Antonio Astone

Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m−2, day 1; folinic acid, 200 mg m−2; and 5-fluorouracil: as a 400 mg m−2 bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m−2, from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.

The Immune Response to Tumors as a Tool toward Immunotherapy

Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes.

Docetaxel and oxaliplatin combination in second-line treatment of patients with advanced gastric cancer

BackgroundIn advanced gastric cancer few data are available on the efficacy or safety of new drug combination regimens after progression following first-line chemotherapy.MethodsPatients with histologically confirmed advanced gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2, progressing after first-line chemotherapy, were eligible. Patients were treated with docetaxel 75 mg/m2 on day 1 and oxaliplatin 80 mg/m2 on day 2, every 3 weeks, until progression or unacceptable toxicity.ResultsBetween May 2002 and April 2005, 38 patients were enrolled. Men accounted for 73.7% of the patients and the median age was 59 years. The primary tumor was not resected in 47.4% of the patients; the peritoneum was the most frequent metastatic site (60.5%). The first-line treatment was cisplatin, epirubicin, and infusional 5-fluorouracil (ECF) in 81.5% of the patients and cisplatin and infusional 5-fluorouracil (CF) in 15.7%. The median number of cycles was 4.3. The treatment was well tolerated, with no toxic deaths. National Cancer Institute (NCI) grade III-IV neutropenia was frequent (26.3%), but no febrile neutropenia was reported. Severe asthenia (15.7%) and severe nausea (15.7%) required dose reductions in 2 patients and treatment discontinuation in another. The overall response rate was 10.5%, and 18 patients (47.3%) experienced disease stabilization (7 of them with significant clinical benefit). Median time to progression was 4.0 months (range, 2–8 months) and median overall survival was 8.1 months (range, 3–26 months). Thirteen patients (34.2%) also received third-line chemotherapy, with an irinotecan-containing regimen, and their median overall survival was higher than that of the other patients (16.3 vs 6.0 months)ConclusionThe combination of oxaliplatin and docetaxel shows only marginal activity as second-line treatment, but it has a good tolerability profile. This suggests that there is room for optimizing the schedule as well as for planning sequential treatments in gastric cancer.

Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies.

Although many drug combination therapies have been proposed, there is no standard therapy for patients with advanced gastric carcinoma. The superiority of combination therapy over monochemotherapy has not been demonstrated convincingly. To explore the role of monochemotherapy, the authors evaluated 5‐fluorouracil (5‐FU), modulated by 6S‐leucovorin (6S‐LV) and a cisplatin‐containing regimen, which was comprised of epirubicin, etoposide, and cisplatin with the addition of the reversal agent lonidamine (EEP‐L).

High-dose folinic acid (HDFA) combined with 5-fluorouracil (5-FU) in first line chemotherapy of advanced large bowel cancer.

The therapeutic activity of 5-FU in large bowel cancer is enhanced by increasing the intracellular pool of reduced folates. We treated 45 patients with advanced colon cancer with HDFA and 5-FU for 5 consecutive days. None had been given previous radio- or chemotherapy. All had measurable disease. Not one complete response was observed. Thirteen of the 39 evaluable patients showed partial response. Median duration of response was 9+ months. The probability of 50% survival was 15 months for all evaluable patients. There was no case of severe toxicity and the principal toxic effects were oral mucositis and diarrhea. To date, HDFA + 5-FU is one of the most effective treatments for large bowel cancer.

Advanced colon cancer: staging and prognosis by CEA test

The carcinoembryonic antigen (CEA) test was studied in 54 patients with advanced stages of colon cancer which was treated with high doses of folinic acid + fluorouracil. The CEA test correlates evaluated included: prognostic value, performance status, metastatic pattern, histologic grading, predictive value for response to chemotherapy, and value differences in cases with partial response to therapy. CEA levels less than 5 ng/ml corresponded to a greater survival time than did levels greater than 5 ng/ml. A correlation of CEA with performance status and with metastatic pattern was demonstrated. A progressive increase in average CEA values corresponded to increases in neoplastic mass. Although CEA levels were not found to be an index for predicting the response to chemotherapy, there was a significant different between pre- and posttreatment levels for partial response. The results suggest that CEA offers an additional criterion for evaluating the response of colon cancer to chemotherapy and it also has a role in the staging of advanced disease.

Real Benefit of Anthracycline-Based Chemotherapy in Elderly and Impaired Patients: a Retrospective Analysis

Non-Hodgkin Lymphoma (NHL) is a frequent cancer in elderly population. Comorbidities often influence the choice among different treatment options; particularly, concern about anthracyclines’ cardiotoxicity induces to select less effective chemotherapy regimens. The present retrospective study includes NHL patients treated in a single institution with and without antracyclines; clinical results have been analysed comparing both elderly (> 70 years) and not-elderly and impaired and not impaired population. 68 patients affected by NHL, diagnosed between 1996 and 2011, have been included. Median OS of whole population was 34 months; there was no significative difference in OS related to age or comorbidities among patients treated with anthracyclines-based regimens. Median OS of elderly patients not treated with anthracyclines resulted significantly lower, irrespectively of comorbidities (20 months); 94% of elderly patients who undergone anthracyclines-based regimen reported symptoms relief and performance status improvement, compared to 75% of elderly not treated with anthracyclines. Results of this retrospective analysis suggest that anthracyclines-based chemotherapy produces a significant improvement in OS and QoL,even in elderly or impaired patients. Comorbidities and age don’t seem absolute contraindications to anthracycline-based chemotherapy.

Vinorelbine and Alternating Cisplatin and Ifosfamide in the Treatment of Non-Small Cell Lung Cancer

In order to explore the activity of a combination of vinorelbine (VNL) and alternating cisplatin (CDDP) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), a phase II study was performed. Seventy chemoradiotherapy naive patients with NSCLC, stage IIIA, IIIB and IV disease, PS (ECOG) ≤2, were treated with CDDP 40 mg/m2 on days 1, 2, 3, IFX 1,800 mg/m2 on days 22, 23, 24 and VNL 30 mg/m2 on days 1, 8, 22, 29 every 6 weeks up to 6 courses. In the 67 evaluable patients, an objective response rate was observed in 47.8 ± 12% (95% CI) with complete responses in 6%; responses occurred more frequently in patients with locally advanced disease (stage IIIA/IIIB) and/or performance status 0. The median duration of survival was 12 months: 19.9 months in stage III patients who received an integrated treatment and 10 months in metastatic disease. The median time to treatment failure was 10.5 months. Toxicity was mainly hematological, even though it was not dose-limiting and easily manageable. This combination seems to be active, and the good safety profile is probably the result of the use of an alternating schedule of CDDP and IFX. Median overall survival was also encouraging in stage IV disease. The prolongation of survival obtained when surgery and/or radiotherapy is applicable needs confirmation through a larger study.

AMAROS Study: Overall Survival in Breast Cancer Subtypes

At a median follow-up of 17 months (range 9e38 months), one patient with liver metastases at presentation had a distant relapse and died without progression within the nasopharynx; 13 patients remain alive with no local regional recurrence, one of whom has developed progression of bone metastases. The 2 year local control and overall survival is 100 and 86%. No patients were feeding tube dependent at 1 year. Although these results are encouraging, they again illustrate the difficulty in drawing conclusions about this group of patients within the UK, as although the radiotherapy protocol and technique in this series were constant, the small numbers of NPC cases presenting in the UK are pathologically heterogeneous. Uncertainty persists as to the optimal timing of chemotherapy in addition to the synchronous component either neoadjuvant or adjuvant. Although adjuvant chemotherapy may remain the international standard, neoadjuvant chemotherapy remains attractive due to early exposure to systemic drugs in a disease with a high rate of distant metastases. Appropriate radiotherapy dose fractionation also remains controversial, with a recent randomised trial suggesting that more toxicity may be seen with accelerated fractionation [2]. Given such controversy, pathological diversity and a small cohort of patients in the UK, we would echo Roques [3] in their call for collaboration at the very least in the contouring of these cases. National UK proton centres offer an opportunity to centralise care for infrequent cancers such as NPC. Proton therapy will allow highly conformal radiotherapy with the additional advantage of a reduced integral dose. Clinical advantages include the potential to reduce long-term neurocognitive toxicity [4]. However, proton therapy is associated with increased vulnerability to uncertainty, including relative biological effectiveness, set-up variation and anatomy change, which can compromise the ability to maintain accurate dosimetry throughout. Strategies are currently under evaluation to tackle such risks and will be necessary to maintain high local control rates while the reduction in morbidity is explored [5].

A response in advanced post-menopausal breast cancer during treatment with the luteinising hormone releasing hormone agonist--Zoladex.

Luteinising hormone releasing hormone (LHRH) agonists are currently undergoing clinical trials in the treatment of advanced breast cancer in pre-menopausal women. Clinical responses are attributed to the suppression of the pituitary-ovarian axis, with a reduction in circulating levels of gonadal steroids similar to that produced by castration. In the present case report, we report a partial response to a LHRH analogue in a post-menopausal woman refractory to other endocrine treatments. This response cannot be explained with a chemical castration and confirms the possible direct anti-tumor effect of Zoladex.