1 The Royal Marsden Hospital NHS Trust, Sutton, Surrey; 2 Kent Cancer Centre, Maidstone, Kent; 3 Chest Clinic, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester, UK; 4 Lungenabteilung, Allgemeines Krankenhaus, Hamburg, Germany; 5 University Department of Oncology, Leicester Royal Infirmary, Infirmary Square, Leicester, UK; 6 Klinika Chemioterapii, Centrum Oncologii Oddzial w Krakowie, Kraków, Poland; 7 ASKLEPIOS Fachklinik, Munchen Gauting, Abteilung Onkologie, Robert Koch Allee 2, München-Gauting, Germany; 8 Krankenhaus Großhansdorf, Pneumolog-Onkolog. Ambulanz, Großhansdorf, Germany
Received 25 November 2003; revised 22 January 2004; accepted 3 February 2004
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This open-label, randomised phase III study was designed to further investigate the clinical activity and safety of SRL172 (killed Mycobacterium vaccae suspension) with chemotherapy in the treatment of non-small-cell lung cancer (NSCLC).
Patients and methods:
Patients were randomised to receive platinum-based chemotherapy, consisting of up to six cycles of MVP (mitomycin, vinblastine and cisplatin or carboplatin) with (210 patients) or without (209 patients) monthly SRL172.
Results:
There was no statistical difference between the two groups in overall survival (primary efficacy end point) over the course of the study (median overall survival of 223 days versus 225 days; P = 0.65). However, a higher proportion of patients were alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (90%), than in the chemotherapy alone group (83%) (P = 0.061). At the end of the treatment phase, the response rate was 37% in the combined group and 33% in the chemotherapy alone group. Patients in the chemotherapy alone group had greater deterioration in their Global Health Status score (14.3) than patients in the chemotherapy plus SRL172 group (6.6) (P = 0.02).
Conclusion:
In this non-placebo controlled trial, SRL172 when added to standard cancer chemotherapy significantly improved patient quality of life without affecting overall survival times.
Key words: NSCLC, chemotherapy, immunotherapy, SRL172
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although advanced-stage NSCLC (stage IIIb/IV) remains a non-curable disease, chemotherapy has been shown to increase symptom control, improve quality of life, be cost-effective and increase survival rates (median and 1-year) [5]. Most patients newly diagnosed with late-stage NSCLC and a good performance status will be treated with chemotherapy. Modern platinum combination chemotherapy regimens produced an overall response rate of 20% with a median survival of 7.9 months and 1-year survival of 33% [6]. In the UK MIC2 study, chemotherapy provided overall response rates of 33%, 1-year survival of 26% and median survival of
7 months [7].
SRL172 is a suspension of killed Mycobacterium vaccae, a rapidly growing mycobacterium that normally grows as an environmental saprophyte. It has several functions relevant to its activity in cancer, including activation of antigen-presenting cells (APCs), Th1 adjuvant properties, suppression of pre-existing Th2 responses (via activation of regulatory T cells), and activation of natural killer (NK) cells [8]. A switch to a Th2 cytokine profile in cancer has been described, for example, in colorectal cancer [9], NSCLC [10] and small-cell lung cancer (SCLC) [11].
The activity of SRL172 in various forms of cancer has been suggested in a number of phase I and II clinical studies in malignant melanoma [12], mesothelioma [8] and prostate cancer [13]. This current study was designed following initial results suggesting a 29% survival benefit in a small randomised phase II study in NSCLC [14] and a similar result in SCLC [15]. These studies raised the possibility of synergy between chemotherapy and SRL172. This trial aimed to investigate the efficacy and safety of SRL172 in the treatment of patients with surgically unresectable locally advanced or metastatic NSCLC, when given in addition to standard chemotherapy.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The protocol and its amendments were approved by the appropriate Independent Ethics Committee (IEC) for each participating centre. The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and with the principles stated in the Declaration of Helsinki. Written informed consent was obtained from all patients.
Patient selection
Male or female patients aged at least 18 years, with histologically and/or cytologically confirmed unresectable NSCLC (stages IIIa, IIIb and IV) were eligible for the study. Patients were to have measurable lesions in at least one site, which had not been previously irradiated, an European Organisation for Research and Treatment of CancerWorld Health Organisation (EORTCWHO) performance status of <2 and life expectancy of >3 months in the opinion of the investigator.
Patients were excluded if they had severe, active, uncontrolled infection requiring systemic antibiotics, antivirals or antifungals; if they had received previous chemotherapy for NSCLC; if they had evidence of central nervous system (CNS) metastases or if they had any previous or concurrent malignancy (except adequately treated carcinoma in situ of the cervix, basal cell carcinoma of the skin and/or non-melanoma skin cancer or if previous malignancy was more than 5 years prior and there were no signs of recurrence). They must not have received depot corticosteroids in the 6 weeks prior to day 0 or chronic systemic corticosteroids in the 2 weeks prior to administration of the study drug. Patients who had previously received SRL172 were also excluded.
Treatment schedule
Patients were screened to ensure that 400 evaluable patients were enrolled. Following a screening period of up to 28 days, those who fulfilled the entry criteria and had given written informed consent were stratified by extent of disease as either surgically unresectable stage IIIa or stage IIIb/IV. These patients were then randomised to receive either chemotherapy alone or chemotherapy plus SRL172. Chemotherapy consisted of up to six cycles of MVP [mitomycin C 810 mg/m2; vinblastine 6 mg/m2 (max 10 mg) and cisplatin 50120 mg/m2 or carboplatin AUC of 46 (mg/ml x min) x (EDTA + 25)] on day 0 and weeks 3, 6, 9, 12 and 15. The doses used were according to the standard protocol at each centre, and mitomycin C was excluded at cycles three and five.
SRL172 administration
SRL172 (a suspension of heat-killed M. vaccae NCTC 11659) was supplied in borate-buffered saline at pH 8, 0.1 ml of which contained 1 mg wet weight corresponding to 109 bacilli. A dose of 0.1 ml was given intradermally over the deltoid muscle on day 0 and weeks 4, 8, 12 and 16 during the treatment phase. The vials of SRL172 were supplied and kept in refrigrators at 4°C.
The four phases of the study are illustrated in Figure 1. If there was no disease progression after the initial treatment phase, patients randomised to receive SRL172 entered a maintenance and follow-up phase, during which they could continue to receive SRL172 and were clinically assessed every 8 weeks, until there was clear evidence of disease progression. The patients randomised to receive chemotherapy alone entered a follow-up phase during which they were clinically assessed every 8 weeks, until there was clear evidence of disease progression. After disease progression, patients entered the survival phase of the study during which they were clinically assessed every 12 weeks.
|
Statistical analysis
Survival. The sample size requirements for this study were based on the comparison planned for the primary efficacy parameter, overall survival time. Preliminary results from a pilot study [14] indicated an increase in median overall survival time from 7 months (MVP-treated patients) to 9.5 months (MVP plus SRL172), i.e. a median survival time ratio of 1.4. Estimates from the literature suggested a 1-year survival rate for MVP-treated patients of
10%. Combining these estimates yielded an estimated 1-year survival rate for chemotherapy plus SRL172 patients of
20%. Thus, allowing for a 10% drop out, 80% power and a significance level of 0.02; 200 patients per group (i.e. 400 evaluable patients) were enrolled into the study.
The overall survival curves were compared using a stratified Mantel Haenszel test and KaplanMeier plots of the survival times were performed. The analyses used all information up to the date of death. Patients were censored at the last date they were known to be alive (i.e. last assessment date). Each disease stage was also analysed separately in the same manner. Dichotomous efficacy variables (i.e. proportions of patients with an event) were compared between treatment groups using Fishers exact test and corresponding 95% confidence interval. Time-to-event variables were compared between treatment groups using a Mantel Haenszel test, with presentation of summary statistics derived from KaplanMeier estimates. Duration of event variables were compared between treatment groups using a Wilcoxon rank sum test.
Summary statistics were generated for other efficacy and safety variables. Additional exploratory analyses were conducted, using accelerated failure time (AFT) modelling, to evaluate the influence of covariates on survival time. Subgroup analyses were performed of overall survival and the proportion of patients alive at the end of the treatment phase.
Quality of life. The Global Health Status scale was the primary scale examined for significant treatment differences at the 0.05 level of significance. The null hypothesis was that there was no statistical difference between active treatment groups. Individual scale scores were examined for differences, adjusting for multiplicity using the HochbergBenjamini sequential testing procedure. EORTC assessments were scored according to standard rules as described in the EORTC QLQC30 (EORTC Quality of Life QuestionnaireCore 30) Scoring Manual [16]. All of the scales and single-item measures ranged in score from 0 to 100. A high scale score represented a higher response level (e.g. high score for a functional scale represented a high level of functioning and a high score for a symptom scale represented a high level of symptomatology/problems). The primary quality of life analysis was the evaluation of longitudinal scores in the chemotherapy plus SRL172 group, compared with the chemotherapy alone group using generalised estimating equations, adjusting for covariates.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
The majority of patients enrolled were male (71% overall) and the median age was 61 years. The most frequent histology, reflecting the fact that this was a European study, was squamous cell carcinoma (41%), followed by adenocarcinoma (35%), large cell carcinoma (13%) and other types of carcinoma (11%) [8].
Primary efficacy analysis
The primary efficacy end point for this study was overall survival. The KaplanMeier plot of overall survival is presented in Figure 2. No difference was observed between the treatment groups in overall survival, with a median survival time of 223 days in the chemotherapy plus SRL172 group, compared to 225 days in the chemotherapy alone group (P = 0.65).
|
In this context it is of note that only 46% of patients randomised to the chemotherapy plus SRL172 group received the scheduled number of doses during the treatment phase and 63% of patients did not receive any further injections of SRL172 after the end of the 15-week treatment phase. The mean number of SRL172 injections overall was 4.7 for all patients in the SRL172 group. Also, only 27% of patients in the chemotherapy plus SRL172 group and 28% of patients in the chemotherapy alone group received six courses of MVP. Seventy-seven per cent of patients received three or more MVP courses in this study.
Secondary efficacy analyses
The results from the secondary efficacy analyses were in general in accordance with the results of the primary analysis. None of the prospectively defined secondary efficacy analyses were statistically significant, although there was a trend towards improved time to progression for the chemotherapy plus SRL172 group compared to the chemotherapy alone group (158 days versus 135 days, P = 0.1556).
Overall, in each of the treatment groups, 26% of patients were alive at 1 year. There was a slightly higher proportion of patients alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (186 patients, 90%), than in the chemotherapy alone group (174 patients, 83%). This difference just failed to achieve statistical significance (P = 0.061).
Similar proportions of patients in each treatment group had an objective tumour response during the study (chemotherapy plus SRL172, 37%; chemotherapy alone, 33%) (P = 0.413). There was no significant difference between the treatment groups in the time to an objective tumour response. The median time from objective tumour response to progression was 172 days in the chemotherapy plus SRL172 group and 150 days in the chemotherapy alone group (P = 0.1653). There was no difference between the treatment groups in the time from disease progression to death.
There was no statistically significant difference in survival in different subgroups (male versus female and performance status 0/1 versus 2), although a trend was seen in adenocarcinomas (193 days survival with chemotherapy plus SRL172 compared with 154 days for chemotherapy alone; P = 0.10, 144 patients).
Quality of life
At the end of the 15-week treatment phase, there was a statistically significant difference in the mean change from baseline in the primary quality of life variable, Global Health Status, between the treatment groups (adjusted P-value 0.002), with patients in the chemotherapy alone group (172 patients) having a greater deterioration in their Global Health Status score (14.3) than patients in the chemotherapy plus SRL172 group (179 patients) (6.6). Two methods were used in the analysis: Multiple Imputational Analysis (MIA) (43% imputed) and Last Observation Carried Forward (LOCF) (39% carried forward). Both techniques gave similar results.
Mean changes from baseline (179 patients) in EORTC QLQC30 composite scores in the chemotherapy plus SRL172 group, compared to the chemotherapy alone group, at the end of the treatment phase are presented in Table 3. Missing values in this analysis were accounted for by MIA. Statistically significant differences at the end of the treatment phase were noted in favour of the chemotherapy plus SRL172 group in all other composite components of the QLQC30 questionnaire, except role limited due to physical problems and social functioning where differences were not statistically significant. Statistically significant differences at the end of the treatment phase were also noted in favour of the chemotherapy plus SRL172 group for many of the single items on the QLQC30 questionnaire.
|
|
|
The most frequently occurring events (serious and non-serious) in both treatment groups were anaemia, leucopenia and thrombocytopenia, which were reported by 33.8%, 26.2% and 22.9% of patients in the chemotherapy plus SRL172 group and 25.8%, 23.4% and 16.3% of patients in the chemotherapy alone group, respectively. The differences were not statistically significant. The majority of these types of events were considered by the investigator not to be related to SRL172. A total of 35 patients (16.7%) in the chemotherapy plus SRL172 group reported an injection site reaction. However, in the majority of cases injection site reactions were of a mild intensity, with severe reactions reported in only two patients (1%) overall. There were more patients with NSCLC in the chemotherapy plus SRL172 group who reported chest pain (11%) than in the chemotherapy alone group (4%). However, only one case of chest pain in the chemotherapy plus SRL172 group was considered to be severe, compared to two cases in the chemotherapy alone group. None of the cases of chest pain were considered by the investigator to be related to study medication.
No significant differences between treatment groups were observed in the incidence of abnormal laboratory values, vital signs, physical examination, tumour-related symptoms or chemotherapy toxicities.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Quality of life measures showed an improvement in performance status (for example cognitive functioning and vitality), a reduction in treatment-related adverse effects (including nausea and vomiting and peripheral neuropathy) and relief of cancer-related symptoms (such as bodily pain and dyspnoea) in those additionally receiving SRL172, compared with the chemotherapy alone group (Tables 3 and 4). These improvements in quality of life in the terminal stages of NSCLC may be important given the many concerns regarding the administration of cancer chemotherapy in advanced disease including toxicity, the perceived high cost of treatment [17], the low response rate and moderate impact on long-term survival [7].
Unfortunately, in this study only 30 patients (14%) received one or more SRL172 injections after the treatment phase. This is due to the high drop out in NSCLC studies due to early progressive disease of the order of 50% at 5 months, i.e. at the end of the 15-week treatment phase. Sixty-three per cent of patients did not receive any further injections of SRL172 after the end of the 15-week treatment phase. It is possible that a greater effect of SRL172 might have been observed if a more intensive treatment schedule had been used particularly after the treatment phase. Results from a phase II study of SRL172 in renal cell cancer, in which patients did not receive any chemotherapy and continued with SRL172 throughout follow-up, suggested that monotherapy with SRL172 may offer a similar survival benefit to that conferred by established biological treatments in patients with renal cancer [18].
Safety assessments showed few differences between treatment groups. Although adverse effects were slightly higher with SRL172 and chemotherapy, this was not statistically significant and was likely to be due to increased reporting of the SRL172 plus chemotherapy arm in this non-blinded study. The combination of chemotherapy and SRL172 was well tolerated with mild injection site reactions occurring in 17% of SRL172 patients.
The results from this study suggest that further work with patients in whom chemotherapy treatment is completed or not warranted, would be of interest and would require a placebo control to confirm the quality of life findings. Also, treatment should be given more frequently and/or continued for a longer period.
![]() |
Acknowledgements |
---|
![]() |
FOOTNOTES |
---|
Members are listed in the Acknowledgements.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Jett JR. Current treatment of unresectable lung cancer. Mayo Clin Proc 1993; 68: 603611.[ISI][Medline]
3. Cancer Survival Trends. Office for National Statistics, HMSO 1999; 95.
4. Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In De Vita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th edition. Philadelphia, PA: Lippincott-Raven 1997; 858910.
5. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899909.
6. Schiller JH, Harrington D, Belani CP et al. Comparing regimens for nonsmall-cell lung cancer (ECOG Trial). N Engl J Med 2002; 346: 9298.
7. Cullen MH, Billingham LJ, Woodroffe CM et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 31883194.
8. Mendes R, OBrien MER, Mitra A et al. Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy inpatients with malignant mesothelioma. Br J Cancer 2002; 86: 336341.[CrossRef][ISI][Medline]
9. Pellegrini P, Berghella AM, Del Beato T et al. Dysregulation in Th1 and Th2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression. Cancer Immunol Immunother 1996; 42: 18.[CrossRef][ISI][Medline]
10. Huang M, Wang J, Lee P et al. Human non-small cell lung cancer cells express a type 2 cytokine pattern. Cancer Res 1995; 55: 38473853.[Abstract]
11. Fischer JR, Schindel M, Bulzebruck H et al. Decrease of interleukin-2 secretion is a new independent prognostic factor associated with poor survival in patients with small-cell lung cancer. Ann Oncol 1997; 8: 457461.[Abstract]
12. Maraveyas A, Baban B, Kennard D et al. Possible improved survival of patients with stage IV AJCC melanoma receiving SRL172 immunotherapy: correlation with induction of increased levels of intracellular interleukin-2 in peripheral blood lymphocytes. Ann Oncol 1999; 10: 817824.[Abstract]
13. Hrouda D, Baban B, Dunsmuir WD et al. Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SRL172). Br J Urology 1998; 82: 568573.[ISI][Medline]
14. OBrien MER, Saini A, Souberbielle BE et al. A randomised phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small cell lung cancer and mesothelioma. Br J Cancer 2000; 83: 853857.[CrossRef][ISI][Medline]
15. Assersohn L, Souberbielle BE, OBrien MER et al. A randomised pilot study of SRL172 (Mycobacterium vaccae) in patients with small cell lung cancer (SCLC) treated with chemotherapy. Clin Oncol 2002; 14: 2327.[CrossRef][ISI]
16. Fayers P, Aaronson N, Bjordal K et al. on behalf of EORTC Quality of Life Study Group. EORTC QLQC30 Scoring Manual.
17. Goodwin PJ, Shepherd FA. Economic issues in lung cancer: a review. J Clin Oncol 1998; 16: 39003912.[Abstract]
18. Patel PM, Johnston C, Banks RE et al. SRL172 (a killed Mycobacterium vaccae suspension) vaccination in the treatment of metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 2003; 22: 409 (Abstr).