation in patients with pelvic or para-aortic lymph nodes or recurrent tumor after surgery or radiation therapy. Treatment morbidity has been acceptable. Based on available data, chemotherapy should not be advocated in the standardmanagement of carcinoma of the uterine cervix, and patients and physicians should be strongly encouraged to participate in properly designed prospective clinical trials.

Magnetic resonance imaging/diffusion weighted-imaging (MRI/DWI)-guided high-dose-rate (HDR) brachytherapy and (18)F-fluorodeoxyglucose (FDG) - positron emission tomography/computed tomography (PET/CT)-guided intensity modulated radiation therapy (IMRT) for the definitive treatment of cervical cancer is a novel treatment technique. The purpose of this study was to report our analysis of dose-volume parameters predicting gross tumor volume (GTV) control.We analyzed the records of 134 patients with International Federation of Gynecology and Obstetrics stages IB1-IVB cervical cancer treated with combined MRI-guided HDR and IMRT from July 2009 to July 2011. IMRT was targeted to the metabolic tumor volume and lymph nodes by use of FDG-PET/CT simulation. The GTV for each HDR fraction was delineated by use of T2-weighted or apparent diffusion coefficient maps from diffusion-weighted sequences. The D100, D90, and Dmean delivered to the GTV from HDR and IMRT were summed to EQD2.One hundred twenty-five patients received all irradiation treatment as planned, and 9 did not complete treatment. All 134 patients are included in this analysis. Treatment failure in the cervix occurred in 24 patients (18.0%). Patients with cervix failures had a lower D100, D90, and Dmean than those who did not experience failure in the cervix. The respective doses to the GTV were 41, 58, and 136 Gy for failures compared with 67, 99, and 236 Gy for those who did not experience failure (P.001). Probit analysis estimated the minimum D100, D90, and Dmean doses required for ≥90% local control to be 69, 98, and 260 Gy (P.001).Total dose delivered to the GTV from combined MRI-guided HDR and PET/CT-guided IMRT is highly correlated with local tumor control. The findings can be directly applied in the clinic for dose adaptation to maximize local control.

Purpose To assess the impact on local tumor control of intraoperative ultrasonographic plaque visualization and selective application of transpupillary thermotherapy (TTT) in the treatment of posterior uveal melanoma with iodine-125 (I-125) episcleral plaque brachytherapy (EPB). Methods and Materials Retrospective analysis of 526 patients treated with I-125 EPB for posterior uveal melanoma. Clinical features, dosimetric parameters, TTT treatments, and local tumor control outcomes were recorded. Statistical analysis was performed using Cox proportional hazards and Kaplan-Meier life table method. Results The study included 270 men (51%) and 256 women (49%), with a median age of 63 years (mean, 62 years; range, 16-91 years). Median dose to the tumor apex was 94.4 Gy (mean, 97.8; range, 43.9-183.9) and to the tumor base was 257.9 Gy (mean, 275.6; range, 124.2-729.8). Plaque tilt >1 mm away from the sclera at plaque removal was detected in 142 cases (27%). Supplemental TTT was performed in 72 patients (13.7%). One or 2 TTT sessions were required in 71 TTT cases (98.6%). After a median follow-up of 45.9 months (mean, 53.4 months; range, 6-175 months), local tumor recurrence was detected in 19 patients (3.6%). Local tumor recurrence was associated with lower dose to the tumor base ( P =.02). Conclusions Ultrasound-guided plaque localization of I-125 EPB is associated with excellent local tumor control. Detection of plaque tilt by ultrasonography at plaque removal allows supplemental TTT to be used in patients at potentially higher risk for local recurrence while sparing the majority of patients who are at low risk. Most patients require only 1 or 2 TTT sessions.

PurposeThis pilot study was performed to evaluate whether tumor uptake of (18)F-labeled 3'-deoxy-3'fluorothymidine (FLT), a proliferative radiotracer, at baseline and early during therapy, is predictive of outcome in locally advanced rectal cancer.ProceduresFourteen patients underwent positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and FLT before therapy and PET with FLT approximately 2weeks after initiating neoadjuvant chemoradiotherapy. FLT and FDG uptake were evaluated qualitatively and by maximum standardized uptake value (SUV(max)). Tumor FLT and FDG uptake were correlated with disease-free survival (DFS).ResultsThirteen patients underwent surgery after therapy, one died before surgery with progressive disease. FDG-PET/computed tomography detected regional lymph node metastases in five and FLT-PET was positive in one. High pretherapy FDG uptake (SUV(max) ≥ 14.3), low during-therapy FLT uptake (SUV(max)

Introduction: Intratumoral heterogeneity determined by FDG-PET is a poor prognostic factor in cervical cancer. Cu- ATSM has been used to evaluate hypoxia in cervical cancer. In this study, FDG and 64Cu-ATSM uptake patterns were compared and the prognostic significance of 64Cu-ATSM heterogeneity was determined. Methods: 15 patients with cervical cancer who underwent pretreatment 64Cu-ATSM- and FDG-PET/CT were included. The 64Cu-ATSM- and FDG-PET/CT images were co-registered and tumor volumes were autocontoured for each image set in 10% increments of the SUVmax ranging from 40% to 80%. The hypoxic fraction defined by 64Cu-ATSM uptake was determined. Concordance between 64Cu-ATSM and FDG uptake was determined by Dice’s coefficient. Heterogeneity of 64Cu-ATSM and FDG uptake was calculated as the variance of the 40-80% isothreshold volumes. The association between heterogeneity of 64Cu-ATSM uptake with tumor-specific factors and outcomes was determined. Results: The hypoxic fraction ranged from 0.773 ± 0.013 to 0.087 ± 0.010 as defined by the 40% to 80% Cu-ATSM isothreshold volumes, respectively. Dice’s similarity coefficients for the FDG and 64Cu-ATSM 40 to 80% isothreshold volumes ranged from 0.476 ± 0.012 to 0.112 ± 0.017. Greater 64Cu-ATSM heterogeneity was associated with increased risk of lymph node metastasis at diagnosis (p

Purpose : This is a prospective study to evaluate toxicity and efficacy of concurrent irradiation and three cycles of chemotherapy bolus cisplatin and infusion 5-fluorouracil (5FU) in patients with advanced gynecologic malignancies. Materials and Methods : Patients received cisplatin, 50 mg/m 2 I.V. rapid infusion, and 5-day continuous infusion of 5FU (750 mg/m 2 per day (schedule A) ; or cisplatin 75 mg/m 2 i.v. rapid infusion, and 4-day continuous infusion of 5FU 1,000 mg/m 2 per day (schedule B). Schedule A was given to 25 patients in the first 36 months of the study and was changed to schedule B in an additional 42 patients. All patients received irradiation, which usually consisted of 20 Gy whole pelvis, 30-40 Gy split field, and two intracavitary insertions for a total of 80-90 Gy to point A. Primary cervical cancer occurred in 40 patients with 3 having stage IB bulky, 2 with stage IIA, 5 with stage IIB, 2 with stage IIIA, 23 with stage IIIB, 4 with stage IV, and I with stage IVB. Recurrent cervical carcinoma after radical hysterectomy occurred in 18 patients. The remainder of the patients consisted of two each with stages III and IV endometrial carcinoma, two with stage III vaginal carcinoma, two with stage III vulvar carcinoma, and one with recurrent vulvar carcinoma. Patients were treated from 1985 through 1992. Results : The 5-year overall survivals for patients with stages IB (bulky)-IIB cervical cancer was 70%, 25% for stages IIIA-IVA, and 39% for patients with recurrent cervical carcinoma. All four patients with endometrial carcinoma have recurred and died. Two patients with vulvar carcinoma are alive and free of disease, and one is dead of intercurrent disease. One patient with stage III vaginal carcinoma is alive and free of disease, while the other recurred and died. No significant differences were observed in the toxicity of the two chemotherapy schedules. There were 9/39 (23%) grade 4 and one fatal complication in those with primary cervical carcinoma. The overall fistulae rate was 11% (4/39) with three patients developing rectovaginal fistulae and one having vesicovaginal fistula. Conclusion : Concurrent chemotherapy and irradiation for advanced gynecologic malignancies as administered in this study is highly toxic and fails to demonstrate an obvious survival improvement.

Purpose: The aggressiveness of radiation therapy for patients with medically inoperable endometrial carcinoma is controversial. Patients may die of their underlining medical before succumbing to cancer. We try to identify certain subgroups of patients who might benefit most from an aggressive approach and also investigate the impact of residual tumor present in dilatation and curettage (D&C) specimen obtained in second intracavitary implnat (ICI). Methods and Materials: From 1965 to 1990, 101 patients were treated for clinical clinical Stage I endometrial carcinoma with RT alone due to medical problems. Ages ranged from 39 to years (median 71 years). There were 18 patients with clinical Stage IA and 83 with clinical Stage IB disease. Histology included 44 well-differentiated, 37 moderately differentiatied, and 20 poorly differentiated tumors. Radiation therapy consisted of external beam only in 3 patients, ICI alone in 26, whole pelvis plus ICI in 10, and whole pelvis plus split field plus ICI in 62. A second D&C was performed on 26 patients at the time of the second ICI. Minimum follow-up was 2 years (median, 6.3 years). Results: The 5-year actuarial disease-free survival (DFS) for the studied cohort is comparable to the expected survival of an age-matched population. Pelvic control was 100% for Stage IA and 88% for Stage IB with 5-year disease-free survivals of 80 and 84%, respectively. We also observed a greater diassociation of DFS and overall survival among patients older than 75 years (84 and 55%, respectively) than in younger patients (84 and 78, respectively). This is mainly because older patients succumbed to their medical illness. Well-differentiated disease demonstrated the trend toward a better outcome than moderately or poorly differentiated lesions in Stage IB patients (p = 0.05), but not in Stage IA patients, Aggressive radiation therapy approach showed the trend toward a better result in Stage IB patients 75 years of age or younger. There were two failures among 19 patients with no tumor found in the D&C specimen at the time of second implant. In contrast, seven patients with residual tumor seen in the endometrial sample at the time of second implant remain disease free. Conclusions: Radiation therapy alone is an effective treatment modality for medically inoperable Stage I endometrial carcinoma. Disease-free survival can be translated into longer overall survival in the younger age group, but not in older patients. The latter tend to die of their underlining medical illness. Tumor differentiation influenced the prognosis of Stage IB disease. No tumor seen in the endometrial sampling at the time of second implant did not correlate with a better disease control, and the treatment plan should not be modified on such information.

Purpose: Some studies have described pelvic tumor control and survival rates in invasive carcinoma of uterine cervix when the overall time in a course of definitive irradiation is prolonged. We attempt to confirm or deny these observations and evaluate the impact of timing of brachytherapy on outcome. We also explore the hypothesis that more extensive tumors technically require prolongation of the course of irradiation; thus decreased tumor control and survival in these patients may not necessarily be the result of time/dose factor. Methods and Materials: Records of 1224 patients (Stage IB to III) treated with definitive irradiation (combination of external beam and two intracavitary insertions to deliver doses of 70 to 90 Gy to point A) were reviewed. Follow-up was obtained in 97% of the patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationship between outcome and overall treatment and time of intracavitary insertions was analyzed in each stage and according to tumor size/extent. Results: There was strong correlation between overall treatment time (OTT) and tumor stage (≤ 7 weeks: 81% for Stage IB; 74% for Stage IIA; 52% for Stage IIB; and 47% for Stage III). Interuptions of therapy accounting for prolongation of treatment time ocurred in 25–30% of patients, most frequently because of holidays and weekends and side effects of therapy. Overall treatment time had a major impact on pelvic tumor control in Stages IB, IIA, and IIB; in Stage IB 10-year actuarial pelvic failure rates were 7% with OTT ≤ 7 weeks, 22% with 7.1 to 9 weeks, and 36% with >9 weeks ( p ≤ o .01). For Stage IIA the corresponding values were 14%, 27% and 36% ( p = 0.08), and in Stage IIB pelvic failure rates were 20%, 28%, and 34%, respectively ( p = 0.09). In Stage III, pelvic failure was 30%, 40%, and 505 respectively ( p = 0.08). There was also a strong correlation between OTT and 10-year cause-specific survival (CSS); in Stage IB rates were 86% with OTT of ≤7 weeks, 78% for 7.1 to 9 weeks, and 55% for ≥9 weeks ( p p ≤ 0.01). For patients with Stage IIB, CSS rates were 72% for OTT ≤7 weeks, 60% for 7.1 to 9 weeks, and 70 for >9 weeks ( p = 0.01). Patients with Stage III disease had 45% to 10-year CSS when treatment was delivered in 9 weeks or less and 36% for longer overall ( p = 0.16). In multivariate analysis of patients with Stage IB and IIA, OTT and clinical stage were the most important prognostic factors for pelvic tumor control, disease-free survival, and CSS. Tumor size was a prognostic factor for CSS. In Stages IIB and III, OTT, clinical stage, unilateral or bilateral parametrical invasion, and dose to point A were significant prognostic factors for pelvic tumor control, disease-free survival, and CSS. Prolongation of time had a significant impact on pelvic tumor control and CSS regardless of tumor size, except in Stage IB tumors ≤3 cm. Regression analysis confirms previous reports that prolongation of OTT results in decreased pelvic tumor control rate of 0.85% per day for all patients, 0.37% per day in Stages IB and IIA, 0.68% per day in Stage IIB, and 0.54% for Stage III patients treated with ≥85 Gy to point A. Performance of all intracavity insertions within 4.5 weeks from initiation of irradiation of yeilded decreased pelvic failture rates in some groups of patients (8.8 vs. 18% in Stage IB and IIA tumors ≤4 cm and 12.3 vs. 35% in Stage IBB) ( p ≤ 0.01). Conclusions: Prolongation of treatment time in patients with Stage IB, IIA, IIB, and III carcinoma of the uterine cervix has a significant impact on pelvic tumor control and CSS. The effect of OTT was present regardless of tumor size except in Stage IB tumors ≤3 cm. This may be related to biologic factors such as cell repopulation and increased proliferation resulting from treatment interruptions, in addition to initial clonogenic cells burden. Irradiation for patients with invasive carcinoma of the cervix should be delivered in the shortest possible overall time.

Cervical cancer is a highly prevalent cancer that affects women around the world. With the availability of new technologies, researchers have increased their efforts to develop new drug delivery systems in cervical cancer chemotherapy. In this review, we summarized some of the recent research in systematic and localized drug delivery systems and compared the advantages and disadvantages of these methods.

The purpose of this article is to review the late effects of cancer therapy on the female reproductive tract. The anatomic sites detailed are the vulva, vagina, cervix, uterus, fallopian tubes, and ovaries. The available pathophysiology is discussed. Clinical syndromes are presented. Tolerance doses of irradiation for late effects are rarely presented in the literature and are reviewed where available. Management strategies for surgical, radiotherapeutic, and chemotherapeutic late effects are discussed. Endpoints for evaluation of therapeutic late effects have been formulated utilizing the symptoms, objective, management, and analytic (SOMA) format. Late effects on the female reproductive tract from cancer therapy should be recognized and managed appropriately. A grading system for these effects is presented. Endpoints for late effects and tolls for the evaluation need to be further developed.

Purpose : Definitive radiation therapy alone or combined with surgery in carcinoma of the uterine cervix yields comparable tumor control and survival in Stages I and IIA when patients are adequately treated with either modality. Our 30-year institutional experience is described. Methods and Materials : This is a nonrandomized comparison of treatment results of 415 patients with Stage IB, 137 with Stage IIA, and 340 with Stage IIB carcinoma of the uterine cervix treated with irradiation alone and 197 with Stage IB, 44 with Stage IIA, and 65 with limited Stage IIB treated with pre- or postoperative irradiation and surgery. Irradiation alone consisted of a combination of external beam therapy and intracavitary insertions to deliver doses of 70 to 85 Gy to point A for patients with Stages IB and IIA disease and 80 to 90 Gy for patients with bulky or Stage IIB tumors. For patients treated with irradiation and surgery, various combinations of external beam and intracavitary therapy were used to deliver 60 to 75 Gy to point A. Surgical procedures consisted of radical hysterectomy with or without lymph node dissection in 130 patients with Stage IB, 28 patients with Stage IIA, and 10 patients with limited Stage IIB. Fifty-seven patients had total abdominal or conservative hysterectomy with or without lymph node dissection, and 3 had vaginal hysterectomy. In addition, 51 patients with Stage IIB tumors underwent pelvic lymphadenectomy after definitive irradiation. Results : The 5-year cause-specific survival (CSS) rates for patients with Stage IB nonbulky tumors treated with irradiation alone or irradiation combined with surgery were 90 and 85%, respectively, and the 10-year survival rate was 84% with either modality. In patients with bulky tumors (> 5 cm), the 5-year CSS rates were 61% with irradiation alone and 63% with irradiation plus surgery; at 10 years the rates were 61 and 68%, respectively (p = 0.5). For those with Stage IIA nonbulky tumors, the 5-year CSS rates were 75% with irradiation alone and 83% with combined irradiation and surgery, and 10-year CSS rates were 66 and 71%, respectively. In patients with Stage IIA bulky tumors, the 5-year CSS rates were 69% with irradiation alone and 60% with irradiation plus surgery, and at 10 years, 69 and 44%, respectively (p = 0.05). In patients with Stage IIB nonbulky tumors treated with irradiation alone or combined with surgery, the 5- and 10-year CCS rates were 72 and 65%, respectively; the corresponding survival rates with bulky tumors or bilateral parametrial involvement were 56 and 50%. Incidence of pelvic failures, alone or with distant metastasis, for Stage IB was 10% (43 out of 415) with irradiation alone and 14% (28 of 197) with irradiation plus surgery; for Stage IIA, 17% (23 out of 137) with irradiation alone and 20% (9 out of 44) with irradiation plus surgery; and for Stage IIB, 23% (88 out of 391) with irradiation alone and 29% (4 out of 14) with irradiation plus surgery. Grade 3 sequelae were comparable in both groups (irradiation alone, 5% to 11%; irradiation combined with surgery, 8% to 12%); the differences are not statistically significant. The most frequent major sequelae in 892 patients receiving irradiation only were rectovaginal fistula (13 cases, 1.5%), proctitis (10, 1.1%), small bowel obstruction (16, 1.8%), ureteral stricture (16, 1.8%), and vesicovaginal fistula (8, 0.9%). In 306 patients treated with irradiation plus surgery, the most commonly recorded major sequelae were small bowel obstruction/perforation (13 cases, 4.2%), ureteral stricture (8, 2.6%), vesicovaginal fistula (5. 1.6%), and rectovaginal fistula (4, 1.3%). Conclusion : Irradiation alone or combined with surgery yields comparable pelvic tumor control, survival, and morbidity in patients with Stage IB, IIA, and limited IIB carcinoma of the uterine cervix.

The aim of this pilot study was to explore heterogeneity in the temporal behavior of intratumoral [18F]fluorodeoxyglucose (FDG) accumulation at a regional scale in patients with cervical cancer undergoing chemoradiotherapy. Included in the study were 20 patients with FIGO stages IB1 to IVA cervical cancer treated with combined chemoradiotherapy. Patients underwent FDG PET/CT before treatment, during weeks 2 and 4 of treatment, and 12 weeks after completion of therapy. Patients were classified based on response to therapy as showing a complete metabolic response (CMR), a partial metabolic response (PMR), or residual disease and the development of new disease (NEW). Based on the presence of residual primary tumor following therapy, patients were divided into two groups, CMR and PMR/NEW. Temporal profiles of intratumoral FDG heterogeneity as characterized by textural features at a regional scale were assessed and compared with those of the standardized uptake value (SUV) indices (SUVmax and SUVmean) within the context of differentiating response groups. Textural features at a regional scale with emphasis on characterizing contiguous regions of high uptake in tumors decreased significantly with time (P