Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice.

AIM: The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. PATIENTS & METHODS: This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. RESULTS: Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. CONCLUSION: Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.

Capecitabine in elderly patients with metastatic breast cancer.

AIMS AND BACKGROUND: Capecitabine is the reference treatment for anthracycline- and/or taxane-pretreated metastatic breast cancer (MBC). This study examined its efficacy, tolerability and impact on the quality of life of elderly patients with MBC. MATERIALS AND METHODS: Between January 2002 and December 2009, 75 consecutive elderly patients with MBC received first-line chemotherapy with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks. Endpoints were efficacy, tolerability and clinical-benefit response measured every 3 cycles. RESULTS: Median age was 76 years (range 65-88); median ECOG performance status was 1 (range 0-2); 51 patients (68%) had received adjuvant chemotherapy and all patients had received hormonal therapy. Median exposure was 6 cycles. After 3 cycles, 11 patients (14.7%) had a partial response, one patient experienced a complete response, and 49 patients (65.3%) had stable disease, amounting to a disease control rate of 81.3%. Stable disease was maintained in 45 patients (60%) after 6 cycles, in 21 patients (28%) after 9 cycles, and in 13 patients (17.3%) after 12 cycles. A clinical-benefit response was experienced by 42 patients (56%), indicating a positive impact on quality of life. Treatment was well tolerated, the most common grade 3 events being diarrhea (12%) hand-foot syndrome (8%), and mucositis (8%). Adverse events were managed with dose adjustments and supportive therapy when required. CONCLUSIONS: Our results indicate that capecitabine is active and well tolerated in elderly patients with MBC. This dosing regimen warrants further study in the first-line setting for patients with less aggressive MBC who are not candidates for combination therapy.

Palonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapy.

BACKGROUND: The combination of a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT(3) receptor antagonist is currently the standard antiemetic treatment in patients receiving cisplatin-based high emetogenic chemotherapy (HEC). The aim of this study was to evaluate the efficacy of a combination of palonosetron, a unique second-generation 5-HT(3) receptor antagonist, aprepitant, the only approved neurokinin-1 receptor antagonist, and dexamethasone as antiemetic prophylaxis in patients receiving HEC (cisplatin ≥50 mg/mq). METHODS: Chemotherapy-naïve adult patients, receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v., and aprepitant 125 mg/p.o., 1-h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg p.o. were administered on days 2-3. Primary end point was complete response (CR; no vomiting and no use of rescue medication), during the overall study period (0-120 h). Secondary end points were complete control (CR and no more than mild nausea), emesis-free rate, and nausea-free rate during the acute (0-24 h), delayed (24-120 h), and overall (0-120 h) periods. Safety was also evaluated. RESULTS: A total of 222 patients were included in the study. Median age was 62 years, 76.6% were male and 23.4% female, and most common tumors were lung (66.7%) and head and neck (15.8%); 70.3% of patients achieved CR during the overall study period. Complete control, emesis-free rate, and nausea-free rate were 70.3%, 92.8%, and 59.9%, respectively, during the overall phase. The most commonly reported side effects were constipation (39% of patients) and headache (5%). CONCLUSIONS: This study shows that palonosetron in combination with aprepitant and dexamethasone is effective to prevent chemotherapy-induced nausea and vomiting in patients treated with cisplatin-based HEC.

[Integrated multidisciplinary treatment of colorectal neoplasms]. / Trattamento multidisciplinare integrato delle neoplasie colo-rettali.

In this retrospective study, the modality and advantages of the multidisciplinary diagnostic work-up and therapy regarding colorectal neoplasm were analysed. Over the period 2004-2008, 63 patients underwent multidisciplinary treatment for colorectal cancer. All patients underwent surgery (laparoscopic/open). Exeresis was supplemented by adjuvant chemotherapy in those cases beyond IIA stage; all cases of extraperitoneal rectal and anal canal neoplasms plus one case of carcinoma of the transverse colon, initially inoperable, underwent neoadjuvant radiotherapy plus chemotherapy. The treatment was initiated approximately 3 weeks after the diagnosis. Fifty-four percent of patients with colonic and upper rectal neoplasms were given adjuvant chemotherapy, starting around 4 weeks after surgery. Exeresis was performed in those patients with extraperitoneal rectal and anal canal neoplasms (12.7%) about 6-8 weeks after they had completed neoadjuvant therapy. At the end of the treatment, 76% of the overall total numbers of patients were in good condition (follow-up 4-50 months). The remaining 24% suffered recurrences about 13 months after the treatment for colonic and upper rectal neoplasm, and 8 1/2 months after treatment for extraperitoneal rectal/anal canal neoplasms. Seventy-five percent of the recurring cases underwent treatment again, with 50% success; the others are still undergoing treatment. The best therapeutic results were obtained by programmed integration of the various diagnostic-therapeutic steps according to an algorithm which we elaborated to evaluate all types of neoplasm at any stage of illness.

[Severe postoperative complications in colorectal surgery for cancer. Incidence related to the techniques employed: open versus laparoscopic colectomy]. / Complicanze maggiori postoperatorie nella chirurgia colo-rettale per cancro. Incidenza in rapporto alla tecnica utilizzata: open versus laparoscopica.

In this preliminary retrospective study, severe postoperative complications following surgery for colorectal cancer were analysed, comparing the results obtained with open versus laparoscopic colectomy. Over the period 2005-2007, 50 patients (29 female, 21 male; age range: 32-85 years) underwent surgical treatment for colorectal-anal cancer. Twenty-nine (58%) were submitted to the traditional open technique and 21 (42%) to the laparoscopic technique. No mortality occurred with either technique. None of the cases submitted to laparoscopy presented anastomotic dehiscence or severe intraoperative bleeding. In the group submitted to open surgery, 3 cases of severe complications occurred (10.3%), consisting in acute faecal peritonitis due to immediate dehiscence of the colorectal anastomosis; angulation of the intestinal loop with microdehiscence of the ileo-colic anastomosis; and pulmonary embolism. In the group submitted to laparoscopic surgery, 2 cases of severe complications occurred (9.5%), consisting in enterorrhagia due to haemoperitoneum; and intrafascial haematoma due to haemorrhage of the epigastric artery. The overall complication rate was 10%, corresponding to the minimum values reported in the literature. No statistically significant difference was observed in the incidence of these complications with the two methods employed. A very low incidence of minor complications was observed, limited to repercussions on the postoperative course. Furthermore, the laparoscopic technique led to early canalisation, a reduction in hospital stay, less need of drugs (antibiotics and pain killers) and better aesthetic results. The advantages obtained with the laparoscopic technique, with no significant differences in severe complications, indicate that this approach is preferable to the traditional technique in colorectal surgery for cancer.

Cytoreductive surgery (peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer.

BACKGROUND: Because of scarce data from larger series and nonhomogeneous selection criteria, further information is needed on peritonectomy with hyperthermic intraperitoneal chemotherapy (HIPEC) in managing patients with ovarian peritoneal carcinomatosis. METHODS: In an open, prospective, single-center nonrandomized phase 2 study conducted from November 2000 to April 2007, 47 patients with primary advanced or recurrent ovarian cancer and diffuse peritoneal carcinomatosis were enrolled; 22 underwent primary and 25 secondary cytoreduction plus immediate HIPEC followed by systemic chemotherapy. RESULTS: The overall mean Sugarbaker peritoneal cancer index was 14.9 (range, 6-28). A mean of 6 surgical procedures were required per patient (range, 4-10). In 87.3% of the patients debulking achieved optimal cytoreduction (Sugarbaker completeness of cytoreduction [CC] score 0-1), whereas in 12.7% it left macroscopic residual disease (CC-2 or CC-3). Major complications developed in 21.3% of the patients and the in-hospital mortality rate was 4.2%. The mean overall survival was 30.4 months, median survival was 24 months, and mean disease-free survival was 27.4 months. Five-year survival was 16.7%. Univariate (log-rank test and analysis of variance) and multivariate analyses (Cox proportional-hazard model) identified the CC score as the main factor capable of independently influencing survival. CONCLUSIONS: Peritonectomy procedures combined with HIPEC offer promising long-term survival in patients with diffuse peritoneal ovarian carcinomatosis. They achieve high adequate primary and secondary surgical cytoreduction rates with acceptable morbidity and mortality.

Chronomodulated administration of oxaliplatin plus capecitabine (XELOX) as first line chemotherapy in advanced colorectal cancer patients: phase II study.

BACKGROUND: The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. The aim of the present study was to define the feasibility and efficacy of XELOX administered through a new chronomodulated schedule in untreated advanced colorectal cancer (CRC) patients. METHODS: Chemotherapy-naive patients with advanced CRC were considered eligible for the study accrual. TREATMENT: oxaliplatin 70 mg/m(2) continuous infusion (c.i.) for 12 h (8:00 a.m. to 8:00 p.m.) days 1, 8 plus chronomodulated oral capecitabine 1,750 mg/m(2)/die (h 8:00 a.m. 25% of total dose; h 6:00 p.m. 25% of total dose; h 11:00 p.m. 50% of total dose), days 1-14 every 21 days. RESULTS: Forty-six patients were evaluated for safety and efficacy (male/female, 20/26). Median age was 64 years (range 28-77 years). Median Eastern Cooperative Oncology Group performance status (PS) was 0 (range 0-1). A total of 324 cycles have been administered: median per patient 6 (range 3-10 courses). Median number of metastatic sites was 1. Metastatic sites distribution was as follows: liver (65.2%), lung (34.8%), and nodes (32.6%). Median follow-up was 14 months (range 6.0-40.3 months). In an intent-to-treat efficacy analysis, objective response and stable disease were recorded in 27 (58.6%) and in 16 patients (34.9%), respectively. The median response duration was 8.0 months (95% CI; 5.03-10.96 months). The median time to progression (TTP) was 9.0 months (95% CI; 6.47-11.52 months). The overall survival (OS) was not reached, with a median value > 24 months (95% CI; 23.66-36.30 months). The grade 3 toxicities were diarrhea (8.7%), liver toxicity (13.1%), fatigue (8.7%), neurotoxicity (2.2%), neutropenia (8.7%), and thrombocytopenia (2.2%). CONCLUSION: This regimen resulted of particular interest for patients with untreated metastatic CRC.

Long-term survival in metastatic pancreatic cancer. A case report and review of the literature.

CONTEXT: Pancreatic cancer still remains an incurable disease. The survival rate of patients in all stages of the disease is poor. Overall median survival is 3-5 months with a 12-month survival rate of 10% and a 5-year survival rate less than 5%. CASE REPORT: We report a rare case of a long-term survivor (more than 10 years) of metastatic carcinoma of the pancreas tail controlled with subsequent surgical and chemotherapeutic strategies with an acceptable performance status and quality of life. DISCUSSION: This is the fifth case reported in the literature showing that long-term survival may be achieved even in advanced pancreatic cancer.

A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer.

BACKGROUND: Many emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines. METHODS: A phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines. RESULTS: Twenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1-14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%). CONCLUSION: The schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines.

Continuous infusion of oxaliplatin plus chronomodulated capecitabine in 5-fluorouracil- and irinotecan-resistant advanced colorectal cancer patients.

OBJECTIVES: The aim of the study was to define the feasibility and efficacy of Xelox (capecitabine and oxaliplatin) administered through a new and original schedule in advanced pretreated colorectal cancer (CRC) patients. METHODS: 36 metastatic CRC patients resistant at least to a previous 5-fluorouracil- and irinotecan-based chemotherapy line were included in the study. TREATMENT: Oxaliplatin 70 mg/m2 as continuous infusion for 12 h (8.00 a.m. to 8.00 p.m.) on days 1, 8 plus chronomodulated capecitabine 1,750 mg/m2/day per os (8.00 a.m. 25% of total dose; 6.00 p.m. 25% of total dose; 11.00 p.m. 50% of total dose), on days 1-14 every 21 days. 16 (44.4%) patients had previously received only 1 chemotherapy line for metastatic disease and 20 patients (55.6%) 2 chemotherapy lines. Moreover, 12 patients (33.3%) progressed after a first or second line of oxaliplatin-based regimen as well. RESULTS: Most frequent related G3-4 adverse reactions were diarrhea (11.6%), nausea/vomiting (8.3%), neuropathy (8.3%), mucositis (8.3%), asthenia (16.7%) and hand-foot syndrome (5.5%). G3-4 anemia, leucopenia and liver toxicities were not observed. The overall response rate was 30.6% (11/36 patients). Disease stabilization was observed in 13 patients (36.1%) and progression in 12 patients (34.3%). Between the 12 oxaliplatin-resistant patients, the overall response rate was 25% (3 patients); 6 patients (54.5%) obtained a stable disease, and only 3 patients (25%) progressed. The median overall survival was 11.3 months (95% confidence interval 7.0-15.7 months), the median response duration 2.8 months (95% confidence interval 1.2-5.6 months) and the median time to progression 6.7 months (95% confidence interval 5.7-6.3 months). The 1-year survival rate was 53.8%. CONCLUSIONS: The high overall tumor growth control, the remarkable median time to progression and overall survival and the good safety profile are of particular interest for patients with heavy pretreated metastatic CRC.

Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.

PURPOSE: We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer. PATIENTS AND METHODS: A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m(2) on day 1 with LV 100 mg/m(2) administered as a 2-hour infusion before FU 400 mg/m(2) administered as an intravenous bolus injection, and FU 600 mg/m(2) as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m(2) on day 1 with LV5FU2 regimen). RESULTS: One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed. CONCLUSION: There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile.

Lung cancer and skeletal muscle metastases.

Skeletal muscle metastases from lung cancer are rare, and the optimal treatment strategy is unknown. Three cases of skeletal muscle metastases from lung cancer are described. In 2 patients surgical biopsy of muscle swelling disclosed the presence of the lung tumor; the first patient underwent lung resection to remove the primary lesion, the second was not operable because of the metastatic extension of the disease. In the third patient muscle metastasis was observed and excised after lung resection. Adenocarcinoma, squamous cell, and small cell carcinoma were the histologic types diagnosed. Various regimens of radiotherapy and chemotherapy were adopted. Survival times were 3, 6, and 30 months.

A case of renal cell carcinoma with bone and lymph node metastases.

We present a rare case of renal cell carcinoma (RCC) with a metastatic, mainly osteoblastic lesion of the skull and spread to the lymph nodes. Renal tumors are often associated with bone metastases; these are most often of the osteolytic type, while osteoblastic metastases are extremely rare. In the case presented here, the primary metastasis was a large osteoblastic lesion of the skull that spread to the lymph nodes. The patient has undergone treatment for 20 months with interleukin-2: 3 million IU/day (subcutaneous) for six consecutive days once every four weeks, ie a total weekly dose of 18 million IU.

Interleukin-2, interferon-alpha and medroxyprogesterone acetate in metastatic renal cell carcinoma.

BACKGROUND: Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are the main immuno-biological agents used in the therapy of metastatic renal cell carcinoma (RCC). Unfortunately the promising results obtained in biological studies have not yet been confirmed in clinical studies. One reason is linked to the immunosuppression of metastatic patients which is caused by macrophage products. IL-6 in particular is considered a growth factor for RCC. Medroxyprogesterone acetate (MPA) may interfere with IL-6 macrophage production, possibly causing a synergistic effect in association with IL-2 and IFN-alpha. Therefore the purpose of our study was to evaluate the toxicity and the efficacy of the association between IL-2, IFN-alpha and MPA. PATIENTS AND METHODS: Forty-two consecutive patients with metastatic RCC were enrolled. IL-2 was administered subcutaneously at doses of 4.5 million UI on days 1-5, 8-12, 15-19 and 22-26; IFN-alpha was administered s.c. at a dose of 3 million t.t.w; MPA was administered orally at a dose of 1000 mg daily. This schedule was repeated after a rest of 2 weeks. RESULTS: Toxicity was mild: the main symptoms observed were fatigue and fever. Six CR (14%), five PR (12%), thirteen SD (31%) and seventeen PD (41%) were observed for an overall response rate of 26%. Patients with good PS and low levels of CRP had a better prognosis. CONCLUSION: Considering both the good activity and the low toxicity of this scheme, we think that it could be carried out in normal clinical practice.

Tolerability of Raltitrexed ('Tomudex') in elderly patients with colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is one of the major health problems of the Western world and the proportion of elderly patients with CRC is growing. Raltitrexed ('Tomudex'), a specific thymidylate synthase inhibitor, has shown efficacy and manageable toxicity in elderly CRC patients. In this retrospective study, the tolerability of raltitrexed in patients with CRC was examined in relation to age. PATIENTS AND METHODS: Toxicity parameters, graded according to World Health Organization criteria, were assessed in two patient groups: < 70 and > or = 70 years old. In total, 56% (50 out of 90) of patients treated with raltitrexed (3 mg/m2 as a 15-minute intravenous infusion every 3 weeks) were aged > 70 years (M:F 28:22; Eastern Cooperative Oncology Group performance status 0-1:2 38:12). RESULTS: Overall, 437 cycles of chemotherapy were administered and grade 3-4 toxicity was reported in < 10% of patients. There were no clinically significant differences between the two age groups, apart from grade 3-4 asthenia, which was reported by 6% and 0% of patients aged > or = 70 and < 70 years, respectively. This was in spite of a significantly lower calculated mean creatinine clearance in patients aged > or = 70 years compared with those patients < 70 years of age. CONCLUSION: The raltitrexed toxicity profile does not appear to be significantly influenced by age; however caution is recommended in the management of elderly patients, particularly in the presence of impaired renal function.