Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: A retrospective analysis of potential risk factors

Purpose: In children with locally advanced or recurrent malignant tumours, prognosis can be improved by regional deep hyperthermia (RHT) in combination with platin-based chemotherapy. However, because of the increasing number of patients that achieve long-time remission with this therapy, it is necessary to evaluate long-term sequelae of thermochemotherapy. During the years 1993–2004 one has observed avascular osteonecrosis (AON) of the femoral head after RHT in seven children with pelvic germ cell tumours or rhabdomyosarcomas.

Methods: Although AON may develop in patients with malignancies treated with chemo- or radiotherapy alone, RHT might nevertheless contribute to the occurrence of AON. In order to determine potential risk factors for AON after RHT, this study analysed the relationship of AON to the patient's age, medical history and treatment parameters such as thermal dose equivalent and power output.

Results and conclusions: In the present study AON was associated with young age as well as intensity of hyperthermia indicated by high power levels that exceed 20?W per kg body weight and/or application of eight or more heat sessions as well as additional radiotherapy. Based on this observation, it was assumed that an optimized three dimensional thermal field modelling may be helpful to avoid hazardous temperatures in the femoral heads during RHT treatment and to reduce AON of the femoral heads.     

Multicenter phase II trial of dose-fractionated irinotecan in patients with advanced colorectal cancer failing oxaliplatin-based first-line combination chemotherapy

Background:A multicenter phase II trial was initiated toinvestigate the efficacy and tolerance of a dose-fractionatedadministration schedule of irinotecan in patients with advancedcolorectal cancer pre-treated with fluoropyrimidine/oxaliplatin-basedfirst-line combination chemotherapy. Patients and methods:38 patients with metastatic colorectalcancer, who progressed while receiving or within six months afterwithholding systemic chemotherapy with oxaliplatin in combination with5-fluorouracil/leucovorin or the specific thymidilate synthase inhibitorraltitrexed were enrolled in this study. Treatment consisted ofirinotecan 175 mg/m² given on days 1 and 10. Courses wererepeated every three weeks for a total of six courses unless priorevidence of progressive disease. Results:The overall objective response rate was 21%for all 38 patients (95% confidence interval (95% CI):9.6% to 37.4%). Stable disease was noted in 19 patients(50%), whereas the tumour progressed in 11 (29%). Themedian progression-free survival was 4.8 months (range 1.5 to 10.5).After a median follow-up time of 10 months, 21 patients (55%) arestill alive. Treatment was fairly well tolerated with only 9 of 38patients (24%) experiencing grade 3 or 4 neutropenia. Similarly,nonhaematologic adverse reactions were generally mild; grade 3toxicities included late-onset diarrhoea in 2 (5%), alopecia in 5(13%), and infection in 1 case (3%), respectively. Conclusions:Our data suggest that this dose-fractionatedirinotecan monotherapy schedule has substantial antitumour activity inpatients with flupropyrimidine/oxaliplatin-based pre-treated colorectalcancer. Because of its favourable toxicity profile when compared toprevious experiences with the European standard schedule of 350mg/m² every three weeks, further evaluation of this modifiedregimen seems warranted.     

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.     

Gemcitabine for relapsed or resistant lymphoma

Background:Gemcitabine therapy has not been widely assessed inthe treatment of hematological malignancies. We have examined the efficacy andsafety of gemcitabine in patients with relapsed or resistant lymphoma. Patients and methods:Gemcitabine (1 g/m²) was givenweekly for 7 consecutive weeks, followed by a week off treatment. The drug wasthen given for 3 consecutive weeks, followed by a week off treatment; thisregimen was continued until disease progression or drug intolerance. Fifteenpatients have enrolled. Most have been extensively pre-treated for advanceddiffuse large-cell or mantle-cell lymphoma. Results:The drug was well tolerated; no patient sufferedtreatment-related sepsis, hemorrhage or death. Non-hematopoietic toxicity ledto discontinuation of gemcitabine therapy in two patients. Dose reductions ordelays were required for about two-thirds of treatments. Of 13 evaluablepatients, one had a complete response, 3 a partial response, 3 stable disease,and 6 disease progression. After 6 infusions of gemcitabine, a patient withadvanced Hodgkin's disease has had a complete remission lasting 21 months. Conclusions:Gemcitabine has substantial activity and acceptabletoxicity in heavily pre-treated patients with advanced lymphoma. Further studyis warranted.     

Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer

Purpose: There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC.

Patients and methods: We retrospectively analysed 23 patients with advanced (n?=?2) or metastatic (n?=?21) pancreatic cancer with relapse after G mono first-line chemotherapy (n?=?23). Patients had received G (day 1, 1000?mg/m²) and Cis (day 2 and 4, 25?mg/m²) in combination with RHT (day 2 and 4, 1?h) biweekly for 4 months. We analysed feasibility, toxicity, time to second progression (TTP2), overall survival (OS) and clinical response.

Results: Between October 1999 and August 2008 23 patients were treated. Haematological toxicity was low with no grade 4 event. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%). Median TTP1 was 5.9 months (95% confidence interval (CI): 2.6–9.2), median TTP2 was 4.3 months (95%CI: 1.2–7.4) and OS 12.9 months (95%CI: 9.9–15.9). The disease control rate in 16 patients with available CT scans was 50%.

Conclusion: We show first clinical data of G plus Cis with RHT being clinically active in G-pretreated APC with low toxicity. A prospective controlled phase II second-line clinical trial (EudraCT: 2005-003855-11) and a randomised phase III adjuvant clinical trial offering this treatment (HEAT; EudraCT: 2008-004802-14) are currently open for recruitment.     

Feasibility and morbidity of combined hyperthermia and radiochemotherapy in recurrent rectal cancer--preliminary results

BACKGROUND: The local recurrence rate of colorectal cancer has been significantly reduced due to the use of combined radiochemotherapy. Despite this improvement regarding locally advanced tumour recurrences, the treatment strategy for pre-treated patients remains difficult and unresolved. PATIENTS AND METHODS: We analysed treatment and follow-up data of 14 patients with local recurrence of rectal cancer who were treated with radiation therapy (RT), chemotherapy (CT) and regional hyperthermia (RHT) from November 1997 to December 2001. Nine of these patients had received irradiation and CT (= pre-treated patients) in the past. For this group, 30.6-39.6 Gy RT, 5-fluorouracil (5-FU) as a continuous infusion over 5 days per week (350 mg/m(2)/24 h) combined with RHT twice a week was given. The 5 remaining patients (= not pre-treated) received conformal irradiation of 45 Gy with a boost between 9 and 14.4 Gy, combined with continuous infusion of 5-FU on days 1-4, and 29-33 (500 mg/m(2)/ 24 h), and RHT twice a week. Response to therapy was evaluated by means of computed tomography (CT) or magnetic resonance imaging (MRI) and by clinical follow-up. RESULTS: Among 13 evaluated cases, the overall objective response rate was 54% (5 complete responses, 2 partial responses). At mean follow-up of 13.9 months (range 5-32 months) 7 patients were alive. CONCLUSION: The therapeutic regimen appears to be active in the treatment of local recurrences of rectal cancer. Larger-scaled studies are needed to evaluate the potency of hyperthermia in this therapeutic strategy.     

Cyclophosphamide, adriamycin and dexamethasone (CAD) is a highly effective therapy for patients with advanced multiple myeloma

Background:Patients with advanced multiple myeloma (stage III orprogressive myeloma) received the CAD protocol every three weeks:cyclophosphamide 200 mg/m² i.v./orally days 1–4, adriamycin30 mg/m² i.v. on day 1 and dexamethasone 40 mg p.o. days1–4. Patients and methods:Forty-six patients with a median age ofsixty years (range 34–84 years) were enrolled. According toDurie–Salmon 44 patients were in stage III, 2 in stage II; 6 patientshad renal insufficiency (stage B). Twenty-three patients were pre-treated atleast with melphalane/prednisone. Results:Remission rates were as follows: complete remission4%, partial remission 70%, minimal change 11%, no change11%, progressive disease 4%. After an observation time of 14months the median progression free interval for 33 patients not treated withsubsequent high-dose chemotherapy with stem-cell support was more than 14months. Overall, treatment was well tolerated. After 209 cycles given febrileneutropenia occurred in 11% of cycles including one fatal outcome.Neutropenia or thrombocytopenia grade 3–4 WHO was recorded in 18%and 6% of the cycles, respectively. Conclusions:This study shows that CAD is an effective regimenwith an overall remission rate of 74%. The CAD protocol should befurther evaluated in prospective trials.     

A Phase II Study of Carboplatin and Cyclophosphamide in Advanced Ovarian Carcinoma

Summary

Forty-two patients affected by either stage III and IV ovarian cancer with residual tumor after surgery or recurrent ovarian cancer entered a phase II study of the combination carboplatin 300 mg/m² and cyclophosphamide 600 mg/m² every 28 days.

Thirty-eight patients were evaluable for response and of these 27 obtained complete or partial remission with a 71% overall remission (clinical complete remission 45%; partial remission 26%).

Treatment tolerability was on the whole good. The most frequent side effects were leukopenia (76%), anemia (67%) and nausea/vomiting (60%). Thrombocytopenia was present in 31% of the patients, but nearly always to a mild degree except for one grade 4 case. No other grade 4 side effect was observed. We did not observe any cases of nephrotoxicity and only two patients complained of paresthesia.

This carboplatin-cyclophosphamide combination in advanced ovarian carcinoma produces comparable results, in terms of objective responses, to those obtained with standard cisplatin-based regimens, with suggestion of a better toxicological profile.     

A phase II trial of docetaxel in platinum pre-treated patients with advanced epithelial ovarian cancer: A Japanese Cooperative Study

Background:This phase II study was conducted to evaluate theefficacy and toxicity of docetaxel in Japanese patients with advanced ovariancancer. Patients and methods:Docetaxel was administered at a dose of 70mg/m² intravenously to patients with platinum pre-treated advancedovarian cancer. Treatment was repeated every three weeks. No routinecorticosteroid premedication was given. Results:Ninety patients with advanced ovarian cancer were enteredand sixty were assessable for response. The overall response rate was28% in the assessable patients (95% confidence interval(95% CI): 17.5%–41.4%). CA125 responses were seenin 8 (24%) of 34 assessable patients for CA125 criteria. The 36platinum-refractory patients had a response rate of 25% compared with33% in the platinum-sensitive patients. The predominant toxicity wasneutropenia, with 86% of the patients experiencing grade 3 or 4.Hypersensitivity reactions occurred in 37% of the patients and were notlife threatening. Edema was mild and infrequent. Conclusion:Docetaxel at 70 mg/m² demonstratedeffectiveness as a treatment of both platinum-sensitive andplatinum-refractory ovarian cancer patients, with a low incidence of severehypersensitivity reactions and edema.     

Phase I/II trial of intravenous Doxil® and whole abdomen hyperthermia in patients with refractory ovarian cancer

Objective: A phase I/II study of Doxil® combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects.

Patients and methods: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil® at a dose of 40?mg?m^?2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle.

Results: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60?min after either average vaginal and rectal temperatures of 40°C had been achieved or after 30?min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2–8) and six patients had been previously treated with Doxil®. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3–4 PPE toxicity. Doxil® systemic exposure was higher in those with grade 3–4 PPE compared to those with no PPE. None of the patients had grade 3–4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy.

Conclusions: Therapy with intravenous Doxil® and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.     

Irinotecan combined with docetaxel in pre-treated metastatic breast cancer patients: a phase II study

Purpose: This is a phase II study where a novel chemotherapy combination was tested in pre-treated breast cancer patients: docetaxel and irinotecan have already been established as agents for breast and colorectal cancer, respectively. Methods: Forty-eight (median age 54 years, range 26–77 year) patients, all evaluable, were enrolled. All patients had been pre-treated with anthracycline-combined chemotherapy, 30 of whom were also treated with paclitaxel and 2 with docetaxel. World Health Organization (WHO) performance status was 0–2. The dominant metastasis was in the liver (54.17%), in the lungs (27.08%), in soft tissues (12.50%) and in the skeleton (6.25%). Treatment involved irinotecan infusion 200 mg/m² for 90 min and docetaxel infusion 80 mg/m² for 90 min, repeated once every 3 weeks. Results: Twenty-five (52.08%, 95% confidence interval [CI] 37.95–66.21) patients showed responses: 3 complete (6.25%, 95% CI 0–13.05) and 22 (45.83%, 95% CI 31.74–59.92) partial; the most responsive metastases were observed at the liver site (53.85%). Grade 3 and 4 neutropenia was observed in 18 patients (37.50%); 14 (29.17%) patients developed anaemia and three (6.25%), thrombocytopenia. Concerning non-haematologic toxicity, alopecia and fatigue were common; grade 3 diarrhea was observed in only one (2.08%) patient. Conclusion: The irinotecan-docetaxel combination produces quite a high response rate in pre-treated advanced breast cancer patients.     

Bevacizumab in Combination with Metronomic Chemotherapy in Patients with Anthracycline- and Taxane-Refractory Breast Cancer

Abstract

A vascular endothelial growth factor (VEGF) inhibitor might enhance metronomic chemotherapy in previously treated metastatic breast cancer (MBC) patients. Anthra-cycline and taxane refractory MBC patients were given cyclophosphamide 50 mg p.o. daily, methotrexate 1 mg/kg i.v. every 14 days, and bevacizumab 10 mg/kg i.v. every 14 days. Trastuzumab was added in HER2-overexpressing tumors. 24 patients were enrolled and 22 were evaluable. All tumors had histologic grade II-III and most patients had ≥2 metastatic sites. After a median follow-up of 7.7 months the response rates were: complete response (CR) 0%, partial response (PR) 31.8% (95% CI 13.9-54.9%), stable disease for ≥24 weeks (SD) 31.8% (95% CI 13.9-54.9%). Clinical benefit (CB= CR + PR + SD>24w) 63.6% (95% CI 40.7-82.8%). Median progression-free survival (PFS) was 7.5 months; overall survival (OS) was 13.6 months. HER2-overex-pressing or high proliferative-index tumors had better 6-month PFS (75% vs. 34% in HER-negative tumors P= 0.043; 67% vs. 0% in Ki-67 ≥20% tumors, P = 0.015). Adverse effects were mild. The combination of bevacizumab and a metronomic-based chemotherapy was effective, well tolerated and provided clinical benefit in heavily-treated MBC patients.     

Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS)

Purpose: We report data from phase II trials examining the efficacy of multimodality treatment with neoadjuvant chemotherapy, hyperthermia, surgery, radiation and postoperative thermochemotherapy in adult patients with high-risk sarcomas of the extremities.

Patients and methods: From 1991 to 2001 47 patients with high risk soft tissue sarcoma of the extremities were prospectively treated in two clinical trials with a treatment plan of four cycles of etoposide, ifosfamide and doxorubicin combined with regional hyperthermia followed by surgery, radiation and adjuvant chemotherapy.

Results: Objective response rate assessable in 39 patients was 21% (one complete and seven partial responses). A favourable histological response (>75% tumour necrosis) was observed in 34% of the 35 evaluable patients who had surgical resection. Median overall survival (OS) was 105 months. The five-year probability of local failure-free survival (LFFS), distant disease-free survival (DDFS), event-free survival (EFS) and OS were 48%, 55%, 35% and 57%, respectively. There were no significant differences between responders and non-responders of minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T₅₀) and 90% (T₉₀) at all measured tumour sites. Response to this neoadjuvant regimen predicted for prolonged LFFS (p = 0.0123), but not for OS (p = 0.2). Limb preservation was achieved in 37 patients (79%) and did not result in inferior DDFS (52% versus 50%) or OS (61% versus 50%) at five years (p = 0.8) in comparison to patients who underwent amputation.

Conclusion: Response to combined modality treatment with RHT and neoadjuvant chemotherapy was predictive for an improved LFFS and led to limb preservation in 79% of patients with extremity sarcomas.     

Survival of patients with advanced ovarian cancer treated with intermittent chemotherapy following cytoreductive surgery and adjuvant chemotherapy

Background. The purpose of this study was to report the duration of the progression-free interval (PFI) in advanced ovarian cancer patients who were treated with intermittent maintenance chemotherapy. Methods. Between 1991 and 1998, 25 patients with stage III or IV ovarian cancer were enrolled in a trial of intermittent maintenance chemotherapy. All patients underwent cytoreduction surgery, and received adjuvant chemotherapy, after which they were treated with intermittent maintenance chemotherapy every 3 to 4 months for 2 years. Results. The median PFI in the 25 women in the intermittent chemotherapy group was 25 months, while in the 32 patients in the control group it was 18 months (P = 0.0124). The median survival of women treated with the intermittent chemotherapy was 34 months, and for the control group patients, it was 35 months (P = 0.0672). Multivariate analysis in the intermittent chemotherapy group revealed that the only factor that correlated significantly with PFI was the status after adjuvant chemotherapy (P = 0.0137). In patients with no evidence of disease after the adjuvant chemotherapy, the median survival was 39 months in the intermittent chemotherapy group, and 35 months in the control group (P = 0.0156). The median PFI was 28 months in the intermittent chemotherapy group, and 18 months in the control group (P = 0.0012). Conclusion. It would be warranted to perform intermittent maintenance chemotherapy for patients with advanced ovarian cancer, if a clinically disease-free status could be achieved after completion of the standard treatment procedure. Received: September 3, 2001 / Accepted: December 19, 2001     

Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients?

Background: The main goal of this study was to examine whether the occurrence of hypothyroidism during sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome.

Methods: The study enrolled 81 patients with pathologically proven mRCC who were treated with sunitinib between March 2008 and June 2013.Thyroid function evaluation comprised (free-thyroxine) FT4 and thyroid-stimulating hormone (TSH) before treatment and at day 1 of each 6-week cycle. Survival analysis was performed using the Kaplan–Meier method, and the differences among the groups were determined using the log-rank test.

Results: Hypothyroidism occurred in 30 (37%) of 81 patients within a median 3 months (range 1–18) of treatment initiation. There was a statistically significant correlation between the occurrence of hypothyroidism during treatment and the rate of objective remission (ORR) (hypothyroid patients vs euthyroid patients: 46.7 vs 13.7%, respectively; P?=?0.001). Median progression-free survival (PFS) was 10 (95% CI 6.13–13.8) months in the euthyroid patients, and 17 (95% CI 9.33–24.6) months in the hypothyroid patients (P?=?0.001). The median overall survival (OS) was 39 (95% CI 25.4–52.5) months in the hypothyroid patients and 20 (95% CI 14.7–25.2) months in the euthyroid patients (P?=?0.019).

Conclusions: The occurrence of hypothyroidism during treatment in patients was significantly associated with longer PFS, OS and better ORR in the current study.     

Complete cytoreductive surgery plus HIPEC for peritoneal metastases from unusual cancer sites of origin: results from a worldwide analysis issue of the Peritoneal Surface Oncology Group International (PSOGI)

Abstract

Aim: The aim of this study was to assess the outcomes of patients operated on for peritoneal metastases from unusual cancer sites of origin, meaning apart from peritoneal metastases (PM) from colorectal, gastric and epithelial ovarian carcinomas, pseudomyxoma peritonei and mesothelioma.

Patients and methods: A questionnaire concerning patients treated with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for PM arising from unusual cancer sites of origin was sent to all centres, which routinely performed HIPEC, through the Peritoneal Surface Oncology Group International and the RENAPE network.

Results: Between September 1990 and June 2016, 850 procedures for unusual cases were performed in 781 patients, in 53 centres worldwide. Nearly two-thirds of the procedures were performed for three indications: rare ovarian carcinoma (n?=?224), sarcoma (n?=?189) and neuroendocrine tumours (n?=?127). The median PCI was 12 [0–39]. Grade III–IV postoperative complications occurred in 272 patients (41%). Nineteen patients (2.9%) died postoperatively. After a median follow-up of 46?months, median overall survival (OS) was 39?months [33.18–44.05]. Five-year OS rate was 38.7%. For the three main indications, 5-year OS was significantly greater in patients with PM from rare ovarian carcinoma (57.7%), than that of patients with PM from neuroendocrine tumours (39.9%), and from sarcoma (29.3%) (p?<?0.0001).

Conclusions: CRS and HIPEC appear to be safe and effective in patients with peritoneal metastases from unusual cancer sites of origin, especially from rare ovarian carcinomas, PM from neuroendocrine tumours. The respective roles of CRS and HIPEC remain unclear and should be evaluated.     

High-dose chemotherapy for ovarian carcinoma: Long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT)

Purpose:to determine the outcome of epithelial ovarian cancer in patients registered with the European Group for Blood and Marrow Transplantation (EBMT). Patients and methods:A retrospective analysis was performed on 254 patients with advanced or recurrent disease, median age 46 years (14–63) from 39 centres treated between 1982 and 1996. Only 25% of patients were known to have no or microscopic disease after initial surgery; in approximately 20% the disease status was unknown, the remainder had macroscopic disease. Results:One hundred five patients received high-dose chemotherapy in complete or very good partial remission, twenty-seven in second remission and the remainder in the presence of residual disease. Most received melphalan or carboplatin, or a combination (86%) supported by autologous bone marrow or peripheral blood stem cells. The survival of patients treated in remission was significantly better than in other groups (median 33 vs. 14 months; P = 0.0001). The durability of remission was longer after transplantation in first remission than in second remission (median disease-free survival 18 vs. 9 months; P = 0.005). With a median follow-up of 76 months from diagnosis the median disease-free and overall survival in stage III disease transplanted in remission is 42 and 59 months and for stage IV disease 26 and 40 months. Conclusions:High-dose chemotherapy has a potential benefit for patients in remission. The results support the conduct of randomised studies to determine whether there is a real value from this treatment.     

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy,safety, and antiemetic use in the phase 3 VELIA trial

Background

The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma.

Methods

Patients with previously untreated stage III–IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients.

Results

Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18–1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy.

Conclusions

Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

     

Human ovarian carcinomas: correlation of malignancy and survival with the expression of epidermal growth factor receptors (EGF-R) and EGF-like factors (EGF-F)

We have studied the concentration of epidermal growth factor receptors (EGF-R) in 115 different malignant ovarian tumors (101 ovarian carcinomas) and EGF-like factors (EGF-F) in tissue extracts of 63 different ovarian carcinomas and 20 non-malignant tissues. 36% of ovarian carcinomas are EGF-R positive. The calculated mean EGF-F level of 4.2 ± 1.5 ng mg⁻¹ (range: 0–15 ne mg⁻¹) in ovarian carcinomas is significantly enhanced compared to 1.5 ± 0.7 ng mg⁻¹ (range: 0–4 ng mg⁻¹) of non-malignant tissue extracts. The correlation between EGF-R positive as well as negative ovarian carcinomas and the results of a primary chemotherapy of advanced ovarian carcinomas (n = 92) revealed a significantly higher remission rate of EGF-R positive tumors (66%) compared to EGF-R negative cases (23%). 84% of tumors with progressive disease were EGF-R negative. The mean EGF-F levels were calculated for prognostic subgroups of ovarian carcinomas. Increased EGF-F levels are significantly associated with progressive disease compared to all patients or the remission group. 15/16 cases with EGF-F levels > 5 ng mg⁻¹ showed progressive disease. The overall survival time of patients with tumor tissue EGF-F levels > 3.5 ng mg⁻¹ was worse than that of patients with low EGF-F levels. Multivariate analysis showed that the EGF-F level was, after gracling, the second most important factor for predicting overall survival. Supported by Deutsche Forschungsgemeinschaf (DFG), SFB 31.     

Elective re-irradiation and hyperthermia following resection of persistent locoregional recurrent breast cancer: A retrospective study

Purpose: To analyse the therapeutic effect and toxicity of re-irradiation (re-RT) combined with hyperthermia (HT) following resection or clinically complete remission (CR) of persistent locoregional recurrent breast cancer in previously irradiated area.

Methods and materials: Between 1988 and 2001, 78 patients with high risk recurrent breast cancer underwent elective re-RT and HT. All patients received extensive previous treatments, including surgery and high-dose irradiation (≥50Gy). Most had received one or more lines of systemic therapy; 44% had been treated for ≥ one previous locoregional recurrences. At start of re-RT + HT there was no macroscopically detectable tumour following surgery (96%) or chemotherapy (CT). Re-RT typically consisted of eight fractions of 4Gy, given twice weekly. Hyperthermia was added once a week.

Results: After a median follow up of 64.2 months, three-year survival was 66%. Three- and five-year local control rates were 78% and 65%. Acute grade 3 toxicity occurred in 32% of patients. The risk of late ≥ grade 3 toxicity was 40% after three years. Time interval to the current recurrence was found to be most predictive for local control in univariate and multivariate analysis. The extensiveness of current surgery was the most relevant treatment related factor associated with toxicity.

Conclusions: For patients experiencing local recurrence in a previously radiated area, re-irradiation plus hyperthermia following minimisation of tumour burden leads to a high rate of local control, albeit with significant toxicity. The latter might be reduced by a more fractionated re-RT schedule.