Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRß sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-ß and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1ß concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.

BACKGROUND: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. RESULTS: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. CONCLUSIONS: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine.

BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.

Evaluation of patient quality care in Spain in prevention of nausea and vomiting induced by chemotherapy.

OBJECTIVE: To characterise current management of chemotherapy-induced nausea and vomiting in Spain, as well as professional adherence to antiemetic guidelines. MATERIALS AND METHODS: Retrospective observational study. A multicenter has been designed including 360 patient case files from 18 hospitals. The involvement of pharmacists and nurses was studied, and also indicators of structure, process, and selected outcomes previously recruited from antiemetic guidelines. RESULTS: We found 94.4% of hospitals used a written protocol for managing chemotherapy-induced nausea and vomiting and only 44.4% had educational programs for patients regarding this. Patients were prescribed antiemetic prophylactic treatment for delayed emesis in varying degree between highly and moderately emetogenic chemotherapy (77.8% and 58.9%, respectively). Dexamethasone was the most prescribed antiemetic drug for patients receiving highly and moderately emetogenic chemotherapy (98.3% and 90%, respectively), followed by ondansetron (68.9% and 95%, respectively). Nursing was more involved than pharmacy units in evaluating emetic risk factors in patients (64.7% vs 21.4%), and tracking symptom onset (88.2% vs 57.1%) and adherence to treatment (94.1% vs 28.6%). Pharmacy units were more involved than nursing in choosing the antiemetic treatment (78.6% vs 47%). CONCLUSIONS: Although antiemetic guidelines were used by all hospitals, there were differences in management of chemotherapy-induced nausea and vomiting. Increased education directed towards patients and oncology professionals is needed to improve adherence.

Management of platinum-resistant ovarian cancer with the combination of pemetrexed and gemcitabine.

INTRODUCTION: Platinum resistant ovarian cancer is a current challenge in Oncology. Current approved therapies offer no more of a 20% of response. New therapeutic options are urgently needed. PATIENTS AND METHODS: Patients were treated with the combination of Pemetrexed 500 mg/m(2) d1 and Gemcitabine 1000 mg/m(2) d1,8 in a 21 days basis. RESULTS: 10 platinum-resistant ovarian cancer patients were treated under compassionate use. Mean previous chemotherapy lines were 3.3. Mean administered cycles were 4. Mean CA 125 decrease was on average of 47%, with one patient experiencing a 95% decrease in her CA 125 level. 1 patient had a complete clinical remission, and 2, had partial radiological responses. Mean Progression free survival was 16.5 weeks, and Overall Survival was 21.2 weeks. Treatment was well tolerated. CONCLUSIONS: Deemd to the observed activity, the combination of Pemetrexed and Gemcitabine deserves deeper investigation in platinum-resistant ovarian cancer patients.

A retrospective chart review study describing metastatic melanoma patients profile and treatment patterns in Spain.

PURPOSE: To describe patient characteristics by disease stage, resectability status and current treatment management after first diagnosis of IIIB to IV1c advanced (AM)/metastatic melanoma (MM). METHODS/PATIENTS: Multicentre, retrospective study based on data from medical charts of patients > 18 years at MM first diagnosis, visited by oncologists at 4 reference centres in Spain: Hospital Universitario Gregorio Marañón (Madrid), Hospital General de Valencia (Valencia), Clínica Universidad de Navarra (Pamplona), and Hospital Clínic (Barcelona). RESULTS: Metastatic non-visceral melanoma (IIIB, IIIC, IV M1a) was reported in 139 (48.6%) patients and 40.9% (n = 117) were diagnosed with IV-M1c disease. 160 (55.9%) metastases were resectable. Available therapies under clinical practice were used in 210 patients; 74 were treated under clinical trials (CT). Intention-to-cure surgery (47.6%) was the most common treatment at time of MM diagnosis. Systemic (45.1% overall) therapy included chemo-, targeted- and immunotherapy (19.6%, 14.3%, 8.4%, respectively). At time of data collection, 26 patients were still alive and 120 had progressed to IV-M1c. Median overall survival (OS) was significantly larger in IIIB patients, 28.9 m (25.2-32.7); the shortest for IV-M1c patients, 11.0 m (8.7-13.3). CONCLUSIONS: Novel treatments are undoubtedly a major step forward in AM/MM, however these are often only available in the CT setting because early stages of development or country-specific regulations. Further prospective studies and multifactorial analysis should be performed to clearly identify possible clinical associations for outcome in Spanish patients with AM/MM.

Preliminary results of the combination of bevacizumab and weekly Paclitaxel in advanced melanoma.

BACKGROUND: Pretreated advanced melanoma is a poor prognosis scenario with few, if any, active therapeutic options. The antibody against vascular endothelial growth factor, bevacizumab, has demonstrated increased activity in combination with chemotherapy in many tumors. We intended to evaluate the activity of the combination of weekly paclitaxel and bevacizumab in previously treated metastatic melanoma. PATIENTS AND METHODS: Patients with previously treated metastatic melanoma received paclitaxel 70 mg/m(2) weekly and bevacizumab 10 mg/kg biweekly for 5 consecutive weeks every 6 weeks. RESULTS: Twelve patients were treated. Two patients (16.6%) achieved a partial response and 7 patients (58.3%) stable disease. Responses were seen in soft tissue, lung and brain metastases. Median disease-free and overall survival times were 3.7 and 7.8 months, respectively. Treatment was well tolerated. Main toxicities were grade 3 asymptomatic lymphopenia in 6 patients, grade 3 leucopenia in 2 patients, and grade 3 thrombocytopenia in 1 patient. CONCLUSIONS: Our preliminary results suggest that the combination of bevacizumab and weekly paclitaxel is active and safe in patients with metastatic melanoma, warranting further investigation.

Response of resistant melanoma to a combination of weekly paclitaxel and bevacizumab.

We report here a taxol-bevacizumab-responsive metastatic melanoma case. Although the patient had been heavily pretreated for two years, she did not show any stabilisation or objective response of her disease. After treatment with taxol and bevacizumab combination an impressive response was obtained.

[Small-cell lung cancer]. / Carcinoma microcítico de pulmón.

Small cell lung cancer is one of the most aggressive solid tumors because of its rapid growth and early tendency to spread to distant organs. Nonetheless, it is also one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients with limited disease a chance to become long-term survivors. These characteristics have made this tumor a clinical model to explore various treatment strategies, including concomitant chemotherapy and radiotherapy, alternant chemotherapy, high-dose chemotherapy with hematologic support, or use of whole-brain prophylactic radiotherapy. In addition, in recent years, small cell lung cancer has been used as a platform to develop some new targeted therapy agents or immunotherapeutic approaches.

Durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report.

BACKGROUND: Chemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response. CASE PRESENTATION: A 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life. CONCLUSIONS: This case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Ileal carcinoid tumor with liver metastases and cardiac involvement treated with intraarterial liposomal doxorubicin and valve replacement.

Unless carcinoid are in general slow-growing tumors, some cases could be frankly malignant. The commonest cause of death in patients suffering a carcinoid tumor is liver failure due to tumor progression. When tumors have a fast evolution a multidisciplinary approach must be perform. This case report is an example of this specific situation.

Clinical use of ipilimumab for metastatic melanoma in Spain: towards a more consistent approach.

INTRODUCTION: Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab. MATERIALS AND METHODS: The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1-9, where 1 meant "completely disagree" and 9 meant "completely agree". RESULTS: Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life. CONCLUSIONS: The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear.

Pancreatic neuroendocrine tumors: Challenges in an underestimated disease.

Pancreatic neuroendocrine tumours (PanNETs) are considered a relatively unusual oncologic entity. Due to its relative good prognosis, surgery remains the goal standard therapy not only in localized disease but also in the setting of locally or metastatic disease. Most of the patients are diagnosed in metastatic scenario, where multidisciplinary approach based on surgery, chemotherapies, liver-directed and/or molecular targeted therapies are commonly used. Owing to a deeper molecular knowledge of this disease, these targeted therapies are nowadays widely implemented, being the likely discovery of predictive biomarkers that would allow its use in other settings. This review is focused on describing the different classifications, etiology, prognostic biomarkers and multidisciplinary approaches that are typically used in PanNET.

Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience.

OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.

Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.

PURPOSE: To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT. RESULTS: The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654). CONCLUSION: In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.

Hematopoietic growth factors after HLA-identical allogeneic bone marrow transplantation in patients treated with methotrexate-containing graft-vs.-host disease prophylaxis.

The use of hematopoietic growth factors (HGFs) in the allogeneic transplant setting has sometimes been avoided for fear of stimulating leukemic cell growth and intensifying graft-vs.-host disease (GVHD). However, neither an increase in relapse rate nor an aggravation of GVHD has been routinely described when HGFs are used after allogeneic bone marrow transplantation (allo-BMT). Early outcomes after HLA-matched allo-BMT in 26 patients with hematologic malignancies treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) from the day of transplantation were analyzed. Results were compared to those from a series of 38 patients treated earlier with an identical approach, but not scheduled to receive HGFs after transplantation. All patients received a preparative regimen consisting of etoposide, cyclophosphamide, and total-body irradiation and GVHD prophylaxis with cyclosporine and a short course of methotrexate (MTX). The analysis has shown that the duration of neutropenia was significantly decreased in the group of patients treated routinely with HGFs (median 17 vs. 20 days; p < 0.001). These patients also required fewer days of intravenous antibiotic therapy (median 20 vs. 34 days; p < 0.001), had fewer positive blood and tissue cultures (median 2 vs. 12 and 13 vs. 28; p = 0.02 and p = 0.05, respectively), needed fewer packed red blood cell transfusions (median 7 vs. 11; p < 0.03), and were discharged earlier from the hospital (median 33.5 vs. 39 days; p < 0.001). The use of HGFs was not associated with an increase in acute GVHD or early leukemic relapse. No side effects were attributable to the simultaneous administration of MTX and HGF during the neutropenic period. A trend toward better 100-day actuarial survival for patients treated with rhG-CSF or rhGM-CSF did not reach statistical significance. A decrease in the number of early deaths from fungal or bacterial infections was found in the cytokine-treated group (p = 0.05). These data suggest that the early use of rhG-CSF or rhGM-CSF after HLA-matched allo-BMT in hematologic malignancies accelerates engraftment, reduces hospitalization time, and improves outcome, without increasing acute GVHD or early relapse. Because MTX-based prophylaxis regimens are associated with prolonged neutropenia, the routine use of HGFs after transplantation may be particularly useful in regimens including MTX.

Intraoperative radiotherapy for recurrent and/or residual colorectal cancer.

Intraoperative radiotherapy (IORT) is an attractive boosting modality in the combined treatment of recurrent and/or residual colorectal cancer. Twenty seven patients treated with IORT are analysed. Residual disease following resection of the primary tumor was treated in 11 cases (group I). Localized recurrent disease without previous radiotherapy was treated in 11 cases (group II). IORT was used in five additional patients with local recurrences in previously irradiated areas (group III). The treatment program consisted of maximal tumor resection, IORT (10-30 Gy) to the area of residual disease and external beam radiotherapy (46-50 Gy). The median follow-up time for the entire series of patients is 11 months. Local tumor control rates are 90% in group I, 63% in group II and 60% in group III. Toxicity and complications related to IORT observed in this initial experience have been pelvic pain (29%) and lower extremity neuropathy (3%). These early clinical results suggest that the IORT combined with surgery and external beam radiotherapy is feasible in primary and recurrent disease. Local control rates obtained in patients not suitable for curative surgery are encouraging.

A single prior course of BCNU-cisplatin chemotherapy has a significant deleterious effect on mobilization kinetics of otherwise untreated patients.

Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standard-dose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III-IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (i.v.) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 microg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34+ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells x 10(6)/l; P=0.01) and on the fifth (25 vs 58 cells x 10(6)/l; P=0.003), as it was the number of CD34+ cells collected per apheresis (1.3 vs 3.5 x 10(6)/l; P<0.0005). The toxic effect of a single course of BCNU-cisplatin CT led to significant impairment of the filgrastim-induced mobilization response.