levoleucovorin and Exanthema

Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab.. Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash.. A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms.. The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Double-Blind Method; Doxycycline; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Patient Compliance; Pharmaceutical Vehicles; Quality of Life; Skin Cream; Vitamin K 1; Young Adult

This multicentre, randomised, and phase II study evaluated mFOLFOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients (NCT01161316).. Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months.. One hundred ninety-three patients (median [range] age 60 [33-74] years) were randomised (2:1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 [52, 69]%/72 [61, 83]%, p [non-inferiority]<0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 [95% CI 7, 10] months/10 [7,13] months, hazard ratio [HR] = 1.19 [0.80, 1.79]) or overall survival (23 [19, 28] months/27 [18, 36] months, HR = 1.24 [0.85, 1.79]) between arms. The objective response rate was also similar (48 [39, 57]%/39 [27, 52]%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade ≥III AEs: 70%/68%). The most common grade ≥III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade ≥III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%).. This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras)

Cetuximab-induced skin rash Gd3+ occurs in ≥16% patients (pts) (Heinemann et al., Lancet Oncol 15(10):1065-1075, 2014; Van Cutsem et al. J Clin Oncol 27(19):3117-25; 2009b). Survival, response, and toxicity parameters were re-evaluated under a pre-defined skin prophylaxis consistent of vitamin K1 ointment and oral doxycycline.. This is a national, multicenter, phase 4, first-line mCRC (K-RAS wt) trial. Pts received irinotecan 180 mg/m² (d1), FA 400 mg/m² (d1), 5-FU 400 mg/m² (d1), 5-FU 2400 mg/m² (d1-2), and cetuximab [400 mg/m² (d1), and then 250 mg/m² qw], prophylactic 0.1% vitamin K1 ointment qd, and oral doxycycline 100 mg bid.. 1-year PFS rate; secondary objectives: skin side-effects (grade, onset), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) time, and overall survival (OS) time and safety.. Twenty centers recruited 55 patients. Recruitment started Q1 2011 and ended Q3 2013 due to slow accrual. Characteristics were in line with CRYSTAL trial except for age and colonic location. 1-year PFS rate was 25.9%, mOS 21.8 months (m), and mPFS 8.5 m. ORR was 63.0%, DCR 77.8%. Rash Gd2+ occurred in 42.6% [median onset was 4.0 weeks (w)]; paronychia Gd2+ occurred in 22.2% (median onset 15.4w.); skin fissures Gd2+ occurred in 31.5% (median onset 19.9 weeks) 7% pts abandoned cetuximab treatment due to toxicity.. Our data reveal encouraging improvements in skin reactions and their time to occurrence due to a pre-defined skin care.

Topics: Adenocarcinoma; Administration, Cutaneous; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemoprevention; Colorectal Neoplasms; Doxycycline; Drug Eruptions; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Ointments; Skin Care; Treatment Outcome; Vitamin K 1

This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer.. The 5-FU dose was selected on the basis of dose-limiting toxicities (DLTs) during part I of the study. Patients received cetuximab (400 mg/m2 initial dose and 250 mg/m2/week thereafter) and every 2 weeks irinotecan (180 mg/m2), FA (400 mg/m2) and 5-FU (either low dose [LD], 300 mg/m2 bolus plus 2,000 mg/m2 46-hour infusion, n = 7; or, high-dose [HD], 400 mg/m2 bolus plus 2,400 mg/m2; n = 45).. Only two DLTs occurred in the HD group, and HD 5-FU was selected for use in part II. Apart from rash, commonly observed grade 3/4 adverse events such as leucopenia, diarrhoea, vomiting and asthenia occurred within the expected range for FOLFIRI. Among 52 patients, the overall response rate was 48%. Median progression-free survival (PFS) was 8.6 months (counting all reported progressions) and the median overall survival was 22.4 months. Treatment facilitated the resection of initially unresectable metastases in fourteen patients (27%): of these, 10 patients (71%) had no residual tumour after surgery, and these resections hindered the estimation of PFS.. The combination of cetuximab and FOLFIRI was active and well tolerated in this setting. Initially unresectable metastases became resectable in one-quarter of patients, with a high number of complete resections, and these promising results formed the basis for the investigation of FOLFIRI with and without cetuximab in the phase III CRYSTAL trial.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Diarrhea; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Exanthema; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis; Treatment Outcome; Vomiting

This phase I study was conducted to establish the dose-limiting toxicities and maximum-tolerated dose of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in combination with FOLFIRI, a standard regimen of irinotecan, leucovorin, and infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer.. The trial used a dose-escalation design beginning with 100 mg/day erlotinib continuously and dose-reduced FOLFIRI (150 mg/m2 i.v. day 1 irinotecan, 200 mg/m2 i.v. leucovorin, 320 mg/m2 i.v. bolus days 1 to 2 5-FU, and 480 mg/m2 i.v. 5-FU infusion over 22 hours, days 1 to 2) administered in 6-week cycles (three FOLFIRI treatments). Plasma sampling was performed for irinotecan, erlotinib, and 5-FU for pharmacokinetic analysis during cycle 1.. The study was halted after six patients at the lowest dose level due to unexpectedly severe toxicities, including disfiguring grade 2 rash (three patients), grade 3 diarrhea (three patients), and grade > or = 3 neutropenia (three patients). All patients required some dose interruption or reduction of either erlotinib or FOLFIRI, and only one patient completed two 6-week cycles of therapy. Five patients had stable disease after one cycle, and one patient had a partial response. No plasma pharmacokinetic interaction was observed that could explain the observed increased toxicity.. FOLFIRI combined with erlotinib causes excessive toxicity at reduced doses. These findings contrast with available data regarding the optimal safety profile of trials combining small molecule epidermal growth factor receptor inhibitors with other conventional chemotherapy and highlight the need to perform safety-oriented studies of such combinations.

Topics: Administration, Oral; Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Metabolic Clearance Rate; Middle Aged; Quinazolines; Treatment Outcome

EGFR inhibitors used in the treatment of metastatic wild-RAS colorectal cancer in combination with chemotherapy are associated with dermatologic side events that are low grade in most cases. We report a case of severe cutaneous toxicity secondary to cetuximab associated with bacterial cellulitis. A 57-year-old woman with metastatic adenocarcinoma of the colon, receiving FOLFIRI and Cetuximab as a first-line treatment, presented with a severe erythematous rash and xerosis resistant to local treatment with moisturizing emollients. Few days later, the patient becomes febrile, and the rash becomes more diffuse with a sandpaper appearance on the face, neck, chest, and flexor creases with exfoliation of large areas of skin. A bacterial cellulitis secondary to a dermatologic severe toxicity of Cetuximab was suspected. The patient started on antibiotics and local treatment with good response. This is a life-threatening cutaneous toxicity of cetuximab with secondary bacterial infection. Early recognition of cutaneous side effects of EGFR inhibitors is important to prevent such type of toxicities.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Cellulitis; Cetuximab; Colorectal Neoplasms; Drug Eruptions; ErbB Receptors; Exanthema; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Skin Diseases

To assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC).. We performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).. One hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70-85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3-4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1-2 skin rash (49.1%), G1-2 diarrhea (21.1%) and G1-2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5-11.4), while the median OS was 18.0 months (95% CI: 16.0-19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832).. This study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Exanthema; Fluorouracil; Humans; Leucovorin; Panitumumab; Rectal Neoplasms

A 56-year-old male patient was admitted due to a "rectal malignant tumor". He suffered from rash and neutropenia after multiple chemotherapy sessions including oxaliplatin, 5-fluorouracil (5- FU), and calcium folinate injection (CF) which are called FOLFOX regimen for short. The rash was treated with methylprednisolone + promethazine + calcium gluconate, and the neutropenia was treated by subcutaneous injection of the Recombinant Human Granulocyte Colony-Stimulating Factor Injection, the symptoms were relieved. Moreover, rashes and neutropenia are known common adverse reactions after intravenous administration of FOLFOX regimen. Based on the patient's symptoms and the timing of drug administration, a diagnosis of "rash and neutropenia due to the use of FOLFOX regimen" was made. Oxaliplatin and CF may also cause allergic reactions, including skin erythema and anaphylactic shock, etc. Once allergic reaction occurs, the fatality rate is higher than that of Penicillin. Therefore, sufficient attention should be paid to the patients reported in this paper who received FOLFOX regimen for multiple times and had multiple rashes and adverse reactions of neutropenia. Medical staff should closely monitored the adverse reactions and changes in vital signs of patients treated with this regimen during chemotherapy, and the chemotherapy regimen should be adjusted or terminated when necessary. The adverse reactions reported in this article deserve clinical attention.

Topics: Antineoplastic Combined Chemotherapy Protocols; Exanthema; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Oxaliplatin; Treatment Outcome

Topics: Aged; Anti-Bacterial Agents; Exanthema; Febrile Neutropenia; Female; Folic Acid; Humans; Leucovorin; Methotrexate; Necrosis; Pancytopenia; Rheumatic Fever; Skin; Stomatitis

Recent approval and introduction into clinical practice of epidermal growth factor receptor inhibitors such as the chimeric monoclonal antibody cetuximab and the fully human monoclonal antibody panitumumab have provided new treatment options for chemotherapy-refractory patients. Here, we report a case of a 47-year-old man with metastatic, chemotherapy-refractory colorectal cancer who achieved long-term partial remission during panitumumab therapy.. A 41-year-old male patient presented with a 24-hour history of abdominal pain and fever. A computed tomography (CT) scan revealed a voluminous and perforated abscess with a suspected tumour lesion in the sigmoid colon. The patient underwent sigmoidectomy and was diagnosed with a poorly differentiated necrotic carcinoma of the sigmoid colon with invasion in 13 of 19 tested lymph nodes. A colonoscopy revealed multiple tubular adenomas and a positron emission tomography CT scan showed multiple and bilateral hyperfixating lumbar-aortic lymph nodes leading to a final tumour classification of T4N2M1. Carcinoembryonic antigen (CEA) was elevated. The patient achieved a partial response following six cycles of FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), then progressed and was enrolled in a trial where he received treatment with FOLFOX4 (oxaliplatin, leucovorin and 5-fluorouracil) with or without a vascular endothelial growth factor inhibitor (PTK787/ZK 222584 [valatinib]). Eight months later he progressed again and was included in a panitumumab (6mg/kg every 2 weeks) monotherapy trial. A partial response was noted after 8 weeks of therapy along with a rapid CEA reduction and decrease in lymph node size. The patient is continuing panitumumab treatment and is still in partial remission after 65 months' treatment. He has non-mutated KRAS and no human-anti-human antibodies have been detected. During treatment the patient has on occasion experienced grade 1-2 diarrhoea as well as folliculitis and acne-like rash up to grade 3 in severity. Cutaneous toxicity was managed with a combination dose interruption/reduction and the use of topical agents. No eye or nail toxicities occurred.. This case shows that long-term responses are possible during panitumumab therapy and that this agent may be an effective long-term treatment option for selected patients with metastatic colorectal cancer. The associated skin toxicities can be successfully managed.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Diarrhea; Exanthema; Fluorouracil; Folliculitis; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Panitumumab; Tomography, X-Ray Computed

Topics: Adolescent; Drug Hypersensitivity; Exanthema; Fever; Humans; Leucovorin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Bevacizumab (Avastin) in combination with intravenous 5-fluorouracil-based chemotherapy as first-line as well as second-line treatment of metastatic colorectal cancer improves survival. Although skin rash (type unspecified) has been described in some patients following infusion of bevacizumab, it is not a common toxicity of bevacizumab, while acneiform rash occurs in more than 90% of patients who receive cetuximab (Erbitux), the severity of which appears to be predictive of response. We report a patient with colorectal cancer who developed a rash secondary to bevacizumab that correlated with response. A 40-year-old patient with stage IV colorectal cancer received FOLFOX-4 and bevacizumab, which he tolerated very well except for a skin rash related to bevacizumab. The rash cleared every time bevacizumab was eliminated from the chemotherapy regimen. When use of bevacizumab was resumed, similar rash reappeared. Therefore, we believe that this observation of the rash emergence was linked to bevacizumab administration. The most common toxicities associated with bevacizumab include hypertension, hemorrhage, gastrointestinal perforation, arterial thromboembolism, wound healing and proteinuria. Exfoliative dermatitis and a nonspecific rash have been reported with bevacizumab. This case report, we believe, is the first report of a possible correlation between a rash and a positive drug response associated with bevacizumab, and may initiate further investigation of similar observation.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Exanthema; Fluorouracil; Humans; Leucovorin; Liver Diseases; Male; Organoplatinum Compounds; Radiography