Background
In recent years, cancer research has progressed significantly at the molecular level. Specifically, the development and clinical introduction of molecular-targeted agents directed at certain molecular mechanisms have been rapidly advancing. The development of molecular targeted therapy has contributed to prolonged survival of patients with several malignancies [
1,
2]. In contrast, various adverse events peculiar to molecular-targeted agents, which are different from conventional cytotoxic anticancer agents, have been identified. For example, rashes and hand–foot syndrome are frequent adverse events, with an incidence of ≥ 80% characteristic of cetuximab and sorafenib, respectively [
3]. In addition, although the incidence is less frequent, serious adverse events, with an incidence of approximately 1.5–2%, such as gefitinib-related interstitial lung disease [
4] and trastuzumab-associated cardiac dysfunction [
5], require attention and awareness.
Delayed wound healing is also a rare but severe and life-threatening adverse event caused by molecular-targeted agents [
6,
7]. Normally, when tissue is damaged, various wound healing factors are released to promote cell growth and angiogenesis, thereby regenerating the damaged tissue. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are key factors that play important roles in the wound healing process [
8,
9]. Therefore, delayed wound healing may occur if these factors are inhibited. In fact, the administration of bevacizumab, a VEGF inhibitor, induces adverse events, such as anastomotic leak and fistula formation, resulting in delayed wound healing [
10,
11]. The incidence of such adverse events is low, approximately 1–2% [
10]. However, because these adverse events may cause serious consequences, the causative drug should be withdrawn 6–8 weeks before and after surgery [
6,
7,
11].
A few articles have reported molecular-targeted agent-induced diastasis of a surgical wound that healed and completely closed months to years after the surgery [
12‐
14]. Here, we report two cases of delayed pharyngeal cutaneous fistula considered to be caused by molecular targeted therapy.
Discussion and conclusions
Pharyngocutaneous fistula is one of the major complications after laryngectomy [
15‐
17], and the reported frequency of fistula ranges from 7.4% to 58.0% [
15,
16]. However, the fistula typically occurs a median of 9–20 (range: 2–28) days after surgery [
16,
18]; thus, a pharyngocutaneous fistula that develops more than several months after surgery is extremely rare. In the usual occurrence of pharyngocutaneous fistulas, which develop in approximately 9–20 days, a metaanalysis indicated that prior radiation therapy exposure [
15,
17], anemia [
15,
17], positive surgical margin [
15,
17], supraglottic subsite or hypopharyngeal tumor site [
15,
17], and chronic obstructive pulmonary disease [
17] have been reported as risk factors. Meanwhile, only one case of fistula that developed a long time after the operation, similar to in our cases, has been reported to date [
13]. As mentioned above, in an unusual case of delayed fistula formation, it is difficult to apply the same risk factors involved in a normal pharyngocutaneous fistula formation. Therefore, in the present cases, a strong role of VEGF and PDGF inhibitors was considered in inhibiting wound healing.
When using molecular-targeted drugs that block signaling pathways related to VEGF and PDGF, which are essential for wound healing, the risk of wound complications must be considered. Drug suspension is recommended for approximately 2 weeks to 2 months before and after surgery, depending on the half-life of each drug, to avoid the risk of wound-related complications [
6]. Wound healing may be difficult to achieve after surgery in patients who have already been administered this type of molecular targeting agent. In such cases, the risk of delayed wound healing can be assumed in advance, and surgery can be planned after a safe withdrawal period, thereby reducing the incidence of wound reopening [
11]. Conversely, in patients who were administered the agent after surgery, healed wounds may reopen because of drug administration.
However, as shown in the present cases, it is rare and difficult to predict the development of delayed-onset wound reopening due to a molecular-targeted drug in patients who underwent surgery months to years ago with complete closure of the surgical wound, even if the drug is associated with a risk of wound healing complications. Rare cases of delayed wound dehiscence caused by molecular-targeted drugs have been reported. Anastomotic leakage resulting from bevacizumab administration 33 months after surgery for colorectal cancer has been reported previously [
12]. A pharyngocutaneous fistula was reported to have developed 23 years after administration of cabozantinib after total pharyngeal–laryngeal esophagectomy [
13]. In addition, the formation of a large deep ulcer was reported after imatinib administration in a patient with skin wounds, 4 years after the wounds healed [
14].
Ramucirumab, the drug used in the first case, is a monoclonal antibody that binds to VEGFR and is used to treat recurrent gastric and colon cancers. A rare incidence of adverse events (1–2%) has been reported after ramucirumab administration, including delayed wound healing and fistula formation [
19,
20]. Imatinib, which is an inhibitor of PDGFR and is used for the treatment of chronic myeloid leukemia, was used in the second case. A high incidence of skin disorders (edema and rash) because of imatinib administration has been reported [
21], but no reports on delayed wound healing or fistula formation incidence have been published. Imatinib has been shown to be effective in keloid scar treatment because it reduces fibroblasts and collagen formation [
22]. It was speculated that imatinib use might result in delayed wound reopening because of the reduced number of fibroblasts and collagen in the wound.
Cancer cure rates have improved with the development of anticancer drugs, and the number of cancer survivors continues to increase. As a result of prolonged survival, the probability of suffering from multiple cancers in a lifetime and receiving various cancer treatments has also increased. In addition, in recent years, cancer treatment strategies have become more complicated because of the dramatically increased use of anticancer drug therapy. Adverse events associated with these treatments have also been complicated, and a new range of unexpected complications has been reported.
Anticancer drug therapy is administered along with measures against various adverse events. However, it may be possible to start anticancer drugs, such as VEGFR or PDGFR, for the treatment of new cancers different from the previous cancer treated by surgical therapy several months to years ago. In such cases, there is a concern that the drugs may be administered without evaluating the risk to the wound from the previous surgery. Although rare, anastomotic leakage makes oral intake impossible for an extended period and interferes with appropriate cancer treatment. The two cases in this report were drug-induced delayed-onset pharyngocutaneous fistulas. Detailed information on this very rare complication must be elucidated to appropriately increase awareness among healthcare professionals involved in cancer treatment.
In conclusion, drug-induced late-onset pharyngocutaneous fistula is rare. However, when it occurs, it significantly lowers the patients’ quality of life and is difficult to treat. Thus, it is indispensable to accumulate more data on such rare cases, and we believe that this report offers more insights into drug-induced late-onset pharyngocutaneous fistula.
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