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Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district

Abstract

Introduction

The antiangiogenic monoclonal antibody aflibercept in association with fluorouracil and irinotecan improves the survival of patients with metastatic colorectal cancer (mCRC) treated previously with oxaliplatin-based therapy. Multiple reports raised the hypothesis that the concomitant use of antiresorptive drugs and antiangiogenic drugs may increase the risk of osteonecrosis of the jaw (ONJ). Some reports have been published regarding cases of ONJ during treatment with bevacizumab for mCRC.

Case description

Here we describe the first reported case of ONJ occurring in a 64-year-old woman with untreated periodontitis and episodic previous pyorrhea occurring during treatment with aflibercept plus FOLFIRI during the expanded-access program.

Conclusions

This case report warrants further investigation into the potential association between the use of anti-VEGF agents and ONJ. Given the serious nature of ONJ, we recommend that particular attention be paid to the oral district prior to treating patients and during treatment with chemotherapy and targeted agents, especially anti-VEGF agents. Such measures could also be useful in reducing the incidence of stomatitis.

Tumori 2016; 102(Suppl. 2): e74 - e77

Article Type: CASE REPORT

DOI:10.5301/tj.5000405

Authors

Agostino Ponzetti, Francesco Pinta, Rosella Spadi, Caterina Mecca, Laura Fanchini, Marcello Zanini, Libero Ciuffreda, Patrizia Racca

Article History

Disclosures

Financial support: None.
Conflict of interest: None of the authors has any financial interest related to this study to disclose.
Authorization to publish the case report and the data from the 2 cases of osteonecrosis of the jaw in the VELOUR trial was obtained from the drug manufacturer (Sanofi, Paris, France) before submission.

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Introduction

The treatment of patients with metastatic colorectal cancer (mCRC) requires a multidisciplinary approach that includes in most cases the administration of intravenous chemotherapy. The sequential use of chemotherapy doublets containing fluorouracil, levofolinic acid and irinotecan and/or oxaliplatin (FOLFIRI and FOLFOX, respectively) or of the triplet FOLFOXIRI and the availability of molecular targeted agents has increased the expected survival of patients with mCRC to more than 24 months (1-2-3). However, in order to achieve the best possible outcome of treatment, prompt recognition and management of possible adverse effects is extremely important.

In the treatment setting of an antiangiogenic agent combined with chemotherapy, the most frequent severe toxicities are asthenia, nausea and vomiting, diarrhea, and cardiovascular effects (hypertension, proteinuria and thrombosis). In addition, the oral cavity is a possible site of distressing side effects and a higher incidence of stomatitis has been noted in several recent clinical trials (Tab. I).

Incidence of stomatitis in recent trials of chemotherapy plus targeted agents for metastatic colorectal cancer

Trial/reference Chemotherapy regimen Stomatitis % (all grades) Stomatitis % (grade 3 or more)
FOLFIRI = irinotecan, fluorouracil and leucovorin; FOLFOXIRI = irinotecan, oxaliplatin, fluorouracil and leucovorin.
VELOUR Aflibercept/FOLFIRI 54.8 13.5
Van Cutsem 2012 (1) FOLFIRI 34.9 5
FIRE-3 Bevacizumab/FOLFIRI 58 7
Heinemann 2014 (2) Cetuximab/FOLFIRI 50 5
TRIBE Bevacizumab/FOLFOXIRI Not available 8.8
Loupakis 2014 (3) Bevacizumab/FOLFIRI Not available 4.3

Osteonecrosis of the jaw (ONJ) is an adverse drug event in the oral cavity that has been typically associated with the use of bisphosphonates; however, bisphosphonate drugs that inhibit osteoclastic bone resorption may also exhibit marked antiangiogenic activity. ONJ is defined as the presence of exposed necrotic bone in the maxillofacial region that does not heal after 6-8 weeks in patients with no history of craniofacial radiation. Possible causes of ONJ are infections, prolonged steroid use, and use of antineoplastic and bone-antiresorptive drugs, especially bisphosphonates and the inhibitor of receptor activator of nuclear factor kappa B ligand, denosumab. On clinical examination, ONJ usually appears as an area of exposed bone in the oral cavity possibly accompanied by pain, swelling, numbness and ulceration of the surrounding soft tissues. Possible mechanisms involved in ONJ induced by bisphosphonates are suppression of bone turnover due to deficient removal of necrotic tissue by osteoclasts, imbalance between osteoblasts and osteoclasts resulting in osteopetrosis, inhibition of T-lymphocyte function, and inhibition of angiogenesis (4-5-6).

In the setting of mCRC, starting in 2008 multiple reports raised the hypothesis that the concomitant use of antiresorptive and antiangiogenic drugs may increase the risk of this serious adverse reaction (7). There were sporadic reports of ONJ during the use of bevacizumab, a monoclonal antibody that binds human vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF with its receptors (Flt-1 and KDR) (Tab. II). A plausible mechanism of ONJ induced by antiangiogenic drugs is the alteration of microvessel integrity, which can compromise the osteons in the jaw (7).

Case reports of jaw osteonecrosis during chemotherapy plus anti-VEGF agents for metastatic colorectal cancer

Reference Age/sex Treatment Cycles before occurrence Treatment outcome
FOLFIRI = irinotecan, fluorouracil and leucovorin; FOLFOX = oxaliplatin, fluorouracil and leucovorin.
Sato 2013 (8) 67/not available Bevacizumab/FOLFOX 5 or 6 Not available
Dişel 2012 (9) 51/male Bevacizumab/FOLFOX 6 Not available
VELOUR, Van Cutsem 2012 (1) Not available Aflibercept/FOLFIRI Not available Not available

Aflibercept is a novel recombinant human fusion protein designed to provide pharmacological blockade of the VEGF pathway through high-affinity binding to the VEGF-A and VEGF-B isoforms and the placental growth factor-1 and 2 isoforms. The phase III VELOUR trial (NCT00561470) showed that aflibercept is an active antiangiogenic agent that, when used in combination with FOLFIRI, improves the overall survival, progression-free survival, and response rate of patients with mCRC who have received prior oxaliplatin-based therapy (1). There were 2 reported cases of ONJ in the experimental arm of VELOUR while there were none in the FOLFIRI control arm (1, 10). One case of ONJ, considered to be related to aflibercept and FOLFIRI, occurred 5 weeks after a tooth extraction (with impaired healing and recovering 3 weeks later), while the other case was not associated with dental surgery but occurred in a patient who had received treatment with bisphosphonates for nearly 10 months at the time of ONJ diagnosis.

Case presentation

Our patient was a 64-year-old woman with no relevant comorbidities other than controlled hypertension and recurrent pyorrhea, who in August 2012 was diagnosed with adenocarcinoma of the transverse colon with unresectable bilateral liver metastases. KRAS analysis demonstrated a wild-type genotype. She received first-line treatment with cetuximab plus capecitabine/oxaliplatin (XELOX) resulting in a partial response lasting 8 months. In April 2013 CT scan revealed disease progression and the patient was included in the expanded-access program of aflibercept in combination with FOLFIRI.

Treatment was started in May 2013. The patient had untreated periodontitis with episodic previous pyorrhea; however, due to the lack of symptoms, no pre-treatment dental specialist consultation was requested. After the first cycle, the patient developed grade (G) 3 diarrhea, G2 stomatitis and G3 neutropenia leading to a 1-week treatment delay. Supportive care was subsequently increased and 3 further cycles were regularly administered. CT scan after 4 cycles revealed no increase in the extent of the liver metastases and showed partial colliquation, amounting to stable disease (SD). The patient then received 5 further cycles of aflibercept/FOLFIRI with a mean delay of 1 week for every cycle due to recurrent G3 neutropenia or G3 stomatitis. G2 periodontal disease started after the fourth cycle (no supportive dental care was introduced at the time) and worsened to G3 after the tenth cycle. CT scan after the ninth cycle demonstrated sustained SD. Meanwhile deep vein thrombosis was reported and the patient was given low-molecular-weight heparin (LMWH) twice daily. According to the protocol the patient continued to receive treatment and no dose reduction was performed.

After the 11th cycle the patient reported nontraumatic avulsion of 2 teeth with concomitant purulent discharge from the right mandible. The chemotherapy was interrupted and the patient was referred to a local dental center. Pantomography and CT Dentals scan (Fig. 1) revealed multiple foci of osteonecrosis of the jaw. The patient underwent laser treatment of the osteonecrosis with partial recovery of the damage.

Dental CT scan revealing multiple foci of osteonecrosis.

After treatment discontinuation, a subsequent CT scan in December 2013 confirmed no change in the liver metastases and the primary colon tumor. Because of the occurrence of ONJ and the prolonged SD, strict follow-up was undertaken. A subsequent CT scan in April 2014 revealed disease progression with peritoneal carcinomatosis. Third-line chemotherapy with raltitrexed was given for 2 cycles, but the general condition of the patient gradually worsened and chemotherapy was then definitively interrupted. Home palliative care was activated, and the patient died in August 2014.

Discussion

The incidence of ONJ in colorectal cancer is very low and its association with chemotherapy for metastatic disease is anecdotal. This is mainly due to the very infrequent occurrence of bone metastasis, with the consequent sporadic use of antiresorptive agents. However, the association of anti-VEGF agents, in particular bevacizumab and sunitinib, with an increased incidence of ONJ has raised recent concern in the oncological community (7), and sporadic case reports on ONJ in patients receiving bevacizumab for mCRC have appeared (8, 9). Moreover, in the VELOUR trial of aflibercept plus FOLFIRI in mCRC, 2 cases of ONJ were reported in the experimental arm (Tab. II) (1, 10).

Here we describe the first reported case of ONJ during treatment with aflibercept plus FOLFIRI during the expanded-access program. This case report warrants further investigation into the potential association between the use of anti-VEGF agents and ONJ. Given the serious nature of ONJ, we recommend that particular attention be paid to the oral district prior to treating patients and during treatment with chemotherapy and targeted agents, especially anti-VEGF agents.

Our patient had not received bevacizumab before aflibercept, but had unresolved chronic periodontitis. ONJ developed after 11 cycles of treatment while the disease was in prolonged SD and the patient was receiving LMWH for DVT; however, to date no association between LMWH and ONJ has been reported. The patient previously experienced G3 stomatitis, but no persistent mouth ulceration was present. Whereas in this case ONJ manifested itself insidiously with nontraumatic avulsion of teeth, this is in accord with a recent Italian study reporting up to a quarter of ONJ cases being misdiagnosed (5). In our patient, treatment with aflibercept/FOLFIRI was interrupted and ONJ was treated with laser therapy. Unfortunately, the patient’s cancer soon proved to be refractory to chemotherapy and she was cared for in a home palliative care setting until death.

In the setting of bone-antiresorptive drugs, preventive dental care before treatment and behavioral recommendations during treatment, i.e., avoiding dental extraction, smoking and alcohol consumption, has demonstrated to be of benefit in reducing the incidence of ONJ (6). We believe that applying these measures to patients undergoing treatment with chemotherapy plus anti-VEGF agents, i.e., bevacizumab and aflibercept, is reasonable especially in patients presenting with chronic periodontitis resulting from poor dental care. The same measures could be useful in reducing the incidence of another important side effect of antineoplastic agents, stomatitis. In the VELOUR trial, grade 3-4 stomatitis occurred in 13% of patients and in the more recent phase III trials involving mCRC the percentage was less than 10% (Tab. I).

In conclusion, particular attention must be paid to the oral district when treating patients with chemotherapy and targeted agents, especially anti-VEGF agents. Multidisciplinary management of patients with preexisting periodontitis or developing ONJ during treatment could be of very high value because it will allow to continue chemotherapy and maintain the dose intensity.

Disclosures

Financial support: None.
Conflict of interest: None of the authors has any financial interest related to this study to disclose.
Authorization to publish the case report and the data from the 2 cases of osteonecrosis of the jaw in the VELOUR trial was obtained from the drug manufacturer (Sanofi, Paris, France) before submission.
References
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Authors

Affiliations

  • Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy

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