IP Arm Research Articles

Weight management in rural health clinics: Results from the randomized midwest diet and exercise trial.

Rural living adults have higher rates of obesity compared with their urban counterparts and less access to weight management programs. Previous research studies have demonstrated clinically relevant weight loss in rural living adults who complete weight management programs delivered by university affiliated interventionists. However, this approach limits the potential reach, adoption, implementation, and maintenance of weight management programs for rural residents. Weight management delivered through rural health clinics by non-physician clinic associated staff, for example, nurses, registered dieticians, allied health professionals, etc. has the potential to improve access to weight management for rural living adults. This trial compared the effectiveness of a 6-month multicomponent weight management intervention for rural living adults delivered using group phone calls (GP), individual phone calls (IP) or an enhanced usual care control (EUC) by rural clinic associated staff trained by our research team. Rural living adults with overweight/obesity (n=187, age∼50years 82% female, body mass index ∼35kg/m2) were randomized (2:2:1) to 1 of 3 intervention arms: GP, which included weekly∼45min sessions with 7-14 participants (n=71), IP, which included weekly∼15min individual sessions (n=80), or EUC, which included one-45min in-person session at baseline. Weight loss at 6months was clinically relevant, that is, ≥5% in the GP (-11.4kg, 11.7%) and the IP arms (-9.1kg, 9.2%) but not in the EUC arm (-2.6%, -2.5% kg). Specifically, 6month weight loss was significantly greater in the IP versus EUC arms (-6.5kg. p≤0.025) but did not differ between the GP and IP arms (-2.4kg, p>0.025). The per participant cost per kg. weight loss for implementing the intervention was $93 and $60 for the IP and GP arms, respectively. Weight management delivered by interventionists associated with rural health clinics using both group and IP calls results in clinically relevant 6months weight loss in rural dwelling adults with overweight/obesity with the group format offering the most cost-effective strategy. Clinical trial registration: ClinicalTrials.gov (NCT02932748).

Oncological outcomes of intraperitoneal chemotherapy in advanced ovarian cancer: BRCA mutation role

IntroductionThe knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. Materials and methodsWe performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. ResultsA total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16–0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37–1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06–043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22–1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. ConclusionThis retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.

In-utero exposure to tenofovir disoproxil fumarate pre-exposure prophylaxis and growth metrics in HIV unexposed breastfed infants in South Africa: a post hoc analysis of the CAP 016 PrEP in pregnancy RCT.

We evaluated growth metrics in HIV unexposed African breastfed infants in the first 18 months of life in association with in-utero exposure to Tenofovir Diphosphate Fumarate (TDF) containing pre-exposure prophylaxis (PrEP). We conducted a secondary data analysis of a TDF-PrEP randomized control trial (CAP016 RCT). Pregnant women without HIV were randomized to initiating TDF-PrEP in pregnancy (Immediate-PrEP-IP) or deferred initiation of TDF-PrEP at cessation of breastfeeding (Deferred-PrEP-DP). Infant weight (W), length (L), and head circumference (HC) were measured at birth and 6, 26, 50, and 74 weeks of age. Stored dried blood spot samples from pregnant women randomized to the IP arm were used to measure tenofovir-diphosphate (TFV-DP) levels. Age-stratified mean weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head circumference-for-age (HCAZ) Z-scores were compared between infants exposed to varying TFV-DP concentrations and infants in the DP arm. A total of 455 mother-infant pairs were included in the secondary analysis, 228 in the IP arm and 227 in the DP arm. WAZ, LAZ, WLZ, and HCAZ scores were comparable between infants in the Deferred-PrEP arm and Immediate-PrEP arm. In a mixed-effects linear regression model adjusting for maternal age, body mass index, socioeconomic and newborn characteristics, in-utero exposure to varying TFV-DP levels was not associated with WAZ (β = -0.52), LAZ (β = -0.46), WLZ (β = -0.43) and HCAZ (β = -0.11) scores over time. There was no evidence of an association between growth metrics in the first 18 months of life and in-utero exposure to TFV-DP among breastfed HIV unexposed infants.

A Randomized Controlled Trial of Two Parenting Interventions on Enhancing Parental Resilience Resources and Reducing Children’s Problem Behaviors in Chinese Cross-Boundary Families: Positive Benefits and Moderation Effects

Daily cross-boundary schooling between Shenzhen and Hong Kong constitutes a constant challenge for Chinese cross-boundary families in terms of parenting burden. To address their most urgent parenting needs, we adapted and evaluated two intervention approaches—improving emotional regulation and providing knowledge about Hong Kong. A cluster randomized controlled trial with repeated assessments (pre-, post-intervention, and one-month follow-up) was adopted to evaluate the intervention effects on the increases of parental resilience resources and reduction of children’s problem behaviors. We further conducted moderation analyses to investigate whether parents with more increases in parental resilience resources would report a greater reduction in children’s problem behaviors. A total of 214 mothers of cross-boundary families were randomly assigned to the emotional regulation arm (ER, n = 120) or the information provision arm (IP, n = 94). Both intervention arms showed positive effects on emotional regulation strategies, and the IP arm outperformed the ER arm in knowledge acquisition. Both arms showed significant and comparable improvements in parental self-efficacy and children’s problem behaviors. Moreover, participants in the IP arm who reported more improvements in parental resilience resources showed a greater reduction in children’s problem behaviors. By adapting two interventions to a new population of cross-boundary families, this trial extended the benefits from parents to children and demonstrated that the improvement of parental resilience resources makes a difference in reducing children’s problem behaviors in the IP arm. Future studies are suggested to focus on parental resilience resources and maximize the benefits on children’s outcomes.

Efficacy and safety of polyherbal formulation as an add-on to standard-of-care in mild-to-moderate COVID-19: A randomized, double-blind, placebo-controlled trial

BackgroundNovel corona virus disease-2019 (COVID-19) pandemic is a significant contributor to morbidity and mortality in affected individuals. Modulating the immune response in COVID-19 is now an established treatment approach. Polyherbal formulations have long been assessed for their potential immune modulating effects and are expected to be beneficial on COVID-19. MethodsThis study aims at assessing the efficacy and safety of polyherbal formulation (referred as IP) in comparison to placebo, as add on to the standard of care (SOC), in patients with mild to moderate COVID-19 patients. Hospitalized RT-PCR positive patients were randomized to either SOC + IP or SOC + Placebo arm. The viral load (VL) was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Immunological parameters were also assessed. The clinical improvement was assessed using a numeric rating scale (NRS) and WHO ordinal scale, and follow-up period was 30 days. ResultsSeventy-two patients were randomized to SOC + IP (n = 39) and SOC + Placebo (n = 33) arms. There was significant reduction in VL in SOC + IP arm from day 0–4 (p = 0.002), compared to SOC + Placebo arm (p = 0.106). Change in the NRS score and WHO score was significant in both arms, however, the difference between the two arms was statistically significant in favour of IP arm. The increase in Th1 response was significant in SOC + IP arm (p = 0.023), but not in SOC + Placebo arm. COVID-19 specific antibodies were numerically higher in the SOC + IP arm. ConclusionThe study finds that polyherbal formulation significantly reduces VL and contributes to immunomodulation and improvement in clinical conditions without side effects.

The More the Better, Only in the Longer Term: A Cluster Randomized Controlled Trial to Evaluate a Compound Intervention Among Mainland Chinese Immigrants in Hong Kong

Barriers to adaptation faced by mainland Chinese immigrants to Hong Kong can be reduced by improving two targets of adaptation: information about negotiating their new environment and psychological well-being. We developed and evaluated a Compound intervention to address these two domains simultaneously and compared its effects to two separate interventions exclusively targeting either information about Hong Kong or psychological well-being. This cluster randomized controlled trial assigned 251 immigrants to an information provision arm (IP, n = 84) targeting knowledge and adaptation difficulties, a psychological well-being enhancement arm (WBE, n = 80) targeting resilience and mental health, or a Compound arm (i.e., IP + WBE, n = 87). The Compound arm showed stronger effects from baseline to postintervention on knowledge than the WBE arm. From postintervention to 6-month follow-up, the Compound arm showed better sustained effects on knowledge and adaptation difficulties than the IP arm and on resilience and mental health than the WBE arm. Additionally, participants in the Compound arm with more baseline depressive symptoms showed greater improvements in adaptation difficulties and general mental health than those with fewer symptoms. The study demonstrated the longer-term effectiveness of the Compound intervention and its greater benefits for immigrants with more depressive symptoms.

Hyperthermic Intraperitoneal Chemotherapy for Treatment of Ovarian and Primary Peritoneal Malignancies: Single Institutional Experience

Objective: To report our institutional experience onhyperthermicintraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery (CRS) for ovarian, fallopian tube and primary peritoneal cancer. Methods: We reviewed charts of patients who underwent CRS and HIPEC. Optimal cytoreduction was defined as residual disease < 1cm. HIPEC was administered using closed technique. The postoperative complications were graded using the Clavien-Dindo classification. Grade III and IV complications were considered as major. Survival was estimated using the Kaplan-Meier method. Results: During the study period, we identified262 patients who underwent HIPEC and CRS. Fifteen of those patients (6%) were diagnosed with gynecologic tumors. Five patients (33%) had primary CRS and HIPEC for primary peritoneal carcinoma and ten patients (66%) had CRS and HIPEC for recurrent ovarian tumors. The median OR time was 327 min.Optimal cytoreduction was achieved in all patients (100%) and 7 patients (47%) had no gross residual disease. Major postoperative complications were reported in five patients (33%). The median follow up was 34 months. The median progression free survival (PFS) was 7 months (95% confidence interval (CI), 1-15 months) for recurrent disease. For the primary disease the median PFS was 26 months (95% CI: 7-26 months) comparable with IP arm in GOG-172. Conclusion: Combination of CRS and HIPEC is a feasible therapeutic modality for patients with ovarian, fallopian tube and primary peritoneal malignancies. Addition of HIPEC to CRS does not seem to increase the rate of grade III and IV postoperative complications and may be associated with survival benefit.

Hyperthermic intraperitoneal chemotherapy for treatment of ovarian and primary peritoneal cancer: Single institutional experience

Objective: To report our institutional experience on hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery (CRS) for ovarian, fallopian tube and primary peritoneal cancer. Methods: We reviewed charts of patients who underwent CRS and HIPEC. Optimal cytoreduction was defined as residual disease < 1cm. HIPEC was administered using closed technique. The postoperative complications were graded using the Clavien-Dindo classification. Grade III and IV complications were considered as major. Survival was estimated using the Kaplan-Meier method. Results: During the study period, we identified 262 patients who underwent HIPEC and CRS. Fifteen of those patients (6%) were diagnosed with gynecologic tumors. Five patients (33%) had primary CRS and HIPEC for primary peritoneal carcinoma and ten patients (66%) had CRS and HIPEC for recurrent ovarian tumors. The median OR time was 327 min. Optimal cytoreduction was achieved in all patients (100%) and 7 patients (47%) had no gross residual disease. Major postoperative complications were reported in five patients (33%). The median follow up was 34 months. The median progression free survival (PFS) was 7 months (95% confidence interval (CI), 1-15 months) for recurrent disease. For the primary disease the median PFS was 26 months (95% CI: 7-26 months) comparable with IP arm in GOG-172. Conclusion: Combination of CRS and HIPEC is a feasible therapeutic modality for patients with ovarian, fallopian tube and primary peritoneal malignancies. Addition of HIPEC to CRS does not seem to increase the rate of grade III and IV postoperative complications and may be associated with survival benefit.

A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck

BackgroundCetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. MethodsWe conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m2)] to intravenous single agent cisplatin (IP) (75mg/m2) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0–2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. Results110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101days, 95% CI: 58.2–143.7days) compared to the IP arm (median 66days, 95% CI; 55.8–76.1days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249days, 95% CI: 222.5–275.5days) compared to the IP arm (median 152days, 95% CI: 104.2–199.8days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). ConclusionOral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting.

Oral Nutritional Support Can Shorten the Duration of Parenteral Hydration in End-of-Life Cancer Patients: A Randomized Controlled Trial

Tube feeding or hydration is often considered for end-of-life cancer patients despite the negative effects on quality of life. The efficacy of oral nutritional support in this setting is unknown. We conducted a randomized trial to compare the efficacies of an amino acid jelly, Inner Power® (IP), and a liquid enteral product, Ensure Liquid® (EL), in terminally ill cancer patients. We randomly assigned patients to 3 arms: EL, IP, and EL+IP. The primary endpoint was drip infusion in vein (DIV)-free survival, which was defined as the duration from nutritional support initiation to administration of parenteral hydration. Twenty-seven patients were enrolled in the study, of whom 21 were included in the intention-to-treat analysis. The median age of the subjects was 69 yr. There were significant differences between the arms with regard to the median DIV-free survival (0.5, 6.0, and 4.5 days in the EL, IP, and EL + IP arms, respectively; P = 0.05). The median overall survival was 7, 9, and 8 days in the EL, IP, and EL + IP arms, respectively. IP may shorten the duration of parenteral hydration in terminally ill cancer patients and does not affect their survival.

A German multicenter, randomized phase III trial comparing irinotecan–carboplatin with etoposide–carboplatin as first-line therapy for extensive-disease small-cell lung cancer

BackgroundThis trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer. Patients and methodsPatients were randomly assigned to receive carboplatin area under the curve 5 mg ·min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1–3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity. ResultsOf 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0–7.0] in the IP arm and 6.0 months (95% CI 5.2–6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4–11.6) and 9.0 months (95% CI 7.6–10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96–1.73, P = 0.095) and 1.34 (95% CI 0.97–1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. ConclusionThis trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.

Camptothecins Compared with Etoposide in Combination with Platinum Analog in Extensive Stage Small Cell Lung Cancer: Systematic Review with Meta-Analysis

Superiority of camptothecin regimens over etoposide-both combined with platinum analogs-in extensive disease small cell lung cancer has been a matter of debate with contradictory findings in randomized trials. A systematic review was sought to elucidate this issue. Randomized controlled trials comparing first-line camptothecin-platinum doublets versus etoposide-platinum doublets in patients with extensive disease small cell lung cancer were searched in MEDLINE, EMBASE, LILACS, and CENTRAL databases, European Society of Medical Oncology, American Society of Clinical Oncology, and International Association for the Study of Lung Cancer meeting sites. Meta-analyses were performed using fixed-effects model. Subgroup analyses were undertaken comparing each type of camptothecin to etoposide-based regimens. The outcomes of interest were overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicities. Eight studies (3086 patients) were included. The meta-analysis of topotecan regimens (TP) was not reliable due to impending heterogeneity. Meta-analysis of trials testing irinotecan combinations (IP) versus etoposide regimens (EP; 1561 patients) stated an OS improvement in favor of IP arm, though with considerable heterogeneity, whose origin seemed to be a Japanese trial. In the analyses without that study (1407 patients left), IP brought a significant improvement in OS (hazard ratio = 0.87; 95% confidence interval 0.78-0.97; p = 0.02; I = 0). IP also increased PFS (hazard ratio = 0.83; 95% confidence interval 0.73-0.95; p = 0.006; I = 0%). There was no impact in RR (absolute RR 56% with IP; 53% with EP; p = 0.17). IP caused more diarrhea (p < 0.0001) but less hematological toxicities (p < 0.001) than EP. The present meta-analysis demonstrates statistically significant OS and PFS benefits of IP over EP regimens in western and eastern patients. Specific characteristics of safety profile should be taken into account when administrating IP chemotherapy.

Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study

BackgroundWe undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix. Patients and methodsOne hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m2, daily, on days 1–3 and cisplatin 70 mg/m2 on day 2) or the same combination with the addition of paclitaxel 175 mg/m2 on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis. ResultsA modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P=0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P=0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P=0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P=0.046) and 0.75 for death (P=0.124) compared with the doublet. ConclusionThe ITP combination merits further investigation in randomized phase III studies.

Intraperitoneal Chemotherapy in Ovarian Cancer Remains Experimental

Furthermore, more patients in the experimental arm (IP chemotherapy) were lost to follow-up, compared with those treated in the control arm (11v five patients). Such differences are not usually a concern. However, there were 127 and 101 patient deaths in the control and IP arms of the trial, respectively, and as few as three additional patient deaths in the IP arm could make the result nonsignificant. The statistical difference between the two arms of the trial is so marginal that these differences in eligiblity or loss of follow-up need to be investigated further. The absolute difference in patients alive (15 patients) was less than those patients lost to follow-up (16 patients; 11 in the IP arm), and this is a very small proportion of the total population. It must be questioned whether such toxic treatment should be introduced as

The Four-Arm Cooperative Study (FACS) for advanced non-small cell lung cancer (NSCLC): A subgroup analysis in elderly patients (pts)

7115 Background: Efficacy and safety in fit, elderly NSCLC pts receiving platinum-based treatment have been reported to be similar to those in younger pts. However, there is controversy about which platinum-based regimens are suitable for the elderly. To compare efficacy and safety of platinum-based chemotherapy regimens in the elderly, we conducted an age specific subgroup analysis on FACS, a phase III randomized trial comparing four platinum-based regimens for advanced NSCLC. Methods: FACS was designed to compare three platinum-based combination regimens to cisplatin (80 mg/m2, day 1) plus irinotecan (60 mg/m2, days 1, 8, 15) (IP) as the reference arm. The experimental regimens were: carboplatin (AUC 6, day 1) plus paclitaxel (200 mg/m2, day 1) (TC); cisplatin (80 mg/m2, day 1) plus gemcitabine (1000 mg/m2, days 1, 8) (GP); cisplatin (80 mg/m2, day 1) plus vinorelbine (25 mg/m2, days 1,8) (NP). Results: Of the 105 pts ≥ 70 years (17% of 602 enrolled pts), 27 were on the IP arm, 27 on TC, 28 on GP, and 22 on NP. Patient characteristics were similar in each arm. Response rates were 26% in IP, 20% in TC, 32% in GP, 50% in NP. Frequency of grade 3 or greater leukocytopenia (IP/TC/GP/NP: 52%/33%/36%/86%) was higher in NP, and thrombocytopenia (IP/TC/GP/NP: 11%/19%/43%/0%) was higher in GP, however anemia (IP/TC/GP/NP: 56%/19%/29%/55%) was lower in TC and GP. Frequency of grade 2 or greater vomiting (IP/TC/GP/NP: 52%/22%/39%/41%) was lower in TC, and diarrhea (IP/TC/GP/NP: 48%/7%/4%/14%) was lower in TC, GP and NP, however, grade 2 or greater sensory neuropathy (IP/TC/GP/NP: 0%/22%/0%/0%) was higher in TC. One year survival rates were 48% for the IP arm, 48% for TC, 61% for GP, and 46% for NP. There were no significant survival differences between IP and each experimental regimen. In addition, no significant differences between ≥ 70 and &lt; 70 years were observed in each treatment regimen regarding hematological and non-hematological toxicities, response rates, and survival, except that grade 3 or greater anemia was significantly higher in ≥ 70 years pts in IP and NP arms. Conclusions: These platinum-based four regimens were similarly active and tolerable for fit, elderly NSCLC pts, and their efficacy and toxicity in the elderly were similar to those in younger pts. No significant financial relationships to disclose.

Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radical Surgery in Patients With Locally Advanced Squamous Cell Cervical Carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study

Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival. Patients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses. Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001). The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.

Treatment of Small Cell Lung Cancer.

Among patients with lung cancer, approximately 15% have small cell lung cancer (SCLC), SCLC is usually staged as either limited and extensive. Extensive-stage SCLC is treated primarily with chemotherapy. A recent Japanese randomized trial compared cisplatin and irinotecan (IP) with cisplatin and etoposide (EP). Patients in the IP arm did significantly better than patients in the EP arm. In the IP arm, the response rate was 84%, and the median overall survival period was 12.8 months. Limited- stage SCLC is usually treated with concurrent chemotherapy and accelerated radiation therapy, and approximately 20% of patients are cured. Future research should focus on optimizing chemotherapy regimens and radiation therapy schedules. The role of molecular targeted drugs in the treatment of SCLC must also be evaluated.

Comparison of navelbine plus ifosfamide and cisplatin versus ifosfamide plus cisplatin in the treatment of advanced non small cell lung cancer

To observe the efficacy and safety of navelbine (NVB) combined with ifosfamide (IFO) and cisplatin (DDP) (NIP regimen) and IFO plus DDP (IP regimen) for advanced non-small cell lung cancer (NSCLC). One hundred and twenty patients with advanced NSCLC pathologically proved were randomly divided into group A (NIP regimen, n=60) and group B (IP regimen, n=60). In group A, 58 patients were evaluable. The response rates were 58.62%(34/58), 65.58%(17/26) and 53.12% (17/32) in whole group, untreated patients, and retreated patients, respectively. The median duration of survival was 11.3 months. One-year survival rate was 40.0%. In group B, 59 patients could be evaluated. The response rates were 40.68%(24/59), 63.33%(19/30) and 17.24%(5/29) in whole group, untreated patients, and retreated patients, respectively. The median duration of survival was 9 months and 1-year survival rate was 36.7%. There was no significant difference in objective response rate among all the patients and the patients with no prior treatment between the two groups ( P > 0.05, P > 0.05). However, among retreated patients, the response rate in group A was remarkably higher than that in group B ( P < 0.05). The main dose limiting toxicity was myelosuppression. Leukopenia at grade III+IV was significantly higher in the NIP arm than in the IP arm ( P < 0.05). NIP yields a higher response rate than IP does in retreated patients, with acceptable toxicity, which can be the first line regimen in the retreatment of advanced NSCLC. IP regimen showes a similar response rate and less toxicity in initial patients, compared with NIP regimen, so it might be considered a relevant regimen in initial patients with advanced NSCLC.

NUCLEOTIDE-METABOLISM AND CHROMOSOME ALTERATIONS IN HUMAN-MALIGNANT MELANOMA XENOGRAFTS

The karyotypes of human melanomas exhibit multiple chromosome alterations. Recurrent deletions of 9p, 10q and 14q arms, which carry genes encoding for enzymes of purine metabolism, were also found in human gliomas, another neuroectodermal tumor previously studied for both cytogenetics and nucleotides metabolism. Postulating that this metabolism might also be modified in melanomas, the activities of eleven enzymes involved in catabolic and synthetic pathways of purine metabolism were measured, in addition to two enzymes of the pyrimidine synthesis. Assays were performed on six melanoma mestastases, five nodal and one cutaneous, after transplantation into nude mice. The purine metabolism was characterized by a more active catabolic than synthetic pathway, a possible imbalance between de novo and salvage pathways for adenylates synthesis, rather in favor of the de novo pathway, and a more active adenylate than guanylate synthesis. The skin metastasis exhibited quite different cytogenetic and metabolic patterns, when compared to the nodal metastases. Considering the relationships between cytogenetic and metabolic data, low activities of methylthioadenosine phosphorylase, adenosine kinase, adenosine monophosphate deaminase, nucleoside phosphorylase and 5'-nucleotidase were observed in melanomas, as well as frequent losses of 9p, 10q, Ip, 14q and 6q arms respectively carrying genes encoding for these enzymes, most of these rearrangements were confirmed by chromosome painting. The two enzymes exhibiting the highest activities were adenosine deaminase and adenylosuccinate lyase, encoded by genes mapped on chromosomes 20 and 22 respectively, frequently in excess in melanomas. Thus, for these tumors, the metabolic pattern roughly parallels the cytogenetic profile, even if the absence of case to case correlation suggests that gene dosage effect, if it occurs, is not the only parameter involved. The main enzymatic and cytogenetic difference between melanomas and gliomas, concerns both adenylosuccinate lyase activity and the balance of chromosome 22, high in melanomas and low in gliomas.