Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer.

BACKGROUND: Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits the insulin-like growth factor 1 receptor. This multicenter, randomized, phase III study investigated the efficacy of figitumumab plus erlotinib compared with erlotinib alone in patients with pretreated, nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (stage IIIB/IV or recurrent disease with nonadenocarcinoma histology) who had previously received at least one platinum-based regimen were randomized to receive open-label figitumumab (20 mg/kg) plus erlotinib 150 mg/day or erlotinib alone every 3 weeks. The primary end point was overall survival (OS). RESULTS: Of 583 patients randomized, 579 received treatment. The study was closed early by an independent data safety monitoring committee due to results crossing the prespecified futility boundary. At the final analysis, median OS was 5.7 months for figitumumab plus erlotinib and 6.2 months for erlotinib alone [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.91-1.31; P = 0.35]. Median progression-free survival was 2.1 months for figitumumab plus erlotinib and 2.6 months for erlotinib alone (HR 1.08; 95% CI 0.90-1.29; P = 0.43). Treatment-related nonfatal serious adverse events occurred in 18% and 5% of patients in the figitumumab arm or erlotinib alone arm, respectively. There were nine treatment-related deaths (three related to both drugs, four related to erlotinib alone and two related to figitumumab). CONCLUSIONS: The addition of figitumumab to erlotinib did not improve OS in patients with advanced, pretreated, nonadenocarcinoma NSCLC. Clinical development of figitumumab has been discontinued. CLINICAL TRIAL ID: NCT00673049.

Intraperitoneal photodynamic therapy of human epithelial ovarian carcinomatosis in a xenograft murine model.

The objective of this investigation was to determine the efficacy of i.p. photodynamic therapy (PDT) against solid, multifocal ovarian carcinoma using a newly described NIH:OVCAR-5 induced murine model. PDT was initiated when diffuse microscopic disease and small multifocal tumor nodules were present, similar to the extent of residual carcinoma that may persist clinically after laparotomy and tumor debulking. The photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA), was administered in a dose of 0.25 mg/kg body weight i.p. 90 min prior to light exposure. An argon-pumped dye laser was used to deliver low intensity light (20 J) i.p. through a cylindrically diffusing fiberoptic tip. Treatment regimens consisted of a series of three to five treatments at 3-7 day intervals, with the extent of macroscopic disease or death from disease being the evaluable outcome parameters for tumoricidal and survival studies, respectively. The mean tumor burden at necropsy for treated animals was 0.034 +/- 0.014 g compared to 0.379 +/- 0.065 g in untreated controls (P<0.001). Survival studies were initiated in two groups at day 7 and day 14 following cell inoculation. The first group received either three or five treatments at 5-day intervals, and both had a significant increase in median survival compared to untreated controls (57 and 53 days, respectively, compared to 43 days, P<0.05). The second group was treated every 7 days until death and also had a significant survival advantage over controls (57 days compared to 47 days, P<0.05). These studies suggest that benzoporphyrin derivative mono acid ring A-mediated PDT is a feasible, well-tolerated, experimental treatment approach that elicits a tumoricidal response against diffuse, solid i.p. disease in tumor-bearing mice, with concomitant prolongation of survival and needs careful optimization.

Experimental photoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1A chlorin(e6) immunoconjugate.

Photoimmunotherapy (using a monoclonal antibody-targeted photosensitizer and red light) may be a strategy to overcome the limitations inherent in photodynamic therapy of liver tumors. The aims of this study were (a) to test the efficacy of selective treatment of hepatic metastases of colorectal cancer in an orthotopic murine xenograft using the murine monoclonal antibody 17.1A conjugated to the photosensitizer chlorin(e6), and (b) to compare the tumor response after the same light dose was delivered at two different fluence rates. Based on previous biodistribution studies that had shown that the photoimmunoconjugate with a polyanionic charge had both a higher absolute tumor chlorin(e6) content and a greater tumor:normal liver ratio than those obtained with a photoimmunoconjugate bearing a polycationic charge, mice were treated 3 h after i.v. injection of the polyanionic 17.1A chlorin(e6) conjugate or unconjugated photosensitizer. Red light was delivered into the liver tumor by an interstitial fiber, and tumor response end points were total tumor weight in the short term and survival in the long term. There was a highly significant reduction (<20% of controls; P = 0.0035) in the weight of the tumors in the mice treated with photoimmunotherapy, and the median survival increased from 62.5 to 102 days (P = 0.015). Photodynamic therapy with free chlorin(e6) produced a smaller decrease in tumor weight and a smaller extension of survival, neither of which were statistically significant. A comparison of photoimmunotherapy with 10 J of light delivered at 30 or 300 mW showed that the higher fluence rate prolonged survival significantly more than the lower fluence rate. This may have been because the high fluence rate gave a contribution of laser-induced hyperthermia to the photodamage. Correlation studies showed that the amount of normal liver remaining at necropsy correlated best with survival. Photoimmunotherapy shows efficacy in destroying liver tumors, and future studies should maximize selectivity to minimize the destruction of normal liver.

Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

Light dosimetry for intraperitoneal photodynamic therapy in a murine xenograft model of human epithelial ovarian carcinoma.

Few studies have been published to date measuring spatially resolved fluence rates in complex tissue geometries. Here the light distributions of three different intraperitoneal light delivery geometries in a murine ovarian cancer model were investigated to assess their influence on the tumorcidal efficacy of photodynamic therapy (PDT). In vivo fluence rate measurements in the peritoneal cavities of mice, with the light intensity being mapped in three transverse planes, were performed using fiber-optic detectors. Three different source fiber designs and placements were tested for their ability to provide uniform irradiation of the peritoneal cavity. The biological response to a PDT protocol comprising three separate treatments administered at 72 h intervals, each consisting of a 0.25 mg kg-1 intraperitoneal injection of benzoporphyrin derivative-mono acid ring A followed 90 min later by delivery of 15 J of 690 nm light, was measured. The tissue response was evaluated by measuring the number of remaining visible lesions and the total residual tumor mass. Fluence rate measurements showed large variations in the fluence rate distribution for similar intended treatments. The most uniform and reproducible illumination was achieved using two 18 mm long cylindrical emitting optical fibers. The biological response was comparable to that produced when a flat-cleaved end optical fiber is used to illuminate the four quadrants of the abdomen sequentially. While a good reproducibility in tumor induction in this animal model exists, no correlation was found between the fluence rate distribution measured in one group of animals and the biological response in a separate group of similarly treated animals. Due to the large intra-animal variability in fluence rate distribution, representative fluence rate mapping in complex tissue geometries is of limited value when applied to an individual PDT treatment. Thus, surveillance of the fluence rate during individual treatments will be required for acceptable PDT dosimetry. To improve the versatility of this particular animal model for PDT research, a large number of extended sources are required to increase uniformity of the illumination in order to reduce unwanted cytotoxic side effects resulting from foci of high fluence rates. In this way, subsequent increase of the total energy delivered to the tumor may be possible.

Deep venous thrombosis associated with large leiomyomata uteri. A case report.

BACKGROUND: The association of deep venous thrombosis (DVT) with uterine leiomyomata has been reported only rarely in the English-language literature. These concomitant findings occurred in a woman with no other known risk factors for development of DVT. CASE: A 49-year-old, Caucasian woman, gravida 3, para 3, with a past medical history significant for large uterine leiomyomata, menorrhagia and anemia, presented with acute edema of the left lower extremity. Doppler studies revealed compression of the left iliofemoral vein with associated thrombosis. No risk factors for DVT were identified. Intravenous heparin was initiated, with eventual preoperative placement of an inferior vena cava Greenfield filter. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed without complications. CONCLUSION: Large uterine leiomyomata are a potential cause of lower extremity venous stasis and resulting thrombosis and can be treated with hysterectomy.

Tuboovarian abscess in postmenopausal women.

A retrospective review was done on all patients at Tampa General Hospital with a surgically confirmed tuboovarian abscess between March 31, 1983, and April 30, 1988. Patients were grouped according to their menopausal status. Sixty-three were identified. Fifty-four were premenopausal and nine postmenopausal. The median ages of the two groups (26 and 52, respectively) were significantly different. The premenopausal patients had a significantly lower median parity and were significantly more likely to have a prior history of gonorrhea and/or pelvic inflammatory disease. The postmenopausal patients were significantly more likely to have contributing medical problems and to have concomitant genital tract pathology. Such pathology, found in 13% of the premenopausal patients, consisted mainly of large leiomyomata uteri. In 3 (33.3%) of the postmenopausal patients there was a strong preoperative suspicion of a coexisting pelvic abscess originating in the genital tract. Two of the patients developed septic shock shortly before surgery. Concomitant pelvic pathology was present in six patients (66.7%), with four of them having genital tract malignancies. An attempt at early recognition and surgical management of tuboovarian abscess is important in postmenopausal women. There is little to be gained by delaying surgical treatment, and the patient is at significant risk of deterioration. In addition, surgical exploration appears to be vital to the recognition and treatment of concomitant pelvic malignancy or other pathologic conditions that may be contributing to the abscess.

Sentinel lymph node detection and microstaging in vulvar carcinoma.

OBJECTIVE: To determine the efficacy of using complementary techniques for detecting sentinel lymph nodes (SLNs) in vulvar carcinoma and to evaluate the utility of microstaging techniques. STUDY DESIGN: Patients with invasive vulvar carcinoma underwent sentinel lymph node detection (SLND) using preoperative lymphoscintigraphy, intraoperative isosulfan blue dye injection and an intraoperative hand-held gamma-detecting probe. Eleven patients were included and a total of 16 groins evaluated. Sentinel nodes identified were excised, bisected and examined in surgical pathology using hematoxylin and eosin (H&E) staining. Pathologically negative SLNs were subjected to additional microstaging via serial sectioning and immunohistochemical staining for cytokeratin. Surgical management of the vulvar cancer and extent of inguinal-femoral lymphadenectomy were individualized based on clinicopathologic parameters, including depth of invasion, location of the tumor and patient performance status. RESULTS: Lymphoscintigraphy, dye and gamma-detector methods led to the total detection of 16, 19 and 17 SLNs, respectively. In two cases the isosulfan blue dye assisted in the isolation of an additional sentinel node over that of the gamma probe. Each method individually identified SLNs in 10/11 patients (91%). A total of 19 sentinel nodes were isolated. One SLN (5%) was positive for metastatic disease using H&E staining. Of the 18 negative SLNs, 2 (11%) had micrometastases (< 0.2 mm) upon serial sectioning and immunohistochemical staining. CONCLUSION: Combined-modality mapping enhances detection of SLNs in vulvar carcinoma. Histologic microstaging improves the detection of micrometastases within SLNs.

Postoperative pelvic irradiation in early stage uterine mixed mullerian tumors.

PURPOSE OF INVESTIGATION: To review our management experience with uterine mixed mullerian tumors (MMTs) in order to evaluate potential prognostic indicators, and assess the efficacy of various treatment modalities. METHODS: A retrospective, clinicopathologic evaluation of 43 patients presenting for treatment of uterine MMTs between 1982 and 1992 was conducted. Diagnostic criteria for inclusion was the presence of both a malignant glandular or squamous epithelial component, and a homologous or heterologous stromal component. RESULTS: Overall 2- and 5-year cancer related Kaplan-Meier survival estimates with 95% confidence intervals were 44 (.28, .59) and 26% [.12, .39], respectively. Survivals were 83 [.62, .99] and 58% [.31, .85] when disease was confined to the uterus, and 22 [.03, .41] and 7% [.01, .20] when disease extended beyond the uterus. Clinical staging was often inaccurate, with 29% of clinical stage I or II disease being upstaged at laparotomy. A significant survival advantage was found in patients with stage I or II disease treated with surgery plus pelvic irradiation (p = 0.001), as compared to those treated with surgery alone. The prognosis after disease recurrence was poor, irrespective of secondary therapy, with a median survival of 11 months. CONCLUSIONS: A therapeutic advantage may be gained from postoperative pelvic irradiation in the treatment of surgical stage I or II uterine MMT.

Recurrent psammocarcinoma of the peritoneum with complete response to tamoxifen therapy.

Psammocarcinoma is a rare type of serous carcinoma arising from the ovary or peritoneum, characterized by massive psammoma body formation, invasiveness, and low-grade cytological features. A case of primary peritoneal psammocarcinoma is presented. Aspects of clinical presentation, diagnosis, and management are described. Emphasis is placed on successful management of recurrent disease using tamoxifen therapy.

Advanced ovarian carcinoma diagnosed during pregnancy in a patient with human immunodeficiency virus infection.

Many malignancies appear to occur with increased frequency and aggressive patterns of spread in patients seropositive for human immunodeficiency virus (HIV). The relationship between HIV infection and cervical neoplasia suggests that these patients present with more advanced disease and demonstrate poor response to therapy. To date, there have been no reported cases of ovarian cancer with concomitant HIV infection. We describe a young, gravid woman with an advanced ovarian carcinoma diagnosed at the time of delivery. Following poor response to cytoreductive surgery and initial chemotherapy, she was found to be HIV-seropositive. She received multiple chemotherapeutic regimens and experienced significant complications associated with her treatment and HIV infection. She progressively deteriorated and died within 13 months of diagnosis. Based on these findings and experience with other HIV-associated malignancies, it is apparent that the conventional approach to therapy is inadequate to treat the advanced and more aggressive form of disease seen in women infected with HIV.

The effect of postsurgical therapy on stage III endometrial carcinoma.

The records of 86 pathologic stage III endometrial carcinoma patients treated at Massachusetts General Hospital between 1974 and 1992 were retrospectively reviewed to identify predictors of poor outcome and to determine the effect of postsurgical therapy on recurrence and survival. Patients underwent TAH/BSO with selective lymphadenectomy and peritoneal washings. Cases prior to 1988 were retrospectively restaged using the FIGO surgical staging criteria. Postoperatively, patients received individualized regimens of EBRT (external beam radiotherapy), brachytherapy, and cytotoxic or hormonal chemotherapy. The 5-year survival and 5-year disease-free survival (DFS) for all patients were 54 and 44%, respectively. Forty-two percent of stage IIIA/B patients recurred in a median time of 14 months. Fifty-four percent of stage IIIC patients recurred in a median time of 16 months. Of patients who recurred, 90% stage IIIA/B and 71% stage IIIC patients recurred at extrapelvic sites. Age greater than 70, high-grade lesions, and fallopian tube metastases were predictive of poor outcome in stage IIIA/B by multivariate analysis. Vascular invasion was the only poor prognostic factor identified by multivariate analysis in stage IIIC disease. No benefit from pelvic EBRT in stage IIIA/B could be identified. Stage IIIC patients had increased DFS and a trend for increased survival with pelvic EBRT. Chemotherapy did not improve survival in either group.

Intraperitoneal photoimmunotherapy of ovarian carcinoma xenografts in nude mice using charged photoimmunoconjugates.

OBJECTIVE: The objective of this study was to compare the efficacy of photoimmunoconjugates with cationic and anionic molecular charges on intraperitoneal photoimmunotherapy of ovarian cancer xenografts in nude mice. METHODS: The photosensitizer chlorin(e6) (c(e6)) was conjugated via a poly-l-lysine linker to the F(ab')(2) fragment of the murine anti-ovarian cancer monoclonal antibody OC125, resulting in a photoimmunoconjugate with a pronounced cationic charge. Alternatively, by succinylating the poly-l-lysine conjugate, a photoimmunoconjugate with a pronounced anionic charge was obtained. A murine model of ovarian cancer derived from intraperitoneal inoculation of NIH:OVCAR-5 cells was employed. The conjugate was injected intraperitoneally followed after 3 h by red light delivered through a fiber into the peritoneal cavity. These photoimmunotherapy treatments were repeated three times, and the results obtained with the anionic and cationic photoimmunoconjugates were compared with those obtained with free c(e6) and control. The extent of residual macroscopic disease and death from disease were the evaluable outcomes for tumoricidal and survival studies, respectively. RESULTS: In contrast to other intraperitoneal photosensitizers, mice showed no systemic toxicity or morbidity from the treatment. In this initial study the mean residual tumor weights in all treatment groups ranged from 33 to 73 mg, as compared with 330 mg in untreated controls (P < 0.0001), and the response to the cationic conjugate was significantly better than that to the anionic conjugate or free c(e6) (P < 0.005). The median survival for mice treated with cationic photoimmunoconjugate was 41 days, compared with 35 days in controls (P = 0.009). CONCLUSION: Photoimmunotherapy with a cationic photoimmunoconjugate produces results superior to those obtained with an anionic conjugate, and further optimization of the treatment regimen may lead to a potential treatment for advanced ovarian cancer.

Vaginal small cell carcinoma mimicking a Bartholin's gland abscess: a case report.

We report a case of a 32-year-old woman with a lesion in the vagina which clinically mimicked a Bartholin's gland abscess, but was demonstrated to be a small cell carcinoma by light microscopy. This tumor is very rare and to our knowledge there are 13 reported cases of primary vaginal small cell carcinoma in the English literature. The mean age of presentation of this neoplasm in the 13 reported cases is 61 with a median survival of 12 months. This case stresses the importance of considering this unusual diagnosis when confronted with a large or recurrent "Bartholin's gland lesion," and underlines the need for careful pathological examination of such specimens.

Stage IB and IIA cervical cancer with negative lymph nodes: the role of adjuvant radiotherapy after radical hysterectomy.

The records of 171 patients with lymph node-negative stage IB and IIA cervical cancer primarily treated with radical hysterectomy and pelvic lymphadenectomy from 1974 to 1992 were retrospectively reviewed to identify poor prognostic factors and evaluate the role of adjuvant pelvic radiotherapy. One hundred sixteen patients (68%) were treated with radical hysterectomy alone (RH) and 55 patients (32%) received adjuvant radiotherapy (RH + RT). Factors predictive of recurrence for the entire group of patients included lymph-vascular space invasion (LVSI) (P = 0.003) and grade 3 histology (P = 0.04). Patients receiving RH + RT were older and more likely to have outer third cervical wall invasion, LVSI, positive margins, > or =2 cm pathologic tumor size, and >4 cm clinical tumor size (all P < 0.05). Overall, 28 patients (16%) developed recurrent disease with no difference between RH and RH + RT groups. After controlling for confounding variables, patients with LVSI who received RH + RT were less likely to develop disease recurrence than patients receiving RH alone (P = 0.04). LVSI is an important prognostic variable in lymph node-negative stage IB and IIA cervical cancer. Although adjuvant pelvic radiotherapy may decrease the risk of recurrence in patients with LVSI, the majority of patients with negative lymph nodes may be treated with radical surgery alone.

Characterization of a xenograft model of human ovarian carcinoma which produces intraperitoneal carcinomatosis and metastases in mice.

A new xenograft model for human epithelial ovarian carcinoma, with extensive intraperitoneal (i.p.) carcinomatosis as the predominant disease manifestation, is described. Cells from the established NIH:OVCAR-5 cell line were injected i.p. into 6- to 8-week-old Swiss nude mice. Comparative analyses between cells cultured in vitro and tumor cells derived ex vivo were performed to assess histologic features, immunohistochemical cell markers, hormonal receptor expression, adhesion to extracellular matrix molecules and chromosomal constitution. Macroscopically, the extent of tumor development appeared to be site-dependent and tumor cell survival was dose-dependent. Advanced disease was characterized by extensive solid tumor burden and ascites with parenchymal invasion, lymphatic metastases and vascular dissemination. Individual tumor nodules exhibited developing neovasculature characterized by the absence of mature basement membrane. Despite some histologic loss of cellular differentiation in advanced disease, antigenic expression was preserved, distinguishing these cells as epithelial in origin. Karyotyping of tumor cells demonstrated multiple numeric and structural chromosomal abnormalities. Serum and ascites CA 125 levels were consistently elevated only in tumor-bearing mice. This new murine model closely resembles the aggressive disease process of human epithelial ovarian carcinoma, in which the efficacy of i.p. and systemic therapeutic modalities can be investigated.