Ifosfamide,carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults

Purpose:?To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5?g?m^?2, carboplatin 100?mg?m^?2 and etoposide 150?mg?m^?2, days 1–4, q 28 days, G-CSF 5?µg?kg^?1 starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy.

Patients and methods:?Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60?min, T_max 42°C).

Results:?The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months.

Conclusion:?These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.     

Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms are associated with toxicity and efficacy in irinotecan monotherapy for refractory pancreatic cancer

Purpose

The aim of this study was to evaluate the efficacy and safety of irinotecan monotherapy in patients with advanced pancreatic cancer (APC).

Methods

Patients with APC refractory to gemcitabine and S-1 were included. Irinotecan (100 mg/m²) was administered on days 1, 8, and 15 every 4 weeks until disease progression or unacceptable toxicity was observed. The relationship between uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms and clinical outcomes was evaluated.

Results

Between January 2007 and December 2011, 231 cycles were delivered in 56 patients. Irinotecan was administered as second-line chemotherapy in 35.7 % of patients and as third-line chemotherapy or later in 64.3 %. A partial response was achieved in two (3.6 %) and stable disease in 23 patients (41.0 %), giving a disease control rate of 44.6 %. The median time to progression (TTP) and overall survival (OS) were 2.9 (95 % confidence interval [CI] 1.8–3.5) months and 5.3 (95 % CI 4.5–6.8) months, respectively. Median survival from the first-line chemotherapy was 19.5 (95 % CI 15.3–23.8) months. Major grade 3/4 adverse events included neutropenia (28.6 %), anemia (12.5 %), and anorexia (10.7 %). Patients with *6 and/or *28 allele(s) (n = 15) were associated with grade 3/4 neutropenia and anorexia but showed longer TTP (5.3 vs. 1.8 months; p = 0.05), and OS (8.0 vs. 4.8 months; p = 0.09) than those without *6 and/or *28 (n = 29).

Conclusions

Salvage chemotherapy with irinotecan was moderately effective and well-tolerated in patients with APC refractory to gemcitabine and S-1. UGT1A1 polymorphisms were associated with toxicity and efficacy.     

Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines

Purpose:To assess the antitumor efficacy and safety of avinorelbine and cisplatin combination in patients with metastatic breastcancer previously treated with anthracyclines. Patients and methods:Fifty-three patients with assessablemetastatic breast cancer with previous exposure to anthracyclines (adjuvantn= 6, palliative n= 47) were studied. Cisplatin 75mg/m² on day 1 was given followed by 25 mg/m²vinorelbine (VNR) on days 1 + 8, in a five-min i.v. infusion. Courses wererepeated every three weeks on an outpatient basis. Treatment continued untildisease progression, excess toxicity or patient refusal. Patients wereclassified according to their response to anthracyclines: anthracyclinerefractory patients were patients who had never responded under ananthracycline regimen. Anthracycline resistant patients were either metastaticpatients who progressed within four months of completing anthracycline-basedchemotherapy or patients who progressed within six months of completion of ananthracycline adjuvant treatment. Patients who progressed four months afterthe end of an anthracycline regimen in metastatic setting or six months afterthe end of an anthracycline regimen in adjuvant setting were considered aspatients previously treated with anthracyclines and were called `relapsed'. Results:Four patients (8%) achieved a complete response(CR) and twenty-two patients (41%) achieved a partial response (PR)with an overall response rate (OR) of 49% (95% confidenceinterval (CI): 35–63). Stable disease (SD) was observed infive patients (9%), twenty-two patients had progressive disease (PD).Responses according to previous sensitivity to anthracycline were as follow:5 refractory patients achieved a PR from 14 patients (36%). Seven ofsixteen resistant patients responded (44%), six with PR and one withCR. Among 23 `relapsed' patients, 14 responses were observed (61%),with 3 CR and 11 PR. There was no statistical difference in RR among the threegroups. The median duration of response for all patients was 7 months, themedian time to progression (TTP) 5 months and median overall survival 12months.All patients were assessed for toxicity. The main toxicity was neutropeniagrade 3 and 4 in 49% of patients. Febrile neutropenia requiringhospitalization was uncommon (2 patients). There were no treatment relateddeaths. Despite potential overlapping neurologic toxicities of the two drugs,only eight patients (15%) developed neuropathy, which was, however,mild (grades 1 and 2). Conclusions:This cisplatin–VNR regimen is well toleratedand active in patients who failed anthracyclines. The response rate, TTP andsurvival data are engouranging and indicate that cisplatin–VNR may havea place as second-line treatment alternative to taxanes or other less activeregimens. If these results can be verified in multi-institution trials, thiscombination of drugs would merit investigation as first-line therapy in thispatient population.     

Phase II Study of Irinotecan plus Leucovorin and Bolus 5-Fluorouracil as First- or Second-Line Chemotherapy in Patients with Advanced Gastric or Esophageal-Gastric Junction Adenocarcinoma

Abstract

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m² intravenously (i.v.), followed by LV 200 mg/m² (i.v.) and 5-FU 450 mg/m² as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatmentrelated deaths.

The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy

BackgroundThis retrospective study was carried out to evaluate the prognostic significance of clinical factors in patients treated for metastatic gastric cancer with second-line chemotherapy.Patients and methodsWe evaluated the prognostic significance of various clinical factors in 126 patients, who were treated with second-line chemotherapy.ResultsMedian progression-free and overall survival (OS) for second-line chemotherapy were 3.3 and 5.3 months, respectively, with an overall response rate of 11.1%. Multivariate analysis identified three independent prognostic factors: performance status: Eastern Cooperative Oncology Group zero to one [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.7–5.4], hemoglobin (Hb) level: ≥10 g/dl (HR 2.2, 95% CI 2.1–2.4) and time-to-progression (TTP) under first-line therapy: ≥5 months (HR 0.5, 95% CI 0.3–0.8). From the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: good (n = 40), intermediate (n = 36) and poor risk group (n = 56). The median survival for good, intermediate and poor risk groups were 13.5, 6.0 and 2.9 months, respectively, whereas the 1-year OS rates were 50.2%, 14.2% and 2.6%, respectively (P = 0.00001).ConclusionsWith inadequate data from randomized controlled trials at the moment, our report indicates that second-line chemotherapy is effective and beneficial in patients with good performance status, higher Hb level along with higher TTP under first-line therapy.     

Prognostic factors and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer treated with immune checkpoint blockage

Our aim was to describe the incidence and characteristics of immune-related adverse events (irAEs) in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and to evaluate their impact on outcome. All cases of NSCLC patients treated with ICIs in the second-line setting between December 2015 and May 2018 were evaluated. Seventy patients were included. Mean age was 65.9?years, and the majority of male (n?=?53, 75.7%), with PS of 0-1 (n?=?62, 88.6%) treated with nivolumab (n?=?51; 72.9%). Thirty-one patients (44.3%) experienced an AE, 5 (7.1%) were grades 3–4. Median OS in patients with AE was 30.1?months (95% CI, 16.7–43.5) compared with 5.1?months (95% CI, 1.2–9.0) in cases without AE (log-rank test: p?=?0.010). The adjusted HR for OS was 0.46 (95% CI, 0.25–0.86) for the irAE occurrence and 3.60 (95% CI, 1.56–8.32) for PS 2-3 group. The development of irAEs was associated with improved patient outcome.     

MWA Combined with TACE as a combined therapy for unresectable large-sized hepotocellular carcinoma

Purpose: To evaluate the efficacy and safety of microwave ablation combined with transcatheter arterial chemoembolization for unresectable large-sized hepotocellular carcinoma.

Materials and methods: Institutional review board approval and informed consent were obtained. Between May 2004 and December 2006, 34 consecutive patients with large unresectable hepatocellular carcinoma (>5?cm) were alternately enrolled in one of two treatment groups: group 1 (n?=?18), in which TACE was performed alone, and group 2 (n?=?16), in which percutaneous ablation of HCC with microwave ablation was performed 2–4 weeks after TACE. All patients were followed up for 2–28 months to observe long-term therapeutic effects and complications in both groups. Tumor reduction rates, median survival time, and cumulative survival rates in both groups were calculated by using the unpaired Student t test and Kaplan-Meier method.

Results: Follow-up images showed reduction in tumor size was seen in 21 patients (61.7%; 7/18 in group 1, 14/16 in group 2), survival rates were better in group 2 than in group 1 (P?=?0.003), during the median follow-up of 8 months, 10 patients (62.5%) remained alive in group 2, whereas 6 patients (33.3%) remained alive in group 1, the mean survival times were 6.13 months?±?0.83 in group 1 and 11.61 months?±?1.59 in group 2.

Conclusion: MWA combined with transcatheter arterial chemoembolization appears to be an effective and promising approach for the treatment of large-sized unresectable hepotocellular carcinoma. However, large-scale randomized clinical trials are needed to determine the future role of this treatment.     

Second-line treatment of small-cell lung cancer with the camptothecin-derivative GI147211: A study of the EORTC Early Clinical Studies Group (ECSG)

Background:GI147211, a 10,11-ethylenedioxy substituted analogueof camptothecin (CPT), was brought into clinical development because of itshigher water solubility and greater potency as compared to topotecan (TPT).The antitumor activity of GI147211 as second-line therapy in small-cell lungcancer (SCLC) was assessed after stratification of patients in refractory (noresponse to initial treatment or relapse within three months from last cycle)and chemosensitive (relapse more than three months from last cycle). Patients and methods:Sixty-seven patients were entered in thestudy and sixty-two were evaluable for response, twenty-eight in therefractory and thirty-four in the chemosensitive group. All patients hadreceived 1 line of chemotherapy; radiation had also been given in 29 cases,6 in the refractory and 23 in the chemosensitive group. GI147211 wasadministered at 1.2 mg/m²/day as 30-min infusion for fiveconsecutive days every three weeks. Results:The overall response rate was 16.6% (11 of 66patients; 95% confidence interval (95% CI):8.5%–27.5%), 10.3% (3 of 29 patients; 95%CI: 2.2%–27%) in the refractory and 21.1% (8 of 37patients; 95% CI: 9.5%–37%) in the chemosensitivegroup. Only partial responses (PR) were observed with a median duration of PRof 4.8 months (5.7 months in the refractory and 5.2 in the chemosensitivegroup). Hematological toxicity consisted mainly of neutropenia (grades3–4 in 25% of cycles) and thrombocytopenia (grades 3–4 in23% of cycles); non-hematological toxicity was mild to moderate andconsisted of nausea (22% of cycles), vomiting (11%), malaise(34%). Conclusions:At the dose and schedule tested GI147211 is an activenew agent for second-line treatment of SCLC; the antitumor activity andtoxicity profile are comparable to those observed with TPT which remains theleading CPT analogue for salvage treatment. Interest has been renewed in theclinical development of GI147211 by preclinical data with the liposomalformulation showing an increased therapeutic index.     

Predictive value of peritoneal cancer index for survival in patients with mucinous peritoneal malignancies treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a single centre experience

Objectives: This study investigated the correlation between the peritoneal carcinomatosis index (PCI) and patient outcome depending on the tumour type.

Background: Peritoneal surface malignancy (PSM) treatment depends on tumour type. Mucinous PSM (m-PSM) is associated with a better prognosis than non-mucinous PSM (nm-PSM). The PCI’s predictive ability has not yet been evaluated.

Methods: We analysed 123 patients with PSM treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) between 2008 and 2015. The m-PSM group (n?=?75) included patients with appendiceal cancer (n?=?15), colorectal cancer (n?=?21), or low-grade appendiceal mucinous neoplasm (n?=?39); the nm-PSM group (n?=?48) included patients with gastric (n?=?18) or colorectal (n?=?30) cancer. The PCI’s predictive ability was evaluated by multiple Cox-proportional hazard regression analysis and Kaplan–Meier curves.

Results: The 5-year survival and PCI were higher in m-PSM patients (67.0%; 20.5?±?12.1) than in nm-PSM patients (32.6%; p?=?0.013; 8.9?±?6.0; p?vs. 68.1%; p?=?0.935). Underlying disease (HR 5.666–16.240), BMI (HR 1.109), and PCI (HR 1.068) significantly influenced overall survival in all patients.

Conclusions: PCI is prognostic in nm-PSM, but not in m-PSM. CRS and HIPEC may benefit not only patients with low PCI, but also those with high PCI and m-PSM.     

Fixed dose-rate infusion of gemcitabine in combination with cisplatin and UFT in advanced carcinoma of the pancreas

Background: Gemcitabine is currently considered the standard treatment for advanced pancreatic cancer (APC). Cisplatin and a fluoropyrimidine have some activity in the treatment of this cancer. The aim of this trial is to evaluate the efficacy and toxicity of a fixed dose-rate infusion of gemcitabine associated with cisplatin and UFT in patients with APC. Patients and methods: Forty-six chemotherapy-naïve patients with APC that was either unresectable or metastatic were included in this phase II study. All of them had Karnofsky performance status ≥50 and unidimensionally measurable disease. Treatment consisted of gemcitabine 1,200 mg/m² given as a 120-min infusion weekly for three consecutive weeks, cisplatin 50 mg/m² on day 1 and oral UFT 400 mg/m²/day (in two to three daily doses) on days 1 to 21; cycles of treatment were given every 28 days. Results: A total of 208 cycles of chemotherapy were given with a median of 4 per patient. Fourteen patients (30%) achieved partial responses (95% CI 19–48%) and 17 (37%) had stable disease. The median time to progression was 5 months, and the median overall survival 9 months. Nineteen patients (49%; 95% CI 32–64%) had a clinical benefit response. Grade 3–4 WHO toxicities were as follows: neutropaenia in 26 patients (57%), with 5 cases of febrile neutropaenia (11%), thrombocytopaenia in 15 (33%), anaemia in six (13%), diarrhoea in 5 (11%), asthenia in 2 (4%) and mucositis in 1 (2%). Seven patients required hospitalisation for treatment-related complications. Conclusion: A fixed dose-rate infusion of gemcitabine associated with cisplatin and UFT is active in patients with APC, though at the cost of considerable toxicity.     

The efficacy and toxicity of irinotecan with leucovorin and bolus and continuous infusional 5-fluorouracil (FOLFIRI) as salvage therapy for patients with advanced gastric cancer previously treated with platinum and taxane-based chemotherapy regimens

Abstract

There is no established standard salvage chemotherapy in the second-line setting for patients with advanced gastric cancer (AGC) pre-treated with platinum and taxane-based chemotherapy. Our study aims to evaluate the safety and efficacy of FOLFIRI regimen (irinotecan with leucovorin and bolus and continuous infusion with 5-fluorouracil) as a salvage chemotherapy regimen in patients with AGC. Medical records of 97 patients with AGC who received second-line FOLFIRI regimen between March 2006 and February 2011 were examined. Complete and partial responses were observed in 3 (3·1%) and 23 (23·7%) patients, respectively. The median time to progression (TTP) was 3·5 months (95% CI: 2·4–4·6) and the median overall survival (OS) was 10·5 months (95% CI: 8·8–12·2). The most common observed grade 3/4 toxicities were neutropenia (23·7%), diarrhea (6·2%), and stomatitis (5·2%). FOLFIRI regimen is safe and effective in the second-line treatment of AGC patients pre-treated with cisplatin and taxanes.     

Vinorelbine in combination with interleukin-2 as second-line treatment in patients with metastatic melanoma. A phase II study of the Hellenic Cooperative Oncology Group

OBJECTIVES: To evaluate the efficacy and toxicity of the combination of vinorelbine and interleukin (IL)-2 in patients with metastatic melanoma as second-line chemotherapy. PATIENTS AND METHODS: Twenty-two patients with histologically confirmed stage IV melanoma previously treated with temozolomide-based chemotherapy--only one regimen of chemotherapy for disseminated disease was allowed--were treated with vinorelbine 30 mg/m2 on days 1 and 15 and IL-2 subcutaneous 9 x 10(6) once daily on days 2-6 and 16-19 every 4 weeks for maximum of six cycles. RESULTS: From January 2000 to July 2001, 22 patients entered the study; the median age was 56 years. Among 20 evaluable patients there were 2 (9.1%) objective responses including 1 complete response and 1 partial response. Five (22.7%) had stabilization of their disease, and 13 (59.1%) progressed. The median time to progression (TTP) was 2.9 months and the median overall survival was 9.1 months. There was a significant difference in TTP in patients who responded or remained stable (median TTP 10.75 months) and those who progressed (median TTP 2.1 months) (p<0.05). There was also a difference in survival in the two groups (p<0.05 (28 vs. 8 months). The most common side effects were flulike symptoms, such as fever, chills, fatigue, and injection site reaction. Grade 3 hematological toxicity rarely occurred. One patient discontinued therapy because of fatigue and anorexia. There were no treatment-related deaths. CONCLUSIONS: The combination of vinorelbine and IL-2 provides clinical benefit in patients recurring or progressing on first-line chemotherapy for metastatic melanoma, with manageable toxicity.     

Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: Results of a single-centre retrospective study

Background: Patients with locally advanced gastric cancer (GC) and/or peritoneal metastases have a poor prognosis despite systemic chemotherapy or palliative surgery. The aim of this retrospective comparative non-randomised study was to evaluate aggressive cytoreduction in combination with hyperthermic intraperitoneal chemoperfusion (HIPEC) as a novel treatment strategy for patients with intraperitoneal disseminated and locally advanced GC.

Patients and methods: Forty-nine GC patients with serosal invasion (n?=?19), limited peritoneal metastases (n?=?20), or disseminated peritoneal metastases and tense ascites (n?=?10) underwent combination therapy with HIPEC. Three matched control groups undergoing standard therapies were retrospectively identified.

Results: Combination therapy for serosa-invasive GC reduced the level of metachronous peritoneal carcinomatosis and increased median survival from 12 months to 22.5 months (p?=?0.001). The median and 1-year survival rates for intraperitoneal disseminated GC patients undergoing therapy with the use of HIPEC were 12 months and 68.8% compared with 8 months and 25%, respectively (p?=?0.004) for control subgroup patients (palliative chemotherapy). The symptomatic use of HIPEC allows effective elimination of recurrent ascites in GC patients.

Conclusion: HIPEC is a well-tolerated and effective method of adjuvant therapy for gastric cancer with high risk of intraperitoneal progression. Cytoreduction followed by HIPEC improves survival in patients with limited peritoneal carcinomatosis of gastric origin.     

Safety and advantages of combined resection and microwave ablation in patients with bilobar hepatic malignancies

Abstract

Background: The multimodality approach has significantly improved outcomes for hepatic malignancies. Microwave ablation is often used in isolation or succession, and seldom in combination with resection. Potential benefits and pitfalls from combined resection and ablation therapy in patients with complex and extensive bilobar hepatic disease have not been well defined.

Methods: A review of the University of Louisville prospective Hepato-Pancreatico-Biliary Patients database was performed with multi-focal bilobar disease that underwent microwave ablation with resection or microwave only included.

Results: One hundred and eight were treated with microwave only (MWA, n?=?108) or combined resection and ablation (CRA, n?=?84) and were compared with similar disease-burden patients undergoing resection only (n?=?84). The groups were comparable except that the MWA group was older (p?=?.02) and with higher co-morbidities (diabetes, hepatitis). The resection group had larger tumours (4 vs. 3.2 and 3?cm) but the CRA group had more numerous lesions (4 vs. 3 and 2, p?=?.002). Short-term outcomes including morbidity (47.6% vs. 43%, p?=?.0715) were similar between the CRA and resection only groups. Longer operative time (164 vs. 126?min, p?=?.003) and need for blood transfusion (p?=?.001) were independent predictors of complications. Survival analyses for colorectal metastasis patients (n?=?158) demonstrated better overall survival (OS) (43.9 vs. 37.6 and 30.5 months, p?=?.035), disease-free survival (DFS) (38 vs. 26.6 and 16.9 months, p?=?.028) and local recurrence-free survival (LRFS) (55.4 vs. 17 and 22.9 months, p?<?.001) with resection only.

Conclusion: The use of microwave ablation in addition to surgical resection did not significantly increase the morbidities or short-term outcomes. In combination with systemic and other local forms of therapy, combined resection and ablation is a safe and effective procedure.     

Second-Line Chemotherapy with Bleomycin,Methotrexate, and Vinorelbine (BMV) for Patients with Squamous Cell Carcinoma of the Head,Neck and Esophagus (SCC-HN&E) Pretreated with a Cisplatin-Containing Regimen: A Phase II Study

Abstract

We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m², and vinorelbine 30 mg/m²) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) [27%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.     

Comparative efficacy of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitor as second-line therapy in patients with metastatic renal cell carcinoma after the failure of first-line VEGF TKI

Sequential therapy is a standard strategy used to overcome the limitations of targeted agents in metastatic renal cell carcinoma. It remains unclear whether a mammalian target of rapamycin (mTOR) inhibitor is a more effective second-line therapy after first-line vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) has failed than the alternative, VEGF TKI. A clinical database was used to identify all patients with renal cell carcinoma who failed at first-line VEGF TKI and then treated with second-line VEGF TKI or mTOR inhibitors in the Asan Medical Center. Patient medical characteristics, radiological response and survival status were assessed. Of the 83 patients who met the inclusion criteria, 41 received second-line VEGF TKI [sunitinib (n?=?16) and sorafenib (n?=?25)] and 42 were treated with mTOR inhibitors [temsirolimus (n?=?11) and everolimus (n?=?31)]. After a median follow-up duration of 23.9?months (95?% CI, 17.8?C30.0), progression-free survival was 3.0?months for both groups [hazard ratio (HR, VEGF TKI vs. mTOR inhibitor)?=?0.97, 95?% CI 0.59?C1.62, P?=?0.92]. Overall survival was 10.6?months for the VEGF TKI group and 8.2?months for the mTOR inhibitor group (HR?=?0.98, 95?% CI 0.57?C1.68, P?=?0.94). The two groups did not differ significantly in terms of disease control rate (51?% for VEGF TKI and 59?% for mTOR inhibitor, P?=?0.75). Second-line VEGF TKI seems to be as effective as mTOR inhibitors and may be a viable option as a second-line agent after first-line anti-VEGF agents have failed.     

Salvage treatment of advanced non-small-cell lung cancer previously treated with docetaxel-based front-line chemotherapy with irinotecan (CPT-11) in combination with cisplatin

Background:A phase II study was conducted in order to determinethe toxicity and efficacy of the combination of CPT-11 and cisplatin, assalvage treatment in patients with advanced non-small-cell lung cancer(NSCLC), progressing after a docetaxel-based front-line regimen. Patients and methods:Thirty-one patients (median age 61 years)with NSCLC, were enrolled. Twenty-six (84%) patients were male,twenty-five (81%) had disease stage IV, and twenty-eight (90%)had a performance status (WHO) 0–1. CPT-11 was administered as a60-minute i.v. infusion at the dose of 100 mg/m² on day 1 and 110mg/m² on day 8; cisplatin was administered at the dose of 80mg/m² on day 8, after CPT-11 administration. Treatment was repeatedevery three weeks. Results:A total of 110 chemotherapy cycles were administered. Inan intention-to-treat analysis 7 patients (23%; 95% confidenceinterval (95% CI): 8%–37%) achieved a partialresponse, 6 (19%) had stable disease, and 18 (58%) progressivedisease. Three of responders had failed a previous docetaxel–carboplatincombination. The median duration of response was 3 months, the median TTP 8months and the median survival for the entire group 8 months. Grade 3–4neutropenia was observed in 16 (52%) patients and in two cases this wasfebrile. Grade 3 and 4 thrombocytopenia occurred in two (7%) patients,respectively. Grade 3 and 4 diarrhea was seen in 10 (33%) patients,grade 2–3 neurotoxicity in 2 (6%), and fatigue grade 2–3in 12 (39%). Other toxicities were mild. Conclusions:The combination of CPT-11 and cisplatin hasmanageable toxicity and interesting activity as salvage treatment of patientswith advanced NSCLC, previously treated with a docetaxel-based front-lineregimen.     

Hyaluronan-Irinotecan improves progression-free survival in 5-fluorouracil refractory patients with metastatic colorectal cancer: a randomized phase II trial

Purpose

The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug.

Methods

Irinotecan-na?ve patients were randomized to receive either irinotecan (350?mg/m²) or HA-Irinotecan (HA 1,000?mg/m² and irinotecan at 350?mg/m²) every 3?weeks for a maximum of eight cycles.

Results

Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P?=?21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P?=?0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4?months (P?=?0.017) and time to treatment failure (4 vs. 1.8?months; P?=?0.007). Median overall survival was 10.1?months for HA-Irinotecan compared to 8.0?months for irinotecan patients (P?=?0.196).

Conclusion

Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone.     

Immune correlates of clinical benefit in a phase I study of hyperthermia with adoptive T cell immunotherapy in patients with solid tumors

Abstract

Purpose: To characterize the T cell receptor (TCR) repertoire, serum cytokine levels, peripheral blood T lymphocyte populations, safety, and clinical efficacy of hyperthermia (HT) combined with autologous adoptive cell therapy (ACT) and either salvage chemotherapy (CT) or anti-PD-1 antibody in patients with previously treated advanced solid tumors.

Materials and methods: Thirty-three (33) patients with ovarian, pancreatic, gastric, colorectal, cervical, or endometrial cancer were recruited into the following therapeutic groups: HT?+?ACT (n?=?10), HT?+?ACT?+?anti-PD-1 inhibitor (pembrolizumab) (n?=?11) and HT?+?ACT?+?CT (n?=?12). Peripheral blood was collected to analyze TCR repertoire, measurements of cytokines levels and lymphocyte sub-populations before and after treatment.

Results: The objective response rate (ORR) was 30% (10/33), including three complete responses (CR) (9.1%) and seven partial responses (PR) (21.2%) and a disease control rate (DCR?=?CR?+?PR?+?SD) of 66.7% (22 of 33). The most common adverse reactions, blistering, subcutaneous fat induration, local heat-related pain, vomiting and sinus tachycardia, were observed in association with HT. IL-2, IL-4, TNF-α, and IFN-γ levels in peripheral blood were significantly increased among the clinical responders (p?<?0.05) while IL-6 and IL-10 were elevated among those with progressive disease (p?<?0.05). Peripheral blood CD8⁺/CD28⁺ T cells increased (p?=?0.002), while the CD4⁺/CD25⁺/CD127⁺Treg cells decreased after therapy (p?=?0.012). TCR diversity was substantially increased among the clinical responders.

Conclusions: Combining HT with ACT plus either CT or anti-PD-1 antibody was safe, generated clinical responses in previously treated advanced cancers, and promoted TCR repertoire diversity and favorable changes in serum IL-2, IL-4, TNF-α, and IFN-γ levels in clinical responders.     

Regional abdominal hyperthermia combined with systemic chemotherapy for the treatment of patients with ovarian cancer relapse: Results of a pilot study

Purpose: Due to the poor prognosis of patients with ovarian cancer relapse (OCR), newer strategies are warranted to improve the therapeutic index. We performed a prospective phase I/II-study of regional abdominal hyperthermia (RHT) combined with systemic chemotherapy in OCR patients in order to evaluate outcome, efficacy and tolerance.

Materials and methods: OCR patients with an Eastern Cooperative Oncology Group status <2, without any thromboembolic disease or severe cardiovascular co-morbidities, and pre-treated with at least one systemic chemotherapy regimen due to epithelial ovarian cancer were enrolled into the present study. RHT was applied using a SIGMA 60 applicator and a Hybrid-System SIGMA-Eye/MRT composed of a 1.5T-MRT and a Sigma-Eye-applicator.

Results: Overall, 36 OCR patients were enrolled. The majority of the patients (>80%) were classified as platinum resistant. The most common chemotherapeutic agent applied was pegylated-liposomal-doxorubicin (47.2%) followed by carboplatin (16.6%) and topotecan (13.9%). One patient (2.8%) achieved a complete remission (CR), 12 patients (33.3%) yielded a partial remission (PR) and 16 patients (44.4%) developed a progressive disease (PD). In platinum-sensitive patients we observed higher response (57.1% versus 31%) and lower progression rates (28.6% versus 48.3%) than in platinum-resistant patients. Eleven patients (30.5%) discontinued treatment due to toxicity. The main toxicity was a haematological one with grade 3/4 anaemia, leucopenia and thrombocytopenia occurring in 13.9%, 5.6% and 8.3%, respectively. Median overall survival was 12 months (range: 1–48), while median progression-free survival was 5 months (range: 0.5–34).

Conclusions: Our results demonstrate the feasibility of RHT combined with systemic treatment. Prospective phase III trials are warranted to evaluate the benefit and efficacy in heavily pre-treated patients with OCR.