- Email: [email protected]
Surgery plus radiation versus neoadjuvant chemotherapy plus radiation in resectable locally advanced laryngeal carcinoma
International Congress Series 1240 (2003) 1023 – 1033
Surgery plus radiation versus neoadjuvant chemotherapy plus radiation in resectable locally advanced laryngeal carcinoma Mahmoud E. El Samaa a, Nivine M.A. Gado b,*, Ahmed Adly Mohamed a, Samer Ahmed Ibrahim a b
a ENT Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Radiation Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, 4 Abaddas St. from Misr and Sudan St. El Dahr, P.O. Box 11271, Cairo, Egypt
Abstract Aim: Locally advanced (stage III and IV) resectable laryngeal carcinoma is treated with both standard treatment (surgery + postoperative radiotherapy) and induction chemotherapy followed by radiotherapy (in responders) or surgery (in nonresponders), then results are compared. Patients and Methods: Eighty patients were randomized in this study; 40 of these patients were assigned to chemotherapy and another 40 patients to the standard surgical line. In the chemotherapy group, three cycles of cisplatin + fluorouracil were given. Clinical tumor response was evaluated after two cycles of chemotherapy, and patients with complete or partial response received a third cycle of chemotherapy followed by 6500 – 7400 cGy in 7 weeks. Patients with no response to chemotherapy, or who are recurrent after chemotherapy and radiotherapy, underwent salvage laryngectomy. Results: After two cycles of chemotherapy, a complete clinical response in the primary tumor was attained in 35% of patients, and a partial clinical response in the primary tumor in 57%. The 2-year survival rate was 69% for the surgery group and 68% for the chemotherapy group. The larynx was preserved in 65% of patients. Conclusion: Induction chemotherapy followed by radiotherapy can be effective in preserving the larynx in a high percentage of stage III and IV resectable laryngeal carcinoma patients without compromising overall survival. D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. Keywords: Laryngeal carcinoma; Tumor; Radiation
* Corresponding author. Tel.: +20-24828206. E-mail address: [email protected] (N.M.A. Gado). 0531-5131/ D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. doi:10.1016/S0531-5131(03)01054-9
1024
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1. Introduction Laryngeal carcinoma accounts for 3– 5% of all cancers. Patients who present with locally advanced disease (stage III and IV) have a poor prognosis with conventional treatment that consists of total laryngectomy or a combination of laryngectomy and postoperative radiotherapy. At least 50% of patients will recur, usually within the first 2 years and overall 5-year survival rates range from 10% to 50% depending on site and stage of disease. In this study, induction chemotherapy or neoadjuvant chemotherapy is given before surgery (in nonresponders) or before radiotherapy (in complete and partial responders) to improve tumor response, and preserve the larynx, so improving the quality of life of patients [1].
2. Methods 2.1. Eligibility of patients All patients had biopsy-proven, previously untreated, resectable (stage III or IV) squamous cell carcinoma of the larynx, according to the American Joint Committee on Cancer. All patients were men ranging in age from 46 to 74 (median 59). Patients were required to have a pretreatment leucocyte count z 4.000/mm3, platelet count z 100,000/mm3, S. creatinine z 1.5 mg/dl, creatinine clearance z 60 ml/min, and Karnofsky performance status of >50. Each patient gave written informed consent. Prior to each cycle, patients had a physical examination, complete blood counts, liver and renal function tests. Eligible patients were randomly assigned to one of two treatment groups. 2.2. Treatment methods 2.2.1. Chemotherapy After overnight hydration with 2 l of 5% dextrose/0.5 normal saline (NS) supplemented with 10 mEq KCl/l, the patients received a bolus of 12.5 g of mannitol, followed by cisplatin (100 mg/m2) on day 1, mixed in 200 ml of NS and administered over 20 min. This was followed by a 4-h infusion of an additional 1 l of 5% dextrose/0.5 NS to which 10 mEq of KCl and 25 g of mannitol had been added. 5 Fluorouracil (5FU) 500 mg/m2/12 h for 5 days mixed in 2 l 5% dextrose/NS followed. Potassium chloride 80 mg and magnesium sulfate 8 mEq were added to the infusate daily. Chemotherapy was repeated on days 1, 22, and 43. Dose modifications for toxicity were based on nadir laboratory data and clinical evaluation. Cisplatin was reduced to 80 mg/m2 if serum creatinine reached 2 –4 mg/m2. No further cisplatin was administered if serum creatinine increased to 4 mg/m2. The dose of 5FU was reduced by 25% for a nadir TLC less than 2000/mm3 and/or platelet count less than 75.000/mm3 and/or grade 3 or 4 mucositis or diarrhea. The initial tumor response was performed after two courses of chemotherapy through indirect laryngoscopy. Response was described separately for the primary tumor site and
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1025
the cervical nodes. A complete response was defined as the complete disappearance of all clinically evident tumor. A partial response was defined as a 50% reduction in the sum of the product of the longest dimension and its perpendicular for each tumor, as compared with the initial tumor dimensions. Patients who failed to achieve at least partial response received no further chemotherapy and underwent immediate surgical resection. Other patients received a third course of chemotherapy, although responding patients who had significant toxicity or who refused a third course of chemotherapy began radiation therapy. A second response evaluation was performed after completion of all chemotherapy, and included endoscopy under anaesthesia with a biopsy of the primary tumor site. 2.2.2. Radiation therapy All patients received radiation therapy, either after chemotherapy or postoperatively. Definitive radiation therapy consisted of 6500– 7400 cGy in 7 weeks. Both the primary site of disease and neck nodes were treated. Radiation was administered with a Co-60 machine operating at 80 cm SSD via opposed lateral portals. Supplemental anterior lower neck portal, calculated at a depth of 3 cm, also was used in all patients. A daily radiation dose of 200 cGy was used, five times per week, with all fields treated daily. The spinal cord was protected at 4500 cGy. Patients irradiated postoperatively received 5500 cGy to the primary site if the surgical margins were free of tumor. Patients with involved surgical margin received 6600 cGy in 6.5 –7 weeks. Two opposed lateral portal and anterior lower neck portal also were used for these patients postoperatively. 2.2.3. Surgery Initial salvage surgery: total laryngectomy was done after second course of chemotherapy to nonresponders and after third course of therapy to patients showing progression of the tumor, as well as after end of radiotherapy by 12 weeks, if persistent tumor was proved. Late salvage surgery was done if tumor recurred where most of late salvage laryngectomy took place within first year of therapy. 2.2.4. Statistical analysis The statistical analyses of patients’ survival and disease-free intervals were based on a comparison of Kaplan Meier curves by the log-rank test. Survival and disease-free intervals were measured from the date of randomization, with a disease-free interval of 0 assigned to patients who were never rendered disease-free. All randomized patients were included in the analysis. Local control was defined as those patients free of recurrence at the primary site for a minimum of 24 months. 3. Results 3.1. Patient population Between August 1999 and August 2001, 80 consecutive patients entered trial. Forty patients received chemotherapy as a primary treatment and another forty patients received
1026
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
the standard therapy (surgery and radiotherapy). The mean age was 59 years with a range of 46 –74 years. All the patients were men. Fourteen patients had stage III and twenty-six patients had stage IV in the chemotherapy arm. Eighteen patients in the surgery arm were stage III and twenty-two were stage IV. The histologic differentiation was described as well differentiated in 14 patients, moderately differentiated in 22, and poorly differentiated in 4 patients in the chemotherapy arm. In the surgery arm, 16 patients were well differentiated, 19 were moderately differentiated and 5 were poorly differentiated as shown in Table 1. There were no significant differences between the two arms with respect to age, sex, T class, N class, stage, tumor site, grade, cartilage invasion, fixation of vocal cords, performance status (Table 1). All patients were cigarette smokers and 40% consumed alcohol and hashish. 3.2. Response to induction chemotherapy Of the 40 assessable patients, 37 (92.5%) responded to two courses of chemotherapy, including 14 (35%) with complete disappearance of all measurable tumor and 23 (57.5%) with partial disappearance of measurable tumor. Three patients (7.5%) who failed to have at least a partial response at their primary tumor site were referred for standard therapy (surgical resection). Table 1 Patients’ characteristics according to treatment Patient characteristics
No. of patients Stage III T2N1 T3N0 T3N1 Stage IV T2N2 T2N3 T3N2 T4N0 T4N1 T4N2 T4N3 Site Glottic Supraglottic Cartilage invasion Fixed V.C. Performance status (Karnofsky score) < 80 z 80
Treatment Surgery
Chemotherapy
All
40 18 5 6 7 22 4 5 5 1 2 3 2
40 14 4 5 5 26 6 7 7 1 2 2 1
80 36
10 30 4 21
11 29 5 24
25 55 9 45
5 35
4 36
9 71
44
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1027
Although 40 patients were supposed to receive the third course of chemotherapy, only 34 patients actually received the third course. One was not assessable for response, one was leucopenic so that he no longer fit the criteria for treatment, one refused further chemotherapy because of side effects that were intolerable to him, and three showed no response to a third course of chemotherapy. Fourteen patients (41.2%) had a complete response at both the primary tumor site and cervical nodes. Sixteen patients (47%) had complete disappearance of the tumor and thirty-one patients (91%) had overall response (complete and partial response) after three courses of chemotherapy. The chemotherapy responses are listed in Table 2. There was one patient who started radiotherapy without a third course of chemotherapy as he refused chemotherapy when the side effects became intolerable to him. After the third course of chemotherapy, endoscopy and biopsy was done to ensure pathological response. Histologically confirmed complete tumor response occurred in 14 (87.5%) of the 16 patients who had a clinical complete response. The overall rate of histologically confirmed complete responses was 65%. 3.3. Chemotherapy toxicity Three patients had transient increases in the serum creatinine level (2– 4 mg/dl) and received a reduced dose of cisplatin (80 mg/m2) in subsequent courses. Nine patients had mild renal impairment with a maximum serum creatinine level of 2.0 mg/dl, which corrected with fluid hydration and required no modification of cisplatin dose. No patient had electrolyte imbalance, and there was no peripheral neuropathy recorded. As regards the haematological toxicity, two patients had grades 1– 2 myelosuppression (WBCs >2000 – < 3000 Ul). Six patients had grades 1 – 2 mucositis (patchy). Gastrointestinal toxicity presented as nausea, vomiting, and diarrhea developed in 10 patients. Six patients had grades 1– 2 gastrointestinal toxicity (occasional vomiting), < 4
Table 2 Response evaluation after two and three courses Response
Primary tumor
Nodes
Overall
No.
%
No.
%
No.
%
After two courses Complete Partial None
14 23 3
35 57.5 7.5
4 12 8
41.2 35.3 23.5
14 21 5
35 52.5 12.5
After three courses Complete Partial None
16 15 3
47.1 44.1 8.8
15 9 6
50 30 20
14 19 1
41.2 55.9 2.9
1028
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
bowel movements (BM/day), while the other four had grade 3 toxicity (3 –4 emesis/day, >4BM/day) (see Table 3). 3.4. Radiation and surgical toxicity complications The frequency and severity of toxic effects due to radiation therapy were similar in both treatment groups (surgery and chemotherapy groups) with respect to skin reaction, anemia, and dehydration. The rate of grade 2 mucositis (patchy membranous mucositis and severe laryngitis) was slightly higher in the chemotherapy group; six patients (15%) than in the surgery group with four patients (10%). Overall, the frequency and types of surgical complications were similar between the treatment groups. However, the incidence of surgical complications tended to be higher for salvage surgery performed after radiation than salvage surgery after chemotherapy alone. 3.5. Overall survival Two patients (2.5%) died during treatment (one in the chemotherapy group due to unrelated causes and one in the surgery group due to a surgical complication). The estimated 2-year survival was 69% (95% confidence interval, 60 –76%) for the surgery group and 68% (95% confidence interval, 60– 75%) for the chemotherapy group ( p = 0.975) (Fig. 1). Actuarial survival for patients grouped according to stage or site showed no statistical differences. Survival rates were similar for the complete responders and nonresponders (who underwent surgical resection after two courses) but they had better survival than those who had only a partial response ( p = 0.069). The disease-free survival for the patients who had a histologically confirmed complete response after three cycles of chemotherapy did not differ significantly from the curve for the surgery group (Fig. 2). Disease-free survival is significantly better in patients who had no histologic evidence of tumor after completion of chemotherapy than those with histologic evidence of resistant disease ( p = 0.0001) (Fig. 2). Table 3 Chemotherapy toxicity Toxicity Renal impairment Grade 1 (Cr V 2 mg/dl) Grade 2 (Cr < 4 mg/dl) Myelosuppression Grade 1 – 2 (WBCs>2000 – < 3000/Al) Mucositis Grade 1 – 2 (patchy) Gastrointestinal Grade 1 – 2 (occasional vomiting, < 4 BM/day) Grade 3 (3 – 4 emesis/day, >4 BM/day)
No. of patients 9 3 2 6 6 4
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1029
Fig. 1. Overall survival of 80 patients randomly assigned to induction chemotherapy and radiation therapy (solid line) or conventional laryngectomy and postoperative radiation (dotted line). Survival rates at 2 years were 69% and 68% for surgery and Chth. group, respectively ( p = 0.975). The median follow-up was 11.5 months.
3.6. Patterns of relapse Overall rates of relapse did not differ significantly between groups but they differ in pattern of relapse where relapse at primary tumor site was more frequent in the chemotherapy group, four patients (10%) than in the surgery group with one patient (2.5%) ( p = 0.001). Regional recurrence was similar in both groups but distant metastasis was more frequent in the surgery group, six patients (15%) than in the chemotherapy group with three patients (7.5%) ( p = 0.001) (see Table 4). 3.7. Preservation of the larynx The larynx was preserved in 26 patients assigned to induction chemotherapy (65%). Fourteen patients (35%) underwent total laryngectomy, six patients before definitive
Fig. 2. Disease-free interval for 80 patients randomly assigned to induction chemotherapy and radiation therapy (solid line) or conventional laryngectomy and postoperative radiation (dotted line). The difference was not statistically significant ( p = 0.12). Those with no histologic evidence of tumor had a better disease-free interval than those with histologic evidence of persistent diseases p = 0.0001.
1030
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
Table 4 Patterns of tumor recurrence according to treatment group Site of recurrence
No. of patients (%) Surgery (n = 40)
Chemotherapy (n = 40)
Primary Regional Distant All
1 2 6 9
4 (10%) 3 (7.5%) 3 (7.5%) 10 (25%)
(2.5%) (5%) (l5%) (22.5%)
radiation therapy, and eight patients after radiation. Four of the eight patients underwent planned laryngoscopy, and a biopsy confirmed the presence of persistent tumor 12 weeks after the completion of radiation. Late salvage laryngectomy for recurrent cancer was required in four patients (10%) after intervals ranging from 6 to 18 months. In the first year of treatment, 75% of the late salvages (three of four patients) occurred. Thus, the rate of salvage laryngectomy for resistant disease before radiation therapy, or within 3 months afterwards, was 25% (10 of 40 patients), and the rate of salvage laryngectomy for late recurrent disease was 10% (4 of 40 patients). When the patients were grouped according to initial tumor characteristics, salvage laryngectomy was required more often in those with glottic cancers (41%) than in those with supraglottic cancers (35%), in those with fixed vocal cords (40%) than in those with mobile vocal cords (38%), and in those with gross cartilage invasion (42%) than in those with no involvement of cartilage (30%), but these differences were not statistically significant ( p = 0.607, 0.102, and 0.147, respectively). Salvage laryngectomy was required, however, in 42% of the patients with stage IV cancers as compared with 30% of the patients with stage III cancers ( p = 0.05), and in 55% of the patients with T4 cancers as compared with 30% of the patients with smaller tumors ( p = 0.001). The estimated rate of larynx preservation after 2 years was 65% (26 of 40 patients). Of these patients, 62.5% (25 patients) remain alive at this writing with no evidence of disease.
4. Discussion Since the prognosis for patients with locally advanced squamous cell carcinoma of the head and neck is poor with the current standard therapy of surgery and/or radiation, attempts to improve on these results are being continued. The concept of a multimodality approach using induction chemotherapy before definitive therapy is gaining wider use in the management of these patients for two reasons: 1. High response rate achieved with standard platinol 100 mg/m2/day at day 1 and infusional 5FU 1000 mg/m2 days 1– 5, an overall response rate (complete and partial) ranging from 80% to 98%, and a clinical complete response rate ranging from 30% to
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1031
50%. A pathological complete response was confirmed by biopsy in 2/3 of clinical complete responders. 2. The response to chemotherapy was generally predictive to radiosensitivity. These results were achieved without reducing the estimated 2-year survival rate, as compared with the rates for the conventional treatment of laryngectomy and postoperative therapy. Because of the substantial impact that the loss of the larynx has on the quality of life, interest in its preservation in advanced laryngeal cancer is not new. In an attempt to preserve the larynx, definitive radiation has been used in selected patients, with laryngectomy reserved for patients with cancer that recurred after radiation but overall rates of cure have generally been reduced [2– 5]. The largest studies found 3-year rates of disease-free survival of 20 –40% for patients with stage III or IV cancers, with larynx preservation in less than half of the cured patients. Croll et al. [6] reported a 3-year survival rate of 52% in 55 patients with T3 or T4 cancer without invasion of the cartilage or regional metastasis, with larynx preservation in 65% of all patients and 73% of the survivals. Similar results were achieved in the current study, although generally in patients with more advanced disease. Nearly two thirds of these patients had supraglottic tumors, and nearly 85% had advanced nodal disease. Such patients are not typically considered good candidates for primary radiation with surgical salvage because of the poor cure rates attained with that therapeutic approach. The high rate of larynx preservation achieved in these patients with advanced cancers suggests that initial chemotherapy enhanced the effectiveness of definitive radiation therapy. To this date, the three-course regimen used here is the most widely used and investigated chemotherapy drug combination for squamous cell carcinoma of the head and neck region. Overall response rates in the literature have been consistently greater than 80% since the first report of this regimen’s efficacy from investigators at Wayne-State University [7,8]. After two courses of chemotherapy, 92% of our patients had responded, including 35% of complete responders. This is comparable to Kish et al. [9], who observed an 89% response rate with 19% complete responders using a similar two-course regimen. After three courses of chemotherapy, 91% of our patients had responded, with 47% of complete responders. This is nearly similar to Spaulding et al. [10] who observed a 98% response rate with 49% of complete responders. One of the potential disadvantages of neoadjuvant chemotherapy is the concern that patients would become ineligible for curative therapy if the tumor progressed during treatment. Because of the repeated evaluation in this study, no patients became unresectable while receiving chemotherapy. The toxicity of chemotherapy was acceptable. Renal toxicity was mild and was only found in a few patients as careful attention to prehydration and diuresis took place. Electrolyte imbalance seen via hypokalemia and hypomagnesemia were not faced due to potassium and magnesium supplements during chemotherapy. Other toxicities like mucositis, myelosuppression, and gastrointestinal disturbances were controllable.
1032
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
Neoadjuvant chemotherapy does not add to the complications of subsequent surgery. Lore et al. [11] found that the risk of fistula formation was less and postoperative infections rare in patients who received preoperative chemotherapy. In these studies, it should be noted that observations about the incidence of complications were made in patients undergoing surgery after chemotherapy to which many of the patients had responded. In our study, it was the nonresponders who undergo surgery where they might have been negatively affected by prior administration of chemotherapy. However, when these patients were compared with the surgery group, there was no difference in the incidence of complications. Similarly, acute complications due to radiotherapy were not significantly different from patients receiving postsurgical or postchemotherapy treatment. This is parallel to Posner et al. [12] whose results showed they found that incidence of acute radiation-related complications did not increase after induction chemotherapy. Survival duration was nearly similar in the two treatment groups when the patients were analysed according to tumor site (glottic vs. supraglottic), tumor stage (stage III vs. stage IV), or response to chemotherapy. The last of these results is of interest because it suggests that in the case of laryngeal cancer, survival of complete responders is similar to nonresponders. This may be due to the surgeon’s ability to obtain wide, oncologically safe surgical margins with standard wide field laryngectomy [13]. Local recurrences were significantly more common and distant metastases less frequent in the chemotherapy group. Seventy-five percent of the local and regional recurrences in advanced laryngeal cancer are detected in the first year after therapy [14,15]. The successful application of neoadjuvant chemotherapy followed by radiotherapy in responders of resectable stage III and stage IV laryngeal carcinoma led to preservation of the larynx in 65% of patients at 2 years. This new approach of treatment requires a high level of skill and cooperation among the various disciplines involved. Adequate compliance from patients, careful documentation of the extent and response of the tumor, and appropriate timing and frequency of surveillance laryngoscopy are essential to the successful treatment of these patients. References [1] B.J. McNeil, R. Weichselbaum, S.G. Pauker, Speech and survival trade offs between quality and quantity of life in laryngeal cancer, N. Engl. J. Med. 305 (1981) 982 – 987. [2] L.W. DeSanto, T3 glottic cancer: options and consequences of the options, Laryngoscope 94 (1984) 1311 – 1315. [3] I. Kazem, P. van den Broek, Planned preoperative radiation therapy vs. definitive radiotherapy for advanced laryngeal carcinoma, Laryngoscope 94 (1984) 1355 – 1358. [4] A.R. Harwood, ENT Group, The management of advanced supraglottic carcinoma by delayed combined therapy, Int. J. Radiat. Oncol. Biol. Phys. 8 (Suppl. 1) (1982) 101 – 102 (Abstract). [5] M.S. Razack, T. Maipang, K. Sako, V. Bakanjian, D.P. Shedd, Management of advanced glottic carcinomas, Am. J. Surg. 158 (1989) 318 – 320. [6] G.A. Croll, G.J. Gerritsen, R.M. Tiwari, G.B. Snow, Primary radiotherapy with surgery reserve for advanced laryngeal carcinoma results and complication, Eur. J. Surg. Oncol. 15 (1989) 350 – 356. [7] A.P.D.E. Meredith, C.J. Randall, H.J. Shaw, Advanced laryngeal cancer: a management perspective, J. Laryngeal. Otol. 101 (1987) 1046 – 1054.
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1033
[8] M. Rooney, J. Kish, J. Jacobs, et al., Improved complete response rate and survival in advanced head and neck cancer after three course induction chemotherapy with 120 hour 5-FU infusion and cisplatin, Cancer 55 (1985) 1123 – 1128. [9] J. Kish, A. Drelichman, J. Jacobs, et al., Clinical trial of cisplatin and 5FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck, Cancer Treat. Rep. 66 (1982) 471 – 474. [10] M.B. Spaulding, S.G. Fischer, G.T. Wolf, et al., Tumour response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma, J. Clin. Oncol. 12 (8) (1994) 1592 – 1599. [11] J.M. Lore, J.A. Bonilla, M.B. Spaulding, et al., Preoperative adjuvant chemotherapy for advanced head and neck cancer: a surgical evaluation, J. Surg. Oncol. 1 (1989) 2 – 6. [12] M.R. Posner, R.R. Weichselbaum, T.J. Fitzgerald, et al., Treatment complications after seguential chemotherapy and radiotherapy with and without surgery in previously untreated squamous cell carcinoma of the head and neck, Int. J. Radiat. Oncol. Biol. Phys. 11 (1985) 1887 – 1893. [13] A.R. Harwood, D.P. Bryce, W.D. Rider, Management of T3 glottic cancer, Arch. Otolaryngol. 106 (1980) 697 – 699. [14] A.R. Harwood, ENT Group, The management of advanced supraglottic carcinoma by delayed combined therapy, Radiat. Oncol. Biol. Phys. 8 (Suppl. 1) (1982) 101 – 102 (Abstract). [15] J.D. Eiband, E.G. Elias, C.M. Suter, et al., Prognostic factors in squamous cell carcinoma of the larynx, Am. J. Surg. 158 (1989) 314 – 317.
Surgery plus radiation versus neoadjuvant chemotherapy plus radiation in resectable locally advanced laryngeal carcinoma Mahmoud E. El Samaa a, Nivine M.A. Gado b,*, Ahmed Adly Mohamed a, Samer Ahmed Ibrahim a b
a ENT Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Radiation Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, 4 Abaddas St. from Misr and Sudan St. El Dahr, P.O. Box 11271, Cairo, Egypt
Abstract Aim: Locally advanced (stage III and IV) resectable laryngeal carcinoma is treated with both standard treatment (surgery + postoperative radiotherapy) and induction chemotherapy followed by radiotherapy (in responders) or surgery (in nonresponders), then results are compared. Patients and Methods: Eighty patients were randomized in this study; 40 of these patients were assigned to chemotherapy and another 40 patients to the standard surgical line. In the chemotherapy group, three cycles of cisplatin + fluorouracil were given. Clinical tumor response was evaluated after two cycles of chemotherapy, and patients with complete or partial response received a third cycle of chemotherapy followed by 6500 – 7400 cGy in 7 weeks. Patients with no response to chemotherapy, or who are recurrent after chemotherapy and radiotherapy, underwent salvage laryngectomy. Results: After two cycles of chemotherapy, a complete clinical response in the primary tumor was attained in 35% of patients, and a partial clinical response in the primary tumor in 57%. The 2-year survival rate was 69% for the surgery group and 68% for the chemotherapy group. The larynx was preserved in 65% of patients. Conclusion: Induction chemotherapy followed by radiotherapy can be effective in preserving the larynx in a high percentage of stage III and IV resectable laryngeal carcinoma patients without compromising overall survival. D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. Keywords: Laryngeal carcinoma; Tumor; Radiation
* Corresponding author. Tel.: +20-24828206. E-mail address: [email protected] (N.M.A. Gado). 0531-5131/ D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. doi:10.1016/S0531-5131(03)01054-9
1024
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1. Introduction Laryngeal carcinoma accounts for 3– 5% of all cancers. Patients who present with locally advanced disease (stage III and IV) have a poor prognosis with conventional treatment that consists of total laryngectomy or a combination of laryngectomy and postoperative radiotherapy. At least 50% of patients will recur, usually within the first 2 years and overall 5-year survival rates range from 10% to 50% depending on site and stage of disease. In this study, induction chemotherapy or neoadjuvant chemotherapy is given before surgery (in nonresponders) or before radiotherapy (in complete and partial responders) to improve tumor response, and preserve the larynx, so improving the quality of life of patients [1].
2. Methods 2.1. Eligibility of patients All patients had biopsy-proven, previously untreated, resectable (stage III or IV) squamous cell carcinoma of the larynx, according to the American Joint Committee on Cancer. All patients were men ranging in age from 46 to 74 (median 59). Patients were required to have a pretreatment leucocyte count z 4.000/mm3, platelet count z 100,000/mm3, S. creatinine z 1.5 mg/dl, creatinine clearance z 60 ml/min, and Karnofsky performance status of >50. Each patient gave written informed consent. Prior to each cycle, patients had a physical examination, complete blood counts, liver and renal function tests. Eligible patients were randomly assigned to one of two treatment groups. 2.2. Treatment methods 2.2.1. Chemotherapy After overnight hydration with 2 l of 5% dextrose/0.5 normal saline (NS) supplemented with 10 mEq KCl/l, the patients received a bolus of 12.5 g of mannitol, followed by cisplatin (100 mg/m2) on day 1, mixed in 200 ml of NS and administered over 20 min. This was followed by a 4-h infusion of an additional 1 l of 5% dextrose/0.5 NS to which 10 mEq of KCl and 25 g of mannitol had been added. 5 Fluorouracil (5FU) 500 mg/m2/12 h for 5 days mixed in 2 l 5% dextrose/NS followed. Potassium chloride 80 mg and magnesium sulfate 8 mEq were added to the infusate daily. Chemotherapy was repeated on days 1, 22, and 43. Dose modifications for toxicity were based on nadir laboratory data and clinical evaluation. Cisplatin was reduced to 80 mg/m2 if serum creatinine reached 2 –4 mg/m2. No further cisplatin was administered if serum creatinine increased to 4 mg/m2. The dose of 5FU was reduced by 25% for a nadir TLC less than 2000/mm3 and/or platelet count less than 75.000/mm3 and/or grade 3 or 4 mucositis or diarrhea. The initial tumor response was performed after two courses of chemotherapy through indirect laryngoscopy. Response was described separately for the primary tumor site and
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1025
the cervical nodes. A complete response was defined as the complete disappearance of all clinically evident tumor. A partial response was defined as a 50% reduction in the sum of the product of the longest dimension and its perpendicular for each tumor, as compared with the initial tumor dimensions. Patients who failed to achieve at least partial response received no further chemotherapy and underwent immediate surgical resection. Other patients received a third course of chemotherapy, although responding patients who had significant toxicity or who refused a third course of chemotherapy began radiation therapy. A second response evaluation was performed after completion of all chemotherapy, and included endoscopy under anaesthesia with a biopsy of the primary tumor site. 2.2.2. Radiation therapy All patients received radiation therapy, either after chemotherapy or postoperatively. Definitive radiation therapy consisted of 6500– 7400 cGy in 7 weeks. Both the primary site of disease and neck nodes were treated. Radiation was administered with a Co-60 machine operating at 80 cm SSD via opposed lateral portals. Supplemental anterior lower neck portal, calculated at a depth of 3 cm, also was used in all patients. A daily radiation dose of 200 cGy was used, five times per week, with all fields treated daily. The spinal cord was protected at 4500 cGy. Patients irradiated postoperatively received 5500 cGy to the primary site if the surgical margins were free of tumor. Patients with involved surgical margin received 6600 cGy in 6.5 –7 weeks. Two opposed lateral portal and anterior lower neck portal also were used for these patients postoperatively. 2.2.3. Surgery Initial salvage surgery: total laryngectomy was done after second course of chemotherapy to nonresponders and after third course of therapy to patients showing progression of the tumor, as well as after end of radiotherapy by 12 weeks, if persistent tumor was proved. Late salvage surgery was done if tumor recurred where most of late salvage laryngectomy took place within first year of therapy. 2.2.4. Statistical analysis The statistical analyses of patients’ survival and disease-free intervals were based on a comparison of Kaplan Meier curves by the log-rank test. Survival and disease-free intervals were measured from the date of randomization, with a disease-free interval of 0 assigned to patients who were never rendered disease-free. All randomized patients were included in the analysis. Local control was defined as those patients free of recurrence at the primary site for a minimum of 24 months. 3. Results 3.1. Patient population Between August 1999 and August 2001, 80 consecutive patients entered trial. Forty patients received chemotherapy as a primary treatment and another forty patients received
1026
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
the standard therapy (surgery and radiotherapy). The mean age was 59 years with a range of 46 –74 years. All the patients were men. Fourteen patients had stage III and twenty-six patients had stage IV in the chemotherapy arm. Eighteen patients in the surgery arm were stage III and twenty-two were stage IV. The histologic differentiation was described as well differentiated in 14 patients, moderately differentiated in 22, and poorly differentiated in 4 patients in the chemotherapy arm. In the surgery arm, 16 patients were well differentiated, 19 were moderately differentiated and 5 were poorly differentiated as shown in Table 1. There were no significant differences between the two arms with respect to age, sex, T class, N class, stage, tumor site, grade, cartilage invasion, fixation of vocal cords, performance status (Table 1). All patients were cigarette smokers and 40% consumed alcohol and hashish. 3.2. Response to induction chemotherapy Of the 40 assessable patients, 37 (92.5%) responded to two courses of chemotherapy, including 14 (35%) with complete disappearance of all measurable tumor and 23 (57.5%) with partial disappearance of measurable tumor. Three patients (7.5%) who failed to have at least a partial response at their primary tumor site were referred for standard therapy (surgical resection). Table 1 Patients’ characteristics according to treatment Patient characteristics
No. of patients Stage III T2N1 T3N0 T3N1 Stage IV T2N2 T2N3 T3N2 T4N0 T4N1 T4N2 T4N3 Site Glottic Supraglottic Cartilage invasion Fixed V.C. Performance status (Karnofsky score) < 80 z 80
Treatment Surgery
Chemotherapy
All
40 18 5 6 7 22 4 5 5 1 2 3 2
40 14 4 5 5 26 6 7 7 1 2 2 1
80 36
10 30 4 21
11 29 5 24
25 55 9 45
5 35
4 36
9 71
44
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1027
Although 40 patients were supposed to receive the third course of chemotherapy, only 34 patients actually received the third course. One was not assessable for response, one was leucopenic so that he no longer fit the criteria for treatment, one refused further chemotherapy because of side effects that were intolerable to him, and three showed no response to a third course of chemotherapy. Fourteen patients (41.2%) had a complete response at both the primary tumor site and cervical nodes. Sixteen patients (47%) had complete disappearance of the tumor and thirty-one patients (91%) had overall response (complete and partial response) after three courses of chemotherapy. The chemotherapy responses are listed in Table 2. There was one patient who started radiotherapy without a third course of chemotherapy as he refused chemotherapy when the side effects became intolerable to him. After the third course of chemotherapy, endoscopy and biopsy was done to ensure pathological response. Histologically confirmed complete tumor response occurred in 14 (87.5%) of the 16 patients who had a clinical complete response. The overall rate of histologically confirmed complete responses was 65%. 3.3. Chemotherapy toxicity Three patients had transient increases in the serum creatinine level (2– 4 mg/dl) and received a reduced dose of cisplatin (80 mg/m2) in subsequent courses. Nine patients had mild renal impairment with a maximum serum creatinine level of 2.0 mg/dl, which corrected with fluid hydration and required no modification of cisplatin dose. No patient had electrolyte imbalance, and there was no peripheral neuropathy recorded. As regards the haematological toxicity, two patients had grades 1– 2 myelosuppression (WBCs >2000 – < 3000 Ul). Six patients had grades 1 – 2 mucositis (patchy). Gastrointestinal toxicity presented as nausea, vomiting, and diarrhea developed in 10 patients. Six patients had grades 1– 2 gastrointestinal toxicity (occasional vomiting), < 4
Table 2 Response evaluation after two and three courses Response
Primary tumor
Nodes
Overall
No.
%
No.
%
No.
%
After two courses Complete Partial None
14 23 3
35 57.5 7.5
4 12 8
41.2 35.3 23.5
14 21 5
35 52.5 12.5
After three courses Complete Partial None
16 15 3
47.1 44.1 8.8
15 9 6
50 30 20
14 19 1
41.2 55.9 2.9
1028
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
bowel movements (BM/day), while the other four had grade 3 toxicity (3 –4 emesis/day, >4BM/day) (see Table 3). 3.4. Radiation and surgical toxicity complications The frequency and severity of toxic effects due to radiation therapy were similar in both treatment groups (surgery and chemotherapy groups) with respect to skin reaction, anemia, and dehydration. The rate of grade 2 mucositis (patchy membranous mucositis and severe laryngitis) was slightly higher in the chemotherapy group; six patients (15%) than in the surgery group with four patients (10%). Overall, the frequency and types of surgical complications were similar between the treatment groups. However, the incidence of surgical complications tended to be higher for salvage surgery performed after radiation than salvage surgery after chemotherapy alone. 3.5. Overall survival Two patients (2.5%) died during treatment (one in the chemotherapy group due to unrelated causes and one in the surgery group due to a surgical complication). The estimated 2-year survival was 69% (95% confidence interval, 60 –76%) for the surgery group and 68% (95% confidence interval, 60– 75%) for the chemotherapy group ( p = 0.975) (Fig. 1). Actuarial survival for patients grouped according to stage or site showed no statistical differences. Survival rates were similar for the complete responders and nonresponders (who underwent surgical resection after two courses) but they had better survival than those who had only a partial response ( p = 0.069). The disease-free survival for the patients who had a histologically confirmed complete response after three cycles of chemotherapy did not differ significantly from the curve for the surgery group (Fig. 2). Disease-free survival is significantly better in patients who had no histologic evidence of tumor after completion of chemotherapy than those with histologic evidence of resistant disease ( p = 0.0001) (Fig. 2). Table 3 Chemotherapy toxicity Toxicity Renal impairment Grade 1 (Cr V 2 mg/dl) Grade 2 (Cr < 4 mg/dl) Myelosuppression Grade 1 – 2 (WBCs>2000 – < 3000/Al) Mucositis Grade 1 – 2 (patchy) Gastrointestinal Grade 1 – 2 (occasional vomiting, < 4 BM/day) Grade 3 (3 – 4 emesis/day, >4 BM/day)
No. of patients 9 3 2 6 6 4
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1029
Fig. 1. Overall survival of 80 patients randomly assigned to induction chemotherapy and radiation therapy (solid line) or conventional laryngectomy and postoperative radiation (dotted line). Survival rates at 2 years were 69% and 68% for surgery and Chth. group, respectively ( p = 0.975). The median follow-up was 11.5 months.
3.6. Patterns of relapse Overall rates of relapse did not differ significantly between groups but they differ in pattern of relapse where relapse at primary tumor site was more frequent in the chemotherapy group, four patients (10%) than in the surgery group with one patient (2.5%) ( p = 0.001). Regional recurrence was similar in both groups but distant metastasis was more frequent in the surgery group, six patients (15%) than in the chemotherapy group with three patients (7.5%) ( p = 0.001) (see Table 4). 3.7. Preservation of the larynx The larynx was preserved in 26 patients assigned to induction chemotherapy (65%). Fourteen patients (35%) underwent total laryngectomy, six patients before definitive
Fig. 2. Disease-free interval for 80 patients randomly assigned to induction chemotherapy and radiation therapy (solid line) or conventional laryngectomy and postoperative radiation (dotted line). The difference was not statistically significant ( p = 0.12). Those with no histologic evidence of tumor had a better disease-free interval than those with histologic evidence of persistent diseases p = 0.0001.
1030
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
Table 4 Patterns of tumor recurrence according to treatment group Site of recurrence
No. of patients (%) Surgery (n = 40)
Chemotherapy (n = 40)
Primary Regional Distant All
1 2 6 9
4 (10%) 3 (7.5%) 3 (7.5%) 10 (25%)
(2.5%) (5%) (l5%) (22.5%)
radiation therapy, and eight patients after radiation. Four of the eight patients underwent planned laryngoscopy, and a biopsy confirmed the presence of persistent tumor 12 weeks after the completion of radiation. Late salvage laryngectomy for recurrent cancer was required in four patients (10%) after intervals ranging from 6 to 18 months. In the first year of treatment, 75% of the late salvages (three of four patients) occurred. Thus, the rate of salvage laryngectomy for resistant disease before radiation therapy, or within 3 months afterwards, was 25% (10 of 40 patients), and the rate of salvage laryngectomy for late recurrent disease was 10% (4 of 40 patients). When the patients were grouped according to initial tumor characteristics, salvage laryngectomy was required more often in those with glottic cancers (41%) than in those with supraglottic cancers (35%), in those with fixed vocal cords (40%) than in those with mobile vocal cords (38%), and in those with gross cartilage invasion (42%) than in those with no involvement of cartilage (30%), but these differences were not statistically significant ( p = 0.607, 0.102, and 0.147, respectively). Salvage laryngectomy was required, however, in 42% of the patients with stage IV cancers as compared with 30% of the patients with stage III cancers ( p = 0.05), and in 55% of the patients with T4 cancers as compared with 30% of the patients with smaller tumors ( p = 0.001). The estimated rate of larynx preservation after 2 years was 65% (26 of 40 patients). Of these patients, 62.5% (25 patients) remain alive at this writing with no evidence of disease.
4. Discussion Since the prognosis for patients with locally advanced squamous cell carcinoma of the head and neck is poor with the current standard therapy of surgery and/or radiation, attempts to improve on these results are being continued. The concept of a multimodality approach using induction chemotherapy before definitive therapy is gaining wider use in the management of these patients for two reasons: 1. High response rate achieved with standard platinol 100 mg/m2/day at day 1 and infusional 5FU 1000 mg/m2 days 1– 5, an overall response rate (complete and partial) ranging from 80% to 98%, and a clinical complete response rate ranging from 30% to
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1031
50%. A pathological complete response was confirmed by biopsy in 2/3 of clinical complete responders. 2. The response to chemotherapy was generally predictive to radiosensitivity. These results were achieved without reducing the estimated 2-year survival rate, as compared with the rates for the conventional treatment of laryngectomy and postoperative therapy. Because of the substantial impact that the loss of the larynx has on the quality of life, interest in its preservation in advanced laryngeal cancer is not new. In an attempt to preserve the larynx, definitive radiation has been used in selected patients, with laryngectomy reserved for patients with cancer that recurred after radiation but overall rates of cure have generally been reduced [2– 5]. The largest studies found 3-year rates of disease-free survival of 20 –40% for patients with stage III or IV cancers, with larynx preservation in less than half of the cured patients. Croll et al. [6] reported a 3-year survival rate of 52% in 55 patients with T3 or T4 cancer without invasion of the cartilage or regional metastasis, with larynx preservation in 65% of all patients and 73% of the survivals. Similar results were achieved in the current study, although generally in patients with more advanced disease. Nearly two thirds of these patients had supraglottic tumors, and nearly 85% had advanced nodal disease. Such patients are not typically considered good candidates for primary radiation with surgical salvage because of the poor cure rates attained with that therapeutic approach. The high rate of larynx preservation achieved in these patients with advanced cancers suggests that initial chemotherapy enhanced the effectiveness of definitive radiation therapy. To this date, the three-course regimen used here is the most widely used and investigated chemotherapy drug combination for squamous cell carcinoma of the head and neck region. Overall response rates in the literature have been consistently greater than 80% since the first report of this regimen’s efficacy from investigators at Wayne-State University [7,8]. After two courses of chemotherapy, 92% of our patients had responded, including 35% of complete responders. This is comparable to Kish et al. [9], who observed an 89% response rate with 19% complete responders using a similar two-course regimen. After three courses of chemotherapy, 91% of our patients had responded, with 47% of complete responders. This is nearly similar to Spaulding et al. [10] who observed a 98% response rate with 49% of complete responders. One of the potential disadvantages of neoadjuvant chemotherapy is the concern that patients would become ineligible for curative therapy if the tumor progressed during treatment. Because of the repeated evaluation in this study, no patients became unresectable while receiving chemotherapy. The toxicity of chemotherapy was acceptable. Renal toxicity was mild and was only found in a few patients as careful attention to prehydration and diuresis took place. Electrolyte imbalance seen via hypokalemia and hypomagnesemia were not faced due to potassium and magnesium supplements during chemotherapy. Other toxicities like mucositis, myelosuppression, and gastrointestinal disturbances were controllable.
1032
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
Neoadjuvant chemotherapy does not add to the complications of subsequent surgery. Lore et al. [11] found that the risk of fistula formation was less and postoperative infections rare in patients who received preoperative chemotherapy. In these studies, it should be noted that observations about the incidence of complications were made in patients undergoing surgery after chemotherapy to which many of the patients had responded. In our study, it was the nonresponders who undergo surgery where they might have been negatively affected by prior administration of chemotherapy. However, when these patients were compared with the surgery group, there was no difference in the incidence of complications. Similarly, acute complications due to radiotherapy were not significantly different from patients receiving postsurgical or postchemotherapy treatment. This is parallel to Posner et al. [12] whose results showed they found that incidence of acute radiation-related complications did not increase after induction chemotherapy. Survival duration was nearly similar in the two treatment groups when the patients were analysed according to tumor site (glottic vs. supraglottic), tumor stage (stage III vs. stage IV), or response to chemotherapy. The last of these results is of interest because it suggests that in the case of laryngeal cancer, survival of complete responders is similar to nonresponders. This may be due to the surgeon’s ability to obtain wide, oncologically safe surgical margins with standard wide field laryngectomy [13]. Local recurrences were significantly more common and distant metastases less frequent in the chemotherapy group. Seventy-five percent of the local and regional recurrences in advanced laryngeal cancer are detected in the first year after therapy [14,15]. The successful application of neoadjuvant chemotherapy followed by radiotherapy in responders of resectable stage III and stage IV laryngeal carcinoma led to preservation of the larynx in 65% of patients at 2 years. This new approach of treatment requires a high level of skill and cooperation among the various disciplines involved. Adequate compliance from patients, careful documentation of the extent and response of the tumor, and appropriate timing and frequency of surveillance laryngoscopy are essential to the successful treatment of these patients. References [1] B.J. McNeil, R. Weichselbaum, S.G. Pauker, Speech and survival trade offs between quality and quantity of life in laryngeal cancer, N. Engl. J. Med. 305 (1981) 982 – 987. [2] L.W. DeSanto, T3 glottic cancer: options and consequences of the options, Laryngoscope 94 (1984) 1311 – 1315. [3] I. Kazem, P. van den Broek, Planned preoperative radiation therapy vs. definitive radiotherapy for advanced laryngeal carcinoma, Laryngoscope 94 (1984) 1355 – 1358. [4] A.R. Harwood, ENT Group, The management of advanced supraglottic carcinoma by delayed combined therapy, Int. J. Radiat. Oncol. Biol. Phys. 8 (Suppl. 1) (1982) 101 – 102 (Abstract). [5] M.S. Razack, T. Maipang, K. Sako, V. Bakanjian, D.P. Shedd, Management of advanced glottic carcinomas, Am. J. Surg. 158 (1989) 318 – 320. [6] G.A. Croll, G.J. Gerritsen, R.M. Tiwari, G.B. Snow, Primary radiotherapy with surgery reserve for advanced laryngeal carcinoma results and complication, Eur. J. Surg. Oncol. 15 (1989) 350 – 356. [7] A.P.D.E. Meredith, C.J. Randall, H.J. Shaw, Advanced laryngeal cancer: a management perspective, J. Laryngeal. Otol. 101 (1987) 1046 – 1054.
M.E. El Samaa et al. / International Congress Series 1240 (2003) 1023–1033
1033
[8] M. Rooney, J. Kish, J. Jacobs, et al., Improved complete response rate and survival in advanced head and neck cancer after three course induction chemotherapy with 120 hour 5-FU infusion and cisplatin, Cancer 55 (1985) 1123 – 1128. [9] J. Kish, A. Drelichman, J. Jacobs, et al., Clinical trial of cisplatin and 5FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck, Cancer Treat. Rep. 66 (1982) 471 – 474. [10] M.B. Spaulding, S.G. Fischer, G.T. Wolf, et al., Tumour response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma, J. Clin. Oncol. 12 (8) (1994) 1592 – 1599. [11] J.M. Lore, J.A. Bonilla, M.B. Spaulding, et al., Preoperative adjuvant chemotherapy for advanced head and neck cancer: a surgical evaluation, J. Surg. Oncol. 1 (1989) 2 – 6. [12] M.R. Posner, R.R. Weichselbaum, T.J. Fitzgerald, et al., Treatment complications after seguential chemotherapy and radiotherapy with and without surgery in previously untreated squamous cell carcinoma of the head and neck, Int. J. Radiat. Oncol. Biol. Phys. 11 (1985) 1887 – 1893. [13] A.R. Harwood, D.P. Bryce, W.D. Rider, Management of T3 glottic cancer, Arch. Otolaryngol. 106 (1980) 697 – 699. [14] A.R. Harwood, ENT Group, The management of advanced supraglottic carcinoma by delayed combined therapy, Radiat. Oncol. Biol. Phys. 8 (Suppl. 1) (1982) 101 – 102 (Abstract). [15] J.D. Eiband, E.G. Elias, C.M. Suter, et al., Prognostic factors in squamous cell carcinoma of the larynx, Am. J. Surg. 158 (1989) 314 – 317.