Therapies directed against multiple signaling pathways have been validated in the clinical setting as effective anticancer treatments. The combination of different agents is particularly helpful in patients with multiple cancer diagnoses, while data on cross-toxicity are frequently missing, as for imatinib and cetuximab plus platinum drugs.
We present the case of a 76-year-old man with advanced laryngeal squamous cell carcinoma and chronic myeloid leukemia (CML). Combined treatment with imatinib mesylate and cetuximab plus carboplatin was well-tolerated by the patient, who did not develop neutropenia. By an interdisciplinary approach with hematology specialists, the anticipated neutropenia was managed by the temporary interruption of imatinib treatment when the white blood cell (WBC) count nadir was expected to occur.
Although treatment with imatinib, carboplatin, and cetuximab can be associated with hematologic toxicities, a combination regimen based on the concomitant administration of these 3 drugs and on the discontinuation of imatinib at the predicted nadir of WBC count was feasible and well-tolerated in a patient with concomitant CML and locally advanced laryngeal squamous cell carcinoma.
Our report indicates the feasibility of combination imatinib and cetuximab plus carboplatin in a case of multiple cancer diagnoses, provided that the treatment with imatinib is modulated according to the expected bone marrow depression.
Tumori 2016; 102(Suppl. 2): e1 - e2
Article Type: CASE REPORT
AuthorsLaura Pala, Cristiana Bergamini, Martina Imbimbo, Roberta Granata, Laura Locati, Salvatore Alfieri, Lisa Licitra, Paolo Bossi
- • Accepted on 28/01/2016
- • Available online on 14/03/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
A multistep process enabling tumor growth and metastatic dissemination can lead normal cells to the neoplastic state by constitutive activation of components of multiple signaling pathways. The design of novel anticancer agents targeting these aberrant tumorigenic pathways was one of the hallmarks of drug development over the past decades.
Imatinib mesylate (Gleevec®) is an orally active, selective inhibitor of tyrosine kinase receptors with potent activity directed to the fusion protein product of the
Cetuximab (Erbitux®), a monoclonal antibody directed against the epidermal growth factor (EGF) receptor (EGFR), has been approved in head and neck squamous cell carcinoma for the treatment of recurrent/metastatic disease with a platinum combination after having shown better results over chemotherapy alone (2).
Besides the widely accepted approach of combining targeted drugs with chemotherapeutic agents, the therapeutic efficacy of the combination of molecularly targeted anticancer agents simultaneously blocking multiple pathways has recently been proven (3). This strategy may also prevent or slow down the development of resistance to these drugs (3). Moreover, patients with multiple cancers may need concomitant therapies with different anticancer targeted agents. Therefore, efficacy evaluation of a given combination therapy needs to include the analysis of possible cross-toxicity among the agents used. In particular, no data are available for combined therapy with imatinib and cetuximab plus platinum compounds. We report the case of a patient diagnosed with 2 distinct types of cancer and receiving 2 different targeted therapies.
A 76-year-old man presented in June 2012 with worsening dysphonia. The patient was admitted to our hospital for diagnostic microlaryngoscopy and laboratory examination revealed the presence of a relevant leukocytosis, with a white blood cell (WBC) count of 60.43 × 103/µL. Therefore, a bone marrow biopsy was performed with a diagnosis of chronic myeloid leukemia (CML) Philadelphia (Ph)-positive with BCR/ABL1 t(9;22) translocation. The patient was started on targeted imatinib mesylate therapy (400 mg daily) and a good hematologic response was reported.
In July 2012, a vocal cord biopsy was performed. Pathologic evaluation supported the diagnosis of invasive locally advanced carcinoma of the larynx, stage T3N0. Following this diagnosis, a total laryngectomy and right radical neck dissection were performed simultaneously. The patient received postoperative larynx and neck radiotherapy from December 2012 to January 2013 (total dose 70 Gy). In August 2013, magnetic resonance imaging was performed and a relapse of disease was documented in the right latero-cervical lymph nodes, not suitable for salvage surgery. Consequently, from September to December 2013, chemotherapy with carboplatin AUC5 (450 mg total dose) every 21 days was administered in combination with cetuximab at a starting dose of 400 mg/mq, followed by 250 mg/mq weekly. Upon consultation by the hematologist, imatinib therapy was temporarily discontinued at the expected nadir of WBC for 8 days at every cycle (from day 9 to day 15), then resumed if WBC count recovered. The patient underwent 6 cycles in absence of any hematologic toxicity.
In February 2014, a computed tomography scan was performed, which revealed the progression of the latero-cervical lymph node, with bulky appearance, prompting cessation of the treatment.
The case presented here shows the feasibility of the combined treatment of imatinib mesylate and carboplatin plus cetuximab, managing neutropenia by temporary interruption of imatinib treatment at the expected nadir of WBC count.
Imatinib is generally well-tolerated, with minimal extramedullary grade 3 toxicity, albeit with frequent hematologic toxicity. Grade 3 neutropenia is reported in 35%-45% of patients, and grade 3 thrombocytopenia occurs in 20%-25% of patients (4). The myelosuppression developing in some patients during imatinib therapy may be the result of the suppression of normal progenitors, due to the potent inhibitory effect of this drug on c-Kit, a tyrosine kinase involved in early hematopoiesis (5).
Multiple distinct mechanisms may be responsible for cetuximab-associated neutropenia. EGF and EGF-like proteins play important roles in several cellular processes, such as cell proliferation and differentiation, and wound healing as well (6). Cetuximab, by targeting EGFR signaling, might inhibit the proliferation of neutrophils and the EGF-regulated expression of tumor necrosis factor-α, an important proinflammatory activator of neutrophils (6).
A meta-analysis shows that carboplatin is associated with a significant risk of neutropenia in patients with advanced cancer receiving concurrent chemotherapy (7). In addition, grade 3-4 neutropenia and thrombocytopenia occur in 15%-48% of cases, according to different studies, during combination therapies of platinum compounds plus cetuximab for recurrent or metastatic head and neck and nasopharyngeal carcinoma (8, 9).
The concomitant administration of paclitaxel and imatinib causes an unacceptable myelosuppression when imatinib is administered continuously. However, the combination of intermittently dosed imatinib and paclitaxel is reasonably well-tolerated (10). Accordingly, we show here that, in a patient with concomitant CML and locally advanced laryngeal squamous cell carcinoma, the combination of imatinib and cetuximab plus carboplatinum was feasible and well-tolerated when imatinib was discontinued at the predicted nadir of WBC count, as a pattern of bone marrow depression.
The authors thank Luca Giacomelli, PhD, and Ambra Corti for editorial assistance.
- Pala, Laura [PubMed] [Google Scholar]
- Bergamini, Cristiana [PubMed] [Google Scholar]
- Imbimbo, Martina [PubMed] [Google Scholar]
- Granata, Roberta [PubMed] [Google Scholar]
- Locati, Laura [PubMed] [Google Scholar]
- Alfieri, Salvatore [PubMed] [Google Scholar]
- Licitra, Lisa [PubMed] [Google Scholar]
- Bossi, Paolo [PubMed] [Google Scholar] , * Corresponding Author (firstname.lastname@example.org)
Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan - Italy