Stefania Marsili

Chemo-Immunotherapy of Metastatic Colorectal Carcinoma With Gemcitabine Plus FOLFOX 4 Followed by Subcutaneous Granulocyte Macrophage Colony-Stimulating Factor and Interleukin-2 Induces Strong Immunologic and Antitumor Activity in Metastatic Colon Cancer Patients

PURPOSE Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to (A) upregulate tumor-associated antigen expression, including carcinoembryonic antigen (CEA) or other target molecules such as thymidylate synthase (TS); and (B) downregulate tumor cell resistance to the death signals induced by tumor antigen-specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy. MATERIALS AND METHODS We describe the results of a translational phase II trial designed to evaluate the toxicity, antitumor activity and immunologic effects of gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose interleukin-2 in colorectal carcinoma patients. The study involved 29 patients (16 males and 13 females with a mean age of 69 years), 21 of whom had received a previous line of treatment, and 19 had liver involvement. RESULTS The treatment was well tolerated and induced very high objective response (68.9%) and disease control rates (96.5%), with an average time to progression of 12.5 months. An immunologic study of peripheral blood mononuclear cells (PBMCs) taken from 20 patients showed an enhanced proliferative response to colon carcinoma antigen and a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25T-reg+). A cytofluorimetric study of the PBMCs of five HLA-A(*)02.01+ patients who achieved an objective response showed an increased frequency of cytolytic T lymphocyte precursors specific for known CEA- and TS-derived epitopes. CONCLUSION The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.

The prognostic role of Beclin 1 protein expression in high-grade gliomas.

High Grade Gliomas (HGG) have a poor outcome, however, prognostic sub-groups of patients may be individuated by some clinico-biological parameters. It was recently demonstrated that the main response of HGG to therapy is autophagic death. Autophagy is involved in tumor suppression, and is defective in HGG, in which we previously found an underexpression of beclin 1 autophagic gene protein product. Underexpression of Beclin 1 protein has been correlated to poor patient outcome in other tumor types. In this paper, the prognostic role of beclin 1 expression in HGG patients was investigated. We firstly evaluated the tumor cell cytoplasmic expression of Beclin 1 protein (BPCE), in a sample of 76 HGG by immunohistochemistry, and compared it with cell proliferation and apoptosis. We found high BPCE score positively correlated with apoptosis, and negatively with cell proliferation (p < 0,05). We then correlated BPCE score with survival and other prognostic parameters (histological grading , MGMT gene methylation status, age, patient performance status according to the Karnofski classification (KPS), extent of surgery, radiation therapy (RT) modality, temozolomide chemotherapy (TMZ CHT), and optimal/suboptimal post-surgical treatment). Forty-seven (61.8%) and twenty-nine (38.2%) patients showed high and low BPCE scores, respectively. BPCE showed statistically significant correlations with survival both at the univariate (p = 0.03) and multivariate analysis (p = 0.037). High BPCE was also positively correlated with high KPS values (p = 0.023), and with the accomplishment of an optimal post-operative therapy (p = 0.037). Furthermore, among patients showing a MGMT methylated gene, survival was significantly higher in cases with a higher BPCE score. BPCE score might be added to pathological evaluation of HGG for prognostic purposes.

Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma.

This randomized study compared the efficacy of epirubicin-based adjuvant chemotherapy on the disease-free interval (DFI) and overall survival of patients with high-risk soft-tissue sarcomas. After curative surgery, 43 of the 88 enrolled patients were assigned to surgery with or without radiotherapy and 45 to surgery plus chemotherapy (26 epirubicin, 19 epirubicin + ifosfamide) with or without radiotherapy. The trial closed prematurely because of poor patient accrual. There was a statistical significant difference in the 5-year disease-free survival of the patients receiving adjuvant chemotherapy with or without radiotherapy (69%) and that of those treated with surgery with or without radiotherapy (44%) (p = 0.01). The 5-year survival of the patients treated with adjuvant chemotherapy with or without radiotherapy was 72% as against 47% of those treated with surgery with or without radiotherapy (p = 0.06). The power of the study was 0.65 for both the DFI and overall survival. The results of the study suggest a possible advantage of epirubicin-based adjuvant chemotherapy in patients with soft-tissue sarcoma at high risk of relapse.

Safety and Potential Benefit of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Carcinomatosis From Primary or Recurrent Ovarian Cancer

To analyze the outcomes of cytoreductive surgery and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer.

Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hr-GM-CSF (Molgramostim) and hr-IL-2: results from a phase Ib clinical trial

Experimental findings suggest that granulocyte-monocyte-colony stimulating factor (GM-CSF) synergistically interacts with interleukin-2 (IL-2) in generating an efficient antigen-specific immune response. We evaluated the toxicity, antitumour activity and immunobiological effects of human recombinant (hr)-GM-CSF and hr-IL-2 in 25 cancer patients who subcutaneously (s.c.) received hr-GM-CSF 150 microg/day for 5 days, followed by hrIL-2 s.c. for 10 days and 15 days rest. Two of the most common side-effects were bone pain and fever. Of the 24 patients evaluable for response, 3 achieved partial remission, 13 experienced stable disease, and 8 progressed. Cytokine treatment increased the number of monocytes, dendritic cells (DC), and lymphocytes (memory T cells) in the peripheral blood and enhanced the antigen-specific immunoreactivity of these patients. Our results show that the hr-GM-CSF and hr-IL-2 combination is active and well tolerated. Its biological activity may support tumour associated antigen (TAA)-specific anticancer immunotherapy by increasing antigen presenting cell (APC) activity and T cell immune competence in vivo.

Hypercalcemia in breast cancer

Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E2 (PGE2) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.

A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma.

Previous results suggest that GEM affects 5-fluorouracil (5-FU) metabolism and pharmacokinetics in cancer patients, while combined with oxaliplatin, levo-folinic acid, and 5-FU (GOLF regimen), at doses achievable in cancer patients, determines high cytotoxic and proapoptotic antitumour activity in colon cancer cells in vitro. On these bases we designed a phase I–II clinical trial testing the GOLF regimen in patients with metastatic colorectal carcinoma, who had received at least a prior line of chemotherapy. In total, 29 patients (20 males and nine females) enrolled in the study received every 2 weeks, gemcitabine (patients #1–3 received 600 mg m−2; patients # 4–6 received 850 mg m−2; while patients # 7–29 received 1000 mg m−2) on the day 1, levo-folinic acid (100 mg m−2) on the days 1 and 2; 5-fluorouracil (400 mg m−2) in bolus injection, followed by a 22-h continuous infusion (800 mg m−2) on the days 1 and 2, and oxaliplatin (85 mg m−2), 6 h after the 5-FU bolus on day 2. The most frequent side effect was grade I–II haematological toxicity. In total, 28 patients were evaluable for response: three achieved a complete response, nine a partial response, 10 had a stable disease, and six progressed. The average time to progression and overall survival of the patients was, respectively, 7.26 and 22 months. Our GOLF combination is well tolerated and seems promising for the treatment of advanced colorectal cancer.

Weekly Low-Dose Docetaxel in Advanced Hormone-Resistant Prostate Cancer Patients Previously Exposed to Chemotherapy

Objective: The aim of this study was to evaluate the activity and tolerability of docetaxel in patients with hormone-resistant prostate cancer previously exposed to chemotherapy. Methods: We enrolled 27 patients with hormone-resistant prostatic cancer that had progressed during first-line chemotherapy. The primary end-point was palliative response defined as a 2-point reduction in the 6-point present pain intensity scale, and an improvement in Karnofsky performance status of one 10-point category. The treatment consisted of weekly docetaxel 25 mg/m² body surface area administered by means of a 1-hour intravenous infusion with corticosteroid premedication. Results: The primary criterion of palliative response was met in 13 patients (48%) after eight treatment cycles; its median duration was 6 months (range 1–8). Mean global quality of life improved in 8 and 10 patients after respectively four and eight treatment cycles. After a median follow-up of 8 months, 21 patients had died: the median survival was 9+ months (range 2–18). Weekly docetaxel was very well tolerated: grade 3 neutropenia occurred in 1 patient and grade 3 anemia in 2. Conclusions: Weekly low-dose docetaxel is an effective and well-tolerated treatment for patients with hormone-resistant prostate cancer previously exposed to chemotherapy.

Weekly chemotherapy in advanced prostatic cancer.

This randomised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients (stage D2) refractory to hormonal therapy. Seventy-two cases were studied: they were randomised in a 2:1 ratio to receive either epirubicin (30 mg m-2 weekly) or doxorubicin (25 mg m-2 weekly); 48 patients received epirubicin and 24 received doxorubicin. After 12 courses of chemotherapy, the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7% and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3% (P = 0.51). Pain intensity, bone and prostatic tumour markers rapidly and significantly decreased in responders. An improvement in physical symptoms, functional conditions and in emotional well-being was observed in the majority of the treated patients. The histological analysis of bone metastases, performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders. Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively (P = 0.014). The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm (P = 0.042). Our data indicate that in advanced prostatic carcinoma, a weekly epirubicin regimen may give rapid palliative results, similar to that of doxorubicin, but with less side-effects.

Weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer previously exposed to docetaxel.

To evaluate the activity and tolerability of weekly high‐dose calcitriol and docetaxel in patients with metastatic hormone‐refractory prostate cancer (HRPC) previously exposed to docetaxel, as patients who progress after docetaxel treatment might be considered for second‐line chemotherapy, but with no standard salvage therapy available we hypothesised that high‐dose calcitriol might restore sensitivity to chemotherapy.