Continuous infusional combination chemotherapy in inflammatory breast cancer: a phase II study

The Breast (2000) 9, 149–155 © 2000 Harcourt Publishers Ltd doi:10.1054/brst.1999.0158, available online at http://www.idealibrary.com on

ORIGINAL ARTICLE

Continuous infusional combination chemotherapy in inflammatory breast cancer: a phase II study R. H. de Boer,1 A. Saini,1 S. R. D. Johnston,1 M. E. R. O’Brien,1,2 P. A. Ellis,3,4 M. W. Verrill,5 J. A. Prendiville,3,6 G. Walsh,1 S. Ashley,1 I. E. Smith1 1 Department of Medicine, Royal Marsden NHS Trust, London, UK; 2Kent Cancer Centre, Maidstone Hospital, Kent, UK; 3 Guys and St Thomas’s NHS Trust, London, UK; 4Kings College Hospital, London, UK; 5Northern Centre for Cancer Treatment, Newcastle General Hospital, UK; Newcastle, UK; 6Queen Mary’s Hospital, Sidcup, Kent, UK S U M M A R Y. Despite the introduction of systemic chemotherapy, inflammatory breast cancer (IBC) remains a disease with a poor prognosis. We performed this phase II study to evaluate the efficacy of infusional chemotherapy as initial treatment in patients with IBC. Fifty-four patients with newly diagnosed IBC were offered infusional chemotherapy and 34 accepted. The schedule consisted of continuous infusional ECF (bolus epirubicin and cisplatin, substituted by carboplatin or cyclophosphamide in some patients) plus continuous 5-FU, given three weekly for six cycles. Following chemotherapy patients went on to have surgery and/or radiotherapy. The chemotherapy was well tolerated and resulted in an overall response rate of 79% with 35% of patients achieving a complete clinical response. The median response duration, time to progression and overall survival were 12 months (4–89+ months), 12 months (4–89+ months) and 23 months (7–89+ months), respectively. Patients had a 5 year disease free and overall survival of 11% and 29%, respectively. Infusional ECF is well tolerated and achieves a high clinical response rate in patients with IBC, but survival results do not appear to be superior to those achieved with conventional bolus chemotherapy schedules. © 2000 Harcourt Publishers Ltd INTRODUCTION

treatment,5 maintenance chemotherapy,6,7 and more recently, high dose chemotherapy with autologous stem cell support.8–10 Although the long-term results of randomized studies of high dose chemotherapy are awaited, other strategies do not appear to have significantly improved outcome. With this in mind, and based upon our observation of very high clinical response rates to infusional 5FU-based chemotherapy in both metastatic/locally advanced disease,11 and large operable primary breast cancers,12 we prospectively assigned patients with true IBC to receive primary infusional chemotherapy as part of multi-modality therapy. The chemotherapy schedule was based upon a continuous logn-term infusion of 5FU delivered by ambulatory pump, in combination with intermittent bolus injections of epirubicin and cisplatin, carboplatin or cyclophosphamide (as part of separate trials).

Inflammatory breast cancer (IBC) is an uncommon disease accounting for 1–4% of all breast cancers.1 The characteristic pathological feature is malignant invasion of dermal lymphatics, but the classic clinical features of erythema and oedema are usually so obvious that skin biopsy is not mandatory for diagnosis.2 It is an aggressive disease characterized by rapid tumour growth resulting in frequent early relapse, both locally and in distant sites, and a poor overall prognosis. Patients treated with local therapies alone have a 5-year survival rate of under 5–10%, reflecting the systemic nature of the disease.3 Despite advances in treatment of IBC with the incorporation of primary chemotherapy as part of a multi-modality treatment approach, patient outlook remains only moderate with 5-year survival figures of between 30–50% in larger studies.4 A number of different strategies have been employed in an attempt to improve outcome. These include schedules incorporating chemotherapy both pre and post locoregional

MATERIALS AND METHODS Patients Fifty four sequential patients referred to the Breast Unit at the Royal Marsden Hospital, London with newly diagnosed

Address correspondence to: I. E. Smith, Head of Section of Medicine, The Royal Marsden NHS Trust, Fulham Rd, London, SW3 6JJ, UK

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untreated IBC between June 1991 and May 1998 were prospectively offered entry into a trial of infusional ECF. The criteria for IBC were defined clinically as a T4 lesion with diffuse brawny induration of the breast and inflammatory change; pathological confirmation was obtained in all cases, although dermal lymphatic involvement was not specifically sought. The eligibility criteria included good performance status (World Health Organisation grade 0–2), adequate renal function (EDTA clearance >60 ml/min), adequate hepatic function (normal bilirubin [< 17 umol], and hepatic enzymes < twice upper limit of normal), adequate bone marrow function (WBC > 3.0 x 109/L, platelets >100 x 109/L), and the ability to manage an indwelling intravenous catheter and infusion pump. Initial staging investigations included clinical examination with two-dimensional tumour measurement and clinical photography, breast ultrasound, full blood count, plasma biochemistry, liver function tests and chest X-ray. Liver imaging (ultrasound or CT scan) and isotopic bone scan were only performed if there was clinical or biochemical suspicion of metastatic disease in these sites. Of the 54 patients, 34 received the infusional ECF chemotherapy schedule as outlined below. The other 20 patients declined infusional chemotherapy treatment; in nearly all patients this was due to concern over the insertion, care or potential complications of the indwelling catheter. These patients went on to receive conventional bolus chemotherapy. Following chemotherapy, patients received the following locoregional therapy: all patients were offered radical radiotherapy to the breast and regional nodes unless this was clinically inappropriate because of progressive disease elsewhere, or refusal; radiotherapy dose and schedule was determined by local practice, and varied from 40–76 Gy given over 4–6 weeks. The extent of breast surgery, if any, was determined by the individual surgeon involved and reflected clinical uncertainty of the value of this procedure in IBC; surgery was mainly influenced by the persistence or not of a palpable residual mass after chemotherapy, and ranged from conservative resection to radical mastectomy.

Chemotherapy regimen The infusional chemotherapy schedule consisted of a continuous infusion of 5FU administered at a dose of 200 mg/m2 every 24 h via an ambulatory Infumed pump and a Hickman line inserted into the subclavian vein. This was combined with bolus i.v. injections of epirubicin 60 mg/m2 and cisplatin (60 mg/m2, n = 12), or carboplatin (AUC 5, n = 10) or cyclophosphamide (600 mg/m2, n = 12), given once every 3 weeks. The reasons for the differences in the

third chemotherapy agent reflects separate trials which demonstrated that carboplatin13 or cyclophosphamide14 could be substituted for cisplatin with less toxicity and without significant loss of efficacy. Antiemetic cover was provided with either ondansetron (8 mg i.v.) or granisetron (3 mg i.v.) combined with dexamethasone (8 mg i.v.) prior to administration of each course, followed by 3 days of oral dexamethasone (4 mg three times daily) and domperidone (20 mg four times daily). Scalp cooling was offered with each course of epirubicin. In an effort to prevent Hickman line-related thrombosis, all patients were treated with low dose warfarin (1 mg/day) for the period the line was in place. Patients received instruction in the care of their Hickman line and their infusion pumps by trained oncology nurses, and were able to change their 5FU infusion bags at home every 7 days. There was no routine use of granulocyte-colony stimulating factor in either treatment group.

Dose modifications Dose modifications were made for toxicity as follows: Myelosuppression If the total neutrophil count was less than 1.0 x 109/L and/or the platelet count was <100 x 109/L, the 5FU was continued but the epirubicin and the cisplatin were delayed for a week. If the WBC/platelet count had recovered then the treatment was administered at full dose. If not then the treatment was delayed by a further week and the doses of both epirubicin and 5FU were reduced by 25%. If there was a greater than 2 week delay, then the doses of both epirubicin and 5FU were reduced by 50%. Nephrotoxicity Before commencing infusional ECF chemotherapy, all patients had measurement of their glomerular filtration rate (GFR) by EDTA clearance to assess eligibility. Further EDTA measurements were performed prior to alternate cycles. If the EDTA clearance was less than 60 ml/min, the dose of cisplatin was reduced by 25%. If an EDTA clearance of less than 50 ml/min was recorded, cisplatin was discontinued and carboplatin was substituted, with the dose determined according to renal function based upon the area under the plasma concentration/time curve (AUC). The actual dose administered was calculated using the Calvert formula: Dose (mg) = target AUC x (GFR + 25), using a target AUC of 5. Palmar-plantar syndrome Toxicity with palmar-plantar erythema is a recognized sideeffect of continuous infusional 5FU. If symptoms were mild

Continuous infusional combination chemotherapy 151 (dryness, erythema and pain) patients continued with the 5FU infusion and were given pyridoxine 50 mg orally three times per day. If symptoms were more severe (blistering and desquamation), pyridoxine was started and 5FU was discontinued until evidence of healing was observed, when 5FU infusion was recommenced with a 25% dose reduction. If severe symptoms developed again then a further 25% reduction was undertaken. Diarrhoea For WHO grade 1 or 2 diarrhoea loperamide was administered, but for more severe/persistent diarrhoea, 5FU was discontinued for one week and restarted with a 25% dose reduction.

Endocrine therapy Patients who were postmenopausal at the time of diagnosis or whose tumours were oestrogen receptor positive/ unknown were treated with tamoxifen 20 mg/day for a period of 2–5 years as part of a separate trial.

RESULTS The characteristics of the 34 patients treated with infusional ECF chemotherapy are shown in Table 1.

Chemotherapy response, time to progression and survival The clinical tumour response is shown in Table 1. The overall response rate for the 34 patients treated with infusional chemotherapy was 79% (95% CI 66–93), with a complete response seen in 12 patients (35%). With a median duration of follow-up at the time of analysis of 47 months in the patients still alive (range 22–89 months), the median duration of response was 12 months (range 4–89+ months), the median time to disease progression was 12 months (range 4–89+), and the median overall survival was 23 months (range 7–89+ months). The 5 year disease free survival and 5 year overall survival figures were 11% and 29% respectively.

Toxicity Assessment of response and toxicity Patients were assessed clinically every 3 weeks with bidimensional tumour measurements. Overall response rates to chemotherapy were determined by assessment of the breast tumour, the axillary lymph nodes, and the inflammatory skin changes. Complete response (CR) was defined as the complete clinical disappearance of any palpable tumour, confirmed independently by two observers, which persisted at least until the completion of chemotherapy. Partial response was defined as a greater than 50% reduction in the product of two perpendicular diameters of the tumour which also persisted at least until the completion of chemotherapy. Progressive disease (PD) was defined by the appearance during chemotherapy of either any new lesion subsequently demonstrated to be a metastases, or by a ≥25% increase in the sum of the products of two perpendicular diameters of any measured lesions over that present at the time of maximum regression. All other patients were recorded as having stable disease (SD). Toxicity for each cycle was recorded prior to the commencement of the following cycle and was assessed using the standard WHO criteria.15

Statistics Differences in patterns of relapse were determined by a x2 text with Yates correction. Response duration, time to progression and survival curves were generated according to the Kaplan-Meier method.

Severe toxicity (WHO grade III/IV) was relatively uncommon (Table 2). The major non-haematological toxicities were alopecia, lethargy, palmar-plantar erythema, and mucositis; the final two toxicities particularly related to infusional 5FU. Nausea and vomiting, neuropathy and Table 1

Patient characteristics and response rates

Patient characteristic Number Median age (range) Treatment E Cisplatin F E Carboplatin F E Cyclo F Menopausal status Pre Peri Post Hysterectomy Nodal Stage N0 N1 N2 N3 Unknown Tumour Diameter (cm) Median (range) Tamoxifen treatment Response rates Complete Response Overall Response Stable Disease Progressive Disease

34 48 (28–61) 12 10 12 21 4 5 4 12 15 5 1 1 9 (5–14) 30 (88%) 12 (35%) 27 (79%)* 6 1

E = epirubicin; F = 5-fluourouracil; *95% CI 66–93.

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Table 2

Chemotherapy toxicity (worst toxicity for any course)

Locoregional therapy

WhO toxicity (%) Non-Haematological Lethargy Nausea/ Vomiting Alopecia Neuropathy Mucositis Constipation Diarrhoea Palmar-Plantar Erythema Haematological Anaemia Neutropaenia Febrile neutropenia Thrombocytopaenia

Grade 0

Grades I–II

Grades III–IV

15 12 6 44 23 32 59 26

70 85 65 56 62 65 28 59

15 3 29 0 15 3 3 15

38 18 82 88

59 38

3 44 18 3

9

constipation were common but in nearly all cases these toxicities were mild. The major haematological toxicity was neutropaenia, with 18% of patients developing febrile neutropaenia requiring in-patient care and administration of antibiotics. There were no treatment-related deaths. Fourteen patients required chemotherapy dose reductions, predominantly (13 patients) due to 5FU related palmar-plantar erythema and mucositis. Ten patients had 5FU reductions of 25% or less and three had a dose reduction in the range of 26–50%. Two patients required a week delay and one patient required a 2 week delay in the administration of their chemotherapy. No patients stopped treatment prematurely due to toxicity.

Locoregional treatment received is summarized in Table 3. Twenty patients had radiotherapy alone, 12 had both radiotherapy and surgery, and two had surgery alone. There appeared to be no significant relationship between the type of locoregional treatment delivered and the response duration, time to progression or overall survival i.e. patients undergoing both surgery and radiotherapy had similar outcomes to patients receiving radiotherapy alone. This comparison held when all patients were analysed and also when analysis excluded those patients with progressive disease during chemotherapy (details will be reported separately). The median delay from day one of the last cycle of chemotherapy to the initiation of locoregional therapy was 40 days (range 21–85 days).

Site of first relapse Excluding one patient who progressed through chemotherapy, 28/33 patients (85%) have relapsed. Fourteen patients developed distant metastases as their site of first relapse (bone n = 5, brain n = 5, lung n = 4, liver n = 4 and soft tisTable 3

Locoregional therapy

Radiotherapy alone Surgery alone Radiotherapy plus surgery Sx→RTx RTx→Sx

20 2 12 9 3

RTx = radiotherapy, Sx = surgery.

Fig. 1 Response duration of patients treated with infusional ECF chemotherapy according to Kaplan-Meier method.

Continuous infusional combination chemotherapy 153

Fig. 2 Time to progression of patients treated with infusional ECF chemotherapy according to Kaplan-Meier method.

sue n = 2), while the other 14 patients first relapsed locally in either the breast/chest wall or axilla. One patient relapsed with local and metastatic disease simultaneously. There appeared to be no significant relationship between the type of locoregional therapy administered and the site of first relapse. In the group of 28 relapsing patients, 12 received surgery as part of their loco-regional treatment (10 had surgery plus radiotherapy and two had surgery alone), while 16 received radiotherapy alone. Of the 12 surgically treated patients five (42%) first relapsed locally. In compar-

ison, in the group of 16 patients treated with radiotherapy alone, seven (44%) relapsed first locally.

DISCUSSION Infusional ECF chemotherapy has been shown to be very active as preoperative/neo-adjuvant chemotherapy in large operable breast cancer with a complete remission rate of 67%,12 which was higher than that reported for conventional

Fig. 3 Survival of patients treated with infusional ECF chemotherapy according to KaplanMeier method.

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chemotherapy. We are currently testing the hypothesis that this might translate into improved survival benefit in a randomized phase III trial against conventional chemotherapy. Our overall clinical response rate of 79% achieved with infusional ECF in this study compares favourably with most previously published response rates using intermittent bolus regimens against IBC (Table 4);16–22 in particular, the complete clinical remission rate of 35% is amongst the highest reported and is higher than the 23% achieved in patients treated with bolus schedules in our own institution (n = 30, unpublished data), although the difference is not significant (P = 0.3). Several investigators have suggested that the achievement of clinical CR in patients with IBC is associated with an improved prognosis,6,17,20 and we were encouraged to hope that our high CR rate might predict for improved survival. Unfortunately, our follow-up results do not appear to support this hypothesis. Although comparison of results between different studies in IBC is difficult because of the rarity of the disease and the small numbers involved, our predicted 5 year overall survival of 29% is no better than that achieved in patients treated with conventional chemotherapy, both in our own series (33%, unpublished data) and elsewhere in the literature (Table 4). It is possible that pathological CR is a better surrogate marker for survival outcome than clinical CR, and other studies have suggested this in both IBC and in early breast cancer.19,23,24 In studies of IBC where histological evaluation Table 4

has been possible, pathological CR has been achieved only in around 10–18% of patients treated with conventional regimens,9 although a study using an intensified FEC regimen which included a 3-day continuous 5FU infusion reported a pathological CR of 26%,25 and a study of high dose chemotherapy supported by stem cell transplantation reported a pathological CR rate of 39%.9 Meaningful pathological CR rates were not available from our study since a significant number of patients did not have surgery. In particular, this included patients achieving a complete clinical CR where pathological complete remission rates might have been most likely. The infusional ECF schedule was well tolerated. The majority of the toxicities were WHO grade I or II and were controlled with conservative measures. As expected, the use of continuous infusional 5FU resulted in some patients developing significant palmar-plantar erythema and mucositis. These were successfully controlled either by the administration of oral pyridoxine or by dose-reduction. The frequency and degree of haematological toxicity did not appear to be greater than that expected if conventional bolus chemotherapy schedules had been used. It is important to note that the type of locoregional therapy given following infusional chemotherapy did not appear to impact upon patient outcome, either in terms of survival or in terms of site of first relapse. This raises the question as to what is the most appropriate form of locoregional treatment following chemotherapy in IBC; this is an

Studies of primary chemotherapy as part of multi-modality therapy for inflammatory breast cancer published since 1989

Study

Chemotherapy regimen

n

RR %

CRR %

5yr DFS %

5yr OS %

RMH Infusional RMH bolusa Swain16 Thoms17 Fields18 Maloisel19

Continuous Infusional ECF CMF/MMM/FEC/AC CAMF+Tam+Premarin FAC ± VP CAF/CMF FAC + Tam

34 30 45 61 37 43

79 73 98 60 NS 88

35 23 55 16 NS 18

11 25 NR 27 35 48

29 33 NR 35 44 75

Koh20

FAC (24 months) FAC FA(CI)C+VP

40 23 43

80 56 72

15 13 8

35 22 41

37 30 48

Chevallier21

CMF or AVCF AVDF or FAC or VAC F(CI)EC-HD+ oestradiol

64 83 31

56 73 93

6 7 26

18 28 NA

29 39 NA

Rouesse22

AVM + M’ance VCF AVCMF + M’ance VCF

91 79

14b 27a

NS NS

22 40

40 55

ECF – epirubicin, cisplatin (or carboplatin or cyclophosphamide), fluorouracil; CMF – cyclophosphamide, methotrexate, fluorouracil; MMM – mitomycin C, mitoxantrone, methotrexate; FEC – fluorouracil, epirubicin, cyclophosphamide; AC – doxorubicin, cyclophosphamide; CAMF + Tam – cyclophosphamide, doxorubicin, methotrexate, fluorouracil, and tamoxifen; FAC ± VP – fluorouracil, doxorubicin, cyclophosphamide ± vincristine, prednisone; CAF – cyclophosphamide, doxorubicin, fluorouracil; FA(CI)C- fluorouracil, continuous infusion doxorubicin, cyclophosphamide; AVCF – doxorubicin, vincristine, cyclophosphamide, fluorouracil; VAC – vindesine, doxorubicin, cyclophosphamide; F(CI)EC-HD – continuous infusion fluorouracil, epirubicin, cyclophosphamide-higher dose; AVM + M’ance VCF – doxorubicin, vincristine, methotrexate + maintenance vincristine, cyclophosphamide, fluorouracil; AVCMF – doxorubicin, vincristine, cyclophosphamide, methotrexate, fluorouracil. RR – Response rate; CCR – Clinical complete response; DFS – Disease free survival; OS – Overall survival; RMH – Royal Marsden Hospital; NR – Not reached; NS – Not stated; NA – Not available; a-unpublished data; b-measured after three cycles of chemotherapy.

Continuous infusional combination chemotherapy 155 issue that remains unresolved due to a paucity of randomised clinical trials. In conclusion, our results show that infusional ECF chemotherapy is well tolerated and achieves high clinical response rates, both overall and complete, in patients with IBC. However, disease-free and overall survival results do not appear to be better than results achieved with conventional bolus chemotherapy schedules in a similar group of patients at The Royal Marsden Hospital, or when compared with reports in the literature. A randomized phase III trial would be required to determine this properly.

12. 13.

14.

15. 16.

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