Katia Cannita

Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity

At present, the various mechanisms involved in 5-fluorouracil (5-FU)-correlated cardiotoxicity remain to be elucidated and a universally accepted prophylaxis or treatment for this specific toxicity is not available. Although it may improve time to progression, survival and clinical benefit, a 5-FU-based regimen usually has to be discontinued if a patient experiences cardiotoxicity. Here, we describe our experience with three cases of 5-FU-associated cardiotoxicity. The angina-like pain that appeared approximately 95 h after beginning 5-FU therapy was apparently independent of the drugs administration modality. In the two patients receiving 5-FU 12-h flat continuous infusion from 22.00 to 10.00 h (5-FU 12-h c.i.) in combination with other drugs, the dose of 5-FU was reduced by 10–20% and patients received prophylactic transepidermal nitroglycerin. In the third patient, 5-FU administration modality was changed and prophylactic therapy was not given. By taking these precautions, the patients no longer complained of anginal pain and none of them discontinued chemotherapy.

The Supportive Care Task Force at the University of L’Aquila: 2-years experience

The Supportive Care Task Force (SCTF) was established within the Medical Oncology Department at the University of L’Aquila in May 2002. The missions of the SCTF were to allow systematic evaluation and treatment of symptoms, to warrant continuity of care in all phases of disease and to provide medical oncology residents with training in the treatment of symptoms. A medical oncologist, two senior residents in medical oncology and a registered nurse comprised the SCTF. A psychiatrist, two neurologists, a dietician, and two physiotherapists served as consultants or on a part-time basis. Four beds in two-bedded rooms inside the Medical Oncology Department were reserved to SCTF. A close integration with the physicians of the Medical Oncology Department was realised. The only criterion to admission was the presence of uncontrolled symptoms. Patients were evaluated and monitored with the visual analogue scale for pain and with the Edmonton Symptom Assessment Scale (ESAS). The Palliative Prognostic Score (PaP Score) was employed to assess the prognosis. Non-clinical needs were evaluated with the Need Evaluation Questionnaire (NEQ). Protocols for the treatment of common symptoms were available in written form for consultation by physicians, residents and nurses. From 1 May 2002 to 31 May 2004, we observed 208 patients: 111 women and 97 men. The median age was 64.7 (range 28–90) years. Fifty-four patients (25.9%) were admitted more than once, for a total of 285 admissions. One hundred ninety-nine admissions (69.5%) were for supportive care while 86 admissions (30.5%) were for supportive care and active treatment. The most frequent symptoms were asthenia and anorexia. We registered excellent results regarding the treatment of pain, nausea and dyspnea while psychological symptoms, anorexia and asthenia proved more difficult to treat.Two hundred twenty patients were discharged: 142 (49.8%) home; 76 (26.7%) to the Home Care Service and two (0.7%) to others units of the hospital. Sixty-five (22.8%) died in our unit.

Poker association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

BackgroundThis phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC).MethodsSimon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks.ResultsFifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%.ConclusionPoker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered.Trial registrationOsservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34

Effectiveness of Liver Metastasectomies in Patients With Metastatic Colorectal Cancer Treated With FIr-B/FOx Triplet Chemotherapy Plus Bevacizumab

BACKGROUND Intensive medical treatment increases resection rate of liver metastases in patients with metastatic colorectal cancer (MCRC). The effectiveness of liver metastasectomies was evaluated in patients with MCRC who were treated with previously reported FIr-B/FOx (triplet chemotherapy plus bevacizumab). PATIENTS AND METHODS Fifty patients with MCRC enrolled in the reported phase II study were classified according to involved metastatic sites (liver-only metastatic site, multiple metastatic sites) and the extent of liver metastases (single, multiple). Surgical resectability of liver metastases was evaluated at baseline and every 3 cycles of FIr-B/FOx treatment. The resection rate of liver metastases, activity, and efficacy were evaluated; progression-free survival (PFS) and overall survival (OS) were compared by using the log-rank test. RESULTS Patients with liver MCRC were 33 of 50 consecutive unselected patients with MCRC: liver limited, 22 patients; multiple metastatic sites, 11 patients. Liver metastasectomies were performed in 13 patients: 26% of 50 patients with MCRC, 39% of 33 patients with liver MCRC. In patients with liver-only MCRC, a secondary liver surgery was performed in 54%: 6 of 9 single and 6 of 13 multiple liver metastases. Also, 1 liver and lung metastasectomy was performed. Pathologic complete responses were achieved in 2 patients (15%). The conversion rate of unresectable liver metastases was 83%. Objective response rate, PFS, OS were, respectively: 84%, 11 and 23 months in 33 liver MCRC; 86%, 17 and 44 months in 22 liver-limited patients. PFS and OS were significantly increased in patients with liver-limited metastases compared with multiple metastatic sites and single compared with multiple liver metastases. CONCLUSION The FIr-B/FOx regimen may increase the resection rate of liver metastases and improve clinical outcome of patients with liver-only MCRC.

Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease

BackgroundBevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated.MethodsTumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test.ResultsIn all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively.ConclusionsThe KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.

High sensitivity of detection of TP53 somatic mutations by fluorescence-assisted mismatch analysis

We analyzed exons 5–9 of the TP53 gene in 41 breast cancers using direct sequencing, PCR‐SSCP (single‐strand conformation polymorphism), and fluorescence‐assisted mismatch analysis (FAMA), to test the level of specificity and sensitivity of each method. A major issue for the correct detection of TP53 somatic mutations in primary tumors is often represented by the large amount of normal DNA, which can cause excessive dilution of the mutant allele, with consequent possible false‐negative results. High sensitivity upon dilution of the mutant allele has been demonstrated for FAMA, a method based on the chemical cleavage of a mismatch within heteroduplex DNA molecules. Exons 5–9 of the TP53 gene were analyzed by FAMA using only two long bifluorescent fragments. Differences in sensitivity, accuracy, and specificity were observed among the above‐mentioned procedures. Thirteen of the 41 samples (31.7%) revealed TP53 genetic alterations by automated sequencing, 19 samples (46.3%) were positive for SSCP, whereas 14 samples (34%) showed variants detectable by FAMA. Seven samples were positive in SSCP, but negative in both FAMA and sequencing assays; however, 2 SSCP‐negative samples revealed evident signals by FAMA, indicating the presence of TP53 mutations. One of the latter samples showed the alteration by sequence analysis, whereas the other failed to reveal the mutation signal even by sequencing, as a consequence of the very small amount of the mutant allele resulting from the excess of contaminating normal DNA. Our results show that FAMA may represent a suitable and accurate assay for the routine diagnosis of TP53 somatic mutations in DNAs from solid tumor biopsies.

Worse prognosis of KRAS c.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx)

Background Prognosis of KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients (pts) treated with bevacizumab (BEV)-containing chemotherapy is not significantly different. Since specific KRAS mutations confer different aggressive behaviors, the prognostic role of prevalent KRAS mutations was retrospectively evaluated in MCRC pts treated with first line FIr-B/FOx, associating BEV to triplet chemotherapy. Methods Tumor samples were screened for KRAS codon 12, 13 and BRAF V600E mutations by SNaPshot and/or direct sequencing. MCRC pts <75-years-old were consecutively treated with FIr-B/FOx: weekly 12 hour-timed-flat-infusion/5-fluorouracil (900 mg/m2 on days 1,2, 8, 9, 15, 16,22, 23), irinotecan plus BEV (160 mg/m2 and 5 mg/kg, respectively, on days 1,15); and oxaliplatin (80 mg/m2, on days 8,22). Pts were classified as liver-limited (L-L) and other/multiple metastatic (O/MM). Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. Results Fifty-nine pts were evaluated at a median follow-up of 21.5 months. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). The objective response rate (ORR), PFS and OS were, respectively: c.35 G > A mutant, 71%, 9 months, 14 months; other than c.35 G > A mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (P = 0.002), KRAS/BRAF wild-type (P = 0.03), other MCRC patients (P = 0.002), other than c.35 G > A (P = 0.05), other codon 12 (P = 0.03) mutant pts. OS was not significantly different compared to c.35 G > T KRAS mutant (P = 0.142). Conclusions KRAS c.35 G > A mutant status may be significantly associated with a worse prognosis of MCRC pts treated with first line FIr-B/FOx intensive regimen compared to KRAS/BRAF wild type and other than c.35 G > A mutant pts.

The prevalent KRAS exon 2 c.35 G>A mutation in metastatic colorectal cancer patients: A biomarker of worse prognosis and potential benefit of bevacizumab-containing intensive regimens?

Bevacizumab-containing chemotherapy differently predict increased efficacy in KRAS exon 2 mutant and wild-type metastatic colorectal cancer (MCRC) patients. Mutant compared to wild-type status did not significantly affect progression-free survival (PFS) and overall survival (OS) in patients fit for first line bevacizumab-containing FIr-B/FOx regimen, and after progression. In patients unfit for intensive regimens, mutant status significantly affected PFS, while not OS. Codon 12 KRAS mutations differentially affect GTPase function, and confer worse clinical behaviour. Prognostic relevance of the prevalent c.35 G>A KRAS mutation was retrospectively evaluated. Fit c.35 G>A mutant patients showed significantly worse OS compared to wild-type and to other mutant. After progression and in unfit patients, c.35 G>A mutation affected significantly worse PFS and OS. c.35 G>A mutant status does not significantly affect worse PFS in patients fit for first line FIr-B/FOx, and it may depend upon effectiveness of anti-VEGF-containing intensive regimen.

Triplet Chemotherapy in Patients With Metastatic Colorectal Cancer: Toward the Best Way to Safely Administer a Highly Active Regimen in Clinical Practice

A major problem concerning the addition of more drugs in a chemotherapy combination is designing a proper schedule assuring the balance between dose intensity of each drug, efficacy of the combination, and tolerability lessening the burden of drug toxicity. We evaluated triplet chemotherapy-based intensive regimens proposed as first-line treatment in patients with metastatic colorectal cancer. Using a FOLFOXIRI (5-fluorouracil [5-FU], irinotecan, and oxaliplatin) combination regimen, patients with metastatic colorectal cancer now have the possibility of longer survival, but disappointingly, with increased toxicities. Triplet chemotherapy regimen according to 5-fluorouracil, irinotecan /5-fluorouracil, oxaliplatin, characterized by timed flat-infusion 5-FU administration, without leucovorin, obtained efficacy equivalent to other reported similar combination regimens (5-FU, irinotecan, and oxaliplatin), with increased received 5-FU dose intensity and lower grade 3 to 4 neutropenia. To guarantee the proper balance between dose intensities, efficacy, and toxicity, triplet chemotherapy schedules could be further improved by abrogation of folinic acid and bolus 5-FU, a new and easy modality of 5-FU administration, such as timed flat-infusion 5-FU, associated with alternating irinotecan and oxaliplatin; this could favor diffusion of this intensive treatment in clinical practice.

Assessment and treatment of symptoms among Italian medical oncologists

ObjectivesThis work was conducted to evaluate symptoms assessment and use of patient-tailored protocols in clinical practice among Italian medical oncologists.MethodsA questionnaire based on four topics (assessment of symptoms, assessment of a specific symptom, assessment of pain, use of patient-tailored protocols of treatment) was administered to 250 Italian medical oncologists.Results: Of these oncologists, 43.7% used multiple symptoms tools and 37.9% used symptom specific tools; 58.9% used some instrument to assess pain. More than a third of the respondents (35.5%) used patient-tailored protocols. No statistical differences were found regarding region of residency, availability of consultants in pain therapy and/or palliative care, colleagues with main interest on palliative care, and beds dedicated to palliative care. Statistically significant differences were found regarding the position (staff/resident) in three out four topics.ConclusionsAmong Italian medical oncologists, the instruments used for assessment of symptoms are poorly employed. Even when these instruments are used, patient-tailored protocols are rarely administered.