Induction Chemotherapy in Advanced Head and Neck Cancer

Auris'Nasus'Larynx (Tokyo) 21,186-192 (1994)

Induction Chemotherapy in Advanced Head and Neck Cancer Mamoru TSUKUDA, M.D., Izumi MOCHIMATSU, M.D., Toshiyuki KOKATSU, M.D., Shigeru FURUKAWA, M.D., Seiichiro YUYAMA, M.D., Hiroyuki ENOMOTO, M.D., and Akira KUBOTA, M.D.* Department of Otorhinolaryngology, Yokohama City University School of Medicine, Kanagawa, Japan; and Department of Head and Neck Surgery, Kanagawa Cancer Center, Kanagawa, Japan

*

Induction chemotherapy, followed by definitive treatment, was performed in patients with advanced squamous-cell carcinoma of the head and neck. In this study, carried out between 1984 and 1991, testing the effectiveness of multimodality therapy in patients with previously untreated advanced (stage III and IV) squamous-cell carcinoma of the pharynx, patients received two different induction chemotherapy regimens: cisplatin, vincristine (Oncovin) plus peplomycin (COP), and cisplatin plus continuous 120-hr 5-fluorouracil (5-FU) infusion (CF) for two courses. Overall response rates (complete response plus partial response) to each of the two induction chemotherapy regimens were high: 76 and 82%, respectively. Superior complete response rate in the group receiving CF therapy was 16% versus 10% for COP therapy. Responders to induction chemotherapy had significantly better survival compared with nonresponders. The toxicity of these two regimens was tolerable and manageable. It is indispensable to develop the more efficacious chemotherapy regimen with the potential to induce complete disappearance of tumors in patients with advanced head and neck carcinomas. The prognosis of patients with advanced squamous-cell carcinomas of the head and neck still remains poor. Despite many advances in surgery and radiation therapy, these two modalities unfortunately do not contribute to complete tumor control for advanced stage III and IV squamous-cell carcinomas. With this mind, numerous investigators have used induction chemotherapy before conventional therapy in an attempt to down-stage the tumor, improve local therapy, and prolong survival. Higher response rates have been reported in previously untreated head and neck carcinomas, primarily utilizing regimens that contain cisplatin in combination with other agents. 1-5 Recent reports have emphasized the potential benefit of cisplatin based chemotherapy for the treatment of advanced head and neck cancer in response rates and overall survival. 6 This study was undertaken to establish the feasibility and to confirm the effectiveness of induction chemotherapy using cisplatin-based chemotherapy before definitive therapy in two institutes in Japan. PATIENTS AND METHODS

Patients. Between January 1984 and December 1991, 36 nasopharyngeal, 41 oropharyngeal, and 37 hypopharyngeal squamous cell carcinoma cases were considered eligible and were submitted to this trial, as shown in Table 1. These patients had stage III or IV tumors with no clinical or radiographic evidence of metastases beyond the regional lymph node (Mo). The Received 3 December 1993; accepted 16 May 1994. Correspondence should be addressed to: Mamoru Tsukuda, Department of Otorhinolaryngology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236 Japan. 186 Auris'Nasus'Larynx (Tokyo) Vol. 21 (1994)

Table 1. Patient characteristics. Primary site No. of patients Median age (range) Sex (male/female) Performance status 0

2

Histological grading Well differentiated Moderately differentiated Poorly differentiated Stage III IV

Nasopharynx

Mesopharynx

Hypopharynx

36 51 (16-73) 29/7

41 58 (30-72) 34/7

37 63 (45-71) 34/3

24 9 3

27 11 3

22 11 4

4" lOb 22C

5 24 12

22 5

4 32

31

10

10

9 28

A pathological finding of nasopharyngeal carcinoma was classified according to the recommendations of the World Health Organization. "keratinizing, b non-keratinizing, undifferentiated. C

stage distribution was determined according to VICC classification (1987). All patients were previously untreated and had a performance status of 0, 1, and 2 [World Health Organization (WHO) criteria]. All patients were initially treated with two cycles of induction chemotherapy consisting of two regimens followed by definitive treatments. Chemotherapy. Two chemotherapy regimens were used in this study. The first regimen consisted of two cycles of vincristine 1 mg/m 2 iv on day 1 and cisplatin 60 mg/m 2 iv on day 2, followed by peplomycin,1 a derivative of bleomycin, 5 mg/m2/day im from day 3 to 7 (COP therapy). Between January 1984 and December 1987, 12 cases of nasopharyx (NPC), 16 of mesopharyx (MPC), and 13 of hypopharyx (HPC) were treated with this chemotherapy. The second regimen started in January 1988. This regimen consisted of two cycles of cisplatin 60 mg/m 2 iv on day 1, followed by a 120-hr continuous infusion of 5-fluorouracil (5-FV) 1,000 mg/m2/day (CF therapy). Twenty-four cases of NPC, 25 of MPC, and 24 of HPC were treated with this modality. These chemotherapy courses were repeated every 3 weeks. Dose reduction due to toxicity was not needed. Toxicity was evaluated by physical signs and laboratory data. The response to chemotherapy was assessed 4 weeks after completion of the second course of chemotherapy. Patients were considered to have complete response (CR), if there was no evidence of disease at their primary sites or regional lymph nodes. Those having a partial response (PR) had a 50% or greater shrinkage of tumors. No change (NC) was less than 50% decrease in clinical size of locoregional tumors. Progressive disease (PD) was greater than 25 % increase of tumors at their primary sites or regional lymph nodes and/or the appearance of new lesions. Definitive therapy. In nasopharyngeal and oropharyngeal carcinoma cases after two courses of induction chemotherapy, a definitive treatment was radiation which was delivered in daily fractions of 1.8 to 2 Gy. Total doses ranged from 64 to 70 Gy. Patients with hypopharyngeal carcinoma after induction chemotherapy were treated with surgery of pharyngo-laryngo-cervical esophagestomy, radical neck dissection in disease site, and modified neck dissection in opposite site, followed by 50 Gy postoperative radiation. However, 6 of 37 cases in HPC refused surgical treatment, and curative irradiation of 70 Gy in 35 fractions was performed in these 6 cases after induction chemotherapy. Auris'Nasus'Larynx (Tokyo) Vol. 21 (1994)

187

Statistical methods. Survival data was calculated from the first day of treatment in the study until death and estimated as described by Kaplan-Meier survival plots8 that were analyzed by the generalized Wilcoxon method. 9 RESULTS

Response rate The response rates to each of the two regimens were high and similar between COP and CF, 76 and 82%, respectively (Table 2) . CR rate in CF therapy was superior to that of COP one (16% vs 10%), whereas these response rates were not significantly different by the chi-square test. There was no statistically significant difference in response rate to induction chemotherapy between stage III and IV cancer (78% vs 80%) (Table 3). The response rate in histological differences was also analyzed, but a significant difference was not detected in this study (data not shown) . Toxicity Toxicities encountered during induction chemotherapy are summarized in Table 4. The grades of all toxicities were grade 1 or 2, scored according to the WHO criteria. Pulmonary toxicity as well as rash and fever were encountered in COP group patients who received peplomycin. Pulmonary toxicity (grade 1 in all cases) in the COP group was reversible. Renal impairment in six cases of grade 1 and four cases of grade 2 in this study was encountered and was associated with the cisplatin component of each regimen. Renal toxicity was reversible in all patients with hydration. Nausea and vomiting were common in both groups. Myelosuppression was more frequent in the CF group, which received the high dose of 5-FU chemotherapy. Survival data Minimum follow-up time is 5.0 months and median follow-up time is 40.1 months for the entire patient population. Thirty-six-month and 60-month survival rates were compared between the two regimens (Fig. 1). There was no significant difference between groups who received COP therapy and those treated with CF therapy. Those achieving a CR or a PR after induction chemotherapy had significantly improved survival figures compared with patients in NC and PD at 60 months (CR, PR vs NC plus PD: Table 2. Response rate to different regimens. Regimen COP CF

No. of patients

41 73

Response

Response rate (%)

Complete response rate ( % )

CR

PR

NC

PD

CR + PR/total

CR/total

4 12

27 48

8

2 0

76 82

10

13

16

COP: cisplatin. vincristine (Oncovin). peplomycin; CF: cisplatin. 5-ftuorouracil. Table 3. Stage

III IV

Response rate in stage III and stage IV. No. of patients

23 91

Response CR

PR

NC

4 12

14 61

4 17

188 Auris ·Nasus·Larynx (Tokyo) v ol. 21 (1994)

PD

Response rate (%)

Complete response rate ( % )

CR + PR/total

CR/total

78 80

17 13

Table 4.

Incidence of toxicity to chemotherapy. COP (41 cases) Leukopenia Thrombocytopenia Nausea/vomiting Diarrhea Stomatitis Renal Rash Fever Alopecia Pulmonary Phlebitis Hearing impairment

3 1 39

CF (73 cases) 17

3 4

2 70 4 23 6

6

3

14 6 2

16 2

3

COP: cisplatin, vincristine (Oncovin), pep10mycin; CF: cisplatin, S-fluorouracil.

~

,

.~

~

"0

&'

CF(n~73)

.D

COP(n~4I)

:cc

a. cG 0

40

U

~ a. 20

'--"""!""-:-:--C::--::-:-.....,.,.--::-:--;O:-:-:--::':"---:!60 12 18 24 30 36 42 48 54

Fig. 1. Probability of survival in months according to the type of induction chemotherapy given in patients with pharyngeal carcinoma. There was no significant difference in the survival rate at 36 and 60 months between the two regimens.

months

CR(n~16)

"0 60

PR(n~75)

'"

:cc .g 40

.

a. c ,r~

20 NC+PD(n~23)

L-......-1..,.2-1..,.8-2~4-3O~...,36",.--4,.,.2-48..,.-...,5,.,.4--=60

Fig. 2. Probability of survival in months according to response to induction chemotherapy in patients with pharyngeal carcinoma. There was a significant difference at 36 and 60 months in CR vs NC plus PD (p <0.001), and PR vs NC plus PD (p<0.001), but no significant difference in CR vs PRo

months

67%, 60% vs 10%) (p < 0.(01). However, there was no significant difference between CR and PR cases at 36 and 60 months. DISCUSSION

In patients with locally advanced head and neck squamous-cell carcinomas, the combination therapy of surgery, and radiation has been applied to improve the poor prognosis. UnfortunateAuris'Nasus'Larynx (Tokyo) Vol. 21 (1994)

189

ly, the overall survival of this group of patients continues to be disappointing. The concept of a multimodality approach using cisplatin-based induction chemotherapy before definitive therapy is gaining wider use in the management of these patients. Cisplatin-based induction chemotherapy before definitive surgery and/or radiation has produced significant tumor regression in patients with locally advanced tumors and complete regression. I-6 These dramatic responses to chemotherapy have led to the expectation that induction chemotherapy is effective in improving survival rates in head and neck cancer patients. It was reported that patients achieving complete response (CR) after induction chemotherapy had an improved survival rate as compared with those with residual disease,IO-16 however, it is unclear whether this chemotherapy can improve long-term control and survival of patients with less than partial response or not. 17-20 Between 1984 and 1991, we applied two cisplatin-based regimens into previously untreated (stage III and IV) squamous-cell carcinomas of the pharynx. The response to chemotherapy and the efficacy of induction chemotherapy on survival of these advanced cancer cases were studied. At the beginning of the application of induction chemotherapy in our two institutes, we used the combined chemotherapy of cisplatin, vincristine (Oncovin), and peplomycin (COP therapy). COP therapy was a modified regimen of COB therapy (cisplatin, vincristine plus bleomycin) using peplomycin instead of bleomycin by Amer et aLI From 1988, as an induction chemotherapy, we started to use the combined therapy of cisplatin and 5-FU (CF therapy) which had shown good responsiveness in head and neck carcinomas. 2.4.5 The response rates of the two regimens in previously untreated pharyngeal carcinomas were almost the same in this study. This result was similar to Rooney's report lO in which the response rates of different regimens were similarly high in patients with advanced stage after two courses of COB or CF therapy. Similarly, Ensley et aF I reported that the overall response rate to two courses of COB or CF therapy was not significantly different. Several studies have established that the type of chemotherapy regimen used and the number of courses strongly influenced the response to cisplatin-based induction chemotherapy. 10.21 With regard to the number of courses, there was a negative study22 in which patients who failed to demonstrate any response after two courses of chemotherapy did not respond after a third course. We, too, observed this phenomenon. There was no significant difference between stage III and IV groups in response rate and in complete response rate to chemotherapy. In some studies, the overall disease stage was not found to be a significant factor for response to induction chemotherapy.17.23 On the contrary, other authors have reported that the disease stage was predictive of the overall response. 15. 24 There was no significant difference among histological grading of squamous-cell carcinoma (data not shown). Some results have described on a positive relationship between histological differentiation and response rate. 21 .25 In our study, 36-month and 60-month survival rates according to the type of induction chemotherapy were similar. This result supports another studylO in which the survival rates between COB and CF therapy were similar. The importance of response to chemotherapy was seen in our analysis. A complete response to chemotherapy would seem to be one of the factors that correlates with prolonged disease control. 6.10.12-16.26.27 Induction chemotherapy may be beneficial for patients who achieve complete response after chemotherapy. However, whether the outcome of patients with advanced head and neck cancer who achieve anything less than a PR could be improved or not, has not been clarified. Hill et al 17 reported that response to their chemotherapy protocol and survival correlated with tumor site, with particular benefit for oral cavity, mesopharyngeal, and nasopharyngeal carcinomas, but they found no correlation with hypopharyngeal carcinomas. On the other hand, Dimery et aP8 reported that there was no statistical difference in overall survival rates in 190 Auris'Nasus'Larynx (Tokyo) Vol. 21 (1994)

advanced stage nasopharyngeal carcinoma patients treated with radiation alone or combination chemotherapy and sequential radiation therapy, due to a similar incidence in the occurrence of distant metastasis. Toohill et al 2s described that high response rates to CF therapy did not result in improved survival for advanced head and neck cancer patients in a prospective, randomized trial. Schuller et al 29 demonstrated that in a prospective, randomized trial to evaluate whether induction chemotherapy could improve survival in patients with advanced stage resectable squamous-cell carcinomas, there was no benefit in survival using preoperative chemotherapy. Also, Jacobs et aP9 randomized 462 patients with advanced head and neck cancer to standard therapy, induction chemotherapy (cisplatin and bleomycin) plus standard therapy and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. There was no significant difference in the survival rate and disease-free survival rate between standard therapy and induction chemotherapy followed by standard therapy, whereas the addition of maintenance chemotherapy was advantageous. Furthermore, Jacobs et al 30 conducted a non-randomized pilot study using chemotherapy consisting of three courses of cisplatin and 5-FU infusion for advanced resectable head and neck carcinoma. Chemotherapy was administered prior to surgery in 42 patients (induction) and after surgery in an additional 29 patients (sequential). Five-year survival rates between these two groups were not significantly different (27% for the induction group vs 23% for the sequential group). Vokes et al 20 presented long-term outcome data on a series of 51 prospectively evaluated patients with locally advanced head and neck cancer treated with cisplatin and 5-FU as induction chemotherapy. Despite the high response rates achieved with CF induction chemotherapy (overall response rate of 90% with a CR rate of 43%), the overall survival rate was poor, because of only a pathologial CR of 24% in a clinical CR of 43%. They emphasized new regimens with a particularly higher histological CR rate should be investigated. We agree with this concept. Studies at our own institute have been focusing on the identification of new chemotherapeutic regimens. 3l REFERENCES

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