Multi-institutional Prospective Randomized Trial Research Articles

From Bragg Peaks to Adaptive Fields—The Need for Evidence-Based Adoption of New Technologies in Radiotherapy

This Viewpoint discusses the need for multi-institutional prospective randomized trials of new technologies in radiotherapy to improve the therapeutic ratio and safety of radiotherapy treatments.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol

The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy×2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy×3 fx to 5 mm, 5 to 5.5 Gy×4 fx to 5 mm, and 6 Gy×5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy×3 and 5 to 5.5 Gy×4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy×5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy×3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. Experimental short-course VCB of 11 Gy×2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

PO29 Presentation Time: 7:40 AM: Dosimetric Review to Organs at Risk from Short Course Adjuvant Vaginal Cuff Brachytherapy in Early Endometrial Cancer Compared to Standard of Care (SAVE)

<h3>Purpose</h3> To evaluate dosimetric characteristics to organs at risk (OARs) from short course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared to standard of care in a multi-institutional prospective randomized trial. <h3>Materials and Methods</h3> 108 patients requiring VCB were randomized to an experimental short course arm (11 Gy x 2Fx to surface) and standard of care arms: 7 Gy x 3Fx to 5mm, 5-5.5 Gy x 4Fx to 5mm, and 6 Gy x 5Fx to surface. Rectum, bladder, sigmoid, small bowel, and urethra were contoured retrospectively on the planning CT and doses to OARs were compared by arm. Absolute doses for each OAR (D2cc and D0.1cc), and from each fractionation scheme, were converted to 2 Gy equivalent dose (EQD2; α/β=3 Gy). Each standard of care arm was compared to the experimental arm separately using a one-way analysis of variance, followed by pairwise comparisons using Tukey's HSD test. Additionally, treatment planning system reported point doses (mid cylinder) to the vaginal mucosa was converted to EQD2 (α/β=10 Gy) and evaluated. <h3>Results</h3> The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra when compared to the 7 Gy x3 and 5-5.5 Gy x4 fractionation schemes; however, the experimental arm did not differ statistically from the 6 Gy x5 fractionation scheme. For small bowel doses, none of the standard of care fractionation schemes were statistically different than the experimental arm (see fig. 1f). The highest D2cc EQD2 doses to the examined critical structures were observed to come from the most common dose fractionation scheme of 7 Gy x 3Fx (see fig. 1a-e). The data revealed similar results for the D0.1cc EQD2 doses for the urethra. Furthermore, average reported EQD2 doses to the vaginal mucosa were 40.32 Gy (σ=1.97 Gy) for 11 Gy x2, 56.53 Gy (σ=6.29 Gy) for 7 Gy x3, 47.81 Gy (σ=2.97 Gy) for 5-5.5 Gy x 4, and 41.69 Gy (σ=1.29 Gy) for 6 Gy x 5. With a short median follow up of one year, there have been no isolated vaginal recurrences. <h3>Conclusions</h3> Doses to OARs were generally low; however, in the highest quintile significant doses can be delivered with VCB. Experimental short course VCB of 11 Gy x 2Fx to the surface provides a comparable biologic effective dose to standard of care courses. Experimental short course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD2 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late side effects.

IMPPACT (Intravenous Monotherapy for Postoperative Perforated Appendicitis in Children Trial): Randomized Clinical Trial of Monotherapy Versus Multi-drug Antibiotic Therapy.

Perforated appendicitis is the most common cause of intraabdominal abscess (IAA) in children. The optimal postoperative antibiotic regimen to reduce IAA has evolved in the last decade from triple-drug to 2-drug therapy (CM). Recent retrospective studies show decreased infectious complications with monotherapy PT. To date prospective comparative data are lacking. Therefore, a prospective randomized trial comparing PT versus CM was conducted. A multi-institutional prospective randomized trial was performed in children with perforated appendicitis comparing postoperative antibiotic regimens PT or CM. The primary outcome was 30-day postoperative IAA formation. Perforation was strictly defined as a hole in the appendix or fecalith in the abdomen, documented with intraoperative photographs. One hundred sixty-two patients were enrolled during the study period. No differences in age, weight, or duration of presenting symptoms were identified. In addition, length of stay, duration of intravenous antibiotic treatment, discharge oral antibiotic treatment, and antibiotic-related complications did not differ between groups. Compared to the CM group, the PT group had significantly lower IAA rate [6.1% vs 23.8%, odd ratio (OR) 4.80, P = 0.002], lower postoperative computed tomography imaging rate (13.9% vs 29.3%, OR 2.57, P = 0.030), and fewer emergency room visits (8.8% vs 26.4%, OR 3.73, P = 0.022). Multivariate logistic regression analysis found the use of CM versus PT (OR 9.21, P = 0.021) to be the most significant predictor for developing IAA. In children with perforated appendicitis, postoperative monotherapy with PT is superior to standard 2-drug therapy with CM and does not increase antibiotic-related complications or antibiotic exposure duration.

Epidural versus PCA Pain Management after Pectus Excavatum Repair: A Multi-Institutional Prospective Randomized Trial.

Postoperative pain control remains the primary reason for inpatient stay after minimally invasive repair of pectus excavatum. In a previous study, our group reported that early pain control was better in patients managed with a thoracic epidural, while late pain control was better in patients managed with patient-controlled analgesia (PCA). After revising our epidural transition and modifying the PCA protocol, we conducted a multi-institutional prospective randomized trial to evaluate these two pain control strategies. Patients were randomized to epidural or PCA following minimally invasive repair of pectus excavatum with standard protocols for each arm. Primary outcome was length of stay with secondary variables including mean patient pain scores, complications, and parental satisfaction. Scores were pooled for the two groups and reported as means with standard deviation. Results were compared using t-tests and one-way analysis of variance with p-value < 0.05 determining significance. Sixty-five patients were enrolled, 32 epidural and 33 PCA. Enrollment was stopped early when we developed an alternative strategy for controlling these patients' pain. There was no difference in length of stay in hours between the two arms; epidural 111.3 ± 18.5 versus PCA 111.4 ± 51.4, p = 0.98. Longer operative time was found in the epidural group. Nine patients in the epidural group (28%) required a PCA in addition to epidural for adequate pain control. Mean pain scores were lower on postoperative day 0 in the epidural group compared with the PCA groups, but were otherwise similar. In our prospective randomized trial, PCA is just as effective as thoracic epidural in decreasing early postoperative pain scores after minimally invasive repair of pectus excavatum.

Salvage Stereotactic Radiosurgery is Associated with Improved Overall Survival Compared to Whole Brain Radiation in the Setting of Progressive Brain Metastases

Brain metastasis velocity (BMV) is a recently defined metric that is highly prognostic for overall survival (OS) after distant brain failure (DBF) following stereotactic radiosurgery (SRS). At time of first DBF, BMV can be calculated by dividing the number of brain metastases (BrM) by the amount of time (unit of years) since initial SRS. A proposed utility for BMV has been to help triage patients to proper salvage therapy after SRS failure based on low (BMV of <4), intermediate (BMV 4-13), and high (BMV>13) risk groups. The purpose of this study was to determine the effect of salvage modality (SRS or whole brain radiation therapy [WBRT]) on OS at the time of first salvage therapy for each BMV risk group. Patients from nine academic centers were treated with upfront SRS alone for BrM. BMV was defined as the number of new BrM at first DBF divided by the time (years) since first SRS for to create a unit of BrM/year. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 new BrM/year, respectively. Time-to-event outcomes were estimated using Kaplan-Meier method. For patients in the low, intermediate, and high-risk groups, OS was calculated by stratifying by salvage SRS or WBRT. A univariate and multivariate model (MVA) was created to evaluate OS after first DBF based on patient characteristics and salvage treatment with SRS vs WBRT. Two thousand and eighty patients were included in the study. Median OS from initial SRS was 10.2 mo (95% Confidence Interval [CI] 9.7-11.0 mo). Nine hundred and thirteen (32%) had a DBF treated with salvage SRS or WBRT. The median OS after first DBF for patients who received salvage SRS was 13.1 mo (CI 11.2-16.5 mo), 9.6 mo (CI: 7.8-11.9 mo) and 6.0 mo (CI: 4.9-9.2 mo) for patients with BMV < 4, BMV 4-13, and BMV > 13, respectively. In contrast, for patients who received salvage WBRT for DBF, median OS after initial DBF was 6.6 mo (CI: 5.0-12.7), 4.7 mo (CI: 3.9-8.6) and 3.9 mo (CI: 2.8-5.2) for patients with BMV < 4, BMV 4-13, and BMV > 13, respectively. Compared to patients who received WBRT as salvage therapy, SRS was associated with improved OS after first DBF for BMV < 4 (log-rank p=0.005), BMV 4-13 (p=0.005) and BMV >13 (p=0.0006). Salvage with SRS (vs. WBRT) remained a significant predictor of survival after DBF in multivariate models that included the covariates of age, recursive partitioning analysis class, number of BrM at time of first DBF, and histology for BMV <4 (Hazard Ratio [HR] 0.56, p=0.002), BMV 4-13 (HR 0.60, p=0.005), and BMV >13 (HR 0.48 p<0.001). Salvage SRS after progressive BrM was associated with a higher OS compared to patients treated with WBRT. This was observed across all BMV risk groups and remained significant on MVA. Initial steps have been taken to validate these findings in a multi-institutional prospective randomized trial.

Lobectomy and limited resection in small-sized peripheral non-small cell lung cancer.

Although lobectomy is the standard surgical procedure for non-small cell lung cancer (NSCLC), recent studies show favorable outcomes after limited resection in patients with small-sized peripheral tumors. We conducted a randomized controlled trial of such patients to estimate postoperative outcomes and pulmonary function following these surgical techniques. Between 2005 and 2008, eligible patients with tumors of 2 cm or less were randomly assigned 1:1 to undergo lobectomy or limited resection; 32 and 33 NSCLC patients in each group, respectively, were analyzed. The primary end points were 5-year overall survival (OS) and disease-free survival (DFS), while the secondary end points were postoperative pulmonary function including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). The 5-year OS rates were 93.8% and 90.9% in the lobectomy and limited resection groups, respectively (P=0.921). The 5-year DFS rates were 93.8% and 90.9% in the lobectomy and limited resection groups, respectively (P=0.714). These rates did not differ significantly between the two resection groups. The median postoperative/preoperative FVC ratios were 84.1% and 90.0% in the lobectomy and limited resection groups, respectively, while the median postoperative/preoperative FEV1 ratios were 81.9% and 89.1%, respectively. Both ratios were significantly higher in the limited resection group (P=0.032 and P=0.005 for FVC and FEV1 ratios, respectively). A similar outcome, with more preserved postoperative pulmonary function, was observed in patients who underwent limited resection compared to those who underwent lobectomy. Ongoing large-scale multi-institutional prospective randomized trials of lobar versus sublobar resection in patients with small peripheral NSCLCs will hopefully provide definitive information about intentional limited resection of small peripheral tumors.

HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges

In the era of targeted cancer therapy, there is growing interest in developing novel therapeutic strategies against endometrial carcinoma, especially its most biologically aggressive variant, serous adenocarcinoma. Several publications have demonstrated that a significant proportion of uterine serous carcinomas show HER2 overexpression and/or amplification, suggesting that HER2 may be a promising therapeutic target. Case reports have already shown clinical response to trastuzumab, a humanized monoclonal immunoglobulin (Ig) G1 antibody against HER2, and patients are currently being enrolled in a multi-institutional prospective randomized trial to evaluate the therapeutic efficacy of trastuzumab. To review current data on HER2 testing and targeted therapy against HER2/neu in endometrial carcinoma. Review of the literature and personal experience of the authors. Parallel to the clinical studies, there is a need to develop standardized criteria for HER2 testing in endometrial carcinoma that reflect the unique biological and pathogenetic features of these tumors and correlate with clinical response to therapy. This article presents a comprehensive review of the current state of HER2-based therapy and HER2 testing in endometrial carcinoma.

Postoperative long-term evaluation of interposition reconstruction compared with Roux-en-Y after total gastrectomy in gastric cancer: prospective randomized controlled trial

Background The postoperative clinical superiority of the interposition of jejunum reconstruction (INT) to Roux-en-Y reconstruction (RY) after total gastrectomy has not been clarified. Postoperative quality of life (QOL) was evaluated between the 2 methods by a multi-institutional prospective randomized trial. Methods A total of 103 patients with gastric cancer were prospectively randomly divided into groups for RY (n = 51) or INT reconstruction (n = 52) after total gastrectomy. They were stratified by sex, age, institute, histology, and degree of lymph node dissection. Postoperatively, body mass index (BMI) and nutritional conditions were measured serially, and QOL and postoperative squalor scores were evaluated at 3, 12, and 60 months and compared between the 2 groups. Results After removing patients who did not complete the follow-up survey or censured cases, 24 patients in the RY group and 18 patients in the INT group were clinically available and their postoperative status was assessed. QOL scores were increased and complication scores were improved in the postoperative periods ( P < .01). Postoperative BMI significantly deteriorated compared with preoperative BMI in each group. The postoperative QOL and complication scores at 60 months after surgery were significantly better than those at 3 months after surgery in each group ( P < .01). However, there was no significant difference of QOL scores and postoperative complication scores between the 2 reconstruction groups. The nutritional condition in the INT group was nearly the same as that in the RY group. Conclusions Although our patient sample was small and patients who did not complete the follow-up survey were present, we could not identify any clinical difference between INT and RY after total gastrectomy 60 months after surgery. The safer and simpler RY method may be a more suitable reconstruction method than INT after total gastrectomy.

Second Primary Melanomas: Incidence and Outcome

The objective of this study was to determine the incidence of multiple primary melanomas (MPM) and other cancers types among patients with melanoma. Factors associated with development of MPM were assessed in a post hoc analysis of the database from a multi-institutional prospective randomized trial of patients with melanoma aged 18 to 70 years with Breslow thickness 1 mm or greater. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis. Forty-eight (1.9%) of 2506 patients with melanoma developed additional primary melanomas. Median follow-up was 66 months. Except in one patient, the subsequent melanomas were thinner (median, 0.32 mm vs. 1.50 mm; P < 0.0001). Compared with patients without MPM, patients with MPM were more likely to be older (median age, 54.5 vs. 51.0 years; P = 0.048), to have superficially spreading melanomas (SSM) (P = 0.025), to have negative sentinel lymph nodes (P = 0.021), or to lack lymphovascular invasion (LVI) (P = 0.008) with the initial tumor. On multivariate analysis, age (P = 0.028), LVI (P = 0.010), and SSM subtype of the original melanoma (P = 0.024) were associated with MPM. Patients with MPM and patients with single primary melanoma had similar DFS (5-year DFS 88.7 vs. 81.3%, P = 0.380), but patients with MPM had better OS (5-year OS 95.3 vs. 80.0%, P = 0.005). Nonmelanoma malignancies occurred in 152 patients (6.1%). Ongoing surveillance of patients with melanoma is important given that a significant number will develop additional melanoma and nonmelanoma tumors. With close follow-up, second primary melanomas are usually detected at an early stage.

Comparison of laparoscopic versus open gastrectomy for gastric cancer: a phase III trial (KLASS trial): Interim reports on morbidity and mortality

4641 Background: Recently, in technical aspects, almost all kinds of open gastric cancer surgeries can be reproduced laparoscopically. However, many controversies exist due to no evidence and no long-term results. There was no prospective multi-center large- scale randomized controlled trial in the world on the long-term outcome of laparoscopic gastric cancer surgery. Korean Laparoscopic Gastrointestinal Surgery Study Group, therefore, proposed a multi-institutional prospective randomized trial on comparing laparoscopy-assisted distal gastrectomy (LADG) versus open distal gastrectomy (ODG) for gastric cancer (KLASS Trial) after the feasibility and validity of these procedures had been evaluated by analyzing retrospective multi-center large series. Methods: Patient eligible criteria are as follows; pathologically proven gastric adenocarcinoma, age: 20 ∼ 80 years, preoperative stage: cT1N0M0, cT1N1M0, cT2aN0M0, no history of other cancer, no history of chemotherapy or radiotherapy, and written informed consent. Primary endpoint of this trial is to elucidate that there is no difference of overall survivals between LADG and ODG groups. The planned sample size per arm is 700 (1,400 in total). First of all, we compared morbidity and mortality between two groups by interim analysis in order to evaluate the safety of this trial. The time of interim analysis was decided on the hypothesis that the morbidity of this trial is not significantly different from that of previous reports on open gastric cancer surgeries (17%∼20%). Results: There were 179 LADG and 163 ODG patients. There was no significant difference between two groups in terms of age, gender, and comorbidity. Postoperative complication rates of LADG and ODG groups were 10.5% (17/179) and 14.7% (24/163), respectively (p=0.137). Reoperations were required in 3 cases of LADG and also 3 cases of ODG patients (p=1.000). Postoperative mortality was 1.1% (2/179) in LADG and 0% (0/163) in ODG patients (p=0.497). Conclusions: There was no significant difference of morbidity and mortality between LADG and ODG patients. This trial, therefore, is acceptable and should be ongoing. No significant financial relationships to disclose.

Surgical and pathological outcomes of laparoscopic surgery for transverse colon cancer.

PurposeSeveral multi-institutional prospective randomized trials have demonstrated short-term benefits using laparoscopy. Now the laparoscopic approach is accepted as an alternative to open surgery for colon cancer. However, in prior trials, the transverse colon was excluded. Therefore, it has not been determined whether laparoscopy can be used in the setting of transverse colon cancer. This study evaluated the peri-operative clinical outcomes and oncological quality by pathologic outcomes of laparoscopic surgery for transverse colon cancer.Materials and methodsAnalysis of the medical records of patients who underwent laparoscopic colorectal resection from August 2004 to November 2007 was made. Computed tomography, barium enema, and colonoscopy were performed to localize the tumor preoperatively. Extended right hemicolectomy, transverse colectomy, and extended left hemicolectomy were performed for transverse colon cancer. Surgical outcomes and pathologic outcomes were compared between transverse colon cancer (TCC) and other site colon cancer (OSCC).ResultsOf the 312 colorectal cancer patients, 94 patients underwent laparoscopic surgery for OSCC, and 34 patients underwent laparoscopic surgery for TCC. Patients with TCC were similar to patients with OSCC in age, gender, body mass index, operating time, blood loss, time to pass flatus, start of diet, hospital stay, tumor size, distal resection margin, proximal resection margin, number of lymph nodes, and radial margin. One case in TCC and three cases in OSCC were converted to open surgery.ConclusionsLaparoscopic surgery for transverse colon cancer and OSCC had similar peri-operative clinical and acceptable pathological outcomes.

Factors Associated With Improved Survival Among Young Adult Melanoma Patients Despite a Greater Incidence of Sentinel Lymph Node Metastasis

We sought to evaluate the factors that affect sentinel lymph node (SLN) metastasis and survival among young melanoma patients (< or =30 y). The Sunbelt Melanoma Trial is a multi-institutional prospective randomized trial of patients aged 18 to 70 y. Statistical analyses were performed to determine if patients < or =30 y of age had a significantly different outcome in terms of SLN metastasis, disease-free survival (DFS), and overall survival (OS) compared to older patients. The median age of the 3031 patients in this study was 50 y (range 18 to 77 y); the 315 patients (10.4%) < or =30 y old were compared with those >30 y old. Of the 1944 patients with follow-up, the median follow-up was 48 mo. On univariate analysis, younger patients were more often female (54.7% versus 40.9%, P < 0.0005), with tumors <4 mm thick (94.9% versus 89.4%, P = 0.001) without ulceration (80.3% versus 70.9%, P < 0.0005) or evidence of regression (93.8% versus 87.8%, P = 0.003), and were less likely to have lentigo maligna (0.0% versus 2.6%) or acral lentiginous (0.4% versus 3.1%, P < 0.0005) subtype. Patient age < or =30 was associated with SLN metastasis on univariate (24.6% versus 19.7%, P = 0.05) and multivariate (OR = 1.77, 95% CI = 1.26-2.49, P = 0.001) analyses. With a median follow-up of 48 mo, younger patients had a significantly improved 5-y DFS (86.2% versus 79.1%, P = 0.036) and OS (89.9% versus 80.1%, P = 0.010). On multivariable Cox regression analysis, however, age group was not a significant independent prognostic factor affecting DFS or OS. Despite a higher rate of SLN metastasis, patients < or =30 y old do not have a worse survival attributable to a more favorable clinicopathologic profile.

Regional hyperthermia combined with radiotherapy for locally advanced non-small cell lung cancers: a multi-institutional prospective randomized trial of the International Atomic Energy Agency

An International Atomic Energy Agency (IAEA)-sponsored, multi-institutional prospective randomized trial was conducted to clarify whether the combination of hyperthermia and radiotherapy improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by radiotherapy alone. Between October 1998 and April 2002, 80 patients with locally advanced NSCLC were randomized to receive either standard radiation therapy alone (RT) or radiation therapy combined with hyperthermia (RT + HT). The primary endpoint was the local response rate. The secondary endpoints were local progression-free survival and overall survival. The median follow-up period was 204 days for all patients and 450 days for surviving patients. There were no significant differences between the two arms with regard to local response rate (P = 0.49) or overall survival rate (P = 0.868). However, local progression-free survival was significantly better in the RT+HT arm (P = 0.036). Toxicity was generally mild and no grade 3 late toxicity was observed in either arm. Although improvement of local progression-free survival was observed in the RT+HT arm, this prospective randomized study failed to show any substantial benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced NSCLC.

The Value of Postoperative Radiotherapy in Renal Cell Carcinoma: A Single-Institution Experience

To evaluate the efficacy of postoperative irradiation in renal cell carcinoma. Forty patients with localized renal cell carcinoma admitted to our hospital between 1986 and 1999 were evaluated. All patients were initially treated with radical nephrectomy. Postoperative radiotherapy was given to 26 of 40 patients (65%). Fourteen patients (35%) received no adjuvant therapy. Median age was 55 years (range, 20-70 years). Twenty-four patients (60%) were men and 16 patients (40%) were women. Histopathological diagnosis was renal cell carcinoma in all of the patients. N+ disease was present in 3 patients (7%). Stage I and II disease was present in 25 patients (63%) and stage III and IV disease in 15 patients (37%). Two patients (5%) had T1a disease, 11 patients (27%) had T1b, 15 patients (38%) had T2, 11 patients (27%) had T3a and 1 (3%) patient had T3b. In the radiotherapy group, renal bed and regional lymphatic fields were irradiated with daily fractions of 180-200 cGy/fraction to a total dose of 46-50 Gy, using parallel opposing fields. The 5-year overall survival rates were 70% in the postoperative radiotherapy group and 20% in the no adjuvant treatment group, showing no significant difference (P = 0.1). The 5-year disease-free survival rates were 66% in the radiotherapy group and 16% in the no treatment group, with a significant difference in both univariate and multivariate analyses (P = 0.045 and P = 0.0007, respectively). Stage III and IV disease, tumor size 27 cm, presence of distant metastasis and lactate dehydrogenase level > 450 U/L were found to be adverse prognostic factors for overall survival in both univariate and multivariate analyses. Analyzing the factors affecting disease-free survival, absence of postoperative radiotherapy and tumor size > or = 7 cm were found to be adverse prognostic factors in univariate and multivariate analyses. Multi-institutional prospective randomized trials using modern radiotherapy techniques such as conformal radiotherapy and intensity-modulated radiotherapy are necessary to evaluate the real role of radiotherapy and its effect on survival in renal cell carcinoma, especially in selected patients with a high risk of local or regional failure.

Regional hyperthermia combined with radiotherapy for uterine cervical cancers: A multi-institutional prospective randomized trial of the international atomic energy agency

Hyperthermia can be used to enhance the effects of radiation, and a combined treatment may, in some circumstances, be an advantage. Uterine cervical cancer is very common in developing countries. The control of locally advanced pelvic tumors is difficult with conventional treatment modalities. Based upon the biologic rationale and in view of the recent advances in heating and thermometry techniques, radiotherapy in combination with hyperthermia was investigated in a multi-institutional prospective randomized trial sponsored by the International Atomic Energy Agency. The primary purpose was to clarify whether the combination of hyperthermia and radiotherapy improves the rate of local control, compared with radiotherapy alone. A total of 110 patients with biopsy-proven, locally advanced carcinoma of the uterine cervix were randomized to treatment by radiotherapy with or without hyperthermia. The patients were stratified by institution, stage, and histologic type. Each patient received external beam radiation therapy and brachytherapy. For the patients randomized to receive hyperthermia, a minimum of five sessions (60 min each, once per week) were administered, employing a radiofrequency (RF) capacitive heating device. Intratumoral temperature was measured at the first hyperthermic treatment, and at least once more during the course of treatment. The equipment and the policies and procedures at each participating institution except one (Pusan) were personally inspected at least once by the corresponding author, to ensure that quality assurance procedures were in place and were followed for treatment according to the protocol guidelines. The median follow-up period was 466 days for all the patients and 512 days for the surviving patients. The two arms were well balanced with regard to the patient factors, tumor factors, and treatment factors. The overall survival rate at 3 years was 73.2%, and the local control rate was 68.5%. There were no significant differences between the patients treated with or without hyperthermia, either with regard to the survival (p = 0.1893) or the rate of local control (p = 0.58). The survival was significantly worse among the patients with Stage IIb disease who received hyperthermia (p = 0.0162) although there was no difference in their rate of local control (p = 0.7988). Further analysis is necessary to determine if the difference in survival is due to a greater incidence of distant metastases or some other cause. Acute Grade 2-3 toxicity was seen in 10/55 patients (18%) treated by hyperthermia and in 2/55 of the patients (4%) treated without hyperthermia (p = 0.01). There was no significant difference in the late toxicity observed in the two arms. This prospective randomized study failed to show any benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced carcinoma of the uterine cervix. The acute toxicity was significantly greater among the patients receiving hyperthermia, and the survival was significantly worse among the Stage IIb patients receiving hyperthermia even though there was no difference in the local control rate.

Treatment and management of the Chiari II malformation: an evidence-based review of the literature.

Multiple surgical strategies exist for the management of the symptomatic Chiari II malformation. To date, no comprehensive analysis of this medical literature in an attempt to seek out standards or guidelines has been performed, thus serving as the impetus for this present review. A computerized search of the database of the National Library of Medicine was performed on the English-language medical literature between 1966 and 2003. Terms searched for included hindbrain hernia, Chiari II, Arnold-Chiari, surgery, decompression, syringomyelia, and CSF shunts. All literature found was reviewed with associated references from these sources. Each piece of literature reviewed was scrutinized and guidelines developed utilizing the methodology used by the Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries. All data reviewed were deemed to be Class III in nature. No standards or guidelines could be established from the available literature. There is significant debate and variable results in the current neurosurgical literature regarding the evaluation of shunt function vs. Chiari II decompression in patients with symptomatic hindbrain herniation. Multi-institutional prospective randomized trials are needed before any conclusions can be drawn regarding symptomatic Chiari II and its treatment paradigm. Until this time, clinical practice will be based on individual surgeons' experience, training, and personal beliefs.

Laparoscopic port-site metastases: etiology and prevention

Objective The purpose of this article is to summarize current hypotheses for the possible sources of laparoscopic port-site metastasis, to review the results of experimental models that support such hypotheses, and to discuss the potential options for preventing these metastases. Methods We performed a Medline search to identify in vitro and in vivo studies and clinical trials that analyzed port-site metastases associated with laparoscopic surgery. We report the incidence of port-site metastases and causative factors associated with this condition. Results The estimated incidence of port-site metastases in all patients undergoing laparoscopic surgery for malignant disease is approximately 1–2%. Multiple factors are associated with this complication. Among the most common proposed etiologies are the wound implantations caused by the surgical technique and instrumentation; the leakage of insufflation gas through the ports, known as the “chimney effect”; and the impact of pneumoperitoneum on local immune reactions. Several preventive measures, have been suggested, including careful patient selection, lavage of the peritoneal cavity as well as of the port wounds with cytotoxic agents, and modifications of surgical technique. Conclusions Only through the results of well-conducted large multi-institutional prospective randomized trials will we learn not only the true incidence of port-site metastases, but also the potential factors that lead to the occurrence of this complication.

NEOADJUVANT ANDROGEN ABLATION BEFORE RADICAL PROSTATECTOMY IN cT2bNxMo PROSTATE CANCER: 5-YEAR RESULTS

In the initial report of the Lupron Depot Neoadjuvant Prostate Cancer Study Group patients who received 3 months of androgen deprivation had a significant decrease in the positive margin rate. We monitored these patients for 5 years and to our knowledge present the longest followup of any neoadjuvant trial. A multi-institutional prospective randomized trial was performed between February 1992 and April 1994 involving patients with stage cT2b prostate cancer, including 138 who received 3 months of leuprolide plus flutamide before radical prostatectomy and 144 who underwent radical prostatectomy only. Patients were followed every 6 months with serum prostate specific antigen (PSA) testing for 5 years. Biochemical recurrence was defined as PSA greater than 0.4 ng./ml. At 5 years there was no difference in the biochemical recurrence rate. PSA was less than 0.4 ng./ml. in 64.8% of the patients in the neoadjuvant androgen ablation plus prostatectomy and 67.6% in the prostatectomy only group (p = 0.663). Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year followup does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated.