ClSPLATlN=BASED CHEMOTHERAPY IN ADVANCED ADENOID CYSTIC CARCINOMA OF THE HEAD AND NECK L. Dick de Haan, MD, Pieter H. M. De Mulder, MD, Jan B. Vermorken, MD, Jan H. Schornagel, A. Vermey, MD, and Jaap Verweij, MD
Nineteen patients, nine men and 10 women, with advanced adenoid cystic carcinoma (ACC), were treated with cisplatin either alone or in combination with doxorubicin and bleomycin. Median age was 51 years (range: 32-73 years). Two groups of patients were distinguished: Group 1 (N = 10)received single-agent cisplatin (50-120 mg/m2 IV every 4 weeks) for locoregional recurrence (N = 4), pulmonary metastases (N = 5), or as neoadjuvant therapy (N = 1). Five patients failed previous chemotherapy. No objective responses were observed, five patients showed stabilization of their disease for a median duration of 20 months (range: 3-50 months). Group 2 (N = 9) received a combination of cisplatin (20 mg/m2 IV on days 1-5), doxorubicin (50 mg/m2 IV on day l),and bleomycin (30 mg IV on days 1-5), every 3 weeks. A complete remission (CR) was seen in one patient, lasting for 2 years, a partial remission (PR) in two patients (duration: 6 months and 6 years) (33%),and a stable disease (SD) in five patients (median duration: 15 months; range 3-24 months). One patient showed progression from the start. The observed toxicity was acceptable: dose reduction was required in five patients for rnyelosuppression or impairment of renal function; vomiting grade 111 (WHO) was seen in 10 patients. The median progression-free survival was 36 months (range: 7-77 months). Median overall survival was 81 months
From the Department of Medical Oncology (Drs. Haan and Mulder), St. Radboudhospital, Nijmegen; Department of Medical Oncology (Dr Vermorken), Free University Hospital, Amsterdam; Department of Medical Oncology (Dr. Schornagel). University Hospital, Utrecht; Surgical Department (Dr. Verrney), University Hospital, Groningen: Daniel den Hoed Institute (Dr. Verweij), Rotterdam; The Netherlands. Address reprint requests to Dr De Mulder at the Department of Medical Oncology, P 0. Box 9101, 6500 HB. Nijmegen, The Netherlands. Acccepted for publication November 13, 1991
CCC 0148-6403/92/040273-05$04.00 0 1992 John Wiley 8, Sons, Inc.
CDDP in Adenoid Cystic Carcinoma
(range: 14-216 months). The role of cisplatin in this disease remains questionable. 0 1992 John Wiley & Sons, Inc. HEAD & NECK 1992;14:273-277
Adenoid cystic carcinoma (ACC), comprising 4% to 8%of all nonsquamous cell carcinomas in the head and neck region,lP3 continues to represent a difficult clinical problem. This is mainly due to its slow growth pattern, tendency to perineural invasion, and systemic ~ p r e a d . ~ - ~ The prognosis depends largely on adequate initial treatment (ie, major ablative surgery and, if indicated, adjuvant radi~therapy).~-’ Despite efforts to achieve local control, the course of the disease is usually protracted, which is reflected in a median survival of approximately 10 years and characterized by a hi h incidence of local recurrences and metastases.6’$! J’J’ Chemotherapy has been proven to be of limited value in cases of recurrent or metastatic disease. Of the various agents tested, only a few were considered to be active, such as 5-flUOr0uracil, doxorubicin, and ~ i s p l a t i n . l ~ -Cisplatin ~’ given as both a sin le agent13718and in combination therapy 14~16~17fg has resulted in objective tumor regressions. Single-agent therapy yielded objective res onse rates, varying between 40% and 64%.1 3 , l tPooled data from studies with cisplatin-based polychemotherapy, including doxorubicin, 5-fluorouracil, and cyclosphosphamide, showed a response rate of approximately
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25%14,16,17919 with a median duration varying from 5 to 40 months. In this study we report on a retrospective analysis of 19 patients with advanced ACC who were treated with either cisplatin monotherapy or cisplatin combined with doxorubicin and bleomycin. MATERIALS AND METHODS
This retrospective study comprised 19 patients (nine men, 10 women) with a histologically proven advanced ACC of the head and neck region. Median age was 51 years (range: 32-73 years). Patient characteristics are given in Table 1. Most patients (14 of 19) were initially treated with surgery with or without radiotherapy. Twelve patients had a local recurrence; 14 had distant metastases at the time of the start of chemotherapy. Seven patients received previous chemotherapy. Two groups of patients could be distinguished: group 1 (patients 1- 10) received cisplatin monotherapy and group 2 (patients 11-19) received cisplatin combination therapy (Table 1). Single-agent cisplatin was given at a dose range of 50-120 mg/m2, every 4 weeks. Median num-
ber of cycles given was 3 (range: 1-5). Patients were not treated according to a standard protocol, but the data reflected the experience in the different institutions (JBV, JS, AV, JV). Four patients had locoregional recurrence, previous chemotherapy was accompanied by radiotherapy in all patients. Five patients failed on previous chemotherapy. Group 2 received combination chemotherapy: cisplatin 20 mg/m2 IV on days 1-5, doxorubicin 50 mg/m2 IV on day 1, and bleomycin 30 mg IV on days 1-5, cycles were repeated every 3 weeks. Cisplatin was administered for 4 hours, diluted in 1,000 mL normal saline in between adequate pre- and posthydration, doxorubicin was given as a bolus injection prior to the cisplatin infusion, and bleomycin was infused for 20 hours in the posthydration phase. Median number of cycles was 3 (range: 2-6). All patients received anti-emetic therapy. The patients were all treated in a single institution (Department of Medical Oncology, St. Radboudhospital, Nijmegen) according to a defined protocol. Only one patient had had previous chemotherapy. None of the indicator lesions were previously irradiated. Evaluation was per-
Table 1. Patient characteristics. Distant metastases
Previous chemotherapy (total dosage)
Agelsex
Site of tumor
Group 1 1 2 3 4 5 6
62/F 32/F 49lM 64lF 67/M 34lM
Submandibular gland Parotid gland Maxillary Parotid gland Parotid gland Mouth (floor)
Surgery SurgerylRT SurgerylRT SurgerylRT SurgerylRT RT/CT
Yes No Yes Yes Yes No
Pulmonary Pulmonary No No Pulmonary Osseous
7 8
491F 42lM
Maxillary Lacrimal gland
Sinus surgery SurgeryiRT
Yes Yes
9 10 Group 2 11 12 13 14 15
741F 51/M
Tongue (base) Parotid gland
CT Surgery
No Yes
Pulmonary Pulmonarylosseousl cerebral No No
18
55lM 73lM 69lF 47lM 43/M 501F 60lM 39lF
19
481F
Oro/pharynx Larynx Parotid gland Submandibular gland Submandibular gland Nasopharynx Submandibular gland Maxillary sinus Mouth (floor)
CT RT SurgerylRT Surgery/RT Surgery RT Surgery Surgery Surgery
No No No No No Yes Yes Yes Yes
No Pulmonary Osseous/pleura Osseous/pulmonary Pulmonary Osseous Pulmonary Pulmonary Pulmonary
16 17
Initial therapy
Local recurrence
Patient
5-FU Doxorubicinl5-FU DoxorubicinE-FU Doxorubicin/tj-FU Doxorubicinl5-FU CDDP (adjuvant therapy following RT) None None None None None None None None None None None None Combination of BLEO, VLB, MTX, CYCLO, and 5-FU
~~
5-FU = 5-Nuorouracil, MTX = methofrexate, CDDP = cisplatin, BLEO = bleomycin, BLB
=
vinblastm, CYCLO = cyclophosphamide, RT
=
radiotherapy,
CT = chemotherapy
274
CDDP in Adenoid Cystic Carcinoma
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formed after two cycles, unless early progression necessitated discontinuation of treatment. In case of an objective response or stable disease, chemotherapy was continued. A maximum of six cycles was given, special attention was given to cardiac, renal, and pulmonary function. Definition of response and response duration was according to the WHO criteria. RESULTS
An overview of tumor response is given in Table 2. In group 1 no objective responses were observed. Stable disease (SD)was observed in five cases with a median duration of 6 months (range: 3-50 months). Of these patients, only one patient is still alive. Progressive disease (PD) was noted in five patients. The median interval between diagnosis and initiation of cisplatin chemotherapy was 59 months (range: 0-216 months). Median overall survival was 78 months (range: 14-222 months). Three objective responses were observed in group 2: one complete remission (CR) and two
partial remissions (PR). The patient with a CR was a 73-year-old man who was initially seen with pulmonary metastases 7 months after radiotherapy for a laryngeal ACC. CR was seen after two cycles. In total six cycles were given, the response duration was 21 months. Two patients showed a PR. In one patient (a 55-year-old man), polychemotherapy was given as primary treatment for an irresectable ACC of the oropharynx. After three cycles a PR was obtained, but the tumor was still considered irresectable; in total, six cycles were administered without further regression and the treatment was completed with radiotherapy. At the time of this analysis, the patient was still in an ongoing PR. The second patient with a PR was a 47-yearold man who presented with an ACC of the submandibular gland, which was initially treated with surgery and radiotherapy. After a relapsefree interval of 122 months pulmonary and osseous metastases developed. After two cycles of polychemotherapy a PR of the pulmonary lesions was observed; however, the third cycle was dis-
Table 2. Tumor response Patient Chemotherapy* Group 1 1 CDDP 2 CDDP 3 CDDP 4 CDDP 5 CDDP 6 CDDP 7 CDDP 8 CDDP 9 CDDP 10 CDDP Group 2 11 CDB 12 CDB 13 CDB 14 CDB 15 CDB
16 CDB 17 CDB 18 CDB 19 CDB
Dosage/m2 (number of cycles)
Indicator lesion
Type of response
Duration
(mo)
120 mg (5) 120 rng (2), 80 mg (3) 120 mg (2), 80 mg (3) 80 rng (3) 50 mg (3) 80 mg (2), 60 mg (1) 80 mg (2) 100 rng (1) 50 mg (2) 75 mg (3)
Pulmonary Pulmonary Local recurrence Local recurrence Pulmonary Local recurrence/osseous Pulmonary/osseous/cerebral lrresectable Tumor tongue Local recurrence
SD PD SD SD PD PD PD PD SD SD
30 20 3
Full dosage (6)t
Irresectable/tumor orop harynx Pulmonary
Full dosage (6), no B in last 4 cycles Full dosage (2) Full dosage (2) Full dosage (8), in last 3 cycles dose reduction (myeolosuppression) Full dosage (2) Full dosage (3) Full dosage (3) Full dosage (6)
Interval between Dx and (mo) CT
Overall survival (mo)
50 6
41 66 86 62 56 10 95 17 0 216
81 108 110 66 75 14 118 24 50+ 222
PR
77
0
77+
CR
21
7
38
Osseous/pleura Pulmonary/osseous Local recurrence
SD PR SD
3 6 9
22 122 204
130
215
Osseous Osseous/cerebral Pulmonary Local recurrence/pulmonary
SD SD PD SD
14 10 24
22 16 198 44
50 28 202 67
-
-
25
CR = Complete remission; PR = partial remission; SD = stable disease; PD = progressive disease; Dx e q diagnosis. ‘CDDP = Cisplatin; CDB = cisplatin, doxorubicin and bleomycin; for details or regimen, see Materials and Methods. t C (CDDP) 20 mglm” on days 1-5; D (doxorubicin) 50 mglm‘ on day 7; B (bleomycin) 30 mg on days 1-5.
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continued due to mental instability. Shortly afterward the patient died of a nondisease-related event, which explains the short duration of remission (6 months). Five patients showed SD with a median duration of 15 months (range: 3-24 months). One patient showed progression of pulmonary metastatic lesions during polychemotherapy. The median time from diagnosis to the start of polychemotherapy in this group was 22 months (range: 0-204 months). The median overall survival was 67 months (range: 25-215 months). Toxicity in group 1 included the following: nausea/vomiting of grade IV in two patients, grade 111in three, grade I1 in three, grade I in two; nephrotoxicity of grade I in three patients; minor hearing loss in two patients; peripheral neuropathy, not detected; leucocytopenia of grade I in one patient; and no thrombocytopenia of significance. Serious complications due to cisplatin were not encountered. With regard to the toxicity of group 2, more detailed information was available, due to the prospective nature of the study. One of nine patients developed grade I nephrotoxicity. Two patients experienced documented hearing loss in the high-frequency area. Two patients developed transient nonlife-threatening arrhythmias. Signs of heart failure were not observed. In two patients grade I neurotoxicity was reported. With regard to myelotoxicity, four patients showed a grade I11 leucocytopenia (nadir: 1.0-1.9 x 109/L),three showed a grade I1 (2.02.9 x 109/L),and four developed a grade I thrombocytopenia (75-99 x 109/L). Serious infections or bleeding complications were not encountered. Respiratory symptoms were seen in two patients, one had mild symptoms (grade I> due to intrapulmonary disease, the second developed exertional dyspnea (grade 11) as a result of pleural localization and pulmonary embolism. Alopecia of varying degree was observed in all patients from group 2. In general, toxicity was considered manageable. Dose reduction was needed in five patients: three in group 1 (two for nephrotoxicity, one for myelosuppression) and in two in group 2 (due to myelosuppression). No treatment-related deaths were observed.
Toxicity.
DISCUSStON
The two groups described are not comparable with regard to previous treatment and treatment
276
CDDP in Adenoid Cystic Carcinoma
schedule. Therefore, the results of the entire group of 19 patients should be interpreted cautiously. The results found in group 1, indicate that single-agent cisplatin for this small patient group, in part pretreated with radiotherapy or chemotherapy, did not offer any advantage. No objective responses were encountered. This is in contrast with the favorable results, reported by Schramm et al.? with seven of 10 patients (70%) showing a favorable objective tumor regression and subjective response. However, data on previous treatment were not presented in that study. Their results were in accordance with the results described by Suen and Johns,13 where single-agent cisplatin was found to induce an objective response in nine of 14 evaluable cases (65%). The impact on survival could not be defined. More recently, anecdotical cases have been presented in which a PR was obtained with intraarterial cisplatin.20,21 The experience with cisplatin-based polychemotherapy is more extensive, albeit limited to small series of patient^.^^^^'^^'^^,^^,^^ The response rates are highly variable, as might be expected considering the confidence interval limits of such small series. Furthermore, no comparative statements can be made. The combination of cisplatin, doxorubicin, and bleomycin used in the present report (group 2) has not been used previously. Our study is to some extent comparable with the study of Dreyfuss et al.,17who used cyclophosphamide instead of bleomycin. We also observed a response rate of 33% with one CR and two PR (three of nine patients). The response duration of the CR patient is also comparable: 26 months vs 21 months in the present study. In several r e p ~ r t s , ~however, ’ ~ ~ , ~the ~ activity of combination therapy was limited. Two relevant questions remain, first, does this type of chemotherapy have a defined role in relation to the stage of disease, and, second, does chemotherapy have an impact on survival? Several authors have suggested a more favorable response on chemotherapy for locoregional recurrences.12,14,18,19 The results of our study do not support this observation. The role of cisplatin in the neoadjuvant/adjuvant setting remains uncertain due to the paucity of the available literature. In one study on neoadjuvant cisplatinbased polychemotherapy, no responses were observed in three patients.16 There is no experience with cisplatin given in the adjuvant setting.
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The results with a noncisplatin-based regimen as adjuvant treatment was ineffective." In view of these data there is no role for the currently available chemotherapy in the neoadjuvant/adjuvant setting. The impact of cisplatin chemotherapy on survival both in responders and overall is unclear. With cisplatin, CRs have been reported. The duration of these responses are highly variable (7-26 months). Worthwhile is the observation of a prolonged sometimes symptom-free course in the case of a PR or SD after discontinuation of chem~therapy.'~ In the absence of a response it is well recognized that the disease can remain stable without any therapy for a long period of up to 60 months.17 Even spontaneous regression of metastases has been reported.23 These data further emphasize that the course of ACC is highly unpredictable and do not allow conclusions with respect t o the the role of cisplatin in an eventual prolongation of survival. Chemotherapy should probably be restricted to patients with symptomatic and/or rapidly PD. In conclusion single-agent cisplatin in the dose range and schedule used in this study is probably not effective in patients with recurrent or metastatic disease, especially when previous chemotherapy has been given. Cisplatin-based polychemotherapy may show some efficacy in terms of response in non-pretreated patients, although the impact on survival is unknown.
REFERENCES
1. Tannock I, Sutherland D, Osoba D. Failure of shortcourse multiple drug chemotherapy to benefit patients with recurrent or metastatic head and neck cancer. Cancer 1982;49:1358- 1360. 2. Forastiere AA, Natale RB, Takasugi BJ, Goren MP, Vogel WC, Kudla-Hatch V. A phase 1-11 trial of carboplatin and 5-fluorouracil combination chemotherapy in advanced carcinoma of the head and neck. J Clin Oncol 1987;5:190-196. 3. CreaPan ET. O'Fallon JR. Schutt AJ. Rubin J, Woods JE. Cyclgphosphamide, adriamycin and' 24-hour infusion of cis-diamminedichloroplatinum (11) in the management of patients with advanced head and neck neoplasms. Head Neck Surg 1984;6:738-743. 4. Marsh WL, Allen MS. Adenoid cystic carcinoma-biologic behavior in 38 patients. Cancer 1979;43:14631473. ~
CDDP in Adenoid Cystic Carcinoma
5. Vrielinck U G , Ostyn F, van Damme B, van den Bogaert W, Fossion E. The significance of perineural spread in adenoid cystic carcinoma of the major and minor salivary glands. Int J Oral Maxillofac Surg 1988;17:190-193. 6. Matsuba HM, Spector GJ, Thawley SE, Simpson JR, Mauney M, Pikul FL. Adenoid cystic salivary gland carcinoma- a histopathology review of treatment failure patterns. Cancer 1986;57:519-522. 7. Zielke-Temme B, Wannenmacher M. Adenoid cystic carcinoma (cylindroma) in the head and neck. A clinical review of 82 cases. Acta Radio1 Oncol 1978;17:401-413. 8. Conley J, Dingman DL. Adenoid cystic carcinoma in the head and neck (cylindroma). Arch Orolaryngol 1974;100:81-90. 9. Shingaki SS, Saito R, Kawasaki T, Nakjima T. Adenoid cystic carcinoma of the major and minor salivary glands. A clinicoDatholoEtica1 studv of 17 cases. J Maxillofac Surrr 1986;14:63-56. 10. Matsuba HM, Thawley SE, Levine LA, Simpson JR, Maunev M. Adenoid cvstic carcinoma of major and minor saliva& gland origin."Laryngoscope 1984;9&1316- 1318. 11. Tarpley TM, Giasanti JS. Adenoid cystic carcinomaanalysis of fifty oral cases. Oral Surg 1976;41:484-497. 12. Tannoch IF, Sutherland DJ. Chemotherapy for adenocystic carcinoma. Cancer 1980;46:452-454. 13. Suen JY, Johns ME. Chemotherapy for salivary gland cancer. Laryngoscope 1982;92:235- 239. 14. Creagan ET, Woods JE, Schutt AJ, O'Fallon JR. Cyclophosphamide, adriamycin and cisdiamminedichloroplatinum (11) in the treatment of advanced nonsquamous cell head and neck cancer. Cancer 1983;52:2007-2010. 15. Budd GT, Groppe CW. Adenoid cystic carcinoma of the salivary gland- sustained complete response to chemotherapy. Cancer 1983;51:589-590. 6. Venook AP, Tseng A, Meyers FJ, Silverberg I, Boles R, Fu KK, Jacobs CD. Cisplatin, doxorubicin and 5-fluorouracil chemotherapy for salivary gland malignancies: a pilot study of the Northern California Oncology Group. J Clin Oncol 1987;5:951-955. 7. Dreyfuss AI, Clark JR, Fallon BG, Posner MR, Norris CM, Miller D. Cyclophosphamide, doxorubicin and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin. Cancer 1987;60:2869-2872. 18. Schramm VL, Srodes C, Myers EN. Cisplatin therapy for adenoid cystic carcinoma. Arch Otolaryngol 1981;107: 739-741. 19. Creagan ET, Woods JE, Rubin J , Schaid DJ. Cisplatinbased chemotherapy for neoplasms arising from salivary glands and contiguous structures in the head and neck. Cancer 1988;62:2313- 2319. 20. Frustaci S, Barzan L, Tumolo V, et al. Intra-arterial continuous infusion of cisdiamminedichloroplatinum in untreated head and neck cancer patients. Cancer 1986;57:1118-1123. 21. Dimery IW, Lee Y-Y, Hong WK. Intra-arterial chemotherapy in the management of paranasal sinus carcinoma. Cancer Bull 1986;38:58-61. 22. Triozzi PL, Brantley A, Fisher S, Cole TB, Crocker I, Huang AT. 5-Fluorouracil, cyclophosphamide and vincristine for adenoid cystic carcinoma of the head and neck. Cancer 1987;59:887-890. 23. Grillet B, Demedts M, Roelens J, Goddeeris P, Flossion E. Spontaneous regression of lung metastases of adenoid cystic carcinoma. Chest 1984;85:289-291.
I
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Nineteen patients, nine men and 10 women, with advanced adenoid cystic carcinoma (ACC), were treated with cisplatin either alone or in combination with doxorubicin and bleomycin. Median age was 51 years (range: 32-73 years). Two groups of patients were distinguished: Group 1 (N = 10)received single-agent cisplatin (50-120 mg/m2 IV every 4 weeks) for locoregional recurrence (N = 4), pulmonary metastases (N = 5), or as neoadjuvant therapy (N = 1). Five patients failed previous chemotherapy. No objective responses were observed, five patients showed stabilization of their disease for a median duration of 20 months (range: 3-50 months). Group 2 (N = 9) received a combination of cisplatin (20 mg/m2 IV on days 1-5), doxorubicin (50 mg/m2 IV on day l),and bleomycin (30 mg IV on days 1-5), every 3 weeks. A complete remission (CR) was seen in one patient, lasting for 2 years, a partial remission (PR) in two patients (duration: 6 months and 6 years) (33%),and a stable disease (SD) in five patients (median duration: 15 months; range 3-24 months). One patient showed progression from the start. The observed toxicity was acceptable: dose reduction was required in five patients for rnyelosuppression or impairment of renal function; vomiting grade 111 (WHO) was seen in 10 patients. The median progression-free survival was 36 months (range: 7-77 months). Median overall survival was 81 months
From the Department of Medical Oncology (Drs. Haan and Mulder), St. Radboudhospital, Nijmegen; Department of Medical Oncology (Dr Vermorken), Free University Hospital, Amsterdam; Department of Medical Oncology (Dr. Schornagel). University Hospital, Utrecht; Surgical Department (Dr. Verrney), University Hospital, Groningen: Daniel den Hoed Institute (Dr. Verweij), Rotterdam; The Netherlands. Address reprint requests to Dr De Mulder at the Department of Medical Oncology, P 0. Box 9101, 6500 HB. Nijmegen, The Netherlands. Acccepted for publication November 13, 1991
CCC 0148-6403/92/040273-05$04.00 0 1992 John Wiley 8, Sons, Inc.
CDDP in Adenoid Cystic Carcinoma
(range: 14-216 months). The role of cisplatin in this disease remains questionable. 0 1992 John Wiley & Sons, Inc. HEAD & NECK 1992;14:273-277
Adenoid cystic carcinoma (ACC), comprising 4% to 8%of all nonsquamous cell carcinomas in the head and neck region,lP3 continues to represent a difficult clinical problem. This is mainly due to its slow growth pattern, tendency to perineural invasion, and systemic ~ p r e a d . ~ - ~ The prognosis depends largely on adequate initial treatment (ie, major ablative surgery and, if indicated, adjuvant radi~therapy).~-’ Despite efforts to achieve local control, the course of the disease is usually protracted, which is reflected in a median survival of approximately 10 years and characterized by a hi h incidence of local recurrences and metastases.6’$! J’J’ Chemotherapy has been proven to be of limited value in cases of recurrent or metastatic disease. Of the various agents tested, only a few were considered to be active, such as 5-flUOr0uracil, doxorubicin, and ~ i s p l a t i n . l ~ -Cisplatin ~’ given as both a sin le agent13718and in combination therapy 14~16~17fg has resulted in objective tumor regressions. Single-agent therapy yielded objective res onse rates, varying between 40% and 64%.1 3 , l tPooled data from studies with cisplatin-based polychemotherapy, including doxorubicin, 5-fluorouracil, and cyclosphosphamide, showed a response rate of approximately
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273
25%14,16,17919 with a median duration varying from 5 to 40 months. In this study we report on a retrospective analysis of 19 patients with advanced ACC who were treated with either cisplatin monotherapy or cisplatin combined with doxorubicin and bleomycin. MATERIALS AND METHODS
This retrospective study comprised 19 patients (nine men, 10 women) with a histologically proven advanced ACC of the head and neck region. Median age was 51 years (range: 32-73 years). Patient characteristics are given in Table 1. Most patients (14 of 19) were initially treated with surgery with or without radiotherapy. Twelve patients had a local recurrence; 14 had distant metastases at the time of the start of chemotherapy. Seven patients received previous chemotherapy. Two groups of patients could be distinguished: group 1 (patients 1- 10) received cisplatin monotherapy and group 2 (patients 11-19) received cisplatin combination therapy (Table 1). Single-agent cisplatin was given at a dose range of 50-120 mg/m2, every 4 weeks. Median num-
ber of cycles given was 3 (range: 1-5). Patients were not treated according to a standard protocol, but the data reflected the experience in the different institutions (JBV, JS, AV, JV). Four patients had locoregional recurrence, previous chemotherapy was accompanied by radiotherapy in all patients. Five patients failed on previous chemotherapy. Group 2 received combination chemotherapy: cisplatin 20 mg/m2 IV on days 1-5, doxorubicin 50 mg/m2 IV on day 1, and bleomycin 30 mg IV on days 1-5, cycles were repeated every 3 weeks. Cisplatin was administered for 4 hours, diluted in 1,000 mL normal saline in between adequate pre- and posthydration, doxorubicin was given as a bolus injection prior to the cisplatin infusion, and bleomycin was infused for 20 hours in the posthydration phase. Median number of cycles was 3 (range: 2-6). All patients received anti-emetic therapy. The patients were all treated in a single institution (Department of Medical Oncology, St. Radboudhospital, Nijmegen) according to a defined protocol. Only one patient had had previous chemotherapy. None of the indicator lesions were previously irradiated. Evaluation was per-
Table 1. Patient characteristics. Distant metastases
Previous chemotherapy (total dosage)
Agelsex
Site of tumor
Group 1 1 2 3 4 5 6
62/F 32/F 49lM 64lF 67/M 34lM
Submandibular gland Parotid gland Maxillary Parotid gland Parotid gland Mouth (floor)
Surgery SurgerylRT SurgerylRT SurgerylRT SurgerylRT RT/CT
Yes No Yes Yes Yes No
Pulmonary Pulmonary No No Pulmonary Osseous
7 8
491F 42lM
Maxillary Lacrimal gland
Sinus surgery SurgeryiRT
Yes Yes
9 10 Group 2 11 12 13 14 15
741F 51/M
Tongue (base) Parotid gland
CT Surgery
No Yes
Pulmonary Pulmonarylosseousl cerebral No No
18
55lM 73lM 69lF 47lM 43/M 501F 60lM 39lF
19
481F
Oro/pharynx Larynx Parotid gland Submandibular gland Submandibular gland Nasopharynx Submandibular gland Maxillary sinus Mouth (floor)
CT RT SurgerylRT Surgery/RT Surgery RT Surgery Surgery Surgery
No No No No No Yes Yes Yes Yes
No Pulmonary Osseous/pleura Osseous/pulmonary Pulmonary Osseous Pulmonary Pulmonary Pulmonary
16 17
Initial therapy
Local recurrence
Patient
5-FU Doxorubicinl5-FU DoxorubicinE-FU Doxorubicin/tj-FU Doxorubicinl5-FU CDDP (adjuvant therapy following RT) None None None None None None None None None None None None Combination of BLEO, VLB, MTX, CYCLO, and 5-FU
~~
5-FU = 5-Nuorouracil, MTX = methofrexate, CDDP = cisplatin, BLEO = bleomycin, BLB
=
vinblastm, CYCLO = cyclophosphamide, RT
=
radiotherapy,
CT = chemotherapy
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formed after two cycles, unless early progression necessitated discontinuation of treatment. In case of an objective response or stable disease, chemotherapy was continued. A maximum of six cycles was given, special attention was given to cardiac, renal, and pulmonary function. Definition of response and response duration was according to the WHO criteria. RESULTS
An overview of tumor response is given in Table 2. In group 1 no objective responses were observed. Stable disease (SD)was observed in five cases with a median duration of 6 months (range: 3-50 months). Of these patients, only one patient is still alive. Progressive disease (PD) was noted in five patients. The median interval between diagnosis and initiation of cisplatin chemotherapy was 59 months (range: 0-216 months). Median overall survival was 78 months (range: 14-222 months). Three objective responses were observed in group 2: one complete remission (CR) and two
partial remissions (PR). The patient with a CR was a 73-year-old man who was initially seen with pulmonary metastases 7 months after radiotherapy for a laryngeal ACC. CR was seen after two cycles. In total six cycles were given, the response duration was 21 months. Two patients showed a PR. In one patient (a 55-year-old man), polychemotherapy was given as primary treatment for an irresectable ACC of the oropharynx. After three cycles a PR was obtained, but the tumor was still considered irresectable; in total, six cycles were administered without further regression and the treatment was completed with radiotherapy. At the time of this analysis, the patient was still in an ongoing PR. The second patient with a PR was a 47-yearold man who presented with an ACC of the submandibular gland, which was initially treated with surgery and radiotherapy. After a relapsefree interval of 122 months pulmonary and osseous metastases developed. After two cycles of polychemotherapy a PR of the pulmonary lesions was observed; however, the third cycle was dis-
Table 2. Tumor response Patient Chemotherapy* Group 1 1 CDDP 2 CDDP 3 CDDP 4 CDDP 5 CDDP 6 CDDP 7 CDDP 8 CDDP 9 CDDP 10 CDDP Group 2 11 CDB 12 CDB 13 CDB 14 CDB 15 CDB
16 CDB 17 CDB 18 CDB 19 CDB
Dosage/m2 (number of cycles)
Indicator lesion
Type of response
Duration
(mo)
120 mg (5) 120 rng (2), 80 mg (3) 120 mg (2), 80 mg (3) 80 rng (3) 50 mg (3) 80 mg (2), 60 mg (1) 80 mg (2) 100 rng (1) 50 mg (2) 75 mg (3)
Pulmonary Pulmonary Local recurrence Local recurrence Pulmonary Local recurrence/osseous Pulmonary/osseous/cerebral lrresectable Tumor tongue Local recurrence
SD PD SD SD PD PD PD PD SD SD
30 20 3
Full dosage (6)t
Irresectable/tumor orop harynx Pulmonary
Full dosage (6), no B in last 4 cycles Full dosage (2) Full dosage (2) Full dosage (8), in last 3 cycles dose reduction (myeolosuppression) Full dosage (2) Full dosage (3) Full dosage (3) Full dosage (6)
Interval between Dx and (mo) CT
Overall survival (mo)
50 6
41 66 86 62 56 10 95 17 0 216
81 108 110 66 75 14 118 24 50+ 222
PR
77
0
77+
CR
21
7
38
Osseous/pleura Pulmonary/osseous Local recurrence
SD PR SD
3 6 9
22 122 204
130
215
Osseous Osseous/cerebral Pulmonary Local recurrence/pulmonary
SD SD PD SD
14 10 24
22 16 198 44
50 28 202 67
-
-
25
CR = Complete remission; PR = partial remission; SD = stable disease; PD = progressive disease; Dx e q diagnosis. ‘CDDP = Cisplatin; CDB = cisplatin, doxorubicin and bleomycin; for details or regimen, see Materials and Methods. t C (CDDP) 20 mglm” on days 1-5; D (doxorubicin) 50 mglm‘ on day 7; B (bleomycin) 30 mg on days 1-5.
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continued due to mental instability. Shortly afterward the patient died of a nondisease-related event, which explains the short duration of remission (6 months). Five patients showed SD with a median duration of 15 months (range: 3-24 months). One patient showed progression of pulmonary metastatic lesions during polychemotherapy. The median time from diagnosis to the start of polychemotherapy in this group was 22 months (range: 0-204 months). The median overall survival was 67 months (range: 25-215 months). Toxicity in group 1 included the following: nausea/vomiting of grade IV in two patients, grade 111in three, grade I1 in three, grade I in two; nephrotoxicity of grade I in three patients; minor hearing loss in two patients; peripheral neuropathy, not detected; leucocytopenia of grade I in one patient; and no thrombocytopenia of significance. Serious complications due to cisplatin were not encountered. With regard to the toxicity of group 2, more detailed information was available, due to the prospective nature of the study. One of nine patients developed grade I nephrotoxicity. Two patients experienced documented hearing loss in the high-frequency area. Two patients developed transient nonlife-threatening arrhythmias. Signs of heart failure were not observed. In two patients grade I neurotoxicity was reported. With regard to myelotoxicity, four patients showed a grade I11 leucocytopenia (nadir: 1.0-1.9 x 109/L),three showed a grade I1 (2.02.9 x 109/L),and four developed a grade I thrombocytopenia (75-99 x 109/L). Serious infections or bleeding complications were not encountered. Respiratory symptoms were seen in two patients, one had mild symptoms (grade I> due to intrapulmonary disease, the second developed exertional dyspnea (grade 11) as a result of pleural localization and pulmonary embolism. Alopecia of varying degree was observed in all patients from group 2. In general, toxicity was considered manageable. Dose reduction was needed in five patients: three in group 1 (two for nephrotoxicity, one for myelosuppression) and in two in group 2 (due to myelosuppression). No treatment-related deaths were observed.
Toxicity.
DISCUSStON
The two groups described are not comparable with regard to previous treatment and treatment
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schedule. Therefore, the results of the entire group of 19 patients should be interpreted cautiously. The results found in group 1, indicate that single-agent cisplatin for this small patient group, in part pretreated with radiotherapy or chemotherapy, did not offer any advantage. No objective responses were encountered. This is in contrast with the favorable results, reported by Schramm et al.? with seven of 10 patients (70%) showing a favorable objective tumor regression and subjective response. However, data on previous treatment were not presented in that study. Their results were in accordance with the results described by Suen and Johns,13 where single-agent cisplatin was found to induce an objective response in nine of 14 evaluable cases (65%). The impact on survival could not be defined. More recently, anecdotical cases have been presented in which a PR was obtained with intraarterial cisplatin.20,21 The experience with cisplatin-based polychemotherapy is more extensive, albeit limited to small series of patient^.^^^^'^^'^^,^^,^^ The response rates are highly variable, as might be expected considering the confidence interval limits of such small series. Furthermore, no comparative statements can be made. The combination of cisplatin, doxorubicin, and bleomycin used in the present report (group 2) has not been used previously. Our study is to some extent comparable with the study of Dreyfuss et al.,17who used cyclophosphamide instead of bleomycin. We also observed a response rate of 33% with one CR and two PR (three of nine patients). The response duration of the CR patient is also comparable: 26 months vs 21 months in the present study. In several r e p ~ r t s , ~however, ’ ~ ~ , ~the ~ activity of combination therapy was limited. Two relevant questions remain, first, does this type of chemotherapy have a defined role in relation to the stage of disease, and, second, does chemotherapy have an impact on survival? Several authors have suggested a more favorable response on chemotherapy for locoregional recurrences.12,14,18,19 The results of our study do not support this observation. The role of cisplatin in the neoadjuvant/adjuvant setting remains uncertain due to the paucity of the available literature. In one study on neoadjuvant cisplatinbased polychemotherapy, no responses were observed in three patients.16 There is no experience with cisplatin given in the adjuvant setting.
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The results with a noncisplatin-based regimen as adjuvant treatment was ineffective." In view of these data there is no role for the currently available chemotherapy in the neoadjuvant/adjuvant setting. The impact of cisplatin chemotherapy on survival both in responders and overall is unclear. With cisplatin, CRs have been reported. The duration of these responses are highly variable (7-26 months). Worthwhile is the observation of a prolonged sometimes symptom-free course in the case of a PR or SD after discontinuation of chem~therapy.'~ In the absence of a response it is well recognized that the disease can remain stable without any therapy for a long period of up to 60 months.17 Even spontaneous regression of metastases has been reported.23 These data further emphasize that the course of ACC is highly unpredictable and do not allow conclusions with respect t o the the role of cisplatin in an eventual prolongation of survival. Chemotherapy should probably be restricted to patients with symptomatic and/or rapidly PD. In conclusion single-agent cisplatin in the dose range and schedule used in this study is probably not effective in patients with recurrent or metastatic disease, especially when previous chemotherapy has been given. Cisplatin-based polychemotherapy may show some efficacy in terms of response in non-pretreated patients, although the impact on survival is unknown.
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