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Cancer Investigation, 10(5), 349-355 (1992)
Simultaneous Radiotherapy and Chemotherapy with Carboplatin in Inoperable Squamous Cell Carcinoma of the Head and Neck: A Phase I1 Study Nikolaos Zamboglou, M.D., Ph.D.,' Wolf Achterrath, Ph.D.,2 Thomas Schnabel, M.D.,' Luigi Lenaz, M.D.,2 Christos Kolotas, M.D.,' and Gerd Schmitt, M.D.' Department of Radiation Oncology University of Dijsseldorf Diisseldorf, Germany 2Bristol-MyersSquibb Pharmaceutical Group Princeton, New Jersey
ABSTRACT F$ty-six untreated patients with inoperable squumous cell carcinoma of the head and neck were treated with carboplatin 70 mglm2 i.v. daily on days 1-5 and 2933 in combination with simultaneous conventional radiation up to a target volume dose of 50 Gy. Depending on tumor response and upon recommendation of surgeons, 21 of 56 patients underwent surgery after a radiation dose of 50 Gy and two courses of carboplatin. Patients who showed pCR after surgery received no further radiotherapy. In all other patients radiotherapy was continued using a shrinking fietd technique up to a target absorbed dose of 70-74 Gy. Combined modality induced 66% complete remission (CR) and an overall response rate of 98%. After completion of the whole treatment program (combined modality surgery) 53 (94%) of the 56 patients were disease free. The median survival for all patients is 25+ months and the percentage of two-year survivors is 53%. Myelosuppression was the most frequent toxicity, but rarely was severe; leukopenia und thrombocytopenia of WHO grade 3 occurred in 21% of the patients. No other toxicities ubove WHO grade 2 occurred. Nephrotoxicity , neurotoxicity and ototoxicity were not seen. The addition of carboplatin did not increase the rate of surgical complication over that expected for preoperative radiotherapy. Two patients died of pulmonary embolism after surgery. Combined modality with carboplatin and
*
349 Copyright 0 1992 by Marcel Dekker, Inc.
Zamboglou et al.
350
simultaneous radiation is a highly active and well-tolerated regimen for untreated patients with inoperable squamous cell carcinoma of the head and neck.
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INTRODUCTION Squamous cell carcinomas of the head and neck respond well to radiotherapy when diagnosed in early stages, but show limited response if the tumor is advanced and inoperable (1). In the past years encouraging data were reported with a combined treatment using cisplatin (1-5) or cisplatin and 5-fluorouracil- (5-FU) based regimens (6- 10) and simultaneous irradiation as firstline treatment in advanced head and neck cancer. Carboplatin, a second-generation platinum analogue, has shown antitumor activity comparable to that observed with cisplatin in previous studies in patients with recurrent and metastatic head and neck tumors (1 1-17). The major difference between carboplatin and the parent compound was their spectrum of toxicities. The meta-analysis of three randomized trials comparing single-agent carboplatin and cisplatin in advanced ovarian cancer showed that carboplatin induced statistically significantly less nephrotoxicity, ototoxicity, neurotoxicity, and nausea/ vomiting than cisplatin (18). These advantages allow easy outpatient treatment. Furthermore, carboplatin has shown potentiation of the antineoplastic activity of radiation comparable to cisplatin in vitro (19,20) and in vivo (19,21). In a Phase 1 study, we had investigated the optimal dose of carboplatin in combination with simultaneous conventional irradiation in untreated patients with inoperable head and neck cancer. The combined modality induced in this Phase I study 12 (80%) complete remissions (CR) and 15 overall responses in 15 patients (3,22). Therefore, a Phase I1 study with the optimal dose of carboplatin in combination with simultaneous in-adiation was carried out in untreated patients with inoperable head and neck cancer.
PATIENT SELECTION Eligible patients had histologically proven unresectable squamous cell carcinoma of the head and neck, no prior surgery, chemo- and/or radiotherapy, WHO performance status 5 2 , age 18-75 years, no distant metastases, and life expectancy of at least 3 months. Pretreatment white blood cell counts had to be 24000/pl, platelet counts 2 lOO,OOO/pl,liver and renal functions had to be normal, technetium-diethylenetriamine-pentaacetic acid (y''''lTC-DTPA)clearance and serum electro-
lytes were at the institutional normal range. All patients gave informed consent to participate in this study.
STAGING AND FOLLOW-UP PROCEDURES Pretreatment evaluations consisted of complete medical history, physical examination, and laboratory work up with complete hemogram (differential and platelet count), serum bilirubin, serum glutamate oxcloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), creatinine, and ""'TC-DTPA clearance. The staging procedures included panendoscopy , nuclear magnetic resonance (NMR) and computer tomography (CT) of the head and neck, chest x-ray, or other tests as indicated to rule out suspected distant metastatic disease. Stage of disease was determined according to the UICC classification (23). The size of neoplastic lesions was determined in Weeks 4 and 6 after the start of carboplatin and radiation and in Week 6 after completion of radiation. Complete laboratory work up was performed before and after each cycle of carboplatin and in Week 6 after completion of radiation. 9'"'TC-DTPA-clearance was repeated in Week 6 after the start of treatment. Complete blood counts and clinical toxicities were monitored weekly during treatment. After completion of treatment, follow-up examinations were conducted every 3 months.
TREATMENT PLAN This study was designed as a nonrandomized Phase I1 study. Carboplatin was given at a dose of 70 mgim' i.v. over 30 minutes daily on Days 1-5 and 29-33, without pre- and posthydration. Each dose of carboplatin preceded the radiation by 30 minutes. Low-dose antiemetics were administered if indicated. Radiation therapy consisted of daily fractions of 2,O Gy on Days 1-5 in Weeks 1-5 and in Weeks 8 and 9 up to a total tumor dose of 70-74 Gy. Patients with progressive disease after the first course of carboplatin and a radiation dose of 30 Gy or any time thereafter were withdrawn from the protocol. Their subsequent treatment was decided on an individual basis.
Phase I1 Study of Carboplatin
Patients demonstrating clinically complete disappearance of disease and patients with resectable residual disease after combined modality were considered candidates for subsequent surgery upon recovery from myelosuppression. Patients who showed a pathological complete response after two courses of carboplatin, a radiation dose of 50 Gy, and after interposed surgery were not considered for further, radiotherapy.
TREATMENT RESPONSElTOXICITY
35 1
Table I Patients’ Characteristics
No of patients F / M ratio Median age
56 12144 57 (range 36-77)
Median WHO performance status
2 (range 0-2) (n = 5 ) (n = 22) ( n = 29)
0
I 2
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Stage o j disease
Patients were considered evaluable for response and toxicity if they had received at last one cycle of carboplatin and a radiation dose of 30 Gy. Clinical (c) tumor response was classified according to WHO criteria (24). Pathologic (p) response was defined as follows: pCR was absence of disease, pPR was presence of microscopic and macroscopic residual tumor in the resection material. Response analysis was carried out by two independent investigators:one radio-oncologist and one head and neck surgeon. Toxicity was evaluated by worst event for each organ system using the WHO scale (24). Median diseasefree survival and median survival time were calculated by the Kaplan-Meier method (25). Survival was calculated from the first day of treatment.
RESULTS
T2 T3 T4
NO 1
NI
1
5 4
3
1
N2a I 3 2
N2b
N2c
N3
4 3
6 8
10
4
Tumor sites
Oral cavity Oropharynx Hypopharynx Epipharynx Larynx Oral cavity / oropharynx Oropharynx / hypopharynx Oropharynx / epipharynx Hypopharynxl larynx Oral cavity/oropharynx/epipharynx Oral cavityloropharynxl hypopharynx Oral cavity / epipharynx / oropharynx
(n = 17) (n = 5 ) (n = 5 ) (n = 1) (n = 2) (n = 13) (n = 5) (n = 2) (n = 2) (n = I ) (n = 2) (n = 1)
Dijjerentiation
A total of 56 patients entered the study. All patients had received two courses of carboplatin and a total radiation dose of 50-74 Gy and were evaluable for response and toxicity. Their clinical characteristics and the anatomical sites of disease are summarized in Table 1.
Response Rates, Response Duration, and Survival After two cycles of carboplatin and a radiation dose of 50 Gy, 13 (23%) cCR, 42 (75%) cPR, and one no change (NC) were achieved in 56 patients. Between Weeks 4 and 6 after completing a radiation dose of 50 Gy, 2 I patients (13 cCR and 8 cPR) underwent surgery as determined by the surgeons. Surgery involved radical neck dissection in I2 patients and suprahyoidal dissection in 9 patients. In 7 (54%) of the 13 patients with cCR, the CRs were pathologically confirmed (pCR). In 6 (46%) patients microscopic residual disease was found in the resection material and they were classified as pPR. In the 8 patients with cPR the tumor had been downstaged to operable disease. After surgery, all 8 patients were
Well Moderate Poor
(n (n (n
= =
2) 44)
= 10)
disease free but macroscopic residual disease was found in their resection material and therefore they were classified as pathologic partial responders (pPR). Severe complications following surgery were wound healing impairment in 8 of 12 patients with radical neck dissection and in 3 of 9 patients with suprahyoidal dissection. Out of 12 patients with radical neck dissection, 2 died of lung embolism. In the other 35 patients (34 PR/I NC), the tumor remained inoperable and irradiation was continued up to total target dose of 70-74 Gy. In 24 (71%) of 34 patients, the PRs were converted into cCRs, while 10 patients remained in PR and one patient in the NC status. Eight of these 10 partial responders underwent salvage surgery. The residual tumor was removed, resulting in a no evidence of disease (NED) status. The resection material of 3 patients was disease
Zarnboglou et al.
352 Table 2
Table 3
Clinical Response by Stage of DiJeuse According to TNM Clussificution
Ciinicd Response by Stiige of Lymph Node Involvement in Stcrgr T4
CR
NO
3
3
3
NI
4
3
4
N2a
2
I
2
N2b
3
2
3
N2c
8
4
8
,'95% Confidence limits.
N3
10
5
10
free (residual fibrosis); the 5 other patients had residual tumor. The patients with residual fibrosis were classified as pathologic complete responders, the other patients as pathologic partial responders. Severe complications following limited surgery were not seen. The summarized results showed that 37 (66%) cCR, 55 (98%) overall responses, and one NC were achieved in 56 patients after two cycles of carboplatin and a total radiation dose of 50-74 Gy (95% confidence limits for CR 53-79% and CR PR 94-102%). A total of 29 patients with objective responses after combined modality underwent surgery. Ten (35%) pCR and 19 (65%) pPR were seen. Clinical response by stage of disease and responses in stage T4 depending on lymph node involvement are shown in Tables 2 and 3. The CR rate was
slightly higher for stage T3 NO-3 (70%) than for stage T4 NO-3 (60%). After completion of the whole treatment program (carboplatin + simultaneous radiation t surgery) 53 (95%) of 56 patients were disease free (CR or NED). Survival was calculated for all 56 patients after a follow-up period ranging from 18 to 37 months (median 25 months). Of 56 patients 26 (46%) were free of disease on last clinical examination. The estimated median survival for all patients is 25 months, the median disease-free survival is 18 months (Fig. 1). The actuarial one- and two-year survival rates are 82% and 53% respectively. The estimated disease-free survival rate for one year is 64%, for two years 50%.
~~
CR N(%)"
CR -t PR N(%)"
~
T2 NO-3
3
3
3
T3 NO-3
23
16 (70%)
22 (95%)
(51-89%) T4 NO-3
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+ PR
No. of patients
No. of patients
Stage
30
18 (60%) (42-78%)
30 ( 100%)
+
Stage
CR
+
survival probability (YO)
100 80
~
............. -
.............. ....... ............... ........
1
t
...... ........
....................
60 -
I
........ 1 ............ ........................................
L ..............
40 20 -
0
I 0
1 2 3
'
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
4 5 6
months
Figure 1 Overall survival -(
)
and disease-free survival (. ...........) for all patients entered into the study.
Phase I1 Study of Carboplatin
353
Table 4 Worst Toxicities Reported According to WHO Scale WHO grade No, of patients (%)
0
1
2
3
4
Leukopenia
21 (38%)
16 128%)
8 (14%)
9 (16%)
2 (4%)
Thrombocytopenia
34 (61%)
8 (14%)
7 (12%)
4 (8%)
3 (5%)
Nausealvomiting
50 (89%)
3 (5%)
3 (5%)
0
0
0
2 (4%)
42 (75%)
1 1 (21%)
0
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Stomatitis
Relapse
Toxicity
Thirty patients (54%)developed recurrent tumors following response. Twenty seven patients had locoregional relapse including 9 isolated lymph node recurrences. Three patients developed pulmonary metastases without any evidence of local recurrence. Twenty four of the 26 patients who died had only local disease, three of them suffering from a second tumor, and it is uncertain whether this second cancer was the cause of death. Two out of three patients with pulmonary metastases died.
The worst toxicities related to combined modality according to WHO criteria are outlined in Table 4. Myelosuppression was the major side effect (Table 4). Leukopenia of grade 3 and 4 occurred in 16% and 4%, thrombocytopenia of these degrees in 8% and 5% of the patients, respectively. The degrees of hematologic toxicity were comparable after the first and second cycle of carboplatin (Table 5). Nadirs of leukocytes and thrombocytes were observed between days 19 and 26 with
Table 5 Phase 11 Studies with Carboplatin, Cisplatin, or Cisplatinl.5-FU-based Regimens in Combination with Simultaneous Radiation in Inoperable Head and Neck Cancer Survivors Radiation No. of No. of CR CR PR after months Reference Chemotherapy dose Gy patients studies N% N% 12/24
+
Cisplatin
60-74
309
5
202 ( 6 5 % )
(60-70%)
259 (84%) (80-88%)
60-80155-60
1-5
6-8
Cisplatin15-Fu
60-72
I05
3
61 (58%) (48-68%)
100%
ne 75/ne 60
Cisplatin15-Fu
70
59
I
48 (81%)
59 (100%)
72/52
9
43 (100%)
ne155
10
55 (98%) (94-102%)
82/53
Own data
Folinic acid Cisplatinl5-Ful
(7 1-91 %) 60
43
I
Vindesine Carboplatin 'Results of two studies.
33 (77%) (64-90%)
50-74
56
1
37 (66%) (53-79%)
Zamboglou et at.
354
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recovery between days 23 and 28. Stomatitis of grade 3 was observed in 21% of patients. Even though no prophylactic antiemetics were given, vomiting of grade 2 occurred in only 5% of the patients, vomiting of grade 3/4 was not seen. These results confirm the observation that the frequency of carboplatininduced vomiting decreases significantly when a daily schedule of 5 days is adapted, as opposed to single intermittent bolus (26). No nephrotoxicity, measured by laboratory tests and 99"TC-DTPAclearance, and no neurotoxicity or ototoxicity occurred. Taste impairment and dry mouth were observed in 87% and 85% of patients, respectively.
DISCUSSION One area of current investigation in inoperable advanced squamous cell carcinoma of the head and neck is the design of more active and less toxic treatment strategies with the aim to improve the cure rate and the quality of life of patients. Earlier studies with cisplatin or cisplatin/5-FU-based regimens and simultaneous radiation had shown that these combined modalities are highly active as first-line treatment in inoperable head and neck cancer (1-10). The combined modalities induced 55-8 1Yo CR and more than 90% overall responses ( I -10). The median survival time is 24 to 48 + months and the percentage of two-year survivors is 50-60% ( I ,3,6,9,10): These data suggest that the combined modality approach leads to an increase of median survival and the percentage of two-year survivors by approximately 20% compared with radiation alone (1,3,6,9, 10,27). Treatment with cisplatin and cisplatin/5-FU in combination with simultaneous radiation is limited by vomiting and nephrotoxicity, induced mainly by cisplatin ( I ,2,6,7). In order to develop a treatment of similar activity but less toxicity, several Phase I studies with carboplatin and simultaneous radiation were carried out in patients with advanced squamous cell carcinoma of the head and neck (3,22,28-31), resulting in CR and overall response rates comparable to cisplatin and cisplatin/5FU-based regimens with simultaneous radiation (3,69,27). In our study, carboplatin and simultaneous radiation were administered at a dose schedule that can routinely be given to previously untreated patients with head and neck cancer in an outpatient setting. In the present Phase 11 study, carboplatin in combination with conventional simultaneous radiation induced 66%CR and 98% overall responses. The median survival
+
time for all patients is 25 months and the rate of oneand two-year survivors is 82% and 53%, respectively. These results are remarkable considering 46% of patients had two or more tumor sites. The first-line treatment with carboplatin and simultaneous radiation in inoperable head and neck cancer leads to CR, overall response rates and a percentage of one or two years survivors comparable to cisplatin or cisplatin/5-FU 2 folinic acid and cisplatin/5-FU/vindesine (1-10) (Table 5 ) . Carboplatin induced in combination with simultaneous radiation in the administered dose schedule, less or similar hematologic toxicities as compared with cisplatin and cisplatin/5-FU-based regimens (1,2,6,7,9). The nonhematologic organ toxicities, especially nephrotoxicity, vomiting, and stomatitis of WHO grade 3 were significantly less frequent after combined modality with carboplatin. Nephrotoxicity occurred in more than 30% of patients treated with cisplatinbased regimens (1,6,7), whereas no nephrotoxicity was observed in our study. The incidence of vomiting and stomatitis of WHO grade 3 is >22% and 31-50%, respectively, after treatment with cisplatin and cisplatin/5-FU-based regimens (1,6,7,9). No vomiting of WHO grade 3, and only 21% stomatitis of WHO grade 3 subjects were observed after carboplatin and simultaneous radiation. Preoperative radiotherapy with 50 Gy retards healing of pharyngeal and cutaneous suture lines and results in a high incidence of complications (32). In our experience, the addition of carboplatin to radiotherapy did not increase the incidence of postoperative complications, which was higher in patients receiving radical surgery than after limited resection. In conclusion, carboplatin with simultaneous radiation in patients with inoperable head and neck cancer resulted in antineoplastic activity comparable to cisplatin and cisplatin/5-FU-based combined modalities, but it induced fewer nonhematologic toxicities. The encouraging results of our study warrant the comparison of the efficacy of this treatment with conventional treatment strategies in prospective randomized studies. Address reprints requests to Nikolaos Zamboglou, M.D., Ph.D., Department of Radiation Oncology, University of Diisseldorf, Moorenstrasse 5, W-4000 Diisseldorf I Germany.
REFERENCES I.
Al-Sarraf M, PajakTF, Marcia1 VA et al: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. Cancer 59:259-265, 1987.
Phase I1 Study of Carboplatin 2
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17.
Bloom EJ, Green MD, Cooper JS et al: Concomitant use of cisplatinum (CDDP) chemotherapy and radiation therapy (RT) in the treatment of advanced head and neck cancer. Proc ASCO 4:137, 1985. Zamboglou N, Pape H, Schnabel Th et al: Kombinierte Radiotherapie mit Cis- oder Carboplatin bei fortgeschrittenen KopfHdls-Tumoren. Strahlenther Onkol 165, 647-651, 1989. Haselow RE, Adams GS, Oken MM, et al: Cis-platinum (DDP) with radiation therapy (RT) for locally advanced unresectable head and neck cancer. Proc ASCO 2:160, 1983. Gasparini G , Recher G, Favretto S, et al: Simultaneous cisplatinum (CDDP) and radiotherapy (RT) in inoperable or advanced squamous cell carcinoma of the head and neck (H&N). Proc ASCO 8:170, 1989. Taylor IV SG, Murthy AK, Caldarelli DD et al: Combined simultaneous cisplatin/ fluorouracil chemotherapy and split course radiation in head and neck. J Clin Oncol 7:846-856, 1989. Adelstein DJ, Sharan VM, Earle AS et al: Chemoradiotherapy as initial management in patients with squamous cell carcinoma of the head and neck. Cancer Treat Rep 70:761-767, 1986. Vannetzel JM, Juillard JC, Clin R et al: Cyclical combined chemotherapy and radiation therapy in head and neck cancers: Results of a Phase 1-11 study. Proc ASCO 5:148, 1986. Wendt TG. Hartenstein RC, Wustrow TPU et al: Cisplatin, tluorouracil with leucovorin calcium enhancement, and synchronous accelerated radiotherapy in the management of locally advanced head and neck cancer: A Phase 11 study. J Clin Oncol 7:471476, 1989. Leyvraz S, Pasche P, Bernasconi S et al: Accelerated hyperfractionated radiotherapy alternating with chemotherapy for advanced ENT carcinoma. Proc ECCO 5:P-0344, 1989. Eisenberger M, Horned0 J, Silva H. et al: Carboplatin (NSC241-240): An active platinum analog for the treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol4: 15061509, 1986. Al-Sarraf M, Metch B, Kish J. et al: Platinum analogues in recurrent and advanced head and neck cancer. Cancer Treat Rep 711723-726. 1987. Creekmore SP, Micetich KC, Vogelzang N. et al: Low toxicity and significant tumor responses in Phase I1 trials of carboplatin (CBDCA) in head and neck, non-small cell, urothelial, and ovarian cancers. Proc ASCO 4: 144, 1985. Calvert AM, Gumbrell LA, Henk MJ: Paraplatin phase I1 study in head and neck cancer. Proc Sym Paraplatin (Br Transition), London, 25, 1986. de Andres Basauri L, Lopez Pousa L, Alba E et al: Carboplatin: An active drug in advanced head and neck cancer. Cancer Treat Rep 70:1173-1176, 1986. Panettiere FJ, Lehane D, Fletcher WS, et al: Cis-platinum therapy of previously treated head and neck cancer: The Southwest Oncology Group’s Two-dose-per-month-outpatient regimen. Med Pediatr Oncol 8:221-225, 1980. Preusser P, Achterrath W, Niederle N et al: Cisplatin. Arzneimitteltherapie 3:50-65, 1985.
355 18. Rozencweig M, Martin A, Beltangady M et al: Randomized trials of carboplatin versus cisplatin in advanced ovarian cancer. In Carboplatin: Current Perspectives and Future Directions. Edited by PA Bunn, R Canetta, RF Ozols et al. W.B. Saunders, Philadelphia, 1990, pp. 175-186. 19. Douple EB, O’Hara JA, Jones EL: Enhancement of radiation therapy in a murine tumor (MTG-B) UlCC. Lectures and Symposia 14th Int Cancer Congr, Budapest, Vol. 9, 1986, pp. 77-80. 20. Dewit L: Combined treatment of radiation and cis-diamminedichloroplatinum (11): A review of experimental and clinical data. Int J Rad Oncol Biol Phys 13:403-426, 1987. 21. Littbrand B, Bergmann H: The combined effect of carboplatin and irradiation on an osteosarcoma in vivo. Proc ECCO 4:901. 1987. 22. Pape H, Achterrath W, Mardfiotti R et al: Combined carboplatinradiotherapy in patients with advanced squamous carcinoma of the head and neck. J Cancer Res Clin Oncol, I14 (Suppl.):S9, 1988. 23. Kopf-und Halstumoren, In TNM-Atlas, 2nd ed. Edited by B. Spiess, OH Beahrs, P Hermanek, et al. Berlin, Springer Verlag. 1990, pp. 3-55. 24. Miller AB, Hoogstraten B, Staquet M et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981. 25. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 453:475, 1958. 26. Canetta R, Goodlow J, Smaldone L et al: Pharmacologic characteristics of carboplatin: Clinical experience. In Curboplatin (JM8). Current Perspectives and Future Directions. Edited by PA Bunn Jr, R Canetta, RF Ozols, et al. WB Saunders, Philadelphia, 1990, pp. 195-201. 27. Marcia1 VA, Pajak TF, Kramer S et al: Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer. Semin Oncol 15:39-60, 1988. 28. Eisenberger M, Jacobs M, Sinibaldi V et al: Simultaneous treatment with carboplatin and conventional radiation for patients with unresectable squamous cell carcinoma of the head and neck: Preliminary Phase I and I1 results. In Curboplatin (JM8).Current Perspectives and Future Directions. Edited by PA Bunn, R Canetta, RF Ozols, et al. WB Saunders, Philadelphia, 1990, pp 195-201. 29. Jacobs MC, Eisenberger M, Chuh Oh M et al: Carboplatin and radiotherapy for stage IV carcinoma of the head and neck: A Phase 1-11 study. Int J Rad Oncol Biol Phys 17:361-369, 1989. 30. Osoba D, Flores AD, Hay JH et al: Phase I study of concurrent carboplatin and radiotherapy in previously untreated patients with Stage I11 and IV head and neck cancer. Head Neck 13:217-223, 1991. 31. Volling P, Staar S, Achterrath W, Muller RP: Carboplatin plus radiation therapy in head and neck cancer. Sem Oncol 18: 1722, 1991. 32. Donald PJ: Complications of combined therapy in head and neck carcinomas. Arch Otolaryngol 104:329-336. 1978.
Cancer Investigation, 10(5), 349-355 (1992)
Simultaneous Radiotherapy and Chemotherapy with Carboplatin in Inoperable Squamous Cell Carcinoma of the Head and Neck: A Phase I1 Study Nikolaos Zamboglou, M.D., Ph.D.,' Wolf Achterrath, Ph.D.,2 Thomas Schnabel, M.D.,' Luigi Lenaz, M.D.,2 Christos Kolotas, M.D.,' and Gerd Schmitt, M.D.' Department of Radiation Oncology University of Dijsseldorf Diisseldorf, Germany 2Bristol-MyersSquibb Pharmaceutical Group Princeton, New Jersey
ABSTRACT F$ty-six untreated patients with inoperable squumous cell carcinoma of the head and neck were treated with carboplatin 70 mglm2 i.v. daily on days 1-5 and 2933 in combination with simultaneous conventional radiation up to a target volume dose of 50 Gy. Depending on tumor response and upon recommendation of surgeons, 21 of 56 patients underwent surgery after a radiation dose of 50 Gy and two courses of carboplatin. Patients who showed pCR after surgery received no further radiotherapy. In all other patients radiotherapy was continued using a shrinking fietd technique up to a target absorbed dose of 70-74 Gy. Combined modality induced 66% complete remission (CR) and an overall response rate of 98%. After completion of the whole treatment program (combined modality surgery) 53 (94%) of the 56 patients were disease free. The median survival for all patients is 25+ months and the percentage of two-year survivors is 53%. Myelosuppression was the most frequent toxicity, but rarely was severe; leukopenia und thrombocytopenia of WHO grade 3 occurred in 21% of the patients. No other toxicities ubove WHO grade 2 occurred. Nephrotoxicity , neurotoxicity and ototoxicity were not seen. The addition of carboplatin did not increase the rate of surgical complication over that expected for preoperative radiotherapy. Two patients died of pulmonary embolism after surgery. Combined modality with carboplatin and
*
349 Copyright 0 1992 by Marcel Dekker, Inc.
Zamboglou et al.
350
simultaneous radiation is a highly active and well-tolerated regimen for untreated patients with inoperable squamous cell carcinoma of the head and neck.
Cancer Invest Downloaded from informahealthcare.com by Mcgill University on 11/20/14 For personal use only.
INTRODUCTION Squamous cell carcinomas of the head and neck respond well to radiotherapy when diagnosed in early stages, but show limited response if the tumor is advanced and inoperable (1). In the past years encouraging data were reported with a combined treatment using cisplatin (1-5) or cisplatin and 5-fluorouracil- (5-FU) based regimens (6- 10) and simultaneous irradiation as firstline treatment in advanced head and neck cancer. Carboplatin, a second-generation platinum analogue, has shown antitumor activity comparable to that observed with cisplatin in previous studies in patients with recurrent and metastatic head and neck tumors (1 1-17). The major difference between carboplatin and the parent compound was their spectrum of toxicities. The meta-analysis of three randomized trials comparing single-agent carboplatin and cisplatin in advanced ovarian cancer showed that carboplatin induced statistically significantly less nephrotoxicity, ototoxicity, neurotoxicity, and nausea/ vomiting than cisplatin (18). These advantages allow easy outpatient treatment. Furthermore, carboplatin has shown potentiation of the antineoplastic activity of radiation comparable to cisplatin in vitro (19,20) and in vivo (19,21). In a Phase 1 study, we had investigated the optimal dose of carboplatin in combination with simultaneous conventional irradiation in untreated patients with inoperable head and neck cancer. The combined modality induced in this Phase I study 12 (80%) complete remissions (CR) and 15 overall responses in 15 patients (3,22). Therefore, a Phase I1 study with the optimal dose of carboplatin in combination with simultaneous in-adiation was carried out in untreated patients with inoperable head and neck cancer.
PATIENT SELECTION Eligible patients had histologically proven unresectable squamous cell carcinoma of the head and neck, no prior surgery, chemo- and/or radiotherapy, WHO performance status 5 2 , age 18-75 years, no distant metastases, and life expectancy of at least 3 months. Pretreatment white blood cell counts had to be 24000/pl, platelet counts 2 lOO,OOO/pl,liver and renal functions had to be normal, technetium-diethylenetriamine-pentaacetic acid (y''''lTC-DTPA)clearance and serum electro-
lytes were at the institutional normal range. All patients gave informed consent to participate in this study.
STAGING AND FOLLOW-UP PROCEDURES Pretreatment evaluations consisted of complete medical history, physical examination, and laboratory work up with complete hemogram (differential and platelet count), serum bilirubin, serum glutamate oxcloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), creatinine, and ""'TC-DTPA clearance. The staging procedures included panendoscopy , nuclear magnetic resonance (NMR) and computer tomography (CT) of the head and neck, chest x-ray, or other tests as indicated to rule out suspected distant metastatic disease. Stage of disease was determined according to the UICC classification (23). The size of neoplastic lesions was determined in Weeks 4 and 6 after the start of carboplatin and radiation and in Week 6 after completion of radiation. Complete laboratory work up was performed before and after each cycle of carboplatin and in Week 6 after completion of radiation. 9'"'TC-DTPA-clearance was repeated in Week 6 after the start of treatment. Complete blood counts and clinical toxicities were monitored weekly during treatment. After completion of treatment, follow-up examinations were conducted every 3 months.
TREATMENT PLAN This study was designed as a nonrandomized Phase I1 study. Carboplatin was given at a dose of 70 mgim' i.v. over 30 minutes daily on Days 1-5 and 29-33, without pre- and posthydration. Each dose of carboplatin preceded the radiation by 30 minutes. Low-dose antiemetics were administered if indicated. Radiation therapy consisted of daily fractions of 2,O Gy on Days 1-5 in Weeks 1-5 and in Weeks 8 and 9 up to a total tumor dose of 70-74 Gy. Patients with progressive disease after the first course of carboplatin and a radiation dose of 30 Gy or any time thereafter were withdrawn from the protocol. Their subsequent treatment was decided on an individual basis.
Phase I1 Study of Carboplatin
Patients demonstrating clinically complete disappearance of disease and patients with resectable residual disease after combined modality were considered candidates for subsequent surgery upon recovery from myelosuppression. Patients who showed a pathological complete response after two courses of carboplatin, a radiation dose of 50 Gy, and after interposed surgery were not considered for further, radiotherapy.
TREATMENT RESPONSElTOXICITY
35 1
Table I Patients’ Characteristics
No of patients F / M ratio Median age
56 12144 57 (range 36-77)
Median WHO performance status
2 (range 0-2) (n = 5 ) (n = 22) ( n = 29)
0
I 2
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Stage o j disease
Patients were considered evaluable for response and toxicity if they had received at last one cycle of carboplatin and a radiation dose of 30 Gy. Clinical (c) tumor response was classified according to WHO criteria (24). Pathologic (p) response was defined as follows: pCR was absence of disease, pPR was presence of microscopic and macroscopic residual tumor in the resection material. Response analysis was carried out by two independent investigators:one radio-oncologist and one head and neck surgeon. Toxicity was evaluated by worst event for each organ system using the WHO scale (24). Median diseasefree survival and median survival time were calculated by the Kaplan-Meier method (25). Survival was calculated from the first day of treatment.
RESULTS
T2 T3 T4
NO 1
NI
1
5 4
3
1
N2a I 3 2
N2b
N2c
N3
4 3
6 8
10
4
Tumor sites
Oral cavity Oropharynx Hypopharynx Epipharynx Larynx Oral cavity / oropharynx Oropharynx / hypopharynx Oropharynx / epipharynx Hypopharynxl larynx Oral cavity/oropharynx/epipharynx Oral cavityloropharynxl hypopharynx Oral cavity / epipharynx / oropharynx
(n = 17) (n = 5 ) (n = 5 ) (n = 1) (n = 2) (n = 13) (n = 5) (n = 2) (n = 2) (n = I ) (n = 2) (n = 1)
Dijjerentiation
A total of 56 patients entered the study. All patients had received two courses of carboplatin and a total radiation dose of 50-74 Gy and were evaluable for response and toxicity. Their clinical characteristics and the anatomical sites of disease are summarized in Table 1.
Response Rates, Response Duration, and Survival After two cycles of carboplatin and a radiation dose of 50 Gy, 13 (23%) cCR, 42 (75%) cPR, and one no change (NC) were achieved in 56 patients. Between Weeks 4 and 6 after completing a radiation dose of 50 Gy, 2 I patients (13 cCR and 8 cPR) underwent surgery as determined by the surgeons. Surgery involved radical neck dissection in I2 patients and suprahyoidal dissection in 9 patients. In 7 (54%) of the 13 patients with cCR, the CRs were pathologically confirmed (pCR). In 6 (46%) patients microscopic residual disease was found in the resection material and they were classified as pPR. In the 8 patients with cPR the tumor had been downstaged to operable disease. After surgery, all 8 patients were
Well Moderate Poor
(n (n (n
= =
2) 44)
= 10)
disease free but macroscopic residual disease was found in their resection material and therefore they were classified as pathologic partial responders (pPR). Severe complications following surgery were wound healing impairment in 8 of 12 patients with radical neck dissection and in 3 of 9 patients with suprahyoidal dissection. Out of 12 patients with radical neck dissection, 2 died of lung embolism. In the other 35 patients (34 PR/I NC), the tumor remained inoperable and irradiation was continued up to total target dose of 70-74 Gy. In 24 (71%) of 34 patients, the PRs were converted into cCRs, while 10 patients remained in PR and one patient in the NC status. Eight of these 10 partial responders underwent salvage surgery. The residual tumor was removed, resulting in a no evidence of disease (NED) status. The resection material of 3 patients was disease
Zarnboglou et al.
352 Table 2
Table 3
Clinical Response by Stage of DiJeuse According to TNM Clussificution
Ciinicd Response by Stiige of Lymph Node Involvement in Stcrgr T4
CR
NO
3
3
3
NI
4
3
4
N2a
2
I
2
N2b
3
2
3
N2c
8
4
8
,'95% Confidence limits.
N3
10
5
10
free (residual fibrosis); the 5 other patients had residual tumor. The patients with residual fibrosis were classified as pathologic complete responders, the other patients as pathologic partial responders. Severe complications following limited surgery were not seen. The summarized results showed that 37 (66%) cCR, 55 (98%) overall responses, and one NC were achieved in 56 patients after two cycles of carboplatin and a total radiation dose of 50-74 Gy (95% confidence limits for CR 53-79% and CR PR 94-102%). A total of 29 patients with objective responses after combined modality underwent surgery. Ten (35%) pCR and 19 (65%) pPR were seen. Clinical response by stage of disease and responses in stage T4 depending on lymph node involvement are shown in Tables 2 and 3. The CR rate was
slightly higher for stage T3 NO-3 (70%) than for stage T4 NO-3 (60%). After completion of the whole treatment program (carboplatin + simultaneous radiation t surgery) 53 (95%) of 56 patients were disease free (CR or NED). Survival was calculated for all 56 patients after a follow-up period ranging from 18 to 37 months (median 25 months). Of 56 patients 26 (46%) were free of disease on last clinical examination. The estimated median survival for all patients is 25 months, the median disease-free survival is 18 months (Fig. 1). The actuarial one- and two-year survival rates are 82% and 53% respectively. The estimated disease-free survival rate for one year is 64%, for two years 50%.
~~
CR N(%)"
CR -t PR N(%)"
~
T2 NO-3
3
3
3
T3 NO-3
23
16 (70%)
22 (95%)
(51-89%) T4 NO-3
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+ PR
No. of patients
No. of patients
Stage
30
18 (60%) (42-78%)
30 ( 100%)
+
Stage
CR
+
survival probability (YO)
100 80
~
............. -
.............. ....... ............... ........
1
t
...... ........
....................
60 -
I
........ 1 ............ ........................................
L ..............
40 20 -
0
I 0
1 2 3
'
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
4 5 6
months
Figure 1 Overall survival -(
)
and disease-free survival (. ...........) for all patients entered into the study.
Phase I1 Study of Carboplatin
353
Table 4 Worst Toxicities Reported According to WHO Scale WHO grade No, of patients (%)
0
1
2
3
4
Leukopenia
21 (38%)
16 128%)
8 (14%)
9 (16%)
2 (4%)
Thrombocytopenia
34 (61%)
8 (14%)
7 (12%)
4 (8%)
3 (5%)
Nausealvomiting
50 (89%)
3 (5%)
3 (5%)
0
0
0
2 (4%)
42 (75%)
1 1 (21%)
0
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Stomatitis
Relapse
Toxicity
Thirty patients (54%)developed recurrent tumors following response. Twenty seven patients had locoregional relapse including 9 isolated lymph node recurrences. Three patients developed pulmonary metastases without any evidence of local recurrence. Twenty four of the 26 patients who died had only local disease, three of them suffering from a second tumor, and it is uncertain whether this second cancer was the cause of death. Two out of three patients with pulmonary metastases died.
The worst toxicities related to combined modality according to WHO criteria are outlined in Table 4. Myelosuppression was the major side effect (Table 4). Leukopenia of grade 3 and 4 occurred in 16% and 4%, thrombocytopenia of these degrees in 8% and 5% of the patients, respectively. The degrees of hematologic toxicity were comparable after the first and second cycle of carboplatin (Table 5). Nadirs of leukocytes and thrombocytes were observed between days 19 and 26 with
Table 5 Phase 11 Studies with Carboplatin, Cisplatin, or Cisplatinl.5-FU-based Regimens in Combination with Simultaneous Radiation in Inoperable Head and Neck Cancer Survivors Radiation No. of No. of CR CR PR after months Reference Chemotherapy dose Gy patients studies N% N% 12/24
+
Cisplatin
60-74
309
5
202 ( 6 5 % )
(60-70%)
259 (84%) (80-88%)
60-80155-60
1-5
6-8
Cisplatin15-Fu
60-72
I05
3
61 (58%) (48-68%)
100%
ne 75/ne 60
Cisplatin15-Fu
70
59
I
48 (81%)
59 (100%)
72/52
9
43 (100%)
ne155
10
55 (98%) (94-102%)
82/53
Own data
Folinic acid Cisplatinl5-Ful
(7 1-91 %) 60
43
I
Vindesine Carboplatin 'Results of two studies.
33 (77%) (64-90%)
50-74
56
1
37 (66%) (53-79%)
Zamboglou et at.
354
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recovery between days 23 and 28. Stomatitis of grade 3 was observed in 21% of patients. Even though no prophylactic antiemetics were given, vomiting of grade 2 occurred in only 5% of the patients, vomiting of grade 3/4 was not seen. These results confirm the observation that the frequency of carboplatininduced vomiting decreases significantly when a daily schedule of 5 days is adapted, as opposed to single intermittent bolus (26). No nephrotoxicity, measured by laboratory tests and 99"TC-DTPAclearance, and no neurotoxicity or ototoxicity occurred. Taste impairment and dry mouth were observed in 87% and 85% of patients, respectively.
DISCUSSION One area of current investigation in inoperable advanced squamous cell carcinoma of the head and neck is the design of more active and less toxic treatment strategies with the aim to improve the cure rate and the quality of life of patients. Earlier studies with cisplatin or cisplatin/5-FU-based regimens and simultaneous radiation had shown that these combined modalities are highly active as first-line treatment in inoperable head and neck cancer (1-10). The combined modalities induced 55-8 1Yo CR and more than 90% overall responses ( I -10). The median survival time is 24 to 48 + months and the percentage of two-year survivors is 50-60% ( I ,3,6,9,10): These data suggest that the combined modality approach leads to an increase of median survival and the percentage of two-year survivors by approximately 20% compared with radiation alone (1,3,6,9, 10,27). Treatment with cisplatin and cisplatin/5-FU in combination with simultaneous radiation is limited by vomiting and nephrotoxicity, induced mainly by cisplatin ( I ,2,6,7). In order to develop a treatment of similar activity but less toxicity, several Phase I studies with carboplatin and simultaneous radiation were carried out in patients with advanced squamous cell carcinoma of the head and neck (3,22,28-31), resulting in CR and overall response rates comparable to cisplatin and cisplatin/5FU-based regimens with simultaneous radiation (3,69,27). In our study, carboplatin and simultaneous radiation were administered at a dose schedule that can routinely be given to previously untreated patients with head and neck cancer in an outpatient setting. In the present Phase 11 study, carboplatin in combination with conventional simultaneous radiation induced 66%CR and 98% overall responses. The median survival
+
time for all patients is 25 months and the rate of oneand two-year survivors is 82% and 53%, respectively. These results are remarkable considering 46% of patients had two or more tumor sites. The first-line treatment with carboplatin and simultaneous radiation in inoperable head and neck cancer leads to CR, overall response rates and a percentage of one or two years survivors comparable to cisplatin or cisplatin/5-FU 2 folinic acid and cisplatin/5-FU/vindesine (1-10) (Table 5 ) . Carboplatin induced in combination with simultaneous radiation in the administered dose schedule, less or similar hematologic toxicities as compared with cisplatin and cisplatin/5-FU-based regimens (1,2,6,7,9). The nonhematologic organ toxicities, especially nephrotoxicity, vomiting, and stomatitis of WHO grade 3 were significantly less frequent after combined modality with carboplatin. Nephrotoxicity occurred in more than 30% of patients treated with cisplatinbased regimens (1,6,7), whereas no nephrotoxicity was observed in our study. The incidence of vomiting and stomatitis of WHO grade 3 is >22% and 31-50%, respectively, after treatment with cisplatin and cisplatin/5-FU-based regimens (1,6,7,9). No vomiting of WHO grade 3, and only 21% stomatitis of WHO grade 3 subjects were observed after carboplatin and simultaneous radiation. Preoperative radiotherapy with 50 Gy retards healing of pharyngeal and cutaneous suture lines and results in a high incidence of complications (32). In our experience, the addition of carboplatin to radiotherapy did not increase the incidence of postoperative complications, which was higher in patients receiving radical surgery than after limited resection. In conclusion, carboplatin with simultaneous radiation in patients with inoperable head and neck cancer resulted in antineoplastic activity comparable to cisplatin and cisplatin/5-FU-based combined modalities, but it induced fewer nonhematologic toxicities. The encouraging results of our study warrant the comparison of the efficacy of this treatment with conventional treatment strategies in prospective randomized studies. Address reprints requests to Nikolaos Zamboglou, M.D., Ph.D., Department of Radiation Oncology, University of Diisseldorf, Moorenstrasse 5, W-4000 Diisseldorf I Germany.
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Al-Sarraf M, PajakTF, Marcia1 VA et al: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. Cancer 59:259-265, 1987.
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