key: cord-0006581-a76rt2ih
authors: Katano, Mitsuo; Nakamura, Mitsunari; Matsuo, Tatsuya; Iyama, Akihiro; Hisatsugu, Takeharu
title: Effect of granulocyte colony-stimulating factor (G-CSF) on chemotherapy-induced oral mucositis
date: 1995
journal: Surg Today
DOI: 10.1007/bf00311527
sha: c87fb332078d4d4d2d30c389b756c43e88adc1d9
doc_id: 6581
cord_uid: a76rt2ih

In this study, the ability of granulocyte colony-stimulating factor (G-CSF) to treat or prevent chemotherapy-induced oral mucositis in patients with advanced breast cancer was evaluated. A total of 14 patients who received intra-arterial (i.a.) adriamycin (ADM) preoperatively were divided into two groups according to whether or not G-CSF was given. Thus, group A (n=7) was given G-CSF and group B (n=7) was not. G-CSF therapy reduced both the incidence and duration of ADM-induced oral mucositis, and a positive correlation was also seen between the incidence of mucositis and ADM-induced leukopenia (<2,000/mm(3)). Group A was further divided into two subgroups according to whether G-CSF was given after or before the leukopenia had dropped below 2,000/mm(3): group A-1 (n=3) and group A-2 (n=4), respectively. ADM-induced mucositis was observed in two of the three patients in group A-1, but in none of the four patients in group A-2. These results strongly support the idea that G-CSF can effectively treat and prevent ADM-induced oral mucositis.

Oral mucositis is one of the dose-limiting complications of such chemotherapeutic agents as adriamycin (ADM) and 5-fluorouracil (5-FU), ~-s and patients with cyclic neutropenia have regularly recurring symptoms of fever and mucosal ulcers during periods of neutropenia. 9'~° The granulocyte colony-stimulating factor (G-CSF) is a neutrophil-specific growth factor, 11 ' 12 which has been shown to increase the absolute Reprint requests to: M. Katano (Received for publication on Feb. 18, 1994 ; accepted on Nov. 10, 1994) neutrophil count in clinical trials conducted on patients with chemotherapy-induced leukopenia. 13 '14 It has also been demonstrated that G-CSF therapy reduces the frequency of oropharyngeal inflammation in patients with cyclic neutropenia, 9'15'16 a finding supported by Gabrilove et al. a7 who reported that G-CSF reduced the incidence of chemotherapy-induced mucositis. These results indicate that G-CSF can reduce both the hematopoietic and oral toxicity of chemotherapy. In the present study, we evaluated whether the administration of G-CSF could treat or prevent chemotherapy-induced oral mucositis.

A total of 14 patients with breast cancer (7 with primary advanced breast cancer, 5 with inflammatory breast cancer, and 2 with recurrent breast cancer) were treated preoperatively with intra-arterial (i.a.) high-dose adriamycin (ADM) 10 to 40mg every 2-3 days, receiving a total dose of 70-170mg. All the patients had normal neutrophil counts of 3,200-9,500/mm 3 when they were randomized into two groups of 7 patients each, prior to ADM therapy, according to whether G-CSF was to be given (group A) or not (group B). Both groups of patients had similar characteristics in all the factors examined, including age, leukocyte count before ADM therapy, cumulative dosages of ADM, and performance status ( Table 1 ). The group A patients were further divided into two subgroups according to whether the daily subcutaneous (s.c.) injection of G-CSF 125pg was given before (group A-l; n = 4) or after (group A-2; n = 3) the leukocyte counts were likely to drop below 2,000/mm 3. The administration of G-CSF was ceased when the leukocyte counts exceeded 8,000/mm 3. The patients who developed oral mucositis were treated only with conservative therapy using iodine solution for oral hygienic management.

All patients underwent an oral examination 1 to 7 days before ADM therapy, then every day after the ADM therapy had been commenced. The oral examinations were performed at the bedside, and all the soft tissues were evaluated for erythema and ulceration. A definite diagnosis of mucositis was made according to the World Health Organization classification, is and all examinations were performed by a single experienced clinician. In this trial, patients were diagnosed as having mucositis if oral ulceration of at least grade 2 was present, while the tissue was judged to be normal if it was evaluated as grade 0 or 1.

Recombinant human G-CSF (Neutrogin) was provided by Chugai Pharmaceutical (Tokyo, Japan). Briefly, Neutrogin derived from Chinese hamster ovary cells, 19 which is structurally equivalent to natural human G-CSF, 2° was used. Figure 1 shows the serial blood-leukocyte counts. A rapid decrease in the leukocyte count was induced in all the patients following the intra-arterial administration of ADM. All of the seven patients in group A responded to G-CSF with a rapid increase in their On the other hand, the seven patients in group B showed a continuous decrease or a slow increase in their leukocyte counts, to a range of 1,200-3,800/mm 3 14 days after the completion of ADM therapy. Thus, treatment with G-CSF during or after ADM therapy not only induced a rapid increase in the leukocyte count but also reduced the duration of leukopenia (<2,000/mm3). These results indicate that G-CSF can shorten the period of leukopenia or prevent its occurrence.

All seven of the group B patients developed oral mucositis of grade 2 to 4,5-8 days after the commencement of ADM therapy, with a median onset of 6 days. The mean duration of mucositis was 13.7 days, with a range of 8-17 days. The patients had mucositis when the peripheral blood leukocyte counts were less than 2,000/ram 3 ( Table 2 ). Episodes of fever occurred in five of these seven patients, one of whom developed adult respiratory distress syndrome (ARDS).

Mucositis developed in only two of the seven group A patients, occurring 7 days after the commencement of ADM therapy, the mean duration of which was 6.0 days ( Table 2 ). Both these patients had been given G-CSF when the leukocyte count was less than 2,000/mm 3, being part of group A-1 (n = 3). However, none of the four patients in group A-2 who were given G-CSF before the leukocyte counts had dropped below 2,000/mm 3 had mucositis of grade 2 or worse ( Table  3) . Episodes of fever occurred in only one patient from group A-1.

These results indicate that G-CSF may reduce the incidence and duration of mucositis induced by ADM, although this effect may be partly induced by increasing the number of leukocytes, and therefore their functional ability to guard the mucosal barriers more efficiently.

In this report we documented the preliminary results of administering G-CSF therapy to patients with breast cancer complicated by ADM-induced neutropenia and oral mucositis. Our results demonstrate that G-CSF administered as an adjunct to intra-arterial ADM to patients with advanced breast cancer resulted in a significant reduction in the incidence, duration, and severity of oral mucositis. Chemotherapeutic agents induce dose-limiting toxicity not only in bone marrow cells but also in rapidly dividing epithelial cells of the mucosal surfaces. Oral mucositis is frequently induced when 5-FU is administered as a 5-day intensive course with concomitant leucovorin. 2 Mucositis evidently occurs when 5-FU is taken up by the dividing cells of the oral mucosa, which suggests that the mucositis may be induced by a direct toxicity of 5-FU. It has also been reported that the combination of doxorubicin, methotrexate, and vinblastine induces direct injury to oral and intestinal epithelium, and that this toxic injury occurs independently of the myelosuppressive toxic effects of these drugs. 21 It was recently demonstrated that an increase in the serum level of granulocyte-macrophage colony-stimulating factor (GM-CSF) corresponded to an improvement in the oral lesions of herpetic gingivostomatitis. 22 Although it was not ascertained whether the serum level of G-CSF as well as GM-CSF increased in our patients, this finding indicates that G-CSF may play a protective role against inflammation of the oral mucosal epithelium. Mucositis and leukopenia, especially neutropenia, are also frequent complications of combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. 23 Oral infections, especially by the herpes virus, are a frequent cause of oral ulceration in patients receiving intensive chemotherapy. 24 Furthermore, it is well known that primary neutropenic disorders including cyclic neutropenia, 9'a°'15'16 Kostmann's syndrome, 25 and idiopathic neutropenia 26 are frequently complicated by oral ulcerations, which suggests that a significant decrease in the neutrophil count may induce oral mucositis. According to our experiments, mucositis occurred when the neutrophil count decreased to less than 2,000/mm 3, while ADM-induced mucositis became less severe as the neutrophil count increased. Thus, it is to be expected that reducing the period of neutropenia or preventing its occurrence can reduce the incidence and duration of mucositis. G-CSF is a hematopoietic growth factor that promotes the proliferation and differentiation of neutrophils. 11-1~ It also enhances the functional properties of mature cells by increasing phagocytic ability and antimicrobial killing. 27-3° In this study, G-CSF either significantly shortened the duration of chemotherapy-induced leukopenia or prevented its occurrence (Fig. 1) in accordance with reports by many investigators. 13'14'17 G-CSF also decreased both the incidence and duration of fever, indicating that G-CSFoinduced neutrophils have the functional ability to protect the mucosal barriers (Tables 2 and 3 ).

In conclusion, the incidence of both oral mucositis and fever with leukopenia induced by the intra-arterial administration of ADM was significantly reduced in breast cancer patients treated with G-CSF during or after intensive chemotherapy. Moreover, administering G-CSF before the neutrophil count drops below 2,000/mm 3 may be the most effective for preventing ADMoinduced mucositis. However, further investigations on the precise mechanisms of the effect of G-CSF on ADM-induced oral mucositis are still being conducted.

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