Simplified biplanar (0-90°) fluoroscopic puncture technique for percutaneous nephrolithotomy: the learning curve.

PURPOSE: To evaluate the learning curve of the simplified fluoroscopic biplanar (0-90º) puncture technique for percutaneous nephrolithotomy. METHODS: We prospectively evaluated patients with renal stones treated with percutaneous nephrolithotomy by a single institution's fellows employing the simplified bi-planar (0-90º) fluoroscopic puncture technique for renal access. The learning curve was assessed with the fluoroscopic screening time and the percutaneous renal puncture time. Data obtained were compared to a subset of patients operated by a senior surgeon. RESULTS: Eighty-nine patients were included in the study. Forty patients were operated by fellow-1, 39 by fellow-2, and 10 patients by the senior surgeon. Demographic data of all patients between groups were homogeneous, with no difference in gender (p = 0.432), age (p = 0.92), stone volume (p = 0.78), puncture laterality (p = 0.755), and body mass index (p = 0.365). The mean puncture time was 7.5, 4, and 3.1 min for fellow-1, fellow-2, and expert, respectively. The mean fluoroscopic screening time for the puncture was 10, 11, and 5.1 s for fellow-1, fellow-2, and the expert, respectively. Stone cases, both fellows needed to complete 10 procedures to match the senior surgeon in the mean puncture time (p = 0.046); meanwhile, the fluoroscopic screening time was equal even before to complete 10 procedures. CONCLUSION: This study suggests that with the simplified biplanar (0-90º) puncture technique, the fluoroscopic screening time used in the learning process is brief. A novice fellow could require to complete ten cases to flatten the learning curve treating complex stone cases, and a flat learning curve is seen since the beginning when treating simple renal stones.

Flexible ureteroscopy in extreme elderly patients (80 years of age and older) is feasible and safe.

PURPOSE: To compare the safety and efficacy of RIRS in patients ≥ 80 years to a younger population. METHODS: We retrospectively compared the data from patients ≥ 80 years of age undergoing RIRS with the data of a group of patients from 18 and < 80 years. Perioperative outcomes, complications and emergency department visits were compared between two groups. RESULTS: A total of 173 patients were included in the study. Mean age was 44 (27-79) and 81 years-old (80-94), for younger and elderly group, respectively. Elderly patients had higher ASA scores (≥ 3) (28.6% vs 75.8%; p = 0.0001) and Charlson comorbidity index (1.99 vs 7.86; p = 0.0001), more diabetes (p = 0.006) and respiratory comorbidities (p = 0.002). No statistical difference was found between two groups in stone size (p = 0.614) and number (p = 0.152). Operative time (74.48 vs 102.96 min; p = 0.0001) and duration of hospitalisation (1.7 vs 2.9 days; p = 0.001) were longer for the elderly. Intraoperative complication rate did not show differences between the two groups (p = 0.166). Postoperative complications rates were similar between the cohorts (7.7% vs 9.5%; p = 0.682). The success rates were 67.5% in the younger group and 71.4% in the elderly group (p = 0.584). No difference was seen in stone recurrence (p = 0.73). A higher rate of visits to the emergency department was found in younger cohort (23.6% vs 11.6%; p = 0.046), mostly duo to stent-related symptoms. CONCLUSIONS: Despite the higher rate of comorbidity in the elderly group, RIRS was a safe procedure with similar complication rate and outcomes at an expense of higher operative time and hospital stay.

Fluoroless Endourological Surgery for Stone Disease: a Review of the Literature-Tips and Tricks.

PURPOSE OF REVIEW: Urologists are at significant risk due to radiation exposure (RE) from endourological procedures for stone disease. Many techniques described have shown a reduction of RE. The purpose of this article is to review available protocols to decrease RE during such procedures and provide tips and tricks for their implementation. RECENT FINDINGS: Several low-radiation and radiation-free protocols for percutaneous nephrolithotomy and flexible ureteroscopy have been described as an attempt to reduce RE during surgery. Beginning with specific checklists to ensure adequate C-arm usage, fluoroless procedures are based on endoscopic assessment, tactile guidance, and use of ultrasound to avoid fluoroscopy. A specific preoperative checklist and low radiation or complete fluoroless radiation endourological procedures have shown to be effective, feasible, and safe. It is recommended for urologists to be aware of the risks of RE and apply the "ALARA" (As Low As Reasonably Achievable) protocols.

Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Impact of laser fiber tip cleavage on power output for ureteroscopy and stone treatment.

PURPOSE: Holmium:YAG laser is the most used laser for urolithiasis. Generally, we use metallic scissors to cut the fiber tip to restore its effectiveness. Many cleaving methods have been described to avoid fiber damage and to restore its greatest power to the fiber. There is a lack of information regarding which cleaving method should be used and its effect on the fiber. In order to compare these effects, we studied different cleavage methods in terms of power output and its effects on the fiber. METHODS: New single-use 272-µm fibers were used with a holmium:YAG laser lithotripter. Five kinds of fiber tips were compared: a new intact fiber, cleaved with ceramic scissors, cleaved with metallic scissors, first cleaved then stripped and first stripped then cleaved. The fibers were used against synthetic stones (BegoStone®) similar to calcium oxalate monohydrate, with fragmentation (SP, 5 Hz, 1.5 J) and dusting (LP, 15 Hz, 0.5 J) settings. We measured power output at 0, 1, 5, 10 and 15 min. RESULTS: For fragmentation parameters, there was a statistical difference between the 5 groups at 0 and 1 min of laser use (p < 0.05) and none for time period over 1 min (p = 0.077-0.658). For dusting parameters, there was a statistical difference between the 5 groups at 0 min of laser use (p < 0.05) and none for time period over 0 min (p = 0.064-1). CONCLUSION: Cleaving the fiber tip may restore its effectiveness to the fiber, but only for a limited time, although it may preserve the scopes from damage.

The new grasper-integrated single use flexible cystoscope for double J stent removal: evaluation of image quality, flow and flexibility.

BACKGROUND: A new single use digital flexible cystoscope (FC) Isiris α from Coloplast® with an incorporated grasper has been developed to perform double J stent removal. There is a lack of data regarding the comparison of image quality, flexibility and flow between classic cystoscopes and the new Isiris α. MATERIALS AND METHODS: Five different FC were used to compare the image quality, the field of view, the loss of flow and the deflection loss. Two standardized grids, three stones of different composition and a ruler's image were filmed in four standardized different scenarios. These videos were shown to thirty subjects that had to evaluate them. Water outflow was measured in ml/sec in all devices with and without the grasper inside, instruments tip deflection was measured using a software. RESULTS: In the subjective analysis of the image quality Isiris α was the second FC best scored. At 3 cm of distance, the field view of Isiris α was the narrowest. Comparing the water flow in the different FCs, we observed a water flow decrease in all cystoscopes when the grasper was loaded in the working channel. Isiris α deflection and flow increase when the grasper is activated. CONCLUSION: In terms of quality of vision and water flow, the FC Isiris α is comparable to the other digital FC tested. Field of view is narrower. The results displayed a valid alternative to the standard procedure for DJ removal.

Has fluoroless endourology (URS and PCNL) come of age? Evidence from a comprehensive literature review.

INTRODUCTION: Radiation via the use of imaging is a key tool in management of kidney stones. Simple measures are largely taken by the endourologists to implement the 'As Low As Reasonably Achievable' (ALARA) principle, including the use of fluoroless technique. We performed a scoping literature review to investigate the success and safety of fluoroless ureteroscopy (URS) or percutaneous nephrolithotomy (PCNL) procedures for the treatment of KSD. METHODS: A literature review was performed searching bibliographic databases PubMed, EMBASE and Cochrane library, and 14 full papers were included in the review in accordance with the PRISMA guidelines. RESULTS: Of the 2535 total procedures analysed, 823 were fluoroless URS vs. 556 fluoroscopic URS; and 734 fluoroless PCNL vs. 277 fluoroscopic PCNL. The SFR for fluoroless vs. fluoroscopic guided URS was 85.3% and 77%, respectively (p=0.2), while for fluoroless PCNL vs. fluoroscopic group was 83.8% and 84.6%, respectively (p=0.9). The overall Clavien-Dindo I/II and III/IV complications for fluoroless and fluoroscopic guided procedures were 3.1% (n=71) and 8.5% (n=131), and 1.7% (n=23) and 3% (n=47) respectively. Only 5 studies reported a failure of the fluoroscopic approach with a total of 30 (1.3%) failed procedures. CONCLUSION: The ALARA protocol has been implemented in endourology in numerous ways to protect both patients and healthcare workers during recent years. Fluoroless procedures for treatment of KSD are safe and effective with outcomes comparable to standard procedures and could become the new frontier of endourology in selected cases.

Experimental and clinical applications and outcomes of using different forms of suction in retrograde intrarenal surgery. Results from a systematic review.

OBJECTIVE: To identify the latest advances in suction devices and evaluate their effect in Retrograde intrarenal surgery (RIRS) and ureteroscopy for stones. BASIC PROCEDURES: A systematic literature search was performed on 4th January 2023 using Scopus, PubMed, and EMBASE. Only English papers were included; both pediatric and adult studies were accepted. Duplicate studies, case reports, letters to the editor, and meeting abstracts were excluded. MAIN FINDINGS: Twenty-one papers were selected. Several methods have been proposed for suction use in RIRS, such as through the ureteral access sheath or directly to the scope. Artificial intelligence can also regulate this system, monitoring pressure and perfusion flow values. All the proposed techniques showed satisfactory perioperative results for operative time, stone-free rate (SFR), and residual fragments. Moreover, the reduction of intrarenal pressure (induced by aspiration) was also associated with a lower infection rate. Even the studies that considered kidney stones with a diameter of 20 mm or higher reported higher SFR and reduced postoperative complications. However, the lack of well-defined settings for suction pressure and fluid flow prevents the standardization of the procedure. CONCLUSION: Aspiration device in the surgical treatment of urinary stones favours a higher SFR, reducing infectious complications, as supported by the included studies. RIRS with a suction system provided to be a natural successor to the traditional technique, regulating intrarenal pressure and aspirating fine dust.

Entering into 2.0 cystinuric management with a medical digital tool to monitor urine pH: a prospective, randomized study.

BACKGROUND AND OBJECTIVES: Individuals with cystinuria can experiment recurrent lithiasis events due to the relative insolubility of cystine at physiological urine pH, resulting in renal function decline. The Lit-Control® pH Meter is a medical device that accurately allows urine pH self-monitoring. The main objective of this study was to compare the usability of the Lit-Control® pH Meter with the reactive strips for self-monitoring of urinary pH at home by patients with cystinuria, and their overall satisfaction with each tool. PATIENTS AND METHODS: We included 28 patients (9 females and 19 males, age 19-76 years), who were randomly assigned to monitor their urine pH with reactive strips (n = 17) or the Lit-Control® pH-meter (n = 11). RESULTS: After six months of use, the satisfaction with the two methods was similarly high, but the patients rated (0-10 scale) the pH meter better in terms of ease of learning (mean ±â€¯SD, 8.11 ±â€¯0.60 vs. 7.06 ±â€¯1.18; P = 0.038), ease to prepare (8.22 ±â€¯0.67 vs. 7.25 ±â€¯1.18; P = 0.034), and ease of use (8.22 ±â€¯0.67 vs. 7.25 ±â€¯1.39; P = 0.062). Overall, patients did not reach the alkalinization goals (pH between 7.0 and 8.0). CONCLUSIONS: The Lit-Control® pH Meter demonstrated to be an easy-to-use device that can facilitate urinary pH control by cystinuric patients. A prospective study is warranted to assess the correlation between urine pH monitoring, a treat to target approach, and the recurrence of cystine stones.

Assessment of intrarenal temperature dynamics when using holmium and thulium: YAG lasers in an ex vivo porcine kidney model.

AIM: To measure the temperature dynamics at the renal surface and within the urinary tract when using Ho:YAG and Tm:YAG lasers for tissue ablation. MATERIALS AND METHODS: Porcine kidneys were used. Both types of lasers with different configurations and fiber sizes were used through a flexible ureteroscope. The temperature at the renal surface was recorded using a thermal camera while the intrarenal temperature was measured using two thermal probes, the first one at the ureteropelvic junction and the second one at the calyx used for lasering. Temperature was determined at 0.5-1-3-5 and 10 min. RESULTS: Recordings at the ureteropelvic junction and calyx revealed significant increases when using Tm:YAG with the 273 µm (10 W to 50 W) (p ≤ 0.02) and 550 µm (10 W) fiber (p = 0.04). With Ho:YAG there was a significant increase when using 273 µm (at 10 W and 20 W) (p ≤ 0.03) and 365 µm (10 W) fibers (p = 0.04). Regarding fiber size there was a significant difference when using Tm:YAG (at 20 W and 40 W) (p < 0.05). The thermal camera recorded a mean increase of 8 °C in the UPJ while the remaining areas of the kidney did not undergo significant changes. CONCLUSIONS: Temperature changes were greater when using the Ho:YAG laser with respect to Tm:YAG at similar power settings for tissue ablation. The greatest temperature increase was recorded at the UPJ from where the heat dissipated throughout the kidney.

Factors associated with ureteral strictures following ureteroscopy for impacted ureteral stones? A multicenter study by EAU-YAU endourology and urolithiasis working party.

OBJECTIVE: To determine the relation between ureteral stone impaction and ureteral stricture formation and associated factors. MATERIAL AND METHODS: We retrospectively analyzed the medical records of all patients who underwent endoscopic ureteral stone surgery for impacted ureteral stone at three academic institutions in Turkey, United Kingdom and Spain between June 2019 and January 2022. Examined parameters included patient demographics, stone side, size and localization, time between initiation of symptoms and surgery, type of ureteroscopy (rigid/flexible), presence of nephrostomy or double-J stent prior to URS, intraoperative complications (avulsion/perforation, stone-free status, number of procedures required for stone-free status, postoperative imaging results. RESULTS: A total of 41 patients whom 25 were male and 16 were female, from 3 institutions were included the study. The mean age of the patients was 48.2 ±â€¯13.5 years. The median largest diameter of the stones was 9 mm (IQR: 8 mm). Total 14 (34.1%) patients developed ureteral strictures following ureteroscopy. There was no difference between patients who developed ureteral strictures and patients who did not developed strictures in terms of stone laterality, stone location, hydronephrosis and multiplicity, p = 0.58, p = 0.14, p = 0.79 and p = 0.31. Patients who developed ureteral strictures had a higher rate of preoperative urinary diversion such as nephrostomy or DJS, p = 0.000. CONCLUSION: Interruption of urine passage through ureter via urinary diversion such as nephrostomy or DJS stent prior to ureteral stone surgery might lead ureteral stricture formation in the postoperative period.

Does gender influence retrograde intrarenal surgery (RIRS) outcomes? Data from the Flexible Ureteroscopy Outcomes Registry (FLEXOR).

INTRODUCTION AND OBJECTIVES: As well established flexible ureteroscopy (RIRS). There is still no evidence if gender can have any influence on the outcomes and complication when performing. This study aims to evaluate the role that gender has in performing flexible ureteroscopy from a large series of patients. METHODS: This study retrospectively analyzed patients who underwent RIRS for renal stones from January 2018 to August 2021 within the multicentric FLEXOR registry. Demographics, stone characteristics, perioperative findings, results and complications were analyzed and compared between gender groups. RESULTS: A total of 6669 patients were included, 66.1% were male and 33.9% were female. Stone characteristics was comparable between groups. Female patients had significant higher fever and positive urine culture rates (12% vs. 8% and 37% vs. 34%). Also, females had a slight longer hospital stay (3.8 vs. 3.5 days; P < 0.001) and more residual fragments after the procedure (23.03% vs. 20.97 (P = 0.032). Overall complications were slightly significantly higher in women (15.74% vs. 14% (P = 0.042)) mainly at the expense of fever rates (6.9% vs. 5.7%) whereas the risk of sepsis was similar in both groups. A multivariate analysis showed that larger stone size, multiple and lower pole stones seem to have a negative impact in the incidence of residual stones and complications. CONCLUSION: Our real life global study reflects that female gender may have a correlation with a slightly increased residual fragment rate and overall low grade complications. However, women can safely be treated with RIRS with no increased the rate of sepsis with appropriate care.

A New Simplified Biplanar (0-90°) Fluoroscopic Puncture Technique for Percutaneous Nephrolithotomy. Reducing Fluoroscopy Without Ultrasound. Initial Experience and Outcomes.

OBJECTIVE: To present our simplified biplanar fluoroscopic puncture technique, its reduction in the fluoroscopic screening time as well as outcomes and the initial experience for percutaneous nephrolithotomy. METHODS: We performed a retrospective review of 136 patients operated with our simplified 0-90° puncture technique for percutaneous nephrolithotomy between 2015 and 2018. All patients were classified by stone complexity with Guy´s nephrolithometric stone score. The stone-free rate was evaluated by nonenhanced computerized tomography, and residual stones were defined as fragments ≥2 mm. Complications were divided according to the Clavien-Dindo classification. RESULTS: One hundred and thirty-six patients were operated with our puncture technique; 121 patients were performed in supine and 15 in the prone position. Fifty-one were men, and 85 were women with an overall mean age of 44.36 ± 13.23 years. The overall stone-free rate was 62.5%, and 83.8 % after an ancillary procedure. The mean fluoroscopy screening time was 69.47 ± 7.1 and 6 ± 4.1 seconds for the total surgical procedure and the percutaneous puncture, respectively. Complications were present in 25.7%, and no grade IV and V complications were present. CONCLUSION: Our first case series with the 0-90° simplified fluoroscopic puncture technique shows a similar stone-free rate and safety profile but a low fluoroscopic screening time compared to the most common previously reported fluoroscopic puncture techniques non-focused on low radiation protocols. Further studies are required to evaluate the reproducibility, external validation, and the learning curve of our simplified 0-90° technique.

Totally fluoroless retrograde intrarenal surgery technique in prestented patients: tips and tricks.

Treatment of urolithiasis has evolved greatly as retrograde intrarenal surgery (RIRS) has gained popularity nowadays being a gold standard therapy for renal stones up to 2 cm. Endourological procedures are traditionally fluoroscopic guided; thus, an increasing concern is the harm of radiation exposure, especially in the pediatric population. Therefore, performing fluoroless RIRS should be a feasible option for pediatric urologists. Herein, we describe the technique of totally fluoroless RIRS in presented patients and the tips to avoid radiation use at most.

Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial.

Fluconazole is recommended in the prophylaxis of oropharyngeal candidiasis (OPC) in patients undergoing radiotherapy for head-neck tumours; however, the actual effectiveness of fluconazole in this setting remains unclear. Adult patients with cervico-cephalic carcinoma submitted to radical or adjuvant radiotherapy were randomized to 100 mg fluconazole (n = 138) or matched placebo (n = 132) oral suspension once daily from the sixth session of radiotherapy up to the end of treatment. The final analysis of the investigation showed a higher rate of the OPC outbreak-free survival in the fluconazole compared with placebo (P = 0.008 in the log-rank test). The mean time (95% CI) to OPC outbreak was 56 (53-59) days in the fluconazole group and 47 (43-51) days with placebo. The mean duration of radiotherapy was 43.5 and 39.9 days, respectively in the two groups (P = 0.027). Adverse effects were reported in 70.3% of patients in the fluconazole group and in 67.4% with placebo. The results showed prophylaxis with fluconazole given in irradiated patients with head-neck tumours significantly reduces the rate and the time to development of OPC compared with placebo.

Fragmentation targeted at preferred discontinuities: A new concept in endolithotripsy with Holmium laser:YAG. / Fragmentación dirigida a discontinuidades preferentes: un nuevo concepto en endolitotricia con láser Holmium:YAG.

INTRODUCTION: There are currently 3holmium laser, YAG (Ho:YAG) endolithotripsy procedures that are considered basic (fragmentation, pulverisation, "pop-corn" technique). We present the technique of fragmentation targeted at preferred discontinuities (FTPD), a new concept of endolithotripsy by Ho:YAG laser. MATERIAL AND METHODS: The FTPD technique is based on the selective application of energy (targeting a specific preselected point) to an area that is visually prone to the formation of a fracture line or preferred discontinuity (conditioned by the anisotropy of the urolithiasis). The ideal energy regimen (setting) is a high range of working energy (2-3J) with a very low frequency range (5-8Hz) and short pulse width. Between January 2015 to February 2017, the FTPD technique was used in 37 procedures (7 NLP, 16 RIRS, 12 URS, 2 cystolithotomies), with a Ho:YAG laser (Lumenis Pulse 120H®, Tel-Aviv, Israel). Maximum power used: 24W (3J/8Hz) with fibres of 365µ and 273µ (URS, RIRS), and 32W (4J/8Hz) with fibres of 550µ (NLP, cystolithotomy). RESULTS: Strategic improvement was achieved in all cases using the TFPD technique to continue the endolithotripsy or remove fragments. No complications were recorded after the use of this method. CONCLUSIONS: FTPD can be considered a complementary option in combination with the basic methods of fragmentation and pulverisation. In our experience, it constitutes significant progress in optimising the performance of Ho:YAG laser endolithotripsy.

A rare case of adenoid cystic carcinoma of the nasopharynx manifesting as Horner's syndrome: discussion and review of the literature.

Adenoid cystic carcinoma is a malignant tumour involving the salivary glands, rarely developing in the nasopharynx. The biological behaviour of adenoid cystic carcinoma is characterized by slow growth rate, high tendency to local recurrence and metastatic spread. Its histological features are particularly important for prognostic prediction: solid pattern has the worst outcome. Initial presentation of nasopharyngeal adenoid cystic carcinoma with paresis of cranial nerves and Horner's syndrome is infrequent. The Authors present a case of a rare adenoid cystic carcinoma of the nasopharynx, at admission with Horner's syndrome, in a 66-year-old male. Magnetic resonance imaging showed an expansive submucosal lesion of the nasopharynx involving the para-pharyngeal space, tensor and levator veli palati muscles and the apex of petrous bone. Positron emission tomography excluded distant metastasis. Definitive histopathological examination revealed an adenoid cystic carcinoma with mixed cribriform and solid pattern. The patient was treated exclusively with radiotherapy (70 Gy) in 35 fractions with partial reduction of the neoplastic mass.

A randomized trial for the treatment of high-grade soft-tissue sarcomas of the extremities: preliminary observations.

A new trial for evaluating the effectiveness of adjuvant chemotherapy in high-grade soft-tissue sarcomas of the extremities in adult patients is presented. All patients after local treatment were randomized into two arms, one without further therapy and the other to receive adjuvant chemotherapy (Adriamycin [Farmitalia-Carlo Erba, Milan, Italy], 450 mg/m2). The preliminary results of the study are reported at a median observation period of 27.6 months. Of the 59 patients who entered the study, 79.1% in the chemotherapy group are without sign of disease, whereas the corresponding figure in the nonadjuvant chemotherapy group is 54.3%. The difference between the two groups is statistically significant (P less than .005, log rank test). These preliminary observations encourage continuation of the study.

Paclitaxel and radiotherapy: sequence-dependent efficacy--a preclinical model.

The optimal sequence of a paclitaxel-radiation combination was investigated in vitro in two human colon adenocarcinoma cell lines, HT29 and LoVo. Three schedules of combined treatment were tested by clonogenic and flow cytometric assays. Paclitaxel was given 24 h prior to a single radiation shot (first schedule) or 24 h (second schedule) or 48 h (third schedule) before 3 days of concomitant radiation. Dose-response data were fit to a linear quadratic model, and mean inactivation dose and sensitizer enhanced ratio were calculated. In HT29 cells, the first and second schedule resulted in an additive effect, whereas a supraadditive interaction was observed with the third combination schedule. This effect was obtained with amounts of paclitaxel lower than IC50, which did not result in cell cycle perturbation, and with low radiation dose (2 Gy) that may be given in a clinical setting. LoVo cells were less sensitive to combined treatment than HT29 cells, switching from infraadditive (first and second schedule) to additive interaction (third schedule). Posttreatment recovery studies of third schedule showed a loss of cell survival in HT29 cells but not in LoVo cells. In contrast to LoVo cells, the third schedule in HT29 cells was able to induce perturbation of cell cycle kinetics, an effective impairment of DNA repair, and apoptotic cell death. HT29 and LoVo cells showed constitutional different characteristics: HT29 cells were more sensitive to paclitaxel exposure, less radiosensitive, and had a different cell cycle redistribution after radiation exposure than LoVo cells; moreover, HT29 cells showed a major propensity to undergo apoptosis. These results suggest that the radiosensitizing effect of paclitaxel was strictly schedule dependent, and the inhibition of DNA repair, cell cycle redistribution, and apoptosis could be the mechanisms for the induction of radiosensitization by paclitaxel.

Paclitaxel and radiotherapy in the treatment of advanced non-small cell lung cancer.

Sixteen patients affected by previously untreated non-small cell lung cancer stage IIIB or IV received radiotherapy and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) as radiation sensitizer in an open, nonrandomized pilot study to find the maximum tolerated dose of the drug concomitantly combined with radiation. Paclitaxel was given as a 3-hour infusion once weekly at a dose escalating by 10 mg/m2/wk for every patient cohort, starting at 40 mg/m2/wk and continuing to 80 mg/m2/wk. Conventionally fractionated (2 Gy/d for 5 d/wk for 5 weeks) radiotherapy up to 50 Gy was delivered to the primary tumor and mediastinum with a 6-mv linear accelerator. Hematologic toxicity has been very low; grade 3 World Health Organization nonhematalogic toxicities have been registered only at the 80 mg/m2/wk dose level. Seven patients achieved a major response, three patients had stable disease, and five patients progressed; three patients are still responding, whereas the others are relapsed and five of them died of disease. The median duration of response was 5 months. Paclitaxel may be safely combined with radiation at the maximum tolerated dose of 70 mg/m2/wk. Our data seem to confirm the radiosensitizing effect of the drug, independent of the dose level. Low doses of paclitaxel given as a single agent are unable to control metastatic disease.