Long-Term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response.

AIMS: A complete metabolic response (CMR) on early post-treatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a positive prognostic factor for cervical cancer patients treated with definitive chemoradiation, but long-term outcomes of this group of patients are unknown. Patterns of failure and risk subgroups are identified. MATERIALS AND METHODS: Patients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan-Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests. RESULTS: There were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3-4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5-3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0-2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4-5.0) at diagnosis. The 5-year FFR rates for T1-2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3-4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes). CONCLUSIONS: T3-4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation.

FDG-PET/CT: new horizons in anal cancer.

Anal cancer is an uncommon tumor with an incidence of about one case per 100,000 in most countries. Its incidence seems to be increasing because of exposure to human immunodeficiency virus (HIV) and human papillomavirus (HPV). Traditional pretreatment evaluations include physical examination and CT imaging of the pelvis. Current treatment guidelines include fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) as part of the standard pretreatment workup of patients diagnosed with anal cancer. At diagnosis, FDG-PET/CT is used to evaluate primary tumor size, lymph node status and to evaluate for distant metastases. FDG-PET/CT can also be used for radiation therapy treatment planning by clearly defining sites of metabolically active tumor. Posttherapy FDG-PET/CT to determine response to therapy is highly predictive of long-term clinical outcomes. This imaging modality can also be used to evaluate sites of recurrent disease. FDG-PET/CT is an imaging modality which greatly affects the management of patients with anal cancer.

Nuclear imaging and cervical cancer.

The staging of patients with cervical cancer is in accordance with the International Federation of Gynecology and Obstetrics (FIGO) clinical staging system. The traditional and current radiographic imaging studies allowed by FIGO to influence the clinical stage of the disease are the chest X-ray, the intravenous urogram and plain X-rays of the skeleton. The development and use of complimentary imaging studies may guide and direct therapy, but it does not change the clinical stage of the disease. Other X-ray studies that have been used are the barium enema and the lymphangiogram. Both computerized tomography (CT) and magnetic resonance imaging (MRI) have become commonplace in the evaluation of these patients. Most recently, position emission tomography (PET) with CT (PET/CT) is the preferred whole-body imaging study for patients with invasive cervical cancer. Single photon emission computed tomography (SPECT) combined with CT, the SPECT/CT, is also now being utilized in patients with cervical cancer. These new imaging modalities permit increased accuracy in the diagnosis and staging of cervical cancer, improve the selection and guidance of therapy, reduce uncertainties in the monitoring of response to therapy, and provide a means for objective long-term surveillance.

MicroRT-small animal conformal irradiator.

A novel small animal conformal radiation therapy system has been designed and prototyped: MicroRT. The microRT system integrates multimodality imaging, radiation treatment planning, and conformal radiation therapy that utilizes a clinical 192Ir isotope high dose rate source as the radiation source (teletherapy). A multiparameter dose calculation algorithm based on Monte Carlo dose distribution simulations is used to efficiently and accurately calculate doses for treatment planning purposes. A series of precisely machined tungsten collimators mounted onto a cylindrical collimator assembly is used to provide the radiation beam portals. The current design allows a source-to-target distance range of 1-8 cm at four beam angles: 0 degrees (beam oriented down), 90 degrees, 180 degrees, and 270 degrees. The animal is anesthetized and placed in an immobilization device with built-in fiducial markers and scanned using a computed tomography, magnetic resonance, or positron emission tomography scanner prior to irradiation. Treatment plans using up to four beam orientations are created utilizing a custom treatment planning system-microRTP. A three-axis computer-controlled stage that supports and accurately positions the animals is programmed to place the animal relative to the radiation beams according to the microRTP plan. The microRT system positioning accuracy was found to be submillimeter. The radiation source is guided through one of four catheter channels and placed in line with the tungsten collimators to deliver the conformal radiation treatment. The microRT hardware specifications, the accuracy of the treatment planning and positioning systems, and some typical procedures for radiobiological experiments that can be performed with the microRT device are presented.

Gene expression patterns in advanced human cervical cancer.

The purpose of this study was to evaluate gene expression patterns in human cervical tumors by extent of lymph node metastases at diagnosis. Pretreatment whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging was performed in eight patients with invasive squamous cell carcinoma of the cervix to evaluate the extent of lymph nodes metastases. Pretreatment tumor tissue samples were subjected to laser-capture microdissection, and isolated RNA was linearly amplified and hybridized to Affymetrix Human U95A GeneChip microarrays. Molecular FDG-PET imaging revealed that three patients had lymph node involvement in the supraclavicular region and five patients did not. Microarray data were segregated into two groups based on the extent of regional lymph node involvement. Supervised clustering analysis identified 75 of about 12,000 gene transcripts represented on the array whose average expression was at least threefold different. We identified 12 of the 75 transcripts that demonstrated a statistically significant difference in expression between the two patient groups (P < 0.05). Five transcripts were upregulated and seven downregulated. Both overall and cause-specific survivals were different between these two patient groups (P= 0.006). This limited data set identified candidate biomarkers of extent of lymph node metastases that correlated with poor survival outcome.

Postoperative vaginal brachytherapy alone is the treatment of choice for grade 1-2, stage IC endometrial cancer.

The aim was to determine outcome and toxicity in grade 1-2, FIGO stage IC endometrial cancer patients treated with external beam radiotherapy plus vaginal cuff brachytherapy or vaginal cuff brachytherapy alone. Between 1986 and 1999, a total of 132 patients were diagnosed with FIGO stage IC endometrial carcinoma. The median age was 67.5 years (range, 36-88). Median follow-up was 54 months (range, 6-157). Grade 1 disease was present in 64 patients, grade 2 in 45 patients, and grade 3 in 23 patients. Patients with grade 3 disease usually received external radiotherapy and were excluded from this analysis. Of the patients with grade 1-2 disease, 31 received brachytherapy alone and 78 received both external radiotherapy and brachytherapy. Ten (8%) patients experienced failure. Isolated pelvic relapse occurred in five patients. Three patients experienced both distant and local relapse. Two patients had isolated distant relapse. Nine failures occurred in patients treated with both external radiotherapy and brachytherapy. Only one failure occurred in those treated with brachytherapy alone. Overall survival and disease-free survival at 5 years were 85% and 92%, respectively. For those treated with both external radiotherapy and brachytherapy, 5-year locoregional control was 95%. For those treated with brachytherapy alone, 5-year locoregional control was 96.4%. There was no significant survival or local control difference between the two groups. Nine patients (9%) treated with both external radiotherapy and brachytherapy developed Radiation Therapy Oncology Group grade 3-4 toxicity. No patient treated with vaginal cuff brachytherapy alone developed grade 3-4 toxicity (P < 0.001). In patients with well-differentiated (grade 1-2) stage IC endometrial cancer, external beam radiotherapy plus brachytherapy versus vaginal cuff brachytherapy alone achieved equivalent local control and survival. However, vaginal cuff brachytherapy alone produced significantly less toxicity.

Prospective phase I/II study of irradiation and concurrent chemotherapy for recurrent cervical cancer after radical hysterectomy.

The purpose of the present study was to evaluate the long-term toxicity and efficacy of irradiation and concurrent chemotherapy for patients with a pelvic recurrence of cervical cancer after a hysterectomy. This prospective phase I / II study was designed to administer irradiation and three cycles of concurrent chemotherapy with cisplatin and 5-FU to patients with recurrent cervical cancer confined to the pelvis. Initial therapy was a hysterectomy and none received prior pelvic irradiation. A total of 22 patients were entered into the study. Patients received irradiation and three cycles of concurrent cisplatin and 5-FU. The acute toxicity from chemotherapy and irradiation was grade 3 in 18% and grade 4 in 9%. No patient died from a treatment-related complication. Follow-up times ranged from 7.2 to 17.6 years. At last follow-up, 14 patients died of metastatic cervical cancer and eight were alive. The 10- and 15-year overall survivals were 35%. Long-term complications included leg edema, vesico-vaginal, and recto-vaginal fistulae. Pelvic abscesses developed in three of the four patients with a fistula. By logistic regression, the only significant factor for survival was total irradiation dose (P = 0.04). In conclusion, long-term survival with this treatment regimen is possible but is accompanied by significant late toxicity.

Long-term follow-up of RTOG 92-10: cervical cancer with positive para-aortic lymph nodes.

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 x 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.

Current management of patients with invasive cervical carcinoma.

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.

Lymph node staging by positron emission tomography in patients with carcinoma of the cervix.

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.

Cervical cancer: combined modality therapy.

Prospective, randomized studies conducted over the past 10 years have changed the management of patients with advanced cervical cancer. The reviewed studies evaluated the use of surgery, irradiation, and chemotherapy in patients with various stages of cervical carcinoma in the absence and presence of high-risk factors for recurrence. A study by the Radiation Therapy Oncology Group (RTOG) compared pelvic with pelvic plus prophylactic para-aortic irradiation in patients with stages IB (> 4 cm), IIA, and IIB cervical cancer. The 10-year survival advantage was 11% for patients treated with prophylactic para-aortic irradiation. A follow-up study compared pelvic plus prophylactic para-aortic irradiation and brachytherapy with pelvic irradiation, brachytherapy, and chemotherapy with cisplatin and 5-FU in patients with IB-to IVA-stage cervical cancer. Overall and disease-free survivals were significantly improved in patients receiving chemotherapy. In patients with a prevalence of stage IIB and III, the Gynecologic Oncology Group (GOG) demonstrated that treatment with hydroxyurea alone was inferior to cisplatin or cisplatin, 5-FU, and hydroxy-urea in patients treated concurrently with pelvic irradiation and brachytherapy, and the GOG adopted irradiation and weekly cisplatin as standard therapy. Further GOG studies suggest that irradiation and weekly cisplatin chemotherapy without hysterectomy is the optimal treatment for patients with stage IB cervical cancer. High-risk factors for recurrence include tumor size, depth of tumor invasion, lymphovascular space involvement, and lymph node involvement. Prospective, randomized studies conducted by the GOG evaluated the effectiveness of various treatments in patients with high-risk factors. In one study that did not use chemotherapy, the recurrence-free interval was about 10% better for stage IB patients receiving postoperative irradiation after radical hysterectomy and pelvic lymphadenectomy compared with those who received no further therapy. Patients with Stages IB and IIA disease who, following radical hysterectomy and lymph node dissection, are identified as having positive pelvic lymph nodes and positive parametrial involvement, are at higher risk for recurrence and death than the high-risk group described above. An intergroup study conducted by the GOG, RTOG, and Southwest Oncology Group compared postoperative pelvic irradiation alone with postoperative pelvic irradiation plus concurrent chemotherapy in this group of patients. Overall and progression-free survivals were superior for patients receiving chemotherapy, and their greatest survival occurred in patients who received 3 or 4 chemotherapy cycles compared with 1 or 2 cycles or no chemotherapy. These findings are summarized with respect to their implications fortreatment of patients with advanced cervical cancer.

Image-based dose planning of intracavitary brachytherapy: registration of serial-imaging studies using deformable anatomic templates.

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.

Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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 (p < 0.05). 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 (p < 0.001). 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 (p < 0.05). CONCLUSION: In this dosimetric study, we demonstrated that with similar target coverage, normal tissue sparing is superior with IMRT in the treatment of cervical cancer.

Acute phase response during radiotherapy.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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 (p < 0.001). 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). CONCLUSION: 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.

Can costs be measured and predicted by modeling within a cooperative clinical trials group? Economic methodologic pilot studies of the radiation therapy oncology group (RTOG) studies 90-03 and 91-04.

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.

Radiation therapy for carcinoma of the cervix with biopsy-proven positive para-aortic lymph nodes.

PURPOSE: To evaluate local tumor control, cause-specific survival, patterns of relapse, and toxicity in patients with cervical cancer and positive para-aortic lymph nodes treated with radiation therapy alone. METHODS: This is a retrospective chart review of 43 patients with cervical cancer and biopsy-proven positive para-aortic lymph nodes treated with radiation therapy treated from 1965 to 1993. There were 15 patients with clinical Stage I disease, 12 with Stage II, and 16 with Stage III. Patients were treated with external irradiation to the pelvis and para-aortic regions combined with brachytherapy. None received chemotherapy. RESULTS: The 5-year overall survival rate was 32% and the median overall survival was 2.2 years. The 5-year cause-specific survival rate was 49% and the median cause-specific survival was 2.7 years. The cause-specific survivals at 5 years were 47% for Stage I, 64% for Stage II, and 46% for Stage III. Tumor recurrence occurred in 20 patients. The sites of recurrence were in the pelvis only in 3, the pelvis and distant metastasis in 9, and distant metastasis only in 8 patients. Severe, grade 3 complications occurred in 2 patients. One patient developed an enterovaginal fistulas and 1 developed radiation myelitis. CONCLUSION: Pelvic and para-aortic irradiation and brachytherapy resulted in a 49%, 5-year, cause-specific survival. Clinical tumor stage did not effect outcome. The majority of relapses occurred at distant sites. Toxicity was acceptable. Systemic chemotherapy should be considered as adjunctive therapy for these patients.

Cervical tumor control evaluated with ICRU 38 reference volumes and integrated reference air kerma.

PURPOSE: The purpose of this investigation was to evaluate the relationship of ICRU 38 reference volumes and integrated reference air kerma to primary cervical tumor control. MATERIALS AND METHODS: This retrospective study includes 1253 women with carcinoma of the uterine cervix treated with radiotherapy. Patients were treated from 1959 to 1993 at the Mallinckrodt Institute of Radiology. There were 39 women with stage Ia disease, 211 with stage Ib1, 88 with stage Ib2, 580 with stage 2, and 335 with stage 3 disease. Most patients with stage Ia disease were treated with low dose rate brachytherapy alone. All other patients were treated with external irradiation and low dose rate brachytherapy. External irradiation doses ranged from 8.2-63.8 Gy to the whole pelvis and an additional parametrial boost to deliver a total of 65-75 Gy to Point P depending on tumor stage. Low dose rate brachytherapy was delivered to the primary tumor with doses ranging from 40x10(4)-60x10(4) Gy cm(2) (integrated reference air kerma; IRAK). Isodose reference volumes (60-160 Gy) and point A doses were determined for all patients. Tumor control was defined as control of the primary cervical cancer with or without failure at other pelvic or distant sites. RESULTS: The mean 60 Gy volume was calculated to be 139.5 cm(3) for stage Ia, 200.4 cm(3) for stage Ib1, 270.9 cm(3) for stage Ib2, 235 cm(3) for stage 2, and 293.4 cm(3) for stage 3. No patient with stage Ia disease had a failure in the cervix. For stage Ib1 tumors the mean 60 Gy volume was 219.1 cm(3) for those who failed in the cervix and 199.9 cm(3) for those who did not fail (P=0.73). For stage Ib2 tumors the mean 60 Gy volume was 354.4 cm(3) for those who failed and 260.2 cm(3) for those who did not fail (P=0.004). The mean 60 Gy volume was 249.3 cm(3) for those with stage 2 disease who failed and 233.8 cm(3) for those who did not fail (P=0.02). For patients with stage 3 cancer the mean 60 Gy volume was 321.6 cm(3) for those who failed and 287.3 cm(3) for those who did not fail (P=0.20). Reference volumes from 70-160 Gy were not statistically different within each stage for those who failed in the cervix compared to those who did not fail. Cervical recurrences by clinical stage did not have statistically significant differences for mean IRAK except for stage II disease (P=0.001). CONCLUSION: Analysis of the 60-160 Gy reference volumes and IRAK failed to demonstrate a consistent positive increasing correlation of these values to primary cervical tumor control.

Comparison of clinical outcome in black and white women treated with radiotherapy for cervical carcinoma.

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.