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Original Article
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Volume 353:123-132 July 14, 2005 Number 2
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Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
Frances A. Shepherd, M.D., José Rodrigues Pereira, M.D., Tudor Ciuleanu, M.D., Eng Huat Tan, M.D., Vera Hirsh, M.D., Sumitra Thongprasert, M.D., Daniel Campos, M.D., Savitree Maoleekoonpiroj, M.D., Michael Smylie, M.B., Ch.B., Renato Martins, M.D., Maximiliano van Kooten, M.D., Mircea Dediu, M.D., Brian Findlay, M.D., Dongsheng Tu, Ph.D., Dianne Johnston, Andrea Bezjak, M.D., Gary Clark, Ph.D., Pedro Santabárbara, M.D., Ph.D., Lesley Seymour, M.D., Ph.D., for the National Cancer Institute of Canada Clinical Trials Group

 

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ABSTRACT

Background We conducted a randomized, placebo-controlled, double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non–small-cell lung cancer after the failure of first-line or second-line chemotherapy.

Methods Patients with stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo.

Results The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects.

Conclusions Erlotinib can prolong survival in patients with non–small-cell lung cancer after first-line or second-line chemotherapy.

Lung cancer is the leading cause of cancer death among men and women in North America.1 In advanced non–small-cell lung cancer, chemotherapy offers symptomatic relief and modest improvement in survival2; responses are brief, with a median time to progression of three to five months. Second-line chemotherapy with docetaxel can prolong survival after platinum-based therapy for non–small-cell lung cancer.3,4 However, there is at present no defined role for third-line chemotherapy. The futility of offering third-line chemotherapy was demonstrated by Massarelli et al.,5 who reported a response rate of only 2 percent and a median survival of four months. Shepherd et al.6 showed that among patients treated with docetaxel after the failure of two or more chemotherapy regimens, survival was identical to that among patients treated with supportive care.

The epidermal growth factor receptor (EGFR) family is part of a complex signal-transduction network that is central to several critical cellular processes. Since EGFR is often found in non–small-cell lung cancer cells,7,8 it has been the focus of efforts to develop new agents that target the EGFR pathway. Erlotinib (Tarceva, OSI Pharmaceuticals) and gefitinib (Iressa, AstraZeneca) inhibit the tyrosine kinase activity of EGFR and have been studied extensively.9,10,11,12 In randomized phase 2 trials of gefitinib (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2),10,11 the tumors of 10 to 20 percent of patients who were previously treated with platinum-based regimens responded, and in a phase 2 trial of erlotinib among previously treated patients with non–small-cell lung cancer in which 10 percent or more of the cells expressed EGFR, the response rate was 12.3 percent.12 These promising rates are perhaps higher than those possible with other forms of chemotherapy,3,4,5,6 but it is unknown whether treatment with an EGFR inhibitor prolongs survival. For this reason, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted a trial (BR.21) to compare erlotinib with placebo after the failure of standard chemotherapy for non–small-cell lung cancer. The inclusion of a control group receiving placebo was considered ethical in view of the lack of benefit from further chemotherapy after the failure of standard treatment.5,6

Methods

Study Design

This international, phase 3, randomized, double-blind, placebo-controlled trial of erlotinib after the failure of first-line or second-line chemotherapy for non–small-cell lung cancer was designed by the NCIC CTG. Patients were randomly assigned in a 2:1 ratio to receive oral erlotinib at a dose of 150 mg daily or placebo. Randomization was performed centrally by Applied Logic Associates (Houston), with the use of the minimization method.13 Patients were stratified according to center, Eastern Cooperative Oncology Group performance status (0 or 1 vs. 2 or 3, with higher scores indicating greater impairment), best response to prior therapy (complete or partial response vs. stable disease vs. progressive disease), number of prior regimens received (one vs. two), and exposure to prior platinum therapy (yes vs. no).

The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate (complete and partial), duration of response, toxic effects, and quality of life. Responses were assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST),14 and toxic effects were assessed according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0). The European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30) and the quality-of-life questionnaire for patients with lung cancer (QLQ-LC13) were used to evaluate patients' quality of life.

The protocol was approved by the ethics review boards at all participating institutions, and all patients provided written informed consent. Support was provided by the NCIC and OSI Pharmaceuticals. Data were collected, managed, and analyzed by the NCIC CTG, and the manuscript was written by members of the NCIC CTG. OSI Pharmaceuticals reviewed the final manuscript and provided comments on it. Confidentiality was maintained by both the NCIC CTG and OSI Pharmaceuticals. The study chair, Dr. Shepherd, and the physician coordinator, Dr. Seymour, reviewed all the data and confirmed their completeness and accuracy.

Eligibility Criteria

Patients 18 years of age or older with an Eastern Cooperative Oncology Group (ECOG) performance status between 0 and 3 were eligible in the presence of documented pathological evidence of non–small-cell lung cancer. The patients had to have received one or two regimens of combination chemotherapy and not be eligible for further chemotherapy. Patients 70 years of age or older may have received therapy with one or two single agents. Patients had to have recovered from any toxic effects of therapy and were randomly assigned to the study treatment at least 21 days after chemotherapy (14 days after treatment with vinca alkaloids or gemcitabine) and 7 days after radiation. Adequate hematologic and biochemical values were required.

Patients with prior breast cancer, melanoma, or hypernephroma were ineligible, as were those with other malignant diseases (except basal-cell skin cancers) within the preceding five years. Other exclusion criteria were symptomatic brain metastases, clinically significant cardiac disease within one year, ventricular arrhythmias requiring medication, and clinically significant ophthalmologic or gastrointestinal abnormalities.

Study Procedures

Within seven days before randomization, a history and physical examination were obtained and hematologic and biochemical testing, chest radiography, and assessments of toxic effects and quality of life were obtained. Computed tomographic scans of the chest and abdomen were obtained within 28 days before randomization. For a patient to be evaluated for a response, at least one measurable lesion was required, but measurable disease was not mandatory for eligibility. Only patients with measurable disease were included in the analyses of complete or partial response.

Administration of the study medication was to start within two days after randomization. For grade 2 diarrhea, loperamide was recommended without reduction of the dose of erlotinib. For grade 3 diarrhea, the study treatment was withheld until the diarrhea was grade 1 or less, and then erlotinib at a dose of 100 mg daily was started. For grade 1 or 2 rash, treatment modification was not recommended. For grade 3 rash, treatment was withheld, the rash was treated symptomatically, and erlotinib at a dose of 100 mg daily was restarted when the rash was grade 1 or less.

History taking, physical examination, and hematologic and biochemical testing were performed every four weeks, and radiologic investigations every eight weeks. Patients' quality of life was evaluated every four weeks in countries with validated versions of the questionnaires.

EGFR Expression

Separate written consent for optional tissue banking and correlative studies was obtained. EGFR expression was determined with the use of immunohistochemistry in a central laboratory that used Dako kits (DakoCytomation). Positivity was defined as more than 10 percent of cells staining at any intensity for EGFR.

Statistical Analysis

The trial was designed to detect, with 90 percent power and a two-sided type I error of 5 percent, a 33 percent improvement in median survival from four months as estimated in the placebo group. For the final analysis, 582 deaths were required and were projected to occur with a sample size of 700 patients enrolled over a period of 14 months with 6 months of follow-up. The required number of deaths had occurred by January 2004, and the database was locked as of April 23, 2004. There was no interim analysis. Tumor responses were validated centrally for the first 333 patients in the trial.

The stratified log-rank test, accounting for stratification factors at randomization (except center) and EGFR protein expression (positive vs. negative vs. unknown), was used to compare progression-free survival and overall survival between treatment groups. Exploratory forward stepwise regression analyses with the use of the Cox model were performed to adjust for treatment effect and to identify prognostic factors for progression-free survival and overall survival. Candidate covariates included EGFR expression, stratification factors (except center), sex, age (60 years or less vs. more than 60 years), race or ethnic group (Asian vs. others), prior radiotherapy (yes vs. no), histologic subtype of cancer (adenocarcinoma vs. others), and smoking status (smoker vs. nonsmoker vs. unknown). Race was self-reported or determined by study personnel and was not based on country of domicile. Fisher's exact test was used to compare response rates between levels of potential predictors and rates of toxic effects between treatments. Times to deterioration (a 10-point increase from the baseline score) for cough, dyspnea, and pain were identified prospectively as the primary end points for the analysis of quality of life15 and were analyzed with the use of the log-rank test, with adjustment according to the Hochberg method16 for the comparison of multiple end points. All P values were two-sided.

Results

Patient Characteristics

Between August 2001 and January 2003, 731 patients were randomly assigned to erlotinib (488) or placebo (243). Twenty-two patients (12 assigned to erlotinib and 10 assigned to placebo) were ineligible for the following reasons: three prior chemotherapy regimens (9); single-agent chemotherapy for patients less than 70 years of age (2); inadequate time since the last treatment (5); abnormal biochemistry results (4); and symptomatic brain metastases (2). All 731 patients were included in the efficacy analyses, and 727 treated patients (485 assigned to erlotinib and 242 assigned to placebo) were included in the safety analyses. Eight patients assigned to erlotinib (1.6 percent) and 18 assigned to placebo (7.4 percent) received other EGFR inhibitors after study medication was discontinued. The groups were balanced with respect to baseline characteristics and important prognostic variables (Table 1).

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  		Table 1. Baseline Characteristics of the Patients.

 
Response and Survival

In patients with at least one target lesion, the lesions were evaluated according to RECIST (427 patients assigned to erlotinib and 211 assigned to placebo). In the erlotinib group, the rates of complete response and partial response were 0.7 percent and 8.2 percent, respectively (median duration, 7.9 months); in the placebo group, the rate of partial response was less than 1 percent (P<0.001), but these responses were not externally validated. In an intention-to-treat analysis of all patients randomly assigned to treatment, the disease-control rate (i.e., the rate of complete or partial responses and stable disease) in the erlotinib group was 45 percent; 38 percent of the patients had progressive disease, and among the remaining 17 percent progression was not confirmed. The likelihood of a response to erlotinib (Table 2) among patients with non–small-cell lung cancer was not significantly altered by performance status, prior treatments, prior response, or age, but it was higher among women (P=0.006), nonsmokers (P<0.001), Asians (P=0.02), patients with adenocarcinoma (P<0.001), and patients in whom 10 percent or more of the tumor cells expressed EGFR (P=0.10). In multiple logistic-regression analyses, never having smoked (P<0.001), the presence of adenocarcinoma (P=0.01), and EGFR expression (P=0.03) were associated with responsiveness to erlotinib.

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  		Table 2. Analysis of Responses to the Study Treatment.

 
At the time of analysis, 587 deaths had occurred (378 in the erlotinib group and 209 in the placebo group). Figure 1 shows Kaplan–Meier curves for overall survival and progression-free survival. Median overall survival in the erlotinib group was 6.7 months, and in the placebo group it was 4.7 months (adjusted hazard ratio, 0.70; 95 percent confidence interval, 0.58 to 0.85; P<0.001). In the Cox regression analysis, erlotinib remained associated with longer survival (P=0.002), as did Asian origin (P=0.01), adenocarcinoma on histologic examination (P=0.004), and never having smoked (P=0.048 vs. current or past smoking). Table 3 shows the exploratory subgroup analyses. Although the sample sizes may be inadequate to detect small or moderate differences, a benefit from erlotinib was apparent in most of the subgroups. The interaction between treatment and the covariate defining the subgroup was statistically significant only for smoking status. At the time of analysis, 682 patients had had progression of disease (450 in the erlotinib group and 232 in the placebo group). Median progression-free survival was 2.2 months in the erlotinib group and 1.8 months in the placebo group (adjusted hazard ratio, 0.61; 95 percent confidence interval, 0.51 to 0.74; P<0.001). In the Cox model, treatment with erlotinib (P<0.001) and never having smoked (P<0.01 for the comparison with current or past smoking) were associated with longer progression-free survival.


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  		Figure 1. Kaplan–Meier Curves for Overall Survival (Panel A) and Progression-free Survival (Panel B) among All Patients Randomly Assigned to Erlotinib or Placebo.

P values were adjusted for stratification factors (except center) and epidermal growth factor receptor expression.

 
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  		Table 3. Analysis of Survival.

 
Toxic Effects

Four patients who underwent randomization did not receive treatment. Table 4 shows that 19 percent of the erlotinib group required dose reductions because of drug-related toxic effects, as compared with 2 percent of the placebo group, most frequently because of rash (12 percent) and diarrhea (5 percent); 26 patients (5 percent) discontinued erlotinib because of drug-related toxic effects, as compared with 4 patients (2 percent) receiving placebo. There was a higher incidence of infection among the erlotinib patients, which may reflect longer follow-up (P<0.001). There were similar rates of pneumonitis and pulmonary fibrosis in the two groups. Two patients died of pneumonitis (one in each group).

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  		Table 4. Toxic Effects and Dose Modifications among 727 Patients Receiving the Study Drugs.

 
Quality of Life

Compliance was similar in the two groups. Patients who had responded to the quality-of-life questionnaire at baseline and had one follow-up assessment were included in the analysis. The median time to deterioration with regard to cough (4.9 months among patients receiving erlotinib and 3.7 months among those receiving placebo, P=0.04 with Hochberg adjustment), dyspnea (4.7 months and 2.9 months, respectively; adjusted P=0.03), and pain (2.8 months and 1.9 months, respectively; adjusted P=0.04) in favor of erlotinib. These results are consistent with response-based analyses of the quality of life, which found that more patients receiving erlotinib had improvement in cough, pain, and dyspnea and in the domain of overall physical function (further information is in the Supplementary Appendix, available with the complete text of this article at www.nejm.org).

Discussion

Docetaxel is the only agent known to prolong survival among patients with disease progression after cisplatin-based chemotherapy for non–small-cell lung cancer.3,4,17 Few options are available for the treatment of patients with disease progression after docetaxel or those who are not eligible for second-line chemotherapy.5,6 Clearly, new treatments are needed for such patients.

Expression of EGFR is common in non–small-cell lung cancer.18,19,20 Several agents that target EGFR are in various phases of clinical evaluation.9,21 The orally active EGFR tyrosine kinase inhibitors gefitinib and erlotinib have been evaluated in several trials. In the IDEAL 1 trial,10 patients with non–small-cell lung cancer with disease progression after platinum-based chemotherapy were randomly assigned to receive gefitinib, at a dose of 250 mg or 500 mg daily. There were no differences between the two doses with respect to response rate, time to progression, or median survival. The response rates were also similar whether gefitinib was used as second-line treatment (17.9 percent of patients) or third-line treatment (19.8 percent of patients). In the IDEAL 2 trial,11 which enrolled symptomatic patients in whom two or more chemotherapy regimens containing platinum and docetaxel had failed, the response rates were 12 percent and 9 percent, respectively, for the two dose levels. More adverse events were seen with the dose of 500 mg in both trials, but discontinuation of treatment because of toxic effects was uncommon at either dose. In a phase 2 trial of erlotinib, the response rate was 12 percent, and response did not correlate with level of EGFR in the tumor.12

In our trial, the response rate of 8.9 percent was similar to rates reported for erlotinib and gefitinib.10,11,12 Some investigators have reported that responsiveness to EGFR inhibitors correlates with sex, histologic type, race or ethnic origin, and smoking status.10,11,21 We also found that response was higher among Asians, women, patients with adenocarcinoma, and lifetime nonsmokers. Contrary to previous reports,12 the response rate in our trial was higher when 10 percent or more of tumor cells expressed EGFR.

Activating mutations in the EGFR gene have been found to predict a response to gefitinib.22,23,24,25,26,27 The results of our assays for the number of copies and mutation status of the EGFR gene are published in this issue of the Journal.28 Higher response rates were found among patients with high numbers of gene copies and mutations, but the difference was significant only for gene copies.

Because none of the early trials10,11,12 had a placebo control group, it is not possible to determine whether EGFR-inhibitor therapy was superior to palliative treatment. In our placebo-controlled trial, erlotinib did provide clinically meaningful prolongation of survival. According to the Kaplan–Meier estimates, the median survival was prolonged by two months, and 31 percent of patients treated with erlotinib were alive at one year, as compared with 22 percent in the placebo group. The two-month prolongation of survival is similar to that achieved with docetaxel in the setting of second-line chemotherapy,3,4 even though half the patients in our trial were treated after both first-line and second-line chemotherapy. In this trial and another trial,3 a significant prolongation of survival was achieved despite response rates of less than 10 percent, perhaps because a high proportion of the patients had durable stable disease while receiving treatment. Survival in this trial appears to be longer than what was achieved in a similar trial of gefitinib, although the response rates were similar in both studies. The characteristics of the patients in these two trials, however, may have differed somewhat.29

Exploratory multivariate analyses showed that only Asian origin, adenocarcinoma on histologic examination, and a history of not smoking were significant independent predictors of survival after adjustment for treatment and other potential predictors. Erlotinib had a beneficial effect on survival in almost all subgroups tested, but only the interaction between smoking status and treatment was significantly predictive of a differential effect on survival. Notably, the presence of EGFR gene mutations was not predictive of a survival benefit from erlotinib in our study.28

In the IDEAL 2 trial,11 gefitinib rapidly reduced symptoms in 35 percent to 43 percent of patients. In our trial, significantly more patients in the erlotinib group than in the placebo group had reductions in dyspnea, pain, and cough. Furthermore, the time to exacerbation of these symptoms was significantly longer in the erlotinib group. The analysis of the quality of life showed that symptom improvement was also associated with significantly improved physical function.

Rash30 and diarrhea are the main toxic effects of EGFR inhibitors.9 They led to dose reduction in 12 percent and 5 percent of patients, respectively, in our trial. Pneumonitis has been reported mainly in Japan following treatment with gefitinib.31 However, four trials of gefitinib or erlotinib combined with chemotherapy for non–small-cell lung cancer reported similar rates of pneumonitis in active-treatment and placebo groups.32,33,34,35 We rarely encountered pneumonitis or pulmonary fibrosis.

In summary, this trial shows that erlotinib, an oral tyrosine kinase inhibitor of EGFR, prolongs survival and decreases symptoms, as compared with placebo, in previously treated patients with non–small-cell lung cancer.

Supported in part by a grant from OSI Pharmaceuticals to the National Cancer Institute of Canada Clinical Trials Group.

We are indebted to Dr. Joseph Pater and Dr. Keyue Ding for their contribution to the trial; to T. Masterson, W. Gollogly, S. Melinyshyn, A. Sadura, M. Whitehead, L. Lafond, K. Hann, J. Ottaway, D. Voskoglou-Nomikos, D. Jones-Moar, T. Boyd, M. Savoie, A. Urton, T. Hanna, T. Feener, and S. Virk of the National Cancer Institute of Canada Clinical Trials Group; and to M. Ptaszynski and B. Geiger of OSI Pharmaceuticals.

* The investigators and centers participating in this National Cancer Institute of Canada Clinical Trials Group study are listed in the Appendix.


Source Information

From the Departments of Medical Oncology and Hematology (F.A.S.) and Radiation Oncology (A.B.), the University Health Network, Princess Margaret Hospital Site, and the University of Toronto (F.A.S., A.B.) — both in Toronto; the Instituto de Cancer Arnaldo Vieira de Carvalho, São Paulo (J.R.P.); the Oncological Institute Ion Chiricuta, Cluj-Napoca, Romania (T.C.); the Department of Medical Oncology, National Cancer Centre, Singapore (E.H.T.); the Department of Oncology, McGill University, Montreal (V.H.); the Faculty of Medicine, Chiangmai University, Chiangmai, Thailand (S.T.); the Confidence Medical Center, San Isidro, Argentina (D.C.); Pramongkutklao Hospital, Bangkok, Thailand (S.M.); Cross Cancer Institute, Edmonton, Alta., Canada (M.S.); the Instituto Nacional de Cancer, Praça da Cruz Vermelha, Rio de Janeiro, Brazil (R.M.); the Instituto Medico Alexander Fleming, Buenos Aires (M.K.); the Oncology Institute, Bucharest, Romania (M.D.); Hôtel Dieu Health Sciences Hospital, St. Catharines, Ont., Canada (B.F.); the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ont., Canada (D.T., D.J., L.S.); and OSI Pharmaceuticals, Boulder, Colo. (G.C., P.S.).

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Appendix

The following investigators and centers participated in this National Cancer Institute of Canada Clinical Trials Group study: A.M. Alvarez, J.L. Martinez, M. Varela, M. Van Kooten, S. Jovtis, Buenos Aires; M. Freue, Lanus, Argentina; M. Rosenthal, Parkville, Australia; D. Yip, Garran, Australia; R. De Boer, Footscray, Australia; S. Ackland, Waratah, Australia; P. Clingan, Wollongong, Australia; D. Campos, San Isidro, Argentina; A. del Giglio, Santo Andre, Brazil; C. Mathias, Bahia, Brazil; I.L Santoro, J.R. Pereira, São Paulo; A.M. Murad, Belo Horizonte, Brazil; R.D.A. Ribeiro, Ceara, Brazil; S. Lago, Porto Alegre, Brazil; J. Vinholes, Porto Alegre, Brazil; R. Martins, Rio de Janeiro; S. Rorke, St. John's, Canada; W. Morzycki, Halifax, Canada; F. Laberge, R. Whittom, Ste.-Foy, Canada; V. Hirsh, J. Ayoub, Montreal; R.W. Gregg, Kingston, Canada; S. Laurie, Ottawa; F. Wierzbicki, Oshawa, Canada; B. Findlay, St. Catharines, Canada; A. Arnold, Hamilton, Canada; L.A. Zibdawi, Newmarket, Canada; J. Meharchand, F. Shepherd, R.L. Burkes, Y.C. Ung, Toronto; J.J. Wilson, Weston, Canada; B. Pressnail, Barrie, Canada; R. Myers, Mississauga, Canada; J. Noble, Sudbury, Canada; D. Walde, Sault Ste. Marie, Canada; S. Navaratnam, Winnipeg, Canada; H.I. Chalchal, Regina, Canada; D.G. Morris, Calgary, Canada; M. Smylie, Edmonton, Canada; D. Fenton, Kelowna, Canada; H. Martins, Victoria, Canada; J. Gutierrez, Las Condes, Chile; U. Gatzemeier, Grobhansdorf, Germany; J. von Pawel, Gauting, Germany; R. Loddenkemper, Berlin; A. Gerogianni, Athens; R. Chan, Pokfulam, Hong Kong; D. Flex, Petach Tikva, Israel; D. Loven, Afula, Israel; M.C. Wollner, Haifa, Israel; H. Biran, Rehovot, Israel; M. Levitt, Tel Hashomer, Israel; A. Cyjon, Zerifin, Israel; J. Lopez, Dviango, Mexico; J. Robles, Mexico City; G. Calderillo, Tlalpan, Mexico; T. Christmas, Auckland, New Zealand; A.B. Simpson, Wellington, New Zealand; M. Dediu, Bucharest, Romania; T.-E. Ciuleanu, Cluj-Napaca, Romania; M. Patran, Sibiu, Romania; L. Miron, Lasi, Romania; L. Ek, Lund, Sweden; B. Bergman, Gothenburg, Sweden; R. Soo, E.H. Tan, Singapore; S. Maoleekoonpairoj, A. Cheirsilpa, Bangkok, Thailand; S. Thongprasert, Chiangmai, Thailand; C.M. Rudin, Chicago; P. Ruff, Johannesburg, South Africa; D.J. Hacking, Westridge, South Africa; S.J. Fourie, Pretoria, South Africa; C. Jacobs, Port Elizabeth, South Africa; C.F. Slabber, Brooklyn Square, South Africa; D.A. Vorobiof, Parklands, South Africa; K. Chi-Hei, Pokfulam, Hong Kong; W. Arpornwirat, Bangkok, Thailand; M. Zukin, Rio de Janeiro.


 

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