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Neoadjuvant Chemotherapy in Maxillary Sinus Carcinoma With Cisplatinum and Peplomycin Intraarterial Infusion
Auris·Nasus·Larynx (Tokyo) 12 (Supp!. II) S 249-S 254, 1985
NEOADJUVANT CHEMOTHERAPY IN MAXILLARY SINUS CARCINOMA WITH CISPLATINUM AND PEPLOMYCIN INTRAARTERIAL INFUSION Yukio INUYAMA, M.D., Masato FUJII, M.D., Juichi TANAKA, M.D., Tetsuro TAKAOKA, M.D., Hyonosuke HOSODA, M.D., Naoyuki KOHNo, M.D., and Shigeji SAITO, M.D. Department of Otorhinolaryngology, School of Medicine, Keio University, Tokyo, 160 Japan
The purpose of this paper is to present our preliminary assessment of a new multimodal treatment including neoadjuvant chemotherapy with cis platinum and peplomycin for maxillary sinus carcinoma. Fifteen patients with squamous cell carcinoma of the maxillary sinus carcinoma seen at Keio University Hospital, with Stage III and IV disease, were enrolled in this trial between January 1982 and January 1985. Regimen of chemotherapy was as follows: day 1,50 mg/m 2 of cisplatinum, intraarterial infusion over 2 hr, days 2-6, peplomycin at a dose of 5 mg/day, intraarterial infusion over 5 hr. Routinely, radiotherapy of 40 Gy by Linac was given to the primary site, concomitantly combined with 5-fluorouracil intraarterial injections only during the first 10 days, 2 weeks after the end of initial chemotherapy. Additional treatment was performed according to the extent of residual tumor. Response to initial chemotherapy revealed that complete response was achieved in 7 and partial response in 6 out of 15 patients with a response rate of 87 %. Nine patients required no surgical intervention while 6 underwent a surgical resection. Median follow-up in this group of patients is 20 months. Thirty-month survival rate calculated by Kaplan-Meier's method was 83 %. Chemotherapy toxicity was mild in most cases. This pilot study does not provide conclusive survival information, but the results obtained are encouraging. In Japan, maxillary sinus carcinoma is generally regarded as a relatively common disease as compared with the United States and Europe and it has been thought that
chronic sinusitis was closely related to its occurrence (SAKAI, 1974). Since the prognosis of this awful disease remains poor, various treatment modalities have been tried so far. But there were still many controversies about the choice of treatment. In our department, 222 patients with maxillary sinus carcinoma were treated during the period 1957-1981. Overall 5-year determinate survival rates were 31 %. Among many treatment modalities conducted, the best result was obtained in the group of patients treated with preoperative bleomycin intraarterial injection, but we could not avoid extensive surgical resections including the eye, the palate and the cheek in many cases. Meanwhile SATO et al. (1971) reported a new treatment modality which consisted of tumor reduction surgery, radiotherapy at the low total dose and 5-fluorouracil and BUdR intraarterial infusion also at low total dose. As a result they achieved not only high 5year survival but also the preservation of important maxillo-facial structures and functions. Many Japanese researchers took a great interest in this treatment and tried it. But the results did not always appear to be successful and differed from one institution to another. So we have started a new multimodal treatment including neoadjuvant chemotherapy with cisplatinum and peplomycin for maxillary sinus carcinoma since 1982. The purpose of this paper is to present our
Y. INUYAMA et al.
S 250
preliminary assessment of this new treatment. Materials and Methods Fifteen patients with squamous cell carcinoma of the maxillary sinus seen at Keio University Hospital, with Stage III and IV disease, were enrolled in this trial between January 1982 and January 1985. All patients were clinically staged according to the Japanese Joint Committee staging system. Patient characteristics are shown on Table I. All 15 evaluable patients received their chemotherapy before the definitive treatment. The treatment protocols are outlined in Figs. 1 and 2. All patients were hospitalized to receive the exploratory antrotomy and the cannulation into the superficial temporal artery. On the day before chemotherapy, patients received
Table 1. Patient characteristics. Patients treated Sex Male Female Age Mean Median Range Performance status
15 13 2 58 55 49-72 0 1 2 3 4
11 2 2
Stage I II III
13 2
IV
(Keio Univ., 1982-1985)
CT
Antrotomy
Catheterization
j
Biopsy
j
CT
CT
Biopsy
Biopsy
j
j
9 wk
3 Chemotherapy
D
CPDD 50mg/m 2 is 2hr. d 1 PEP 5mg ie 5hr. d3-1 Radkltherapy
D
c::::=J
5-FU250mgldxll ia bolus
CPDD PEP
Linac(DGy/26da)'s (KaloUniv.1I!Z.1-)
Fig. 1. Multimodal treatment for maxillary sinus carcinoma-fundamental treatment.
Gross(+)---_, Surgery_---'(""Re""'co~nst""ruc""tio""'n)
~(MlCrosCOPiC(+) Completion of fundamental
Gross( ~) Microscopic( +)- Linae 20 Gy
therapy
i
,,'
/""
""",
-',
Microscopic(-)
i
I
+
-"Gross( -) Microscopic( -) ~ Adjuvant therapy (Keio Univ.
1~82.1.-)
Fig. 2. MuItimodal treatment for maxillary sinus carcinoma-additional treatment.
pretreatment hydration. On day 1, 50 mg/m 2 of cisplatinum (CPDD) was administered by intraarterial infusion over 2 hr together with intravenous hydration and mannitol diuresis. Patients received additional posttreatment hydration on day 2. On days 2-6, peplomycin (PEP) at a dose of 5 mg/day was administered by intraarterial infusion over 5 hr. All patients received 2 courses of combination chemotherapy with the interval of 2 weeks. At the end of the second course of chemotherapy, response to chemotherapy was evaluated by CT scan. Several specimens for biopsy were taken from the maxillary antrum. Routinely, radiotherapy of 40 Gy by Linac was given to the primary tumor site, concomitantly combined with 5-fluorouracil (5FU) intraarterial injections only during the first 10 days. We defined the treatment conducted up to this time as fundamental treatment. At the completion of fundamental treatment, response was evaluated by CT scan and histologic changes were also examined through biopsy. Additional treatment was performed according to the extent of residual tumor. When an apparent tumor was observed on gross appearance or CT scan, a surgical resection was performed. But if cancer cells were detected only by histological examinations, additional radiotherapy of 20 Gy was given. The response was evaluated again at the end of the additional radiotherapy. When viable cancer cells still remained, a surgical resection was chosen. Meanwhile if no cancer cells were detected, patients proceeded to adjuvant therapy including oral chemo-
Y. INUYAMA et
therapy such as UFT, a mixture of uracil and futraful, and biological response modifier such as PSK, OK-432, bestatin, or forphenicino!. When no cancer cells were detected at the completion of the fundamental treatment, some patients received adjuvant therapy without additional radiotherapy and some patients underwent additional radiotherapy of 20 Gy followed by adjuvant therapy. Response to treatment was defined as follows: CR (complete response), disappearance of all clinically detectable diseases; PR (partial response), 50% or more decrease in all measurable lesions and unequivocal improvement in evaluable but non-measurable lesions with no new lesions developing; NC (no change), less than 50% decrease and less than 25% increase in measurable lesions, with the development of no new lesions; PD (progressive disease), 25% or more increase in measurable lesions or the appearance of new lesions. Results
All 15 patients completed two courses of chemotherapy and were evaluable. The response to combination chemotherapy with cisplatinum and peplomycin revealed that CR was achieved in 7 and PR in 6 out of 15 patients with a response rate of 87%. The complete response rate was 47%. A biopsy was negative in 2 out of 7 complete responders (Table 2). At the completion of radiotherapy of 40
at.
S 251
Gy combined with 5-fluorouracil intraarterial injection, the response was assessed again. As a results, CR was achieved in 8 patients and PR in 5, that is, one partial responder treated with cisplatinum and peplomycin achieved CR after combined radiotherapy and 5-fluorouracil intraarterial injection. A biopsy became negative in 4 cases at the end of fundamental treatment, in which a biopsy was positive at the end of combination chemotherapy. At the completion of fundamental treatment, 2 non-responders and one partial responder received radical resection of the maxilla with orbital exenteration. Out of 3 patients who underwent extensive surgical resections, 2 had intraorbital invasion of tumor and one had destruction of the anterior cranial fossa before chemotherapy. Two complete responders with a negative biopsy progressed to adjuvant therapy without additional radiotherapy. The remaining 10 patients received additional radiotherapy of 20 Gy. At the completion of this therapy, CR was achieved in 8 and PR in 2. Two complete responders who revealed a positive biopsy at the end of fundamental treatment had a negative biopsy after additional radiotherapy. After additional radiotherapy, one partial responder underwent resection of the maxilla and another received a partial resection. One complete responder received a partial resection of maxilla because of osteonecrosis.
Table 2. No. of patients Response to chemotherapy 15 CPDD-PEP ia Response to radiation and chemotherapy" 5-FUia+Linac4OGy 15 Response to additional radiation b Linac 20 Gy 10
CR
Response type PR NC PD
7
6
8
5
8
2
2
o
o o
Biopsies Negative Positive 2
13
6
9
8
2
.. Three patients had surgery and 2 had adjuvant therapy. b Three patients had surgery and 7 had adjuvant therapy. No surgical resection 9 (60%) Radical resection of maxilla 3 } o with orbital exenteration 27% 1 Surgical resection 6 (40%) Resection of maxilla Partial resection 2
l
Y. INUYAMA et al.
S 252 100 .-.... --- - - - -- --- - - -- - - - - - - -- -- - -- - -
:
~
l!!
80
.~
70
~
60 50
-c
~
li;
0.
40
--1 6---------- 83% n=15
Alive NED 11 Alive Recur. 3 Dead Tumor 1
30 20 10
OL----76----T.12~--~1~8---,2~4----3~O,-Months
(Keio Unjv.
1982~lg85)
Fig. 3. Survival and present status in patients with maxillary sinus carcinoma.
Summarizing these results, 9 required no surgical intervention while 6 underwent a surgical resection. Out of 6 patients who underwent a surgical resection, 4 received extensive surgical resections of maxillo-facial region. Median follow-up in this group of patients is 20 months. One patient died of recurrent disease at 24 month. Three patients are alive with recurrent disease and 11 are alive without evidence of disease. Thirty-month survival rate calculated by Kaplan-Meier's method was 83% (Fig. 3). Chemotherapy toxicity was mild in most cases. Nausea and vomiting were common (80%), but were well controlled with administration of metocIopramide before and during cisplatinum administration. Six patients had a temporary increase in BUN levels and one had a temporary increase in creatinine levels. Hematological toxicity was also mild, with leucopenia below 3,000/mm3 in only 2 cases. A slight increase in GOT and GPT levels was observed in one case. All patients subsequently underwent radiotherapy combined with 5-fluorouracil intraarterial injection. Some patients developed a moderate stomatitis during this treatment, which was quite tolerable. Therefore there seemed to be no increased problems in tolerating combined radiotherapy and 5-fluorouracil intraarterial injection following neoadjuvant chemotherapy. Discussion FRAZELL and LEWIS (1963) reported only a
14% 5-year survival in 98 patients with nose and paranasal sinus carcinoma treated by radiotherapy alone and also a 35% 5-year survival by surgery alone. In Japan, surgery followed by postoperative irradiation therapy had been accepted in many institutions as the therapy of choice for maxillary sinus carcinoma during the period 1946-1968, but 5year survival was only 31 % on the average. Preoperative radiation therapy also appeared to be no benefit in improving survival as compared with postoperative radiation. In our department, we have incorporated preoperative intraarterial chemotherapy in the treatment of maxillary sinus carcinoma since 1963. A 52% 5-year survival was obtained in 34 patients treated with preoperative bleomycin intraarterial injection (INUYAMA, 1978). It was the best result among the various treatment modalities we have tried so far. But we could not avoid extensive surgical resections of the maxillo-facial region in about 90% of cases. SATO et al. (1971) reported a new treatment modality which consisted of tumor reduction surgery, radiotherapy at low total dose and 5-fluorouracil and BUdR intraarterial infusion also at low total dose. They achieved not only high 5-year survival rates but also the preservation of important maxillo-facial structures and functions. Many Japanese researchers took a great interest in this treatment and tried it. But the results did not always appear to be successful and differed from one institution to another. Ever since it was shown by WITTES et al. (1977) that cisplatinum was useful in cancer treatment, it has been used as the drug of first choice for the treatment of head and neck squamous cell carcinoma along with methotrexate and bleomycin chiefly in the United States and Europe. Then American researchers such as RANDOLPH et al. (1978), WITTES et al. (1979), and SHAPSHAY et al. (1980) reported that they had high response rate in combined use of cisplatinum and bleomycin. On the other hand, peplomycin is a newly developed derivative of bleomycin, evaluated as no less useful than bleomycin in
Y. INUYAMA et al.
the treatment of head and neck squamous cell carcinoma. We clinically proved these two drugs to be useful (INUYAMA et ai., 1982, 1983a) and at the same time made preclinical investigations for the development of a new combination therapy with these drugs. As a result we developed a new regimen consisted of cisplatinum and peplomycin (INUYAMA et ai., 1983b). The intraarterial administration of this chemotherapy achieved a response rate was as high as 87% in patients with maxillary sinus carcinoma. It is obvious that this chemotherapy is quite useful as neoadjuvant chemotherapy. PEPPARD et ai. (1980) reported that tumor remission increased with the second course of combination of cisplatinum, oncovin, and bleomycin. According to BAKER et al. (1981), one course of cisplatin and bleomycin therapy was given as neoadjuvant chemotherapy, but the response rate was relatively low. In our series, complete response rate increased with the second course of chemotherapy. So that it appears that patients should be given at least two courses of chemotherapy. In Japan, concomitant use of radiotherapy and 5-fluorouracil has been favored in the treatment of head and neck cancer. On the contrary, patients treated with combined radiotherapy and bleomycin analogues often developed intolerably severe stomatitis. Therefore we employed peplomycin together with cisplatinum prior to radiotherapy, as neoadjuvant chemotherapy and subsequently 5-fluorouracil combined with radiation. We considered that this sequential non crossresistant combination was rational from the viewpoint of Goldie-Coldman's hypothesis (GOLDIE and COLDMAN, 1983). Median follow-up in this group of patients is only 20 months, but 30-month survival by Kaplan-Meier's method was as high as 83%. Furthermore we decreased the rate of extensive surgical resections to 27% by multimodal treatment including neoadjuvant chemotherapy, while it was 90% in the group of patients treated with preoperative bleomycin intraarterial injection. As ERVIN et at.
S 253
(1984) emphasized however, maximum standard treatment is necessary in addition to neoadjuvant chemotherapy for increasing local control of maxillary sinus carcinoma. At one time chemotherapy used to be employed only as a palliative treatment, however, chemotherapy has made remarkable progress in the past 20 years. At the present time chemotherapy is utilized in almost every treatment modality and plays an important role in the treatment of head and neck cancer. We took a great interest in neoadjuvant chemotherapy and developed a new multimodal treatment containing it. We are expecting an improvement of the 5-year survival rate and the preservation of important maxillo-facial structures and functions with this treatment. Conclusion
The authors reached the following conclusions: 1. Cisplatinum and peplomycin used intraarterially in combination are effective (CR plus PR=87%) with tolerable and reversible toxicities. 2. Radiotherapy combined with 5-fluorouracil intraarterial injection following initial chemotherapy improved the effectiveness at the histologic level. 3. The rate of extensive surgical resections decreased to 27% by this multimodal treatment. This pilot study does not provide conclusive survival information, but the results obtained are encouraging. This study was supported by Grant-in-Aid for Scientific Research from Japanese Foundation for Multidisciplinary Treatment of Cancer.
References BAKER, S.R., MAKUCH, R.W., and WOLF, G.T.: Preoperative cisplatin and bleomycin therapy in head and neck carcinoma. Arch. Otolaryngol. 107: 683-689, 1981. ERVIN, T.J., WEICHSELBAUM, R.R., FABIAN, R.L., MILLER, D., NORRIS, C.M., POSNER, M.R., ROSE, C., LOCKHART, P., TUTTLE, S.A., MACINTYRE, J.M., and FREI, E., III: Advanced squamous carcinoma of the head and neck.
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Y. INUYAMA et al.
Arch. Otolaryngol. 110: 241-245, 1984. FRAZELL, E. L., and LEWIS, J. S. : Cancer of the nasal cavity and accessory sinuses. A report of the management of 416 patients. Cancer 16: 12931301, 1963. GOLDIE, J.H., and CoWMAN, A.J.: Clinical implications of the phenomenon of drug resistance. In Drug and Hormone Resistance in Neoplasia, Vol. II. Clinical Concepts (Bruchovsky, N., and Goldie, J.H., eds.), CRC Press, Boca Raton, FL, 1983. INUYAMA, Y.: Bleomycin treatment of head and neck carcinoma in Japan. In Bleomycin: Current, Status and New Developments (Carter, S., Crooke, S., and Umezawa, H., eds.), pp. 267-277, Academic Press Inc., New York, 1978. INUYAMA, Y., HORIUCHI, M., KOHNO, N., MASHINO, S., and FUJII, M.: Effect of peplomycin against minor saJivary gland tumors. Cancer Treat. Symp. 1: 79-81, 1983a. INUYAMA, Y., HORIUCHI, M., KOHNO, N., MASHINO, S., FUJII, M., OHTSUKI, J., and TAKAOKA, T.: Clinical effect of cisplatin (NK-801) on head and neck cancer. Jpn. J. Clin. Oncol. 12: 355-362, 1982. INUYAMA, Y., MASHINO, S., and FUJII, M.: Combination chemotherapy with cisplatin and peplomycin in head and neck cancer. Proceedings of 13th International Congress of Chemotherapy, Part 245, pp. 35-37, 1983b. PEPPARD, S.B., AL-SARRAF, M., POWERS, W.E., LOH, J.K., and WEAVER, A.W.: Combination of cisplatinum, oncovin, and bleomycin (COB) prior
to surgery and/or radiotherapy in advanced untreated epidermoid cancer of the head and neck. Laryngoscope 90: 1273-1280, 1980. RANDOLPH, V.L., VALLEJO, A., SPIRO, R.H., SHAH, J., STRONG, E.W., Huvos, A.G., and WITTES, R.E.: Combination therapy of advanced head and neck cancer. Induction of remissions with diamminedichloroplatinum (II), bleomycin and radiation therapy. Cancer 41: 460-467,1978. SAKAI, S.: Maxillary Cancer, pp. 24-25, Kanehara Co., Ltd., Tokyo, 1974 (in Japanese). SATO, Y., MORITA, M., and TAKAHASHI, H.: Combined surgery, radiotherapy and regionaJ chemotherapy in carcinomas of the nose and paranasal sinuses-The therapy which conserves normal form and function. Otologia Fukuoka 17: 89-99, 1971 (in Japanese). SHAPSHAY, S.M., HONG, W.K., and INCZE, J.S.: Prognostic indicators in induction cis-platinum bleomycin chemotherapy for advanced head and neck cancer. Am. J. Surg. 140: 543-548, 1980. WITTES, R.E., CVITKOVIC, E., SHAH, J., GEROLD, F.P., and STRONG, E.W.: cis-Diamminedichloroplatinum (II) (DDP) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat. Rep. 61: 359-366, 1977. WITTES, R.E., HELLER, K., RANDOLPH, V., HOWARD, J., VALLEJO, A., FARR, H., HAROLD, c., GERALD, F., SHAH, J., SPIRO, R., and STRONG, E.: cisDichlorodiammineplatinum (II)-based chemotherapy as initial treatment of advanced head and neck cancer. Cancer Treat. Rep. 63: 1533-1538, 1979.
NEOADJUVANT CHEMOTHERAPY IN MAXILLARY SINUS CARCINOMA WITH CISPLATINUM AND PEPLOMYCIN INTRAARTERIAL INFUSION Yukio INUYAMA, M.D., Masato FUJII, M.D., Juichi TANAKA, M.D., Tetsuro TAKAOKA, M.D., Hyonosuke HOSODA, M.D., Naoyuki KOHNo, M.D., and Shigeji SAITO, M.D. Department of Otorhinolaryngology, School of Medicine, Keio University, Tokyo, 160 Japan
The purpose of this paper is to present our preliminary assessment of a new multimodal treatment including neoadjuvant chemotherapy with cis platinum and peplomycin for maxillary sinus carcinoma. Fifteen patients with squamous cell carcinoma of the maxillary sinus carcinoma seen at Keio University Hospital, with Stage III and IV disease, were enrolled in this trial between January 1982 and January 1985. Regimen of chemotherapy was as follows: day 1,50 mg/m 2 of cisplatinum, intraarterial infusion over 2 hr, days 2-6, peplomycin at a dose of 5 mg/day, intraarterial infusion over 5 hr. Routinely, radiotherapy of 40 Gy by Linac was given to the primary site, concomitantly combined with 5-fluorouracil intraarterial injections only during the first 10 days, 2 weeks after the end of initial chemotherapy. Additional treatment was performed according to the extent of residual tumor. Response to initial chemotherapy revealed that complete response was achieved in 7 and partial response in 6 out of 15 patients with a response rate of 87 %. Nine patients required no surgical intervention while 6 underwent a surgical resection. Median follow-up in this group of patients is 20 months. Thirty-month survival rate calculated by Kaplan-Meier's method was 83 %. Chemotherapy toxicity was mild in most cases. This pilot study does not provide conclusive survival information, but the results obtained are encouraging. In Japan, maxillary sinus carcinoma is generally regarded as a relatively common disease as compared with the United States and Europe and it has been thought that
chronic sinusitis was closely related to its occurrence (SAKAI, 1974). Since the prognosis of this awful disease remains poor, various treatment modalities have been tried so far. But there were still many controversies about the choice of treatment. In our department, 222 patients with maxillary sinus carcinoma were treated during the period 1957-1981. Overall 5-year determinate survival rates were 31 %. Among many treatment modalities conducted, the best result was obtained in the group of patients treated with preoperative bleomycin intraarterial injection, but we could not avoid extensive surgical resections including the eye, the palate and the cheek in many cases. Meanwhile SATO et al. (1971) reported a new treatment modality which consisted of tumor reduction surgery, radiotherapy at the low total dose and 5-fluorouracil and BUdR intraarterial infusion also at low total dose. As a result they achieved not only high 5year survival but also the preservation of important maxillo-facial structures and functions. Many Japanese researchers took a great interest in this treatment and tried it. But the results did not always appear to be successful and differed from one institution to another. So we have started a new multimodal treatment including neoadjuvant chemotherapy with cisplatinum and peplomycin for maxillary sinus carcinoma since 1982. The purpose of this paper is to present our
Y. INUYAMA et al.
S 250
preliminary assessment of this new treatment. Materials and Methods Fifteen patients with squamous cell carcinoma of the maxillary sinus seen at Keio University Hospital, with Stage III and IV disease, were enrolled in this trial between January 1982 and January 1985. All patients were clinically staged according to the Japanese Joint Committee staging system. Patient characteristics are shown on Table I. All 15 evaluable patients received their chemotherapy before the definitive treatment. The treatment protocols are outlined in Figs. 1 and 2. All patients were hospitalized to receive the exploratory antrotomy and the cannulation into the superficial temporal artery. On the day before chemotherapy, patients received
Table 1. Patient characteristics. Patients treated Sex Male Female Age Mean Median Range Performance status
15 13 2 58 55 49-72 0 1 2 3 4
11 2 2
Stage I II III
13 2
IV
(Keio Univ., 1982-1985)
CT
Antrotomy
Catheterization
j
Biopsy
j
CT
CT
Biopsy
Biopsy
j
j
9 wk
3 Chemotherapy
D
CPDD 50mg/m 2 is 2hr. d 1 PEP 5mg ie 5hr. d3-1 Radkltherapy
D
c::::=J
5-FU250mgldxll ia bolus
CPDD PEP
Linac(DGy/26da)'s (KaloUniv.1I!Z.1-)
Fig. 1. Multimodal treatment for maxillary sinus carcinoma-fundamental treatment.
Gross(+)---_, Surgery_---'(""Re""'co~nst""ruc""tio""'n)
~(MlCrosCOPiC(+) Completion of fundamental
Gross( ~) Microscopic( +)- Linae 20 Gy
therapy
i
,,'
/""
""",
-',
Microscopic(-)
i
I
+
-"Gross( -) Microscopic( -) ~ Adjuvant therapy (Keio Univ.
1~82.1.-)
Fig. 2. MuItimodal treatment for maxillary sinus carcinoma-additional treatment.
pretreatment hydration. On day 1, 50 mg/m 2 of cisplatinum (CPDD) was administered by intraarterial infusion over 2 hr together with intravenous hydration and mannitol diuresis. Patients received additional posttreatment hydration on day 2. On days 2-6, peplomycin (PEP) at a dose of 5 mg/day was administered by intraarterial infusion over 5 hr. All patients received 2 courses of combination chemotherapy with the interval of 2 weeks. At the end of the second course of chemotherapy, response to chemotherapy was evaluated by CT scan. Several specimens for biopsy were taken from the maxillary antrum. Routinely, radiotherapy of 40 Gy by Linac was given to the primary tumor site, concomitantly combined with 5-fluorouracil (5FU) intraarterial injections only during the first 10 days. We defined the treatment conducted up to this time as fundamental treatment. At the completion of fundamental treatment, response was evaluated by CT scan and histologic changes were also examined through biopsy. Additional treatment was performed according to the extent of residual tumor. When an apparent tumor was observed on gross appearance or CT scan, a surgical resection was performed. But if cancer cells were detected only by histological examinations, additional radiotherapy of 20 Gy was given. The response was evaluated again at the end of the additional radiotherapy. When viable cancer cells still remained, a surgical resection was chosen. Meanwhile if no cancer cells were detected, patients proceeded to adjuvant therapy including oral chemo-
Y. INUYAMA et
therapy such as UFT, a mixture of uracil and futraful, and biological response modifier such as PSK, OK-432, bestatin, or forphenicino!. When no cancer cells were detected at the completion of the fundamental treatment, some patients received adjuvant therapy without additional radiotherapy and some patients underwent additional radiotherapy of 20 Gy followed by adjuvant therapy. Response to treatment was defined as follows: CR (complete response), disappearance of all clinically detectable diseases; PR (partial response), 50% or more decrease in all measurable lesions and unequivocal improvement in evaluable but non-measurable lesions with no new lesions developing; NC (no change), less than 50% decrease and less than 25% increase in measurable lesions, with the development of no new lesions; PD (progressive disease), 25% or more increase in measurable lesions or the appearance of new lesions. Results
All 15 patients completed two courses of chemotherapy and were evaluable. The response to combination chemotherapy with cisplatinum and peplomycin revealed that CR was achieved in 7 and PR in 6 out of 15 patients with a response rate of 87%. The complete response rate was 47%. A biopsy was negative in 2 out of 7 complete responders (Table 2). At the completion of radiotherapy of 40
at.
S 251
Gy combined with 5-fluorouracil intraarterial injection, the response was assessed again. As a results, CR was achieved in 8 patients and PR in 5, that is, one partial responder treated with cisplatinum and peplomycin achieved CR after combined radiotherapy and 5-fluorouracil intraarterial injection. A biopsy became negative in 4 cases at the end of fundamental treatment, in which a biopsy was positive at the end of combination chemotherapy. At the completion of fundamental treatment, 2 non-responders and one partial responder received radical resection of the maxilla with orbital exenteration. Out of 3 patients who underwent extensive surgical resections, 2 had intraorbital invasion of tumor and one had destruction of the anterior cranial fossa before chemotherapy. Two complete responders with a negative biopsy progressed to adjuvant therapy without additional radiotherapy. The remaining 10 patients received additional radiotherapy of 20 Gy. At the completion of this therapy, CR was achieved in 8 and PR in 2. Two complete responders who revealed a positive biopsy at the end of fundamental treatment had a negative biopsy after additional radiotherapy. After additional radiotherapy, one partial responder underwent resection of the maxilla and another received a partial resection. One complete responder received a partial resection of maxilla because of osteonecrosis.
Table 2. No. of patients Response to chemotherapy 15 CPDD-PEP ia Response to radiation and chemotherapy" 5-FUia+Linac4OGy 15 Response to additional radiation b Linac 20 Gy 10
CR
Response type PR NC PD
7
6
8
5
8
2
2
o
o o
Biopsies Negative Positive 2
13
6
9
8
2
.. Three patients had surgery and 2 had adjuvant therapy. b Three patients had surgery and 7 had adjuvant therapy. No surgical resection 9 (60%) Radical resection of maxilla 3 } o with orbital exenteration 27% 1 Surgical resection 6 (40%) Resection of maxilla Partial resection 2
l
Y. INUYAMA et al.
S 252 100 .-.... --- - - - -- --- - - -- - - - - - - -- -- - -- - -
:
~
l!!
80
.~
70
~
60 50
-c
~
li;
0.
40
--1 6---------- 83% n=15
Alive NED 11 Alive Recur. 3 Dead Tumor 1
30 20 10
OL----76----T.12~--~1~8---,2~4----3~O,-Months
(Keio Unjv.
1982~lg85)
Fig. 3. Survival and present status in patients with maxillary sinus carcinoma.
Summarizing these results, 9 required no surgical intervention while 6 underwent a surgical resection. Out of 6 patients who underwent a surgical resection, 4 received extensive surgical resections of maxillo-facial region. Median follow-up in this group of patients is 20 months. One patient died of recurrent disease at 24 month. Three patients are alive with recurrent disease and 11 are alive without evidence of disease. Thirty-month survival rate calculated by Kaplan-Meier's method was 83% (Fig. 3). Chemotherapy toxicity was mild in most cases. Nausea and vomiting were common (80%), but were well controlled with administration of metocIopramide before and during cisplatinum administration. Six patients had a temporary increase in BUN levels and one had a temporary increase in creatinine levels. Hematological toxicity was also mild, with leucopenia below 3,000/mm3 in only 2 cases. A slight increase in GOT and GPT levels was observed in one case. All patients subsequently underwent radiotherapy combined with 5-fluorouracil intraarterial injection. Some patients developed a moderate stomatitis during this treatment, which was quite tolerable. Therefore there seemed to be no increased problems in tolerating combined radiotherapy and 5-fluorouracil intraarterial injection following neoadjuvant chemotherapy. Discussion FRAZELL and LEWIS (1963) reported only a
14% 5-year survival in 98 patients with nose and paranasal sinus carcinoma treated by radiotherapy alone and also a 35% 5-year survival by surgery alone. In Japan, surgery followed by postoperative irradiation therapy had been accepted in many institutions as the therapy of choice for maxillary sinus carcinoma during the period 1946-1968, but 5year survival was only 31 % on the average. Preoperative radiation therapy also appeared to be no benefit in improving survival as compared with postoperative radiation. In our department, we have incorporated preoperative intraarterial chemotherapy in the treatment of maxillary sinus carcinoma since 1963. A 52% 5-year survival was obtained in 34 patients treated with preoperative bleomycin intraarterial injection (INUYAMA, 1978). It was the best result among the various treatment modalities we have tried so far. But we could not avoid extensive surgical resections of the maxillo-facial region in about 90% of cases. SATO et al. (1971) reported a new treatment modality which consisted of tumor reduction surgery, radiotherapy at low total dose and 5-fluorouracil and BUdR intraarterial infusion also at low total dose. They achieved not only high 5-year survival rates but also the preservation of important maxillo-facial structures and functions. Many Japanese researchers took a great interest in this treatment and tried it. But the results did not always appear to be successful and differed from one institution to another. Ever since it was shown by WITTES et al. (1977) that cisplatinum was useful in cancer treatment, it has been used as the drug of first choice for the treatment of head and neck squamous cell carcinoma along with methotrexate and bleomycin chiefly in the United States and Europe. Then American researchers such as RANDOLPH et al. (1978), WITTES et al. (1979), and SHAPSHAY et al. (1980) reported that they had high response rate in combined use of cisplatinum and bleomycin. On the other hand, peplomycin is a newly developed derivative of bleomycin, evaluated as no less useful than bleomycin in
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the treatment of head and neck squamous cell carcinoma. We clinically proved these two drugs to be useful (INUYAMA et ai., 1982, 1983a) and at the same time made preclinical investigations for the development of a new combination therapy with these drugs. As a result we developed a new regimen consisted of cisplatinum and peplomycin (INUYAMA et ai., 1983b). The intraarterial administration of this chemotherapy achieved a response rate was as high as 87% in patients with maxillary sinus carcinoma. It is obvious that this chemotherapy is quite useful as neoadjuvant chemotherapy. PEPPARD et ai. (1980) reported that tumor remission increased with the second course of combination of cisplatinum, oncovin, and bleomycin. According to BAKER et al. (1981), one course of cisplatin and bleomycin therapy was given as neoadjuvant chemotherapy, but the response rate was relatively low. In our series, complete response rate increased with the second course of chemotherapy. So that it appears that patients should be given at least two courses of chemotherapy. In Japan, concomitant use of radiotherapy and 5-fluorouracil has been favored in the treatment of head and neck cancer. On the contrary, patients treated with combined radiotherapy and bleomycin analogues often developed intolerably severe stomatitis. Therefore we employed peplomycin together with cisplatinum prior to radiotherapy, as neoadjuvant chemotherapy and subsequently 5-fluorouracil combined with radiation. We considered that this sequential non crossresistant combination was rational from the viewpoint of Goldie-Coldman's hypothesis (GOLDIE and COLDMAN, 1983). Median follow-up in this group of patients is only 20 months, but 30-month survival by Kaplan-Meier's method was as high as 83%. Furthermore we decreased the rate of extensive surgical resections to 27% by multimodal treatment including neoadjuvant chemotherapy, while it was 90% in the group of patients treated with preoperative bleomycin intraarterial injection. As ERVIN et at.
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(1984) emphasized however, maximum standard treatment is necessary in addition to neoadjuvant chemotherapy for increasing local control of maxillary sinus carcinoma. At one time chemotherapy used to be employed only as a palliative treatment, however, chemotherapy has made remarkable progress in the past 20 years. At the present time chemotherapy is utilized in almost every treatment modality and plays an important role in the treatment of head and neck cancer. We took a great interest in neoadjuvant chemotherapy and developed a new multimodal treatment containing it. We are expecting an improvement of the 5-year survival rate and the preservation of important maxillo-facial structures and functions with this treatment. Conclusion
The authors reached the following conclusions: 1. Cisplatinum and peplomycin used intraarterially in combination are effective (CR plus PR=87%) with tolerable and reversible toxicities. 2. Radiotherapy combined with 5-fluorouracil intraarterial injection following initial chemotherapy improved the effectiveness at the histologic level. 3. The rate of extensive surgical resections decreased to 27% by this multimodal treatment. This pilot study does not provide conclusive survival information, but the results obtained are encouraging. This study was supported by Grant-in-Aid for Scientific Research from Japanese Foundation for Multidisciplinary Treatment of Cancer.
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Arch. Otolaryngol. 110: 241-245, 1984. FRAZELL, E. L., and LEWIS, J. S. : Cancer of the nasal cavity and accessory sinuses. A report of the management of 416 patients. Cancer 16: 12931301, 1963. GOLDIE, J.H., and CoWMAN, A.J.: Clinical implications of the phenomenon of drug resistance. In Drug and Hormone Resistance in Neoplasia, Vol. II. Clinical Concepts (Bruchovsky, N., and Goldie, J.H., eds.), CRC Press, Boca Raton, FL, 1983. INUYAMA, Y.: Bleomycin treatment of head and neck carcinoma in Japan. In Bleomycin: Current, Status and New Developments (Carter, S., Crooke, S., and Umezawa, H., eds.), pp. 267-277, Academic Press Inc., New York, 1978. INUYAMA, Y., HORIUCHI, M., KOHNO, N., MASHINO, S., and FUJII, M.: Effect of peplomycin against minor saJivary gland tumors. Cancer Treat. Symp. 1: 79-81, 1983a. INUYAMA, Y., HORIUCHI, M., KOHNO, N., MASHINO, S., FUJII, M., OHTSUKI, J., and TAKAOKA, T.: Clinical effect of cisplatin (NK-801) on head and neck cancer. Jpn. J. Clin. Oncol. 12: 355-362, 1982. INUYAMA, Y., MASHINO, S., and FUJII, M.: Combination chemotherapy with cisplatin and peplomycin in head and neck cancer. Proceedings of 13th International Congress of Chemotherapy, Part 245, pp. 35-37, 1983b. PEPPARD, S.B., AL-SARRAF, M., POWERS, W.E., LOH, J.K., and WEAVER, A.W.: Combination of cisplatinum, oncovin, and bleomycin (COB) prior
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