Bristol-Myers Squibb Pharmaceuticals Ltd Taxol Early Breast Cancer SUBMISSION TO THE NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

Transcription

1 SUBMISSION TO THE NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE TAXOL (PACLITAXEL) FOR THE ADJUVANT TREATMENT OF EARLY BREAST CANCER Page 1 of 86

2 Background The purpose of the background section is to summarise and contextualise the decision problem. It should contain the following information. 1.1 Summary of decision problem [maximum 600 words] The purpose of this section is to summarise the decision problem and state the key factors that are addressed in the submission: 1. intervention This submission provides clinical and cost-effectiveness information to support the use of Paclitaxel (Taxol ) in adjuvant breast cancer in the UK. Paclitaxel (Taxol ) is an anti-cancer agent which has been used extensively in the treatment of metastatic breast cancer for almost a decade; it has now been shown to have an important role in the adjuvant treatment of breast cancer at an earlier stage of the disease. Paclitaxel is used in the UK following anthracycline and cyclophosphamide for the adjuvant treatment of operable node positive breast cancer in women who are candidates for cytotoxic chemotherapy. 2. population, including subgroups Women who have been diagnosed with early stage operable breast cancer who are candidates for cytotoxic chemotherapy regardless of oestrogen receptor status. 3. relevant comparator(s) Choice of adjuvant therapy in the UK varies by centre and clinician. Common treatment regimens include AC, EC, ECMF, FAC, FEC and AC+T: A= adriamycin C= cyclophosphamide E= epirubcin Page 2 of 86

3 F= 5-fluorouracil M= methotrexate T= taxane (either paclitaxel or docetaxel as specified) D= docetaxel (Taxotere) P= paclitaxel (Taxol) For this submission the main regimens for comparison are doxorubicin and cyclophosphamide followed by paclitaxel (AC+T), versus doxorubicin and cyclophosphamide (AC) from two studies, the Cancer and Leukemia Group B (CALGB) 9344 trial and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. An additional study is presented comparing doxorubicin and cyclophosphamide followed by paclitaxel, with doxorubicin and cyclophosphamide followed by docetaxel from the North American Breast Cancer Intergroup (NABCI) E1199 trial. Paclitaxel (175 mg/m² i.v.) is licensed in the UK for administration over a period of 3 hours every 3 weeks for four courses, following AC therapy. NSABP B-28 used the identical sequence of AC as CALGB 9344 followed by paclitaxel with a higher dose of 225 mg/m² i.v.. NABCI E1199 which in addition to one trial arm containing paclitaxel 175 mg/m² i.v. every 3 weeks also contained one trial arm with weekly paclitaxel at 80 mg/m² i.v. The trial contained two arms with docetaxel, 100mg/m² i.v. every 3 weeks and weekly 35mg/m² i.v.. 4. outcomes The principal clinical outcomes from these studies are disease free survival (DFS) and overall survival (OS). For the economic analysis the outcome is the cost per quality adjusted life year (QALY). In CALGB 9344, at a median follow-up of nearly 70 months, when administered for 4 courses subsequent to AC chemotherapy, paclitaxel Page 3 of 86

4 resulted in a 17% (p=0.002) reduction in risk of disease recurrence and reduced the risk of death by 18% (p=0.006), as compared to AC chemotherapy alone. The magnitude of the effect of paclitaxel on disease-free survival observed in the NSABP B-28 study is similar to that observed in CALGB 9344 (17% reduction in the risk of relapse). The reduction in the risk of death produced by the addition of paclitaxel compared to AC alone in the NSABP B-28 study failed to reach statistical significance. The addition of paclitaxel resulted in a significant improvement of DFS and in the case of CALGB 9344 also of OS with acceptable toxicity. Overall the safety data in these studies demonstrated an acceptable risk-benefit profile with no unexpected haematological or non-haematological toxicities. In NABCI E1199 DFS and OS were similar in the taxane treatment arms. Neutropenia was more common in the docetaxel exposed patients. Economic modelling based on data from the above studies and the literature found that AC+T (paclitaxel, doxorubicin and cyclophosphamide) was highly cost effective in comparison to AC therapy alone with a mean expected cost per QALY of 4, key issues. The results described and discussed in this submission lead to the conclusion that the addition of paclitaxel to an anthracycline based regimen provides an efficacy benefit that is clinically relevant and cost-effective and support usage of this agent in the adjuvant breast cancer setting in the UK. There may be insufficient capacity in the NHS to meet current and future demand for chemotherapy and service delivery, as considered in the recent report by the Cancer Capacity Coalition. 1 Page 4 of 86

5 1.2 Description of technology under assessment 6. Give the brand name, approved name and where appropriate, therapeutic class. Taxol, paclitaxel, taxane. 7. Does the technology have a UK marketing authorisation/ce marking for the indications detailed in this submission? If yes, please give the date it received it. If no, please state current UK regulatory status, with relevant dates (for example, date of application and/or expected approval dates). The original marketing authorisation for metastatic breast cancer was received in The adjuvant chemotherapy in breast carcinoma indication was approved by the MHRA on the 8th of March Does the technology have regulatory approval outside of the UK? Taxol (paclitaxel) is licensed in 97 countries worldwide. In Europe it is licensed via the Mutual Recognition Procedure. Netherlands is the Reference Member State. Concerned Member States are: Austria, Belgium, Germany, Denmark, Greece, Spain, Finland, France, Ireland, Italy, Luxembourg, Portugal, Sweden and the UK. 9. If the technology has not been launched, please supply the anticipated launch date for the UK. Not applicable. 10. Is the technology subject to any other form of Health Technology Assessment either in the UK or elsewhere? If so, what is the timescale for completion? The Regional Drug and Therapeutics Centre in Newcastle are preparing their assessment with expected publication in Page 5 of 86

6 11. What is the principal mechanism of action of the technology? Paclitaxel (Taxol ) is a taxane anti-cancer drug and one of the two most commonly used agents in this category. Paclitaxel inhibits the functioning of microtubules required for mitotic spindle formation, this consequently blocks cell division and tumour growth. 2,3 Taxanes also induce apoptosis by interrupting signal transduction. 2,4 Weekly paclitaxel schedules appear to demonstrate anti-angiogenic effects. 12. For pharmaceuticals, what formulation(s) (for example, ampoule, vial, sustained release tablet), strength(s) and pack size(s) will be available? Taxol is marketed in Type 1 glass vials (with butyl rubber stopper) which contain contain 30 mg, 100 mg, 150 mg or 300 mg of paclitaxel in 5 ml, 16.7 ml, 25 ml or 50 ml solution respectively. The vials are packaged individually in a carton. Boxes containing 10 cartons are also available. 13. What is the acquisition cost of the technology (minus VAT)? If the unit cost of the technology is not yet known, please provide details of the anticipated unit cost, including the range of possible unit costs. For devices, provide the list price and average selling price. Data exclusivity for Taxol expired in September Below information on the UK list price is provided. However it should be noted that the acquisition cost is significantly lower due to the advent of generic competition and that acquisition cost is either negotiated by local centre or through regional NHS tenders. Taxol is available as a 6mg/mL concentrate for solution for infusion which comes in four different volumes. The NHS list price (excluding VAT) of Taxol in each of these four presentations is outlined below: -1 vial containing 30mg vial containing 100mg Page 6 of 86

7 -1 vial containing 150mg vial containing 300mg 1, Source: December What are the (proposed) main indication(s)? Current anti-cancer indications and dosing regimens for paclitaxel marketed as Taxol are shown in the table below. Table 1: Taxol licensed indications Treatment /Indication Other medications to be used in combination with, before or after paclitaxel Dose/duration of paclitaxel First-line chemotherapy Cisplatin Paclitaxel (175 mg/m 2 i.v.) of ovarian carcinoma administered over 3 hours, followed by cisplatin 75 mg/m 2 every three weeks or paclitaxel 135 mg/m 2, in a 24-hour infusion, followed by cisplatin 75 mg/m 2, with a 3-week Second-line chemotherapy of ovarian carcinoma Adjuvant chemotherapy in breast carcinoma First-line chemotherapy of locally advanced or metastatic breast carcinoma Second-line chemotherapy of metastatic breast carcinoma Treatment of advanced nonsmall cell lung carcinoma (NSCLC) Treatment of AIDS-related Karposi's sarcoma (KS) Single agent Anthracycline and cyclophosphamide (AC) Doxorubicin or trastuzumab (trastuzumab is used in patients over expressing HER-2 and for whom anthracyclin is not suitable) Single agent Cisplatin Single agent interval between courses Paclitaxel (175 mg/m² i.v.) administered over a period of 3 hours, with a 3-week interval between courses Paclitaxel (175 mg/m² i.v.) administered over a period of 3 hours every 3 weeks for four courses, following AC therapy Paclitaxel when used with doxorubicin (50 mg/m 2 ) should be administered 24 hours after doxorubicin. Paclitaxel (220 mg/m² i.v.) administered over 3 hours, with a 3-week interval between courses. In combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m² i.v. over a period of 3 hours, with a 3-week interval between courses) Paclitaxel (175 mg/m 2 i.v.) administered over a period of 3 hours, with a 3-week interval between courses Paclitaxel (175 mg/m 2 i.v.) administered over a period of 3 hours, followed by cisplatin 80 mg/m², with a 3-week interval between courses Paclitaxel (100 mg/m 2 ) administered as a 3-hour intravenous infusion every two weeks Page 7 of 86

8 All patients must be premedicated with corticosteroids, antihistamines, and H 2 antagonists prior to Taxol e.g. dexamethasone 20 mg (8 to 20mg in KS) oral or iv ; diphenhydramine 50 mg i.v (or equivalent antihistamine) and cimetidine 300 mg i.v.or ranitidine 50 mg i.v. 15. What is the proposed course of treatment? For pharmaceuticals, list the dose, dosing frequency, length of course and anticipated frequency of repeat courses of treatment. In adjuvant chemotherapy in breast carcinoma paclitaxel (175 mg/m² i.v.) should be administered over a period of 3 hours every 3 weeks for four courses, following anthracycline and cyclophosphamide (AC), therapy. 16. What other therapies, if any, are likely to be prescribed as part of a course of treatment? Adjuvant therapy will follow surgery. Anthracycline and cyclophosphamide are the standard breast cancer chemotherapy regimens in the UK. Additionally short-term anti-histamine and anti-sickness medications will usually be administered with the chemotherapy. Radiotherapy and hormone antagonist therapy will also usually be considered. 17. For patients being treated with this technology, are there any other aspects that need to be taken into account? For example, are there additional tests or investigations needed for selection, or particular administration requirements, or is there a need for monitoring of patients over and above usual clinical practice for this condition? If yes, provide details. No. 18. For pharmaceuticals, please provide a Summary of Product Characteristics (SPC) or draft SPC as an appendix to the submission. See Appendix 1. Page 8 of 86

9 19. For devices, please provide the (anticipated) CE marking, including the indication for use, (draft) technical manual and details of any different versions of the same device, as an appendix to the submission. Not applicable. 20. What is the current usage of the technology in the NHS? Include details of use in ongoing clinical trials. Paclitaxel is commonly used in the UK for various forms of cancer as detailed in the response to question 14. The response to question 38 provides a list of ongoing trials in the UK and elsewhere. 1.3 Context 21. Please provide a brief overview of the disease and current treatment options. Breast cancer is the most common female cancer in the UK. Prevalence is approximately 950 per 100,000. Prevalence increases with age, 5.6 cases per 100,000 for age 0-44 years, 38.7 cases per 100,000 for age and 55.7 cases per 100,000 for age There are more than 40,000 new cases per year and about 12,500 deaths. 6,7 Survival rates progressively decrease over time going from 91% at 1 year from the diagnosis to 65% at 5 years and stage of disease at diagnosis remains the most important prognostic variable. 8 More than 85% of cases of newly diagnosed breast cancer are detected as a lump in the breast, most commonly first noticed by the patient. Most patients with breast cancer are diagnosed with operable disease, which implies that clinically detectable cancer manifestations are confined to the breast and the ipsilateral axillary lymph nodes. However, most women with primary breast cancer have subclinical metastases and distant metastases are ultimately detected in a high percentage of those treated with apparent curative surgery, with or without radiotherapy. 9 The current multidisciplinary approach to operable disease involves the sequential use of surgery, adjuvant systemic therapy and, in selected cases, Page 9 of 86

10 radiation therapy. Adjuvant systemic therapy has become a standard form of treatment for the purpose of eradicating clinically undetectable, microscopic deposits of tumour cells that, at the time of diagnosis, have already spread from the primary tumour. 22. What was the rationale for the development of the new technology? Paclitaxel was investigated in the adjuvant setting based on well-established activity in the metastatic setting. Following the introduction of the taxanes in the treatment of metastatic breast cancer in the early 1990 s, clinical trials in the US and Europe started integrating taxanes in the adjuvant treatment of breast cancer. The rationale for this was based on the high level of activity shown by paclitaxel in metastatic breast cancer, its different mechanism of action compared to other commonly used agents and its incomplete cross resistance with anthracyclines. 23. What is the suggested place in therapy for this technology with respect to treatments currently available? The mode of action of paclitaxel is different to other classes of anti-cancer medications such as the alkylating drugs, anthracycline antibiotics, antimetabolites and topoisomerase inhibitors. As a result, there is complete or partial lack of cross resistance with other drugs. Paclitaxel can therefore be used in combination or sequentially with other chemotherapy agents to increase treatment efficacy and survival over existing treatment regimens such as doxorubicin and cyclophosphamide (AC). 24. Describe any current variation in services and/or uncertainty about best practice, including cost effectiveness. Choice of therapy in the UK varies by centre and clinician. Adjuvant chemotherapy using taxanes has been well established in clinical practice in several industrialised nations and experience has been gained in many UK centres from taking part in international multi-centre trials. Page 10 of 86

11 25. Provide details of any relevant guidelines or protocols. Several international guidelines are detailed in Appendix 2: International Consensus Guidelines St Gallen 2005, NCCN Guidelines on the treatment of breast cancer 2005 and NIH Consensus Statement on adjuvant therapy for breast cancer Comparator(s) 26. Describe the relevant comparator(s) and provide a justification for your selection. In some cases, comparisons with more than one comparator or combination-therapy comparators will be necessary. The Institute considers the most relevant comparators to be those that the new technology is attempting to displace from UK practice. Choice of adjuvant therapy in the UK varies by centre and clinician. Common treatment regimens include AC, EC, ECMF, FAC, FEC and AC+T: A= adriamycin C= cyclophosphamide E= epirubcin F= 5-fluorouracil M= methotrexate T= taxane (either paclitaxel or docetaxel as specified) D= docetaxel (Taxotere) P= paclitaxel (Taxol) For this submission the main regimens for comparison are doxorubicin and cyclophosphamide followed by paclitaxel (AC+T), versus doxorubicin and cyclophosphamide (AC) from two studies, the Cancer and Leukemia Group B (CALGB) 9344 trial and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. An additional study is presented comparing doxorubicin and cyclophosphamide followed by paclitaxel, with doxorubicin and Page 11 of 86

12 cyclophosphamide followed by docetaxel from the North American Breast Cancer Intergroup (NABCI) E1199 trial. Paclitaxel (175 mg/m² i.v.) is licensed in the UK for administration over a period of 3 hours every 3 weeks for four courses, following AC therapy. NSABP B-28 used the identical sequence of AC as CALGB 9344 followed by paclitaxel with a higher dose of 225 mg/m² i.v.. NABCI E1199 which in addition to one trial arm containing paclitaxel 175 mg/m² i.v. every 3 weeks also contained one trial arm with weekly paclitaxel at 80 mg/m² i.v. The trial contained two arms with docetaxel, 100mg/m² i.v. every 3 weeks and weekly 35mg/m² i.v What are the main differences in the indications, contraindications, cautions, warnings and adverse effects between the proposed technology and the main comparator(s)? (100 word maximum) Paclitaxel (175 mg/m² i.v.) is licensed in the UK for administration over a period of 3 hours every 3 weeks for four courses, following AC therapy. Docetaxel is licensed in the UK in combination with doxorubicin and cyclophosphamide for the adjuvant treatment of patients with operable nodepositive breast cancer. In the adjuvant treatment of operable node-positive breast cancer, the recommended dose of docetaxel is 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 every 3 weeks for 6 cycles. Information on contraindications, cautions, warnings and adverse effects can be found in the relevant Summaries of Product characteristics contained in Appendix 1. 2 Clinical evidence 2.1 Identification of studies 28. Describe the strategies used to retrieve relevant clinical data both from the published literature and from unpublished data held by the company. The Page 12 of 86

13 methods used should be justified with reference to the decision problem. Sufficient detail should be provided to enable the methods to be reproduced, and the rationale for any inclusion and exclusion criteria used should be provided. A systematic literature review was not undertaken for this submission. We limit the extent of this submission to three studies: CALGB 9344 at licensed dose of paclitaxel (175 mg/m 2 q3 weeks). This study was the pivotal registration study. NSABP B-28 had a similar design to the CALGB 9344 study, however a higher dose of paclitaxel (225 mg/m 2 q3 weeks) was utilized. NABCI E1199 which directly compared paclitaxel to docetaxel with both the licensed dose of 175 mg/m 2 three weekly paclitaxel and the unlicensed dose of 80mg/m 2 weekly paclitaxel. The trial contained one arm with 100 mg/m 2 docetaxel q 3 weeks and one arm with weekly 35 mg/m 2 docetaxel. This study was included as this is the only study to provide direct comparison of taxanes in adjuvant breast cancer. 29. the specific databases searched and service provider used (for example, Dialog, DataStar, OVID, Silver Platter), including at least: Medline Embase Medline (R) In-Process The Cochrane Library Not applicable. 30. the date the search was conducted Not applicable. 31. the date span of the search Not applicable. Page 13 of 86

14 32. the complete search strategies used, including all the search terms: Textwords (free text), Subject Index Headings (e.g. MeSH) and the relationship between the search terms (e.g. Boolean) Not applicable. 33. details of any additional searches, for example searches of company databases (include a description of each database) Not applicable. 34. the inclusion and exclusion criteria Comparative studies with paclitaxel for the adjuvant treatment of operable node positive breast cancer in women with outcomes data on disease free and overall survival. 35. the data abstraction strategy. Single extraction with review by another staff member. 2.2 Study selection Complete RCT list 36. Provide a list of all RCTs that compare the intervention with other therapies, including placebo. The list must be complete and will be validated by searches conducted by the assessors. Where data from a single study have been drawn from more than one source (e.g. a poster and a published report) and/or where trials are linked (e.g. an open-label extension to an RCT), this should be made clear. Page 14 of 86

15 Table 2: Included Randomized Controlled Trials. Trial Name (study name used in this submission in bold) CA CALG B 9344 Comparator Cyclophosphamide 600mg/m 2 and doxorubicin 60mg/m 2, 75mg/m 2 or 90mg/m 2 Henderson et al CA NSABP B-28 Cyclophosphamide 600mg/m 2 and doxorubicin 60mg/m 2 Mamounas et al , NABCI E1199 Sparano et al Cyclophosphamide, doxorubicin and docetaxel Relevant RCT list 37. List all randomised trials that compare the technology directly with the main comparator(s). If there are none, state this. Where data from a single study have been drawn from more than one source (e.g. a poster and a published report) and/or where trials are linked (e.g. an open-label extension to an RCT), this should be made clear. As 36 above. 38. Please provide details of relevant ongoing studies from which additional evidence is likely to be available in the next 6 12 months. The following studies were identified by searching the US National Cancer Institute clinical trials website ( and internal sources. Page 15 of 86

16 Phase III Randomized Study of Adjuvant Cyclophosphamide and Doxorubicin Versus Paclitaxel in Women With High-Risk Node-Negative Breast Cancer, CALGB NCT Phase III Randomized Study of Four Schedules of Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Patients With Node-Positive or High- Risk Node-Negative Breast Cancer, SWOG-S0221 NCT Evaluation of Differing Taxanes/Taxane Combinations on the Outcomes of Patients With Operable Breast Cancer, ID NCT Phase III Randomized Study of Three Different Adjuvant Chemotherapy Regimens Comprising Docetaxel, Doxorubicin, and Cyclophosphamide Versus Dose-Dense Doxorubicin, Cyclophosphamide, and Paclitaxel Versus Dose-Dense Doxorubicin, Cyclophosphamide, Paclitaxel, and Gemcitabine in Women With Node-Positive Breast Cancer, NSABP-B-38 NCT Fluorouracil Plus Doxorubicin and Cyclophosphamide (FAC) Versus FAC Plus Weekly Paclitaxel as Adjuvant Treatment of Node Negative High Risk Breast Cancer Patients, GEICAM NCT Phase I/II Randomized Study of Vaccination Comprising p53-infected Autologous Dendritic Cells in Women With p53-overexpressing Stage II or III Breast Cancer Undergoing Neoadjuvant or Adjuvant Chemotherapy and Adjuvant Radiotherapy, MCC-UNMC UNMC NCT Phase II Pilot Study of Adjuvant Paclitaxel, Cyclophosphamide, Filgrastim (G- CSF), and Doxorubicin Followed by Radiotherapy in Patients With Stage II or IIIA Breast Cancer, CWRU-1100 CASE-1100 CWRU NCT NCI-G Phase II Study of Adjuvant Bevacizumab and Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Patients With Resected Lymph Node-Positive Breast Cancer, ECOG-E2104 NCT Page 16 of 86

17 Phase II Study of Adjuvant Chemotherapy Comprising Doxorubicin, Cyclophosphamide, and/or Paclitaxel in Women With Nonmetastatic Invasive Breast Cancer, DUMC R1 NCT A Randomized Trial Comparing the Safety and Efficacy of doxorubicin and cyclophosphamide followed by Taxol (AC T) to that of doxorubicin and cyclophosphamide followed by Taxol plus Herceptin (AC T + H) in Node Positive Breast Cancer Patients who Have Tumors that Over-express HER2, NSABP B-31 CA Phase III Trial of doxorubicin and cyclophosphamide (AC) Followed by Weekly TAXOL With or Without Trastuzumab as Adjuvant Treatment for Women With HER2 Over-expressing or High-Risk Node Negative Breast Cancer, NCCTG N9831 CA FAC vs. FAC followed by TAXOL weekly in high-risk node negative patients, GEICAM A phase III randomized study of epirubicin + cyclophosphamide (EC) followed by TAXOL (T), all given either every 3 or 2 weeks for node-positive breast cancer patients, GIM2. EC Followed by TAXOL or TAXOL/Gemcitabline in Adjuvant Breast Cancer, TANGO. European Cooperative Study of Chemotherapy and Surgery Comparing Adjuvant Doxorubicin Followed by CMF vs. Adjuvant Doxorubicin/Paclitaxel Followed by CMF vs. Primary Doxorubicin/Paclitaxel Followed by CMF in Women with Operable Breast Cancer and T > 2 cm, ECTO CA Phase III Intergroup Trial Comparing Intensive Sequential Chemotherapy Using Doxorubicin, TAXOL and Cytoxan versus High-Dose Chemotherapy and Autologous Bone Marrow Transplantation With Stem Cell Support For Primary Breast Cancer in Women With 4-9 Involved Axillary Nodes, SWOG NCCTG ECOG CALGB CA Page 17 of 86

18 Phase III trial comparing 6FEC100 to 4FEC100 followed by 4 TAXOL in the adjuvant treatment of node-positive breast cancer, AERO B2000. Conventional Treatment with Cyclophosphamide/epirubicin Followed by TAXOL vs. Dose-dense Treatment of Epirubicin Followed by TAXOL as Adjuvant Treatment in Patients with 1-3 Positive Lymph Nodes, Dr. Elling Germany. Dose-dense sequential chemotherapy with epirubicin, TAXOL and cyclophosphamide (ETC) vs. conventional dosed chemotherapy in high-risk breast cancer patients (> 4 +LN), AGO Moebus Germany. Epirubicin + Paclitaxel versus Cyclophosphamide, Epirubicin and 5- Fluorouracil as Adjuvant Treatment of Node Positive Breast Cancer Patients. A Controlled Randomized Phase III Trial, MIG-5. Randomized trial of sequential adjuvant treatment in operable breast cancer patients (N+ or N- with tumors > 2 cm), GEICAM Multicenter, randomized phase III study of adjuvant chemotherapy for axillary positive breast cancer comparing 6 cycles of FEC vs. 4 cy of FEC followed by 8 weekly TAXOL administrations, Michelangelo. Dose-Dense Sequential Chemotherapy with Epirubicin-TAXOL-CMF vs. ET followed by CMF as Adjuvant Treatment in Patients with Operable Breast Cancer, HECOG Fountzilas. 39. A flow diagram of numbers of number of studies included and excluded at each stage should be provided as per the QUORUM statement. Not applicable. 2.3 Summary details of RCTs 40. As a minimum, the summary should include information on the following aspects of the study but the list is not exhaustive. Where there is more than one RCT please tabulate the information. Page 18 of 86

19 Summary details by study are provided below: CALGB 9344 In 1994 the CALGB and three other cooperative groups in the US, (the Eastern Cooperative Oncology Group, ECOG, the Southwest Oncology Group, SWOG and the North Central Cancer Treatment Group, NCCTG), initiated a large randomized study with a 3 x 2 design to evaluate the treatment effects on disease free survival (DFS) and overall survival (OS) of escalating doses of doxorubicin within the AC regimen given for 4 cycles and of the sequential administration of paclitaxel given for 4 additional cycles versus no further treatment in patients with node-positive breast cancer. The study involved 530 sites in the United States, one site in Canada and one site in the Republic of South Africa. From May 12th, 1994 to April 15th, 1997, 3,170 women were randomized to this study that was conducted under the sponsorship of the US National Cancer Institute (NCI) and was part of a Collaborative Research and Development Agreement (CRADA) between NCI and Bristol-Myers Squibb. The primary objectives of the study, with respect to the duration of disease free survival, were to assess the effects of 3 different doses of doxorubicin in combination with a fixed dose of cyclophosphamide, to assess the effects of paclitaxel following 4 courses of AC and to assess the interaction between the addition of paclitaxel and the doxorubicin dose. Secondary objectives were overall survival and toxicity using the same comparisons as for disease free survival. Page 19 of 86

20 Figure 1: CALGB 9344 Study Design AC60/600mg/M 2 q3wks x 4 cycles Taxol 175mg/M 2 3hr infusion q3wks x 4 cycles No Taxol Taxol 175mg/M 2 3hr infusion q3wks x 4 cycles Randomized AC75/600mg/M 2 q3wks x 4 cycles Tamoxifen x 5 yrs No Taxol (estrogen receptor positive) Taxol 175mg/M 2 3hr infusion q3wks x 4 cycles AC90/600mg/M 2 q3wks x 4 cycles G-CSF 5mcg/kg/d-d2 Cipro 750 mg po bid-d5 No Taxol Patients and methods Women with operable, histologically confirmed adenocarcinoma of the breast and histologically involved axillary lymph nodes were randomized after stratification based on the number of histologically positive lymph nodes at surgery (i.e., 1-3, 4-9, or 10) to one of three treatment levels of doxorubicin (i.e., 60, 75, or 90 mg/m 2 ) in combination with a fixed dose of cyclophosphamide (600 mg/ m 2 ) followed by either paclitaxel (175 mg/ m 2 ) for 4 cycles or no further chemotherapy. No chemotherapy or radiation therapy was allowed prior to study entry. Patients who received paclitaxel were premedicated with the standard premedication regimen. Administration of Granulocyte Colony-Stimulating Factor (G-CSF) and ciprofloxacin were required for patients receiving the 90 mg/ m 2 dose of doxorubicin. Tamoxifen was to be administered for five years to all patients with receptor positive tumours at week 24 or after completion of the assigned study treatment regimen. A total of 3,170 women were randomized to this study and 3,121 received therapy: 1,551 patients on the AC regimen (515 patients on the lowdose, 523 on the mid-dose and 513 on the high dose level of doxorubicin) and 1,570 patients on the AC+T regimen (533 on the low-dose, 517 on the middose and 520 on the high-dose level of doxorubicin). Patients were eligible for this study if they had node-positive breast cancer after total surgical removal of the tumour by either a modified radical mastectomy or a segmental mastectomy plus axillary node dissection. Page 20 of 86

21 Treatment consisted of the combination of a fixed dose of cyclophosphamide (600 mg/ m 2 IV) and doxorubicin doses of 60 mg/ m 2 or 75 mg/ m 2 or 90 mg/ m 2 IV every 21 days for a total of 4 courses. Patients randomized to receive further therapy were given 4 courses of paclitaxel at the dose of 175 mg/ m 2 as a 3-hour infusion every 21 days. The efficacy endpoints were DFS and OS. Disease relapse was used to evaluate DFS and was defined as the appearance of local recurrence or distant metastases at any site, or death due to any cause. The planned sample size of 3,000 patients provided 95% power to test for the main effects (dose of doxorubicin and addition of paclitaxel) and greater than 80% power to test for the presence of interaction in the 3 x 2 factorial design. Treatment effect on DFS and OS was assessed by Wald chi-square tests obtained from multivariate Cox regression models incorporating paclitaxel randomization, doxorubicin dose, and four prognostic variables (number of positive nodes, pathological tumour size, menopausal status and tumour oestrogen receptor status). Apart from statistics concerning randomization, all analyses excluded cancelled (non-treated) patients. The intent-to treat analysis was fully consistent with the pre-planned, per protocol analysis. Results All patients treated in this study were women, in the vast majority of cases (94%) younger than 65 years of age, with a comparable distribution between treatment regimens. Nearly two-thirds of all patients (62%) were premenopausal at the initiation of study therapy. Overall, disease characteristics were well balanced between the AC and AC+T treatment arms and among the 6 treatment regimens. Tumour size was less than or equal to 2 cm in 35% of the patients, whereas 13% of the patients had tumours larger than 5 cm. As a consequence, modified radical or radical mastectomy was the type of breast surgery performed in more than two-thirds of the patients and only less than one-third of patients had a lumpectomy. Lymph node involvement of 1-3 nodes was observed in 47% and 46% in the AC and AC+T arms, respectively. Involvement of 4-9 nodes was noted in Page 21 of 86

22 42% of patients in each arm and 12% of patients in each arm had 10 nodes involved. Two-thirds of patients (66%) had tumours that were either ER or PgR positive, and were thus candidates to receive tamoxifen at the end of chemotherapy. More than 95% of patients in both arms of the study completed treatment with AC and the majority of patients randomized to AC+T (85%) completed treatment with paclitaxel following AC. Definitive and mature data for all the 3,121 patients treated in the study (1,551 and 1,570 in the AC and AC+T regimens, respectively) are available, with a median follow-up time of 68 and 69 months, respectively. In the primary analysis on DFS, the effects of increasing doxorubicin dose and adding paclitaxel were assessed in a multivariate Cox proportional hazards model including the main baseline prognostic factors (number of positive nodes, pathological tumor size, menopausal status and tumour oestrogen receptor [ER] status). Complete data for all these variables were available for nearly the entire sample of patients (3,086/ 3,121). After adjusting for the effects of the pre-treatment variables, the addition of 4 cycles of paclitaxel caused a statistically significant reduction in disease recurrence (hazard ratio [HR] of 0.83;95% CI p = 0.002). This hazard ratio indicates an 17% reduction in disease recurrence rate for patients who received paclitaxel following standard treatment with AC compared with patients who only received AC. In contrast, for the other primary endpoint of the 3x2 study design, increasing the doxorubicin dose level did not correlate with an increase in DFS (p = 0.88). The addition of a paclitaxel by doxorubicin interaction term to the above model did not add predictive information for recurrence (p = 0.22). The difference in DFS in favour of the AC+T regimen was observed early in the study, and was maintained throughout the follow-up period. A very small number of patients were censored with short follow-up time (6 patients, 4 and 2 in the AC and AC+T arms, respectively with < 1 year of follow-up and 27 patients, 15 and 12 in the AC and AC+T arms, respectively with < 2 years of Page 22 of 86

23 follow-up). DFS at 12 and 24 months was 92% vs. 95% and 81% vs. 86% for patients in the AC and AC+T arms, respectively and continued to be better for patients treated with AC+T over time. Analysis of the hazards of disease recurrence over time shows that in most time periods, the hazards of disease recurrence favoured AC+T over AC. Results of additional analyses for DFS confirmed the results observed in the primary analysis. In a multivariate model where the data were stratified by the number of positive nodes, treatment with paclitaxel induced a reduction in disease recurrence (hazard ratio of 0.82; p = ), while doxorubicin dose did not correlate with an increase in DFS duration (p = 0.75). Although the study was not designed for subset analyses, subsets known to have prognostic importance in adjuvant breast cancer were defined and analyzed. These subsets were based on number of positive nodes, ER status, oestrogen- and/or progesterone-receptor (PgR) status, tumour size, menopausal status and tamoxifen administration after completion of chemotherapy. The hazard ratios obtained (3% to 31%), showed that the addition of paclitaxel resulted in a reduction in risk of failure compared with AC only, in all patient subsets. DFS was the primary endpoint of this study and the results discussed above clearly indicate that there is a strong benefit in terms of reduction in the risk of disease recurrence. The results in terms of OS are consistent with the DFS findings. At the time of the final analysis, 400 of 1,551 patients (26%) in the AC arm and 342 of 1,570 patients (22%) in the AC+T arm had died. As in the case of DFS, the difference in OS in favour of the AC+T regimen was seen early in the study, and was maintained throughout the follow-up period. A few patients with short follow-up were censored (21 patients, 12 in the AC arm and 9 in the AC+T arm with < 2 years of follow-up time). When the doxorubicin dose and the addition of paclitaxel were assessed in the primary survival analysis using the same multivariate Cox proportional hazards model baseline prognostic factors used for DFS, results were consistent. After adjustment for the effects of the pre-treatment variables, treatment with Page 23 of 86

24 paclitaxel was strongly correlated with increased OS compared to AC only (hazard ratio of 0.82; p = 0.006). This hazard ratio indicated a 18% reduction in risk of death for patients who received further treatment with Taxol after standard AC. In contrast, as shown in the Cox regression analysis, increasing the dose of doxorubicin did not appear to produce any additional benefit in terms of overall survival. Also the addition of the term paclitaxel by doxorubicin interaction to the Cox model did not add predictive information on survival (p = 0.16). With the same limitations mentioned above on the study not being designed for subset analyses, the same prognostic variables considered for DFS were defined for additional survival evaluations (number of positive nodes, ER status, ER and/or PgR status, tumours size, menopausal status and tamoxifen administration after completion of chemotherapy). As in the case of DFS, all hazard ratios but one (small tumour size) indicated that the addition of paclitaxel resulted in a reduction in risk of death compared with AC alone. NSABP B-28 Data from a second large randomized study with a similar design and a similar level of follow-up confirm the benefit of adding paclitaxel to standard chemotherapy in disease free survival. At about the same time that the CALGB study was accruing patients, the NSABP conducted a similarly designed and sized study (study NSABP B-28) with 3,060 patients in women with early breast cancer and positive nodes who were randomized to treatment with AC for 4 courses or AC followed by paclitaxel (AC+T). Final results were presented at the ASCO meeting in The primary objectives of the NSABP B-28 study were to determine whether 4 courses of adjuvant paclitaxel given after 4 courses of adjuvant AC would prolong DFS and OS when compared with 4 courses of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes, Page 24 of 86

25 a population of patients similar to that studied in the pivotal CALGB 9344 study. The NSABP B-28 study was conducted in North America in a total of 208 study centres (200 in the US and 8 in Canada). The dose of paclitaxel selected for the NSABP study (225 mg/m 2 ) is higher than the UK licensed dose. The rationale of this selection by NSABP is that at the time of the study initiation there were data suggesting that a dose response relationship existed with paclitaxel in ovarian and breast cancer. 14,15 Also based on the fact that the maximum tolerated dose of paclitaxel as a 3-hour infusion ( mg/m 2 ) is higher than the conventional single-agent dose of 175 mg/m 2, testing a higher, potentially more effective dose of paclitaxel in the adjuvant setting, the approach was well reasoned. The choice of administering tamoxifen differently than in the CALGB 9344 study (i.e., concomitant with chemotherapy) was based on standard NSABP practice at the time of study initiation. At this time there was no definitive data regarding the optimal sequence of administration for chemotherapy and hormonal therapy. Figure 2: NSABP B-28 Study Design AC60/600mg/M 2 q3wks x 4 cycles + Taxol 225mg/M 2 3hr infusion q3wks x 4 cycles Randomized Tamoxifen x 5 yrs AC60/600mg/M 2 q3wks x 4 cycles Patients and methods Following stratification by number of positive nodes (1-3, 4-9, 10 positive nodes), tamoxifen administration (no, yes) and type of surgery (lumpectomy, mastectomy), patients were randomly assigned to one of two arms. Patients Page 25 of 86

26 randomized to arm I (control) received 4 cycles of AC and patients randomized to arm II received 4 cycles of AC as in arm I, followed by 4 cycles of paclitaxel (AC+T). All patients randomized to AC+T were required to receive the standard pre-medication regimen before each cycle of paclitaxel. Beginning on the first day of administration of their assigned chemotherapy, patients > 50 years of age and those < 50 years of age with tumours that were ER-positive or PgR positive were to receive tamoxifen at 20 mg p.o. daily for 5 years. All patients in either arm who were surgically treated by lumpectomy were to receive in-breast radiotherapy after completion of their assigned chemotherapy and after any toxicity had resolved. Eligible patients included women with invasive breast adenocarcinoma and at least 1 axillary lymph node with demonstrated evidence of tumour on histological examination, who had undergone either a total mastectomy and axillary dissection (modified radical mastectomy) or a lumpectomy and axillary dissection. Patients with any hormone receptor status were eligible, provided they had a determination of ER and PgR performed on the primary tumour prior to randomization. Patients with proven bilateral breast cancer, N2 disease or suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes (unless proven negative at biopsy) were not eligible. Treatment consisted of standard AC chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) i.v. every 21 days for 4 courses in both arms. In addition, patients randomized to AC+T were to receive paclitaxel at the dose of 225 mg/m2 i.v. every 21 days for 4 courses following the completion of AC. Primary endpoints were DFS and OS. In the original protocol, the sample size was determined to ensure a power 0.80 of detecting a decrease of 25% in the death rate of AC followed by paclitaxel compared with AC alone using a 2 sided test with a type I error of 0.05, with a final analysis planned after 380 deaths according to the study design. A total of 2,450 patients were initially required to complete the study in approximately 5 years, with an accrual of 21 Page 26 of 86

27 months. During the study there was a higher than expected discontinuation rate after the AC treatment or during paclitaxel treatment and as a consequence, the protocol was amended to ensure that the sample size would provide 80% power to detect a 22.6% decrease in death rate (instead of the 25% originally planned). With this new hypothesis a higher number of deaths was required prior to final analysis (490) leading to an increased sample size of patients to be accrued (3,050) Results A total of 3,060 patients were randomized (1,529 and 1,531 in the AC and AC+T arms, respectively) between August 1995 and May 1998, with a very small rate of ineligible patients (24 in total, 13 in the AC arm and 11 in the AC+T arm). All patients but 1 have adequate follow-up data. Median time of follow up was 65 and 64 months in the AC and AC+T arms, respectively. Baseline characteristics were well balanced between the 2 treatment arms. All patients were women with a median age of 49 years. The majority had ER+ and/or PgR+ tumors (66%). Since women 50 years old received hormonal therapy irrespective of their paclitaxel-receptor status, a large percentage of patients (84% in each arm) were treated with tamoxifen. About 59% of the patients had tumours of 2 cm in maximum diameter. Seventy percent of the patients in each arm had 1-3 positive nodes on pathologic examination and only 4% of the patients had 10 or more positive nodes. Slightly less than half of the patients were treated with lumpectomy. Compliance to AC treatment was good, with over 98% of the patients completing 4 courses of AC. Among the patients who were randomized to AC+T only 76% completed the 4 cycles of treatment prescribed by the protocol. The primary analyses of DFS and OS were comparisons of DFS and OS duration between treatment arms using a 2-sided log-rank tests stratified by number of positive nodes, tamoxifen administration and type of surgery. Page 27 of 86

28 For DFS, after stratification for the pre-treatment variables, the addition of 4 cycles of paclitaxel produced a highly statistically significant reduction in disease recurrence (hazard ratio of 0.83; p = 0.006). This hazard ratio corresponds to a 17% reduction in disease recurrence rate compared with AC alone. Of note, the DFS curves began to diverge in favour of AC+T at approximately 33 months, and showed a gradual widening over the follow-up period. Hazards of disease recurrence over time following the first 2 years after surgery, where the highest hazards were observed, show a reduction of the risk in the AC+T arm that is maintained and is consistently lower than in the AC arm in the following years. In the analysis of recurrences, crude hazard rates and 5-year cumulative incidence rates by type of event, the hazard ratios associated with disease recurrence, contralateral breast cancer, occurrence of a second cancer and death ranged from 0.53 to 0.90, all favouring AC+T over AC. For OS, after stratification for the pre-treatment variables, there was a reduction in the risk of death for patients treated with AC+T compared to patients treated with AC alone that did not reach statistical significance (hazard ratio of 0.93; p = 0.46). This hazard ratio indicated a 7% reduction in death rate for patients randomized to AC followed by paclitaxel compared with patients who received AC alone. In the Cox proportional hazard model for OS adjusted for baseline covariates, the effect of the addition of paclitaxel was similar to that observed in the primary analysis (hazard ratio of 0.92; p = 0.34). With regard to hormone-receptor status and use of tamoxifen, there was no significant interaction with the effect of paclitaxel for DFS or OS (p = 0.30 and 0.37, respectively). Analyses of the effect of paclitaxel in the subsets of HR+ and HR- patients and in the subsets of patients treated or not treated with tamoxifen indicated that paclitaxel prolonged DFS more in HR+ patients than in HR- patients and more in tamoxifen-treated patients than in patients not treated with tamoxifen. Page 28 of 86

29 This study was not powered to detect statistically significant treatment differences within subsets. However, irrespective of the endpoint (DFS or OS) and of the subset (HR status or tamoxifen treatment), the paclitaxel -treated group constantly benefited more than the control group. NABCI E1199 In 1999 the US National Cancer Institute (NCI), North Central Cancer Treatment Group (NCCTG), Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (CALGB), Eastern Cooperative Oncology Group (ECOG) initiated a large intergroup randomized study to compare the diseasefree survival and overall survival in patients with node-positive or high-risk node-negative operable stage II or IIIA breast cancer treated with docetaxel or paclitaxel after doxorubicin and cyclophosphamide. Patients were stratified according to oestrogen receptor status (positive, negative and unknown), nodal status (0,1-3, 4-9 and at least 10 positive nodes), tumour size ( 5 cm, >5 cm and unknown), and type of prior surgery (mastectomy and breast conservation surgery). Patients were randomized to one of four treatment arms: Arm I (P3): Patients receive doxorubicin i.v. and cyclophosphamide i.v. every 3 weeks for 4 courses (weeks 1-12). Beginning at week 13, patients receive paclitaxel 175mg/m 2 i.v. over 3 hours every 3 weeks for 4 courses. Arm II (P1): Patients receive doxorubicin and cyclophosphamide as in arm I. Beginning at week 13, patients receive paclitaxel 80mg/m 2 i.v. over 1 hour weekly for 12 weeks. Arm III (D3): Patients receive doxorubicin and cyclophosphamide as in arm I. Beginning at week 13, patients receive docetaxel 100mg/m 2 i.v. over 1 hour every 3 weeks for 4 courses. Arm IV (D1): Patients receive doxorubicin and cyclophosphamide as in arm I. Beginning at week 13, patients receive docetaxel 35mg/m 2 i.v. over 1 hour weekly for 12 weeks. Page 29 of 86

30 Methods ( Eligibility criteria included axillary lymph node positive or high-risk (tumour at least 2 cm) node-negative breast cancer. All patients with oestrogen and/or progesterone receptor (ER/PR)-positive disease received a 5 year or longer course of adjuvant hormonal therapy, consisting either of tamoxifen (20 mg daily), an aromatase inhibitor (AI; for post-menopausal women beginning in 2003 at the discretion of the treating physician), or tamoxifen followed by an AI. The primary comparisons included taxane (paclitaxel versus docetaxel) and schedule (every 3 weeks versus weekly). The study had 86% power to detect a 17.5% reduction in failure for either primary comparison. The primary endpoint was disease-free survival (DFS), defined as local, regional, and/or distant relapse, second primary breast cancer, or death without recurrence. Results A total of 4,988 eligible patients were accrued between October 1999 and January The ECOG Data Monitoring Committee advised release of the data after 856 DFS events (82% of total information) occurred after a median follow-up of 46.5 months at the fourth planned interim analysis. DFS events (and relapses or death) for each arm were: P3-230 (199), P1-195 (172), D3-206 (171), D1-225 (192). For the primary analyses, there were no statistically significant differences in the hazard ratios (HR) comparing taxane (0.985; p=0.83) or schedule (1.043; p=0.54) for DFS, and the trialists state that it is unlikely that either comparison could become significant after full planned information is obtained. When comparing the standard arm (P3) to the other arms (with a HR > 1 favouring the experimental arms), no statistical significant differences were found, the HRs were 1.20 (95% confidence intervals [CI] 0.99, 1.46; p = 0.06) for arm P1, 1.13 (95% CI 0.94, 1.36; p=0.20) for arm D3, and 1.03 (95% CI 0.85, 1.23; p=0.78) for arm D1. The incidence of worst grade toxicity (grade 3/4) was 24%/ 6% for arm P3, 24%/ 4% for arm P1, 21% 50% for arm D3, and 39%/ 6% for arm D1. Page 30 of 86