Safety and efficacy of nivolumab therapy in patients with metastatic renal cell carcinoma and impaired kidney function.

INTRODUCTION: Patients with renal insufficiency, usually defined as those with creatinine clearance < 40 mL/min, were excluded from pivotal clinical trials, especially in studies involving nivolumab therapy in patients with renal cell carcinoma (RCC). The aim of the study is to evaluate the efficacy and safety of nivolumab in patients with metastatic RCC (mRCC) stratified according to creatinine clearance. MATERIAL AND METHODS: Data from mRCC patients treated with nivolumab were retrospectively analyzed. Patients were classified into two categories according to their estimated glomerular filtration rate (eGFR); the first category (C1) included patients with eGFR < 40 mL/min/1.73 m2 and the second category (C2) included those with eGFR ≥ 40 mL/min/1.73 m2. RESULTS: Of the 95 patients enrolled, 1. group included 26 patients (27.4%) and 2. group included 69 patients (72.6%). None of the pts in category 1 were on hemodialysis. Overall incidence of adverse events was not statistically different between the two groups (P = .469). The overall response rate ORR was 50% in the first group and 42.0% in the second group (P = .486). Median overall survival (OS) was longer with 23.3 months in the 2. group versus 11 months in the 1. group (P = .415). CONCLUSION: Renal insufficiency is a common problem in patients with advanced renal cancer since they often undergo nephrectomy and their renal function may also worsen while receiving tyrosine kinase inhibitor therapy. We found that there is no significant difference in the safety and efficacy of nivolumab treatment between two groups. Nivolumab appears to be a safe and effective agent in patients with renal impairment.

Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial.

BACKGROUND: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. PATIENTS AND METHODS: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. CONCLUSIONS: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN.

BACKGROUND: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years. PATIENTS AND METHODS: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP. RESULTS: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off. CONCLUSIONS: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC.

Outcomes with durvalumab after chemoradiotherapy in stage IIIA-N2 non-small-cell lung cancer: an exploratory analysis from the PACIFIC trial.

BACKGROUND: The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC. MATERIALS AND METHODS: Patients with unresectable, stage III NSCLC and no disease progression after ≥2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models. RESULTS: Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.33-0.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR = 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status. CONCLUSIONS: Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable.

Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

Retraction to: British Journal of Cancer (2014) 110, 1968-1976; doi:10.1038/bjc.2014.72. It has been brought to our attention that, as a result of a miscommunication, the antibody used in this study in order to determine the expression of p95 HER2 in metastatic breast cancer patients is in fact directed against p95 NBS1, a component of the MRN complex, and is completely unrelated to p95 HER2. Therefore, a relationship between p95 HER2 overexpression and outcome cannot be established based on the results described and we wish to retract our paper. The authors, the editors of British Journal of Cancer, and the referees of this paper are grateful to colleagues in the field who have brought this problem to our attention and we apologise for any confusion that has, inadvertently, been caused.

Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

BACKGROUND: Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ~30-40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively. MATERIALS AND METHODS: Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ(2), Fischer's exact test and Mann-Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and survival curves of subgroups were compared with log-rank test. RESULTS: Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5-13.4 months) and 22 months (95% CI, 9.9-34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6-34 months) and 12.1 months (95% CI, 7.9-16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3-40.4 months) and 29.1 months (95% CI, 8.6-43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5-40.1 months) and 26.8 months (95% CI, 8.1-42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2-4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1-3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18-4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14-3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis. CONCLUSIONS: Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.

Preoperative chemoradiotherapy improves local recurrence free survival in locally advanced rectal cancer.

PURPOSE: Preoperative chemoradiotherapy (pre-CRT) followed by total mesorectal excision (TME) is the recommended therapy for patients with locally advanced rectal cancer (LARC). The primary aim of this study was to compare the rates of local and distant recurrence and overall survival (OS) in LARC patients who received pre-CRT vs postoperative (post) CRT. METHODS: The medical records of 158 rectal cancer patients with clinical stage T3, T4 or N positive disease who received either pre-CRT or post-CRT between 2000-2009 were retrospectively analysed. Pre-CRT employed protracted 5-fluorouracil (5FU) infusion, whereas post-CRT included bolus 5FU and leucovorin concurrently with radiation therapy (RT). Radiation dose was 50.4 Gy in 82% and 45 Gy in 18% of the patients. RESULTS: 158 patients (65 females, 93 males) were analysed. Median age was 56.5 years (range 19-78). Fifty-three (34%) patients received pre-CRT and 105 (66%) post-CRT. Median follow-up was 43.3 months (range 8-182) and 47.6 months (range 9-194) in pre-CRT and post-CRT patients, respectively. After pre-CRT, significant downstaging was achieved. However, the type of surgical resection was not influenced by the administration of pre-CRT in tumors ≥5 cm distant from the anal verge (p=0.3). Pathologic complete response was achieved in 20% of the patients in the pre-CRT group. Local recurrence free survival (LRFS) at 5-years was 89.2% in the pre-CRT and 74.8% in the post-CRT group (p=0.04). Distant recurrence free survival (DRFS) at 5-years was 81.7% and 68.5 % in pre-CRT and post-CRT groups, respectively (p=0.1). OS was similar in the two groups (71.4 vs 64.4%, p=0.9). CONCLUSION: Treatment of LARC with pre-CRT followed by surgery improved LRFS as compared to surgery followed by post-CRT, but failed to improve DRFS or OS in our patient population.

Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial.

BACKGROUND: Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone. METHODS: Updated TROPIC data (cut-off 10 March 2010) were used to compare 2-year survival between treatment groups and assess patient demographics and disease characteristics. Factors prognostic for survival ≥2 years were assessed. Pain and Eastern Cooperative Oncology Group performance status were evaluated in the overall patient population. RESULTS: Median follow-up was 25.5 months. After 2 years, more patients remained alive following cabazitaxel than mitoxantrone [odds ratio 2.11; 95% confidence interval (CI) 1.33-3.33]. Treatment with cabazitaxel was prognostic for survival ≥2 years. Demographics/baseline characteristics were balanced between treatment arms irrespective of survival. Pain at baseline and pain response were comparable between treatment groups. Average daily pain performance index was lower for cabazitaxel versus mitoxantrone (all cycles; 95% CI -0.27 to -0.01; P = 0.035) and analgesic scores were similar. Grade ≥3 peripheral neuropathies were uncommon and comparable between treatment groups. CONCLUSIONS: Cabazitaxel prolongs OS at 2 years versus mitoxantrone and has low rates of peripheral neuropathy. Palliation benefits of cabazitaxel were comparable to those of mitoxantrone. The study was registered with www.ClinicalTrials.gov (NCT00417079).

The role of K-RAS and B-RAF mutations as biomarkers in metastatic colorectal cancer.

PURPOSE: Unlike cetuximab, there is a paucity of biomarkers for bevacizumab as predictors of outcome in metastatic colorectal cancer (mCRC) patients. Obviously exploring the worth of some potential markers in this setting is warranted. The purpose of this study was to investigate the predictive value of the presence of K-RAS and B-RAF mutations on the outcome of patients with mCRC treated with FOLFIRI and bevacizumab combination therapy. METHODS: A total of 172 patients with mCRC were evaluated. K-RAS and B-RAF mutations were analyzed by quantitative PCR. Median progression-free survival (PFS) and overall survival (OS) were compared utilizing chi-square and Mann-Whitney U tests, respectively. RESULTS: Forty-four percent (N=77) of the patients were found to harbor K-RAS mutations and 6 (7.5%) were positive for B-RAF mutations. In baseline no difference in PFS and OS was observed between the groups with or without K-RAS mutation. No relationship was established between K-RAS and B-RAF mutation status and baseline CEA and CA19-9 tumor markers levels. CONCLUSION: K-RAS and B-RAF mutations do not seem to be predictive of treatment outcome as potential biomarkers for bevacizumab therapy in mCRC. However, not only the presence of K-RAS and B-RAF mutations but also the different biological behavior of the various subtypes of mutations should be considered as potential determinants in the final outcome of this disease.

Determining predominating histologic component in malignant mixed müllerian tumors: is it worth it?

Malignant mixed müllerian tumors (MMMT) are highly aggressive tumors, usually diagnosed in advanced stage. Cases of MMMT derive from either ovary or uterus. In our study, we investigated the role of carcinomatous and sarcomatous component on response to chemotherapy and disease outcome. We retrospectively analyzed 25 patients with MMMT who were treated in our outpatient clinic from 1998 to 2003. All the paraffin specimens were reevaluated according to the histopathologic features (primary site and percentages of carcinomatous and sarcomatous component) and the effect of predominant histologic type on response to treatment. Primary tumor sites were ovary and endometrium in 36% and 64% of patients, respectively. Ten of 25 patients (40%) were treated with a combination chemotherapy regimen of cisplatin-ifosfamide (PI) and 7 patients (28%) were treated with paclitaxel-carboplatin (PC) protocol. Despite chemotherapy, 17.6% of patients had progressive disease. The remaining 13 patients (54.2%) responded to chemotherapy. Response rates of patients treated with PC (100%) were remarkably higher than the response rates of patients treated with PI (66.6%). Moreover, patients with predominating carcinomatous component had a higher response rate (87.5%) than patients with predominating sarcomatous component (66.6%). MMMT are highly chemoresponsive tumors, irrespective of primary site. One of the best predictors to response is the histologic pattern. Predominating histopathologic feature (carcinoma or sarcoma) should be taken into consideration in predicting the response and planning the chemotherapy regimen.

Metastasis from breast carcinoma to endometrial polyp.

Metastasis of a breast carcinoma to an endometrial polyp is extremely rare, with only ten cases having been reported in the literature up to now. We present the case of a 60-year-old woman with invasive ductal carcinoma who complained of vaginal bleeding. She underwent hysteroscopy with biopsy. Microscopic examination revealed an endometrial polyp which contained foci of adenocarcinoma. The morphologic features of the tumor were identical to the original breast carcinoma.

Devastating effects of chemotherapy: deafness and acute renal failure in a patient with epithelial ovarian cancer.

Paclitaxel and platinum combination is the standard chemotherapy regimen for patients with advanced epithelial ovarian cancer. The dose-limiting toxicity effects of this combination are myelosuppression and neuropathy. Herein, we report a case of a 71-year-old female with advanced epithelial ovarian cancer who developed bilateral total loss of hearing and acute renal failure related with paclitaxel- and carboplatin-based chemotherapy. Acute renal failure accompanied by complete loss of hearing in patients treated with carboplatin and paclitaxel combination has not been previously reported. This uncommon adverse effect of carboplatin and paclitaxel combination was discussed, and all the literature in English related with the toxicity of paclitaxel and carboplatin were reviewed.

Role of the antiangiogenetic drug paclitaxel on healing of intestinal anastomosis: an experimental study.

BACKGROUND: The aim of intraperitoneal administration of antineoplastic agents is the prevention of the implantation of tumoral cells after surgical intervention or the treatment of peritoneal carcinomatosis. The efficiency of intraperitoneal administration of paclitaxel, which is also an antiangiogenetic agent, has been investigated recently. The aim of this experimental study was to evaluate, taking into consideration its antiangiogenetic properties, the effects of intraperitoneal paclitaxel on healing of end to end colonic anastomosis. METHODS: 42 rats were allocated to 2 main groups (n = 21 for each group) to be evaluated on postperative day 3 (group A) and postoperative day 7 (group B). Each of the two main groups was divided into 3 subgroups (7 rats each). These subgroups were determined as control and two treatment groups administered paclitaxel in a dose of 2.5 mg/kg and 3.5 mg/kg intraperitoneally. Anastomosed segments of colon were harvested on postoperative day 3 or 7 and evaluated to determine bursting pressure of anastomoses, hydroxyproline levels and neovascularization with CD-31. RESULTS: In both groups, there were no significant differences between control and paclitaxel-treated groups with respect to bursting pressure. The level of hydroxyproline showed a significant decrease in all paclitaxel-treated groups compared with control groups (p = 0.001). Neovascularization was found to be decreased significantly on day 3 in the doses of paclitaxel 2.5 mg/kg (6.4 +/- 1.63) and 3.5 mg/kg (5.89 +/- 1.01) compared with control (8.02 +/- 0.88) (p = 0.029 and p = 0.005, respectively). There were no significant differences in neovascularization in either groups on postoperative day 7. CONCLUSION: We suggest that intraperitoneal administration of paclitaxel during surgical procedure decreases the hydroxyproline content and neovessel formation that are necessary for healing of intestinal anastomosis.

Delayed onset bleomycin-induced pneumonitis.

We describe a 39-year-old male patient who developed bleomycin-induced pneumonitis 2 years after completion of chemotherapy for nonseminomatous testicular cancer. Bleomycin sometimes causes fatal pulmonary toxicity, including bleomycin-induced pneumonitis. The central event in the development of pneumonitis is endothelial damage of the lung vasculature due to bleomycin-induced cytokines and free radicals. Pulmonary toxicity usually begins at bleomycin administration. The development of bleomycin-induced pneumonitis up to 6 months after bleomycin therapy has also been reported. We report a patient who developed bleomycin-induced pneumonitis 2 years after the initiation of bleomycin-containing chemotherapy regimens.

Should mammographic screening be done in primary ovarian cancer?: A case control study in Turkish women.

Breast cancer is a significant global health problem. It is the most common malignancy in women. Mammographic screening is recommended for women older than 40 yr for early detection of breast cancer. The aim of this study is to evaluate the role of screening mammography in ovarian cancer independent of age. Eighty-four patients with ovarian cancer were evaluated with bilateral mammography. Two hundred asymptomatic healthy controls with a similar age distribution were also imaged with screening mammography. Mammography results were classified according to the American College of Radiology criteria in five groups. The median age of the study group was 51.4 (range, 27-77) and 49.3 (range, 30-75) in the control group. Screening mammography detected four cases of malignancy (4.8%) in patients with ovarian cancer; two were the primary breast carcinomas(2.5%) and two were metastatic cancers from the ovary. Five subjects (2.5%) among healthy controls were also found to have breast cancer. Although the incidence of primary breast carcinoma was found to be similar in the two groups (2.5%), mammographic imaging detected metastatic disease to the breast from the ovaries. Mammography should therefore be considered in patients with ovarian cancer independent of age.

Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin's lymphoma.

In patients with non-Hodgkin's lymphoma (NHL), there are some well-known tumor-related adverse prognostic factors that may increase the mortality rate. However, secondary factors such as viral hepatitis carriers that may decrease the cure rates are usually ignored. Reactivation of hepatitis B virus (HBV) infection in patients undergoing cytotoxic treatment for NHL is a well-known complication. Charts of 112 patients with NHL were retrospectively analyzed regarding their hepatitis serology, the indirect effects of seropositivity on disease outcome, and the precautions undertaken in these seropositive patients with NHL. Twelve patients (11%) with HBsAg positivity and two patients (1.7%) with antibody to hepatitis C virus positivity were detected. Eight out of 12 patients (67%) with HBsAg positivity and two patients (50%) with anti-HCV positivity showed reactivation of hepatitis during treatment of NHL. No reactivation was detected in four patients seropositive for HBV, who were given lamivudine prophylaxis before the initiation of chemotherapy schedules. Among patients with hepatitis reactivation, two were treated with lamivudine resulting in dramatic improvement and clinical remission of the disease. The remaining six patients with reactivation were left untreated, resulting in four deaths (67%) due to liver failure secondary to HBV and two deaths secondary to delayed treatment of NHL. One patient seropositive for anti-HCV also developed chronic hepatitis C. Determination of hepatitis serology in all patients with NHL before any chemotherapy administration is crucial, but insufficient, if not taken into consideration. In seropositive patients, HBV DNA should be determined and antiviral prophylaxis with lamivudine should be initiated before any treatment.

Do we really benefit from checking tumor markers in detecting recurrence in gastrointestinal cancer?

PURPOSE: To evaluate the role of tumor markers carcinoembryonic antigen (CEA) and CA 19.9 in the early detection of local or systemic recurrence in gastrointestinal malignancies. PATIENTS AND METHODS: Twenty-six patients with operable gastrointestinal cancer, who had elevated levels of either CEA or CA 19.9 or both during the postoperative follow-up period were evaluated. Serum estimation of tumor markers were carried out at 3-month intervals and the imaging and endoscopic procedures were performed at 6-month intervals or when a patient had an elevated tumor marker during follow-up. RESULTS: The difference of mean serum levels of CA 19.9 but not of CEA was found to be statistically significant between the two groups of patients with or without radiographically / endoscopically evident recurrent disease (p < 0.05). CONCLUSION: CA 19.9 was found to be a better, though not specific, indicator of recurrence. The relative small number of patients precludes reaching a firm conclusion. Further studies are needed to establish the role of these markers in determining early recurrence and their impact in overall survival.