Evaluation of response in malignant tumors treated with the multitargeted tyrosine kinase inhibitor sorafenib: a multitechnique imaging assessment.

OBJECTIVE: The purpose of this article is to illustrate the characteristic changes induced in different tumor types by the multitargeted tyrosine kinase inhibitor sorafenib. CONCLUSION: Sorafenib reduces tumor perfusion and thereby induces necrosis and often hemorrhage. Malignant tumors treated with sorafenib undergo both morphologic and functional changes; however, the morphologic changes are less frequent and inadequate for early evaluation of response. Therefore, imaging tools accurately assessing hemorrhage and decrease in tumor perfusion with subsequent necrosis should be the mainstay in monitoring targeted therapy agents.

Randomised phase II trial of trofosfamide vs. doxorubicin in elderly patients with untreated metastatic soft-tissue sarcoma.

Doxorubicin represents the standard first-line treatment for metastatic soft-tissue sarcoma. We assessed the efficacy and safety of trofosfamide in elderly patients. In this controlled phase II trial, we randomly (1:2) assigned 120 previously untreated patients with soft-tissue sarcoma, older than 60 years, with an Eastern Cooperative Oncology Group score of 0-2, to receive either doxorubicin for 6 cycles (arm A) or oral trofosfamide (arm B). The primary end-point was a 6-month progression-free rate (PFR) in the experimental arm (clinical trial information: NCT00204568). Between August 2004 and October 2012, forty and 80 patients were randomly assigned to arm A and arm B, respectively, in 16 centres. The median age was 70 years (range, 60-89). The primary study end-point (6-month PFR) was exceeded, with 27.6% in arm B (95% confidence interval [CI], 18.0-39.1) and 35.9% in arm A: (95% CI, 21.2-52.8). Survival data in terms of progression-free survival were 4.3 months (95% CI, 2.2-6.3) and 2.8 months (95% CI, 1.7-3.6) and in terms of overall survival were 9.8 months (95% CI, 6.7-11.6) and 12.3 months (95% CI, 9.6-16.2), respectively. The number of serious adverse event (SAE) was 59% in arm A and 30.3% in arm B (p = 0.005). Trofosfamide caused more often dyspnoea and low-grade fatigue, whereas with doxorubicin, more often leukocytopenia, neutropenia and mucositis were seen. Discontinuation rates for reasons other than disease progression were 15.4% (arm A) vs. 7.9% (arm B). In an elderly population of patients, oral trofosfamide achieved the estimated primary end-point 6-month PFR and was associated with a favourable toxicity profile compared with doxorubicin.

Surgery of colorectal carcinoma in patients aged over 80.

BACKGROUND: The incidence of colorectal carcinoma increases rapidly in aged patients. We investigated retrospectively the differences in treatment relative to the patients' age. PATIENTS AND METHODS: A total of 394 patients with colorectal carcinoma (group I: > or =80 years, n = 197; group II: 60-79 years, n = 197) were analyzed in an average period of 4 years in relation to surgery, comorbidities, postoperative morbidity, mortality, survival and recurrence. RESULTS: Patients > or =80 years had a significantly higher rate of comorbid conditions (p = 0.04; cardiovascular, p = 0.01; diabetes mellitus, p < 0.05) and more carcinomas in the sigmoid/rectum (72% vs. 67%; p < 0.05). Tumor stage, R0 resection rate, and overall complication rate were not influenced by age. The 30-day mortality rate was significantly higher in group I (12% vs. 3%; p = 0.02). Emergency surgical procedures were required significantly more often in group I (14%) than in group II (5%; p = 0.003). The 5-year survival rate among patients in group I was 30.1% compared to 50.5% among patients in group II (p < 0.0001). CONCLUSIONS: Elderly patients have a higher rate of comorbidity and a higher postoperative 30-day mortality rate. Tumor stage, R0 resection rate, and overall postoperative complication rate do not appear to be influenced by age. The higher rate of emergency operations on patients > or =80 years is associated with the higher 30-day mortality. Even in patients aged > or =80 years, attention should focus on the long-term oncological results, after appropriate assessment of the preoperative risk.

Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer.

OBJECTIVE: To evaluate the progression-free rate (PFR) at 3 months (13+/-1 weeks), antitumor response, time-to-event efficacy endpoints, and toxicity profile of plitidepsin administered as a 3-h continuous i.v. infusion at a dose of 5mg/m(2), every 2 weeks, to patients with chemotherapy pretreated advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a multicenter, non-randomized, exploratory, phase II study. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. PFR (primary efficacy endpoint) and objective response rate (secondary efficacy endpoint) were evaluated according to RECIST, while the toxic profile of plitidepsin was assessed using the NCI-CTC, version 2.0. RESULTS: A total of 21 patients with a median age of 61 years and with locally advanced or metastatic non-resectable NSCLC, who had previously received only one line of chemotherapy in an advanced setting, received a total of 54 cycles of treatment (median of two cycles per patient; range: 1-8). Antitumor activity was seen in 3 (1 PR, 2 SD) out of 17 evaluable patients according to RECIST. One patient was responder for the primary (PFR at 13+/-1 weeks) and secondary efficacy endpoint (stable disease according to RECIST). Other two patients were non-responders for the primary efficacy endpoint, but had stable disease (not confirmed at weeks 13+/-1 due to previous withdrawal due to adverse events). With a median follow-up of 12.3 months, the median time to progression (TTP) and the median overall survival (OS) were 1.2 months and 4.3 months, respectively. The incidence of plitidepsin-related toxicities was low and most of them were mild-to-moderate in severity. The most common side effects were anemia, and asymptomatic and non-cumulative increases of gamma-glutamyltransferase (GGT) and liver transaminase levels. CONCLUSION: This study shows that plitidepsin 3-h continuous i.v. infusion (5mg/m(2)) every 2 weeks, was feasible and well tolerated in patients with pretreated NSCLC. The lack of evidence of antitumor activity precludes further studies with this plitidepsin schedule in this tumor setting.

PTEN and p27Kip1 are not downregulated in the majority of renal cell carcinomas--implications for Akt activation.

Activation of the PKB/Akt pathway is supposed to substantially contribute to the pathogenesis and progression of malignant disease. The present study aimed at determining the occurrence of an impaired PTEN and p27Kip1 expression alone or in combination in a renal cell carcinoma to further clarify the role of Akt-pathway-associated proteins for the development and/or progression of this malignant disease. By using tissue microarray analysis, tissue samples from renal cell cancers and the corresponding benign tissue samples were investigated for expression of the PTEN, pAkt and p27Kip1 protein by immunohistochemistry. Additionally, a Western blot and RT-PCR analysis was performed to verify the results obtained from the immunohistochemical approach and to further clarify the mechanisms underlying the regulation of both proteins in renal cell cancer. Western blot analysis revealed an overexpression of PTEN and p27Kip1 in renal cell cancer samples and a significantly elevated expression of both proteins when compared with the corresponding benign tissue (p<0.0001 and p<0.0005). The latter finding was confirmed by real-time RT-PCR (p<0.05 and p<0.01) and immunohistochemistry (p<0.001 and p<0.0001). PTEN and p27Kip1 expression were positively correlated with each other both in the tumour and benign tissue (p<0.001 and p<0.0001). We concluded that a strong expression of PTEN in renal cell cancer did not block the PI3K-mediated phosphorylation of Akt in the tumour specimens analysed. Furthermore, Akt activation may not result in a decreased p27Kip1, the latter being retained and overexpressed in the majority of renal cell cancers when compared with the corresponding benign renal parenchyma.

Locally advanced and metastatic sarcoma (adult type) including gastrointestinal stromal tumors.

STS belong to the most challenging diseases in oncology that demand all resources of modern clinical oncology. With the improvement of surgical techniques and radiation therapy the majority of patients with localized disease can be cured. However, for patients with locally advanced or metastatic disease chemotherapeutic treatments have not greatly changed the poor outcome of the disease. The introduction of combined chemoradiotherapy as well as isolated limb-perfusion has improved the limb-salvage rate in locally advanced disease but the impact of systemic chemotherapy on overall survival remains a subject of dispute. For patients with metastatic sarcoma long-term survival can only be achieved in a small number of patients with mostly resectable disease. The list of effective drugs for palliative treatment in general still remains short and the duration of remissions usually does not exceed several months. The lack of alternative chemotherapeutic drugs imposes a considerable challenge in daily clinical practice with many young patients exhibiting a good performance status but progressive disease after standard treatment. A variety of new drugs or drug combinations seem to exhibit considerable activity in certain histological sarcoma subtypes, which may soon broaden the armamentarium of drugs for a subset of patients. However, with the vastly improved understanding of the biology and pathology of soft tissue sarcoma an era of opportunities seems to have begun and the recent success in the treatment of gastrointestinal stromal tumors impressively shows how fast a gain in the understanding of oncogenic mechanisms may translate into a highly efficient, clinically useful treatment.

Cell-cycle progression and response of germ cell tumors to cisplatin in vitro.

Testicular germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy. It has been suggested that the chemosensitivity of GCTs can be partially attributed to the preference of apoptosis induction over a p21-mediated G1/S phase cell-cycle arrest following induction of p53. Since cell-cycle progression can be manipulated by a growing number of targeted agents, a thorough understanding of the impact of cell-cycle progression on drug-induced cell death might help to enhance the efficacy of chemotherapy. The aim of this study was to assess the cell-cycle dependence of cisplatin-induced cell death in an in vitro model of GCTs. Cell-cycle progression and induction of apoptosis were assessed by flow cytometry and Western blot analysis of PARP cleavage in the GCT derived cell lines, NT2 and 2102 EP, and compared with the breast carcinoma cell line MCF-7. Response to treatment was assessed in different phases of the cell cycle after synchronization by serum depletion and contact inhibition. Following cisplatin exposure, unsynchronized cells accumulated in G2/M after 28 h. This arrest was reversible at sublethal cisplatin doses (0.5-4.5 microM for 2 h). At higher concentrations, cells accumulated in G2 and died in G2/M-arrest. A 2-h exposure of cells in G2/M with 10 microM cisplatin resulted in a higher apoptotic index 70 h after treatment (74 and 70% for NT2 and 2102 EP, respectively) compared to treatment in G1/S (34 and 38%). Synchronized cells treated in G1 showed PARP cleavage after 48 h following cisplatin exposure, whereas treatment in G2 resulted in PARP cleavage already after 24 h. Cisplatin-induced cell death in GCTs is highly dependent on cell-cycle phase. All crucial events are restricted to the G2/M phase: cisplatin-induced DNA-damage is sensed, the apoptotic process is initiated and eventually executed in this phase of the cell cycle. The cells are most sensitive to cisplatin in this phase of the cell cycle. As far as the development of targeted agents is concerned, inhibition of the cell cycle in G1/S phase is likely to result in a protective effect against cisplatin, whereas agents arresting cells in G2/M may exert a synergistic effect.

A randomised phase II study of pemetrexed versus pemetrexed+erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer.

INTRODUCTION: Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed+erlotinib in patients with advanced non-squamous NSCLC. METHODS: NSCLC stage III-IV patients who failed one prior platinum-based chemotherapy regimen, ≥ 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤ 2 were eligible. Patients received pemetrexed 500 mg/m(2) with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. RESULTS: Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed+erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed+erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed+erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed+erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed+erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in ≥ 5% of patients) in pemetrexed/pemetrexed+erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). CONCLUSIONS: Pemetrexed+erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone.

Definitive radiotherapy and single-agent radiosensitizing ifosfamide in patients with localized, irresectable soft tissue sarcoma: a retrospective analysis.

BACKGROUND AND PURPOSE: Standard therapy for soft-tissue sarcomas remains complete resection. For primary radiotherapy local control rates of 30-45% have been reported. We analyzed retrospectively 11 cases of radiochemotherapy with single-agent ifosfamide in patients with macroscopic soft-tissue sarcomas. PATIENTS AND METHODS: The patients were treated in irresectable high risk situations. Radiation therapy was performed with median 60 Gy. During the first and fifth week the concomitant chemotherapy with ifosfamide was added. Two patients received trimodal therapy with additional regional hyperthermia. RESULTS: The therapy was completed in 73% of the patients. Average local control time was 91 months, median disease-free-survival/overall-survival was 8/26 months. Five-year rates for local control/disease free survival/overall survival were 70%/34%/34%. The limited prognosis is mainly caused by systemic treatment failure. CONCLUSIONS: The data strongly suggest a better outcome of radiochemotherapy with ifosfamide compared to radiotherapy alone and radiotherapy in combination with other radiosensitizers.

PET/CT with 18F-FLT: does it improve the therapeutic management of metastatic germ cell tumors?

UNLABELLED: Because (18)F-FDG PET alone has only limited value in metastatic germ cell tumors (GCTs), we investigated the addition of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) to (18)F-FDG for early response monitoring and prediction of the histology of residual tumor masses in patients with metastatic GCT. METHODS: Eleven patients with metastatic GCT were examined with both (18)F-FDG PET/CT and (18)F-FLT PET/CT before chemotherapy, after the first cycle of chemotherapy (early response), and 3 wk after completion of chemotherapy. In 1 patient with negative (18)F-FLT PET/CT results before chemotherapy, no further (18)F-FLT scanning was performed. PET images were analyzed visually and, using standardized uptake values (SUVs), semiquantitatively. The results were compared with the findings of CT and tumor marker levels and validated by histopathologic examination of resected residual masses, including Ki-67 immunostaining (7 patients), or by clinicoradiologic follow-up for at least 6 mo (4 patients). A responder was defined as a patient showing the presence of necrosis, a complete remission, or a marker-negative partial remission within a minimum progression-free interval of 6 mo. Early treatment response was judged according to the criteria of the European Organization for Research and Treatment of Cancer. RESULTS: Before chemotherapy, reference lesions showed increased (18)F-FDG uptake (mean SUV, 8.8; range, 2.9-15.0) in all patients and moderate (18)F-FLT uptake (mean SUV, 3.7; range, 1.7-9.7) in 10 of 11 patients. After 1 cycle of chemotherapy, mean SUV decreased in responders and nonresponders by 64% and 60%, respectively, for (18)F-FDG (P = 0.8) and by 58% and 48%, respectively, for (18)F-FLT (P = 0.5). After the end of chemotherapy, mean SUV decreased in responders and nonresponders by 85% and 73%, respectively, for (18)F-FDG (P = 0.1) and by 68% and 65%, respectively, for (18)F-FLT (P = 0.8). The results of early and final PET were inconsistent in 6 of 11 patients for (18)F-FDG and in 4 of 10 patients for (18)F-FLT. Both patients with teratoma had false-negative results on both (18)F-FDG and (18)F-FLT. The sensitivity, specificity, positive predictive value, and negative predictive value for detection of viable tumor after 1 cycle of chemotherapy were 60%, 33%, 43%, and 50%, respectively, for (18)F-FDG and 60%, 80%, 75%, and 67%, respectively, for (18)F-FLT PET/CT. The respective values after the end of chemotherapy were 20%, 100%, 100%, and 60% for (18)F-FDG and 0%, 100%, 0%, and 50% for (18)F-FLT PET/CT. CONCLUSION: PET-negative residual masses after chemotherapy of metastatic GCT still require resection, since the low negative predictive value of (18)F-FDG PET for viable tumor cannot be improved by application of (18)F-FLT.

Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.

PURPOSE: This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated. PATIENTS AND METHODS: Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233). RESULTS: The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated. CONCLUSION: KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.

Targeting telomerase activity by BIBR1532 as a therapeutic approach in germ cell tumors.

Germ cell tumors (GCT) possess a high activity of telomerase, a ribonucleoprotein complex compensating the erosion of telomeres during cell division by adding TTAGGG-repeats to the telomeric ends of chromosomes. Cisplatin, the most important drug in the treatment of GCT, preferentially acts on G-rich regions like telomeres. Inhibiting telomerase in tumors can result in telomere shortening and senescence and could increase the efficacy of chemotherapy in refractory patients. The study evaluated the promise of the small molecule telomerase inhibitor BIBR1532 as single agent and assessed a possible synergism with cisplatin in a preclinical model of GCT.GCT-derived cell line 2102EP was cultured with or without 10 microM of BIBR1532. Cell expansion was quantified in population doublings (PD). Telomere length was analyzed by fluorescence in situ hybridization and flow cytometry (flow-FISH). The sensitivity of the cells towards cisplatin was determined by MTT-assay. Telomerase activity was assessed by TRAP assay. After 300 PD, telomere length diminished from 18.5 kb +/- 0.59 kb to 8.9 +/- 0.1 kb in BIBR1532 treated 2102 EP cells as compared to 14.5 +/- 0.0 kb in untreated control cells. Treated cells did not show altered growth kinetics compared to untreated counterparts. Despite effective shortening of telomeres, the sensitivity of the treated cells towards cisplatin did not increase. Concomitant treatment with BIBR1532 and cisplatin did not result in accelerated telomere shortening. Telomere length can be shortened significantly by telomerase inhibition in GCT cell line models. However, possibly in view of their extensive telomere "reserve," telomerase inhibition did neither result in increased sensitivity of 2102 EP cells to cisplatin nor did co-treated cells show accelerated telomere shortening.

Bendamustine hydrochloride in patients with refractory soft tissue sarcoma: a noncomparative multicenter phase 2 study of the German sarcoma group (AIO-001).

BACKGROUND: For patients with advanced soft tissue sarcoma (STS), no standard treatment is established after previous chemotherapy with anthracyclines and ifosfamide. Bendamustine hydrochloride is a bifunctional alkylating agent that is not cross-resistant to other DNA-interacting substances including anthracyclines and oxazaphosphorines. It has shown single-agent activity in refractory lymphoma, myeloma, and some solid tumors. A phase 2 study was initiated to evaluate the efficacy of bendamustine in previously treated patients. METHODS: Thirty-six of 44 screened patients were included and received a total of 101 cycles (median, 2 cycles; range, 1-8 cycles), 21 as second-line treatment and 15 as third-line treatment. The median age was 55 years (range, 18-79 years). Bendamustine was given as an intravenous infusion over 30 minutes at a dose of 100 mg/m(2) on 2 consecutive days and repeated every 28 days. Eighty-eight percent of cycles could be given without dose or schedule modification. RESULTS: The toxicity profile was mild, consisting of National Cancer Institute Common Toxicity Criteria (CTC) grade 3 neutropenia in 11% and grade 3 anemia in 9% of patients. Nonhematologic toxicities were noticed with CTC grade 3 fever in 3% of patients. No other grade 3 toxicity and no treatment-related toxic deaths were observed. The best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 1 partial remission (3%) and disease stabilizations in 31% of patients. Six of 15 patients (40%) with leiomyosarcoma histology achieved stable disease. The estimated 3-month and 6-month progression-free survival rates were 35.3% and 23.5%, respectively, for all histologic subtypes included. CONCLUSIONS: In patients with refractory STS, bendamustine is well tolerated and appears moderately effective, particularly in patients with leiomyosarcoma histology.

Complete remission of relapsing high-grade angiosarcoma with single-agent metronomic trofosfamide.

A limited repertoire of chemotherapeutics is available for the therapy of metastasizing angiosarcoma. Moreover, response rates are typically low and outcomes are unfavorable. Metronomically, dosed oral chemotherapy provides a convenient treatment option and surprisingly high response rates have been published for small patient groups. We report on a case from our clinic, in which a complete response with oral trofosfamide was achieved in a patient suffering from relapsed high-grade angiosarcoma metastasizing to the liver and lung. The patient experienced minimal side-effects from her trofosfamide treatment. Responses like this are encouraging and should make us rethink treatment approaches for metastasizing soft-tissue sarcoma. The mechanism of action of metronomic chemotherapy, although thought to be antiangiogenic in nature, is still unclear, as is the additive effect of angiogenic inhibitors like cyclooxygenase II inhibitors or peroxisome proliferator-activated receptor-gamma agonists. Prospective studies that include the examination of patient samples during treatment are ongoing in order to optimize further development of this novel therapeutic approach.