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Regional induction chemotherapy in locally advanced breast cancer
The Breast (1992) 1,82-86
Regional induction chemotherapy in locally advanced breast cancer R. P. de Dycker*, J. Timrnermann~,
R. L. A. Neumann*
*Dept. of Gynecological Oncology, TDept. of Interventional Radiology, Acad. Marienhospital-Altenessen, University of Essen, Germany
S UMMA R Y. From May 1985 to May 1989 45 patients suffering from primary inflammatory breast cancer were entered in this Phase II trial of preoperative intra-arterial induction chemotherapy (IACT) using mitoxantrone. The aim of this study was to identify a rapid way of achieving operability without additional discomfort to the patient. IACT was performed supraselectively using digital subtraction angiography. After local operability has been achieved, a modiiied radical mastectomy was performed. Postoperatively, premenopausal patients were treated with adjuvant chemotherapy (CMF) and postmenopausal patients with tamoxifen for a period of two years. All tumours showed a good response 4 weeks after the start of treatment and by 8 weeks, 91% of all tumours were operable. Mammography showed tumour regression of more than 50% in almost 75% of the carcinomas. After a median follow-up of 37 months, the overall survival rate was 29% with a median survival time of 50 months. The median disease-free survival time was 24.4 months for all patients and 25% were alive and symptom free after 6 years. The response rate after induction IACT correlated with the number of cycles required to obtain a significant response, with patients treated with one cycle having a median survival time of 54 months, two cycles 39 months and a median survival time of 9 months in patients who had three cycles. INTRODUCTION
increase in the number of drug-resistant phenotypic variants in a growing cell population. Thus appropriate preoperative chemotherapy should not only destroy cells made more sensitive by their kinetic alteration but also prevent cell proliferation and so prevent an increase in resistant cells. Our objectives were firstly to identify a means of achieving operability of inflammatory breast cancers rapidly without additional discomfort to the patient, and secondly to correlate the response rate with overall survival to determine whether response to IACT was a prognostic factor.
Locally advanced T3 and T4 breast cancers with lymph node involvement are generally no longer curable, with occult or even manifest dissemination being the rule. Surgery alone gives a high incidence of locoregional recurrence. Even though cure is not possible, it is important to achieve local control if only to improve quality of life.’ For patients with metastatic (and, therefore, incurable) breast cancer chemotherapy offers only palliation. Thus, any effects of treatment have to be minimal and can not be balanced by the prospect of cure, as in localized disease. According to Hall’ ‘If the disease is incurable the toxic effects of treatment are of major concern.’ As Tamrock noted, ‘When cure remains elusive, it is time to start treating the patient, not just the tumour.’ The two rationales for preoperative chemotherapy are the effects of primary tumour removal on the growth kinetics of metastases and the Goldie-Coldman hypothesesG The former suggests that noncurative reduction of tumour results in an increase in the proliferation of residual tumour cells whereas the Goldie-Coldman hypothesis suggests there is an
PATIENTS AND METHODS From May 1985 to May 1989 45 patients suffering from primary inflammatory breast cancer were entered in this Phase II trial. All breast carcinomas showed inflammatory features and fulfilled Haagensen’s criteria (erythema, diffuse oedema, single or multiple tumours in the breast).7 In all patients the axillary nodal status was clinically Nl or N2. Apart from clinical examination, pretherapeutic staging with chest radiography, liver sonography, bone scintigraphy, computer tomography (CT) of the thoracic wall, mammography and breast sonography was performed. Histological
Correspondence to: R. P. de Dycker M. D., Dept. of Gynecologic Oncology, Acad. Marienhospital-Altenessen, University of Essen, Hospitalstrasse 24,430O - Essen 12, F’RG 82
Regional induction chemotherapy
confirmation was obtained in all patients by means of incision biopsy. IACT was performed supraselectively using digital subtraction angiography. Each cycle consisted of two treatments; in the first, the catheter was inserted via the brachial or femoral artery into the lateral thoracic artery, and in the second, 1 1 days later into the internal mammary artery. The patient was immobilized for the 72 h of the infusion and received subcutaneous heparin as thrombosis prophylaxis (3 x 5 000 IU heparimday ) (4,8-l 1). 30 mg mitoxantrone (Novantrone, Lederle) was administered through each artery at a rate of 10 mg per 24h. A total of 60 mg/cycle mitoxantrone was given. A new cycle was started after 4 weeks if necessary.4.x,” The efficacy of the IACT was evaluated by the disappearance of the inflammatory features and by the regression of the tumour size evaluated by clinical and radiographic measurements. A modified radical mastectomy was performed 4 weeks after the last infusion of mitoxantrone. On mastectomy specimens detailed histological examination and determination of hormone receptor status was performed.J,8,y Postoperatively, all premenopausal patients were treated with 6 cycles of systemic chemotherapy (cyclophosphamide, methotrexate, 5fluorouracil) and postmenopausal women with tamoxifen 30 mg daily for a period of 2 years.“’
RESULTS After only one cycle of IACT all 45 inflammatory breast cancers responded with loss of the inflammatory features and obvious regression of the tumour by 4 weeks, with 66% of tumours becoming operable (Table 1). There was a regression of more than 50% in almost 75% of patients. We found no complete remissions but in only 9% of cases was there a minor response (~30%
I 6
83
Table 1 Study data of the 45 patients with inflammatory breast cancer number of patients
15
menopausal status premenopausal postmenopausal
Z-1 21
number of cycles one cycle two cycles three cycles
patients (r/F) 66% 2.5% 9%
response partial partial minor
patients (9:) 73.39 17.7% 8.8%
rate remission >50% remission <500/o response x308
reduction) (Table 1). The median follow-up of this group of 45 patients is 37.2 months and 22 patients have been followed for more than three years. 29% of our group of patients were still alive with a median survival time of 50 months (Fig. 1). There was a marked difference in median survival time between pre- and postmenopausal women. The group of patients treated with tamoxifen after surgery had a median survival time of 60 months whereas the chemotherapy group had a median survival time of only 39 months. Survival rate. remission rate and duration of remission are inadequate criteria for evaluation and comparison of new treatment modalities especially for palliative treatments in diseases such as metastatic breast cancer which are heterogeneous in their course and symptomatology. The most appropriate assessment of palliative therapy is the disease-free survival time or the time during which tumour growth can be controlled by a certain therapy namely the time to progression. In this group of patients we had a median time to progression of 24.4 months and 25% of all patients were totally disease-free after 6 years. The premenopausal patients had a median time to progression of 19 months and only 14% of the patients are disease-free after 6 years
I 12
Fig. l-Overall
in locally advanced breast cancer
survival rate after 6 years ~ all patients N= 45 ------ premenopausal patients N= 24 -_- postmenopausal patients N= 2 I
Months Fig. 2-Time to progression after 6 years all patients N= 45 ------ premenopausal patients N= 24 -_postmenopausal patients N= 21
50 10 g
3 2
/L
30-
/“’
20-
iz
$ ‘O- ,x’ 0
;I
YjX
‘x
‘L_ ,-o_c-g-o~~
*-*-Y-*_
Y-r
,x Y’
‘x
n
0
1
2 Number
3
of cycles
x
regressionr50’1.
-0-
regression
+-
regression
c30’I. 30-50’1.
Fig. 3-Response rate in correlation to the number of cycles in patients with inflammatory breast cancer
whereas the tamoxifen group had a median disease-free survival time of 30.4 months and 32% of the patients are alive without any symptoms of disease after 6 years
(Fig. 2). A correlation was seen between response to IACT and the overall survival in each group of patients. During the first treatment cycle 77% responded with a reduction in tumour volume of more than 50%, in the group treated with two cycles 50% responded and in patients receiving three cycles the response rates was ~30% (Fig. 3). The overall survival rate in these three groups of patients differed markedly - in the group of patients treated with one cycle we found a median survival time of 54 months and 30% of the patients were alive without any symptoms of disease. In the group treated with two cycles the overall survival rate was 40% but the median survival time was only 39 months. In the group of patients needing 3 cycles all patients died with a median survival time of only 9 months (Fig. 4). All patients treated with more than one cycle of preoperative IACT developed progressive disease with a median time to progression of 27.4 months in the group receiving 2
___ _-_---.
100, , I
ONE CYCLE TWO CYCLES THREE CYCLES
(N=30) [N=ll) ---(N=1 I .___.
I
80-
i .-.-
.-. -.
D :
s6o g 40 -
I I
I.-.-.-.
1
I I I.- ,.-
L_
20-
FigA-Overall survival rate after 6 years in correlation patients with one cycle ------ patients with 2 cycles - - - patients with 3 cycles
to the number of cycles
Regional induction chemotherapy ONE CYCLE
in locally advanced breast cancer
85
(1~30) -
TWOCYCLES lN=‘ll--THREE CYCLES (N= 4) ‘-.-
‘00 y-q+
,
I
6
12
I
‘8
1
L
I
I
30 Months
36
12
48
I
24
Fig. S-Time to progression after 6 years in correlation ~ patients with one cycle ------ patients with 2 cycles -.-.- patients with 3 cycles
cycles and 9 months in the group having 3 cycles. Although patients treated with 1 cycle showed the same median disease-free survival as patients treated with 2 cycles, 34% were alive without symptoms of disease at 6 years (Fig. 5). In all mastectomies, resection margins were histologically free of tumour and free of dermal Iymphatic infiltration. Tumour histology was assessed according to the Bloom and Richardson grading. We found 24 cases of grade III and 15 cases of grade II ductal carcinoma; the other tumours showed a lobular or mixed lobular histology. We confirmed the finding of Sainsbury et al” with the most extensive histological response to treatment being found in the patients with a grade III tumour. Histology revealed in most cases extensive necrosis in the centre of the tumour with dense infiltration of Iymphocytes and plasma cells in the periphery. Using the classification of Shimosato,‘3 the histological evaluation of the effect of chemotherapy showed a grade IIa/IIb response in 12/29 of the resected specimens. In no carcinoma could we diagnose complete histological remission. Toxicity of the treatment is shown in Table 2. Dosage reduction or neutropenia-induced delay in treatment was not seen in 128 courses. Local side effects such as catheter displacement, haematomas and failed cannulations were seen only in the initial phase of our study.
!
I
I
54
60
to the number of cycles
been a notable improvement in the reported 5-year survival rate (from 28%-55%).‘b.‘9” In 1985, we looked for a new treatment modality in the management of primary locally advanced mammary carcinomas. Conventional therapy with systemic chemotherapy and/or irradiation can cause significant side effectsI whereas IACT is well tolerated and side effects are few.“,8,9Local complications occurred in the early phase of
Table 2
Side effects and complications
Local side effects ‘g
Haematomas Extravasation Thrombosis Catheter displacement Vertebral artery symptoms Infections Pain Failed access Aortic aneurysm
1.6 3.’ 1.6 4.0 0.8 0.8 14.4 2.4 0.8
72 H INFUSIONS Feeling of warmth Pain Bleeding-necrosis Temperature rise Circulatory problems Nausea-loss of appetite Fainting
67.2 32.8 14.4 27.2 8.8 16.8 0.R
LONG TERM EFFECTS
DISCUSSION The diagnosis of ‘inflammatory mammary carcinoma’ is based on clinical features described by Haagensen for this rare type of breast turnour.’ This cancer has a very poor prognosis: almost all those affected die of distant metastases within 12-24 months.5.‘“‘8 With the development of cytostatic cancer treatment there has
Temperature/ fever Nausea-loss of appetite Alopecia Diarrhoea Weight loss Thrombosis Stomatitis Leucopaenia c 2500
8.8 16.8 I 7.6 5.6 4.0 5.6
16.8 Il.6 8.8 14.4 8.0
seen
our studies but are now seen infrequently. A rise in temperature was a common finding, possibly due to tumour lysis. The alopecia and stomatitis rates of 17.6% and 16.8% are lower than equivalent doses given by intravenous routes. Dose reduction and delays due to leucopenia were not seen. The benefits of the scheduling of IACT in this study are considerable. The interval between diagnosis and operation was shorter than in other reported series; 91% of the tumours becoming operable after only 8 weeks. Regression of more than 50% was noticed in almost 75% of tumours. Analysing the response rates after successive cycles it is clear that little further tumour regression is seen after 2 cycles of IACT and this technique should probably cease at this time. The median survival time of 60 months in the tamoxifen group and only 39 months in the chemotherapy group demonstrates the marked difference between pre- and postmenopausal women. This is also seen when the time to progression is studied. It is likely that this is due to a preponderence of better prognostic features (oestrogen receptor positive tumours with a low growth fraction) in the postmenopausal group. In inflammatory breast cancer the response to preoperative induction chemotherapy is a prognostic factor in its own right.“,‘3 In our group of patients there was a good correlation between response to IACT and overall survival after 6 years (Fig. 4). All patients who needed treatment with more than 2 cycles died and only patients who responded after one cycle had a worthwhile median survival time of 54 months. A similar correlation was noted with time to progression. These findings are important because T4 tumours have been considered to represent cancers which are no longer curable. For such tumours it is important to select a treatment modality that offers the optimal combination of inhibition of tumour growth and minimal disruption of the patient’s life.4~6,‘9,20,23 On the basis of our results, IACT of primary locally advanced breast cancer fulfils these criteria and can be regarded as an alternative to preoperative intravenous cytotoxic treatment with or without irradiation.4’8 It achieves local operability after two treatment cycles with a response rate of 9 1% and a tumour regression rate greater than 50% in almost 75% of all patients and offers realistic palliation for the patient providing good quality of life.
3. 4.
5.
6. 7. 8.
9.
10.
11.
12.
13.
14.
15. 16.
17. 18.
19.
20.
21.
22.
Acknowledgement The assistance of Mr. Richard Sainsbury publication of this paper is acknowledged.
in
achieving
rapid
23.
24.
References 1. von Foumier D, Kubli F. Rationale for the choice of treatment. In: Kubli F., von Foumier D., Bauer M. (eds): Breast diseases. Springer Verlag Berlin-Heidelberg (1989) 174-208 2. Hall V L, Buchanan R B, Williams CJ. VMP versus VAP in advanced breast cancer - a toxicity study. In Hatt K. J., Robinson
R., McGrath K.(eds): Proceedings of the 3rd United Kingdom Novantrone Symposium. Hampshire; Media Medica, 1987; 87-90 Tannock I F. Treating the patient, not just the cancer. New Engl J Med 1987; 317: 1534-1535 de Dycker R P, Neumann R L A, Timmermann J, Wever H, Schindler A E. Arterielle regionale Chemotherapie fortgeschrittener Mammacarcinome. Dtsch Med Wochenschr 1988; 113: 1229-1233 Noguchi S, Miyauchi K, Nishizawa Y. Management of inflammatory carcinoma of the breast with combined modality therapy including intraarterial chemotherapy as induction therapy. Cancer 1988; 61: 1483-1491 Stephens F 0. Advanced breast cancer - intraarterial induction chemotherapy. Reg Cancer Treat 1989; 2: 5-8 Haagensen C D. Diseases of the breast. Saunders, Philadelphia (1971) de Dycker R P, Neumann R L A, Timmermann J. Lokoregionale Chemotherapie biem fortgeschrittenen Mammacarcinom. Die lokoregionale Tumortherapie. de Gruyter, Berlin (1988) 103-109 de Dycker R P, Neumann R L A, Timmermann J. Lokoregionale Chemotherapie beim fortgeschrittenen Mammacarcinom eine Alternative in der Primartherapie. Tumor Diagn Ther 1988; 4: 137-141 de Dycker R P, Timmermann J, Neumann R L A, Wever H, Schindler A E. Arterial regional chemotherapy of advanced breast cancer. Journal of Chemotherapy Vol 1. 1989; 4: 1193-l 195 de Dycker R P, Timmermann J, Schumacher T. Arterial regional chemotherapy of advanced breast cancer-4-year survival rate. Recent Advances in Chemotherapy. Lewin-Epstein Ltd. 1990; 784. I-784.2 Sainsbury JRC, Walker V A, Ali H H. A dose-escalation study of mitoxantrone given intra-arterially for breast cancer. Reg Cancer Treat 1991; 5: 243-247 Shimosato Y, Oboshi S, Baba K. Histological evaluation of effects of radiotherapy and chemotherapy for carcinoma. J Clin Oncol1971; 1: 19-35 Chauvergne J, Durand M, Dilhuydy MH, Hoemi B, Germain T, Lagarde C. Traitment des cancers du sein inflammatories. Rev Fr Gynecol 198 1; 227-235 Chu A M, Wood W C, Doucett JA. Inflammatory breast carcinoma treated by radiotherapy. Cancer 1980; 45: 2730-2737 Kusche M, Scharl A, Reusch K, Bohe A. Therapie und Prognose des inflammatorischen Mammakarzinoms. Tumor Diagn Ther 8 (1987) 108-l 14 Rubens R D, Armitage P, Winter P J. Prognosis in inoperable Stage III carcinoma of the breast. Europ J Cancer 1977; 13: 805-811 Thomsen K, Maass H. Therapie der Mammatumouren. In:K-sero, Friedberg V, Ober K G, Thomsen K, Zander J.(eds) Gynokologie und Geburtshilfe,Thieme, Stuttgart, Vol III/l. 1985; 3: 112-l 13 Aigner K R, Walther H, Muller H. Intraarterial infusion chemotherapy for recurrent breast cancer via an implantable system. Reg Cancer Treat 1988; 1: 102-107 Carter R D, Faddis D M, Krementz ET. Treatment of locally advanced breast cancer with regional intraarterial chemotherapy. Reg Cancer Treat 1988; 1: 108-l 11 Hortobagyi G N, Ames F C, Buzdan A V. Management of Stage III primary breast cancer with primary chemotherapy, surgery and radiation therapy. Cancer 1988; 62: 2507-2516 Jacquillat C, Baillet F, Weil M. Results of conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy, and external and interstitial irradiation in 98 patients with locally advanced breast cancer. Cancer 1988; 61: 1977-1982 Koyama H, Wada T, Takahashi Y. Intraarterial infusion chemotherapy as a preoperative treatment of locally advanced breast cancer. Cancer 1975; 36: 1603-1612 Von Hoff D D, Clark G M, Weiss G R, Marshall M H, Buckok J B, Knight W A III, le Maistre C F. Use of in vitro dose response effects to select antineoplastics for high dose or regional administration regimens. J Clin Oncol 1986; 4( 12): 1827-1834
Date received 30 August 199 1 Date accepted 17 October 1991
Regional induction chemotherapy in locally advanced breast cancer R. P. de Dycker*, J. Timrnermann~,
R. L. A. Neumann*
*Dept. of Gynecological Oncology, TDept. of Interventional Radiology, Acad. Marienhospital-Altenessen, University of Essen, Germany
S UMMA R Y. From May 1985 to May 1989 45 patients suffering from primary inflammatory breast cancer were entered in this Phase II trial of preoperative intra-arterial induction chemotherapy (IACT) using mitoxantrone. The aim of this study was to identify a rapid way of achieving operability without additional discomfort to the patient. IACT was performed supraselectively using digital subtraction angiography. After local operability has been achieved, a modiiied radical mastectomy was performed. Postoperatively, premenopausal patients were treated with adjuvant chemotherapy (CMF) and postmenopausal patients with tamoxifen for a period of two years. All tumours showed a good response 4 weeks after the start of treatment and by 8 weeks, 91% of all tumours were operable. Mammography showed tumour regression of more than 50% in almost 75% of the carcinomas. After a median follow-up of 37 months, the overall survival rate was 29% with a median survival time of 50 months. The median disease-free survival time was 24.4 months for all patients and 25% were alive and symptom free after 6 years. The response rate after induction IACT correlated with the number of cycles required to obtain a significant response, with patients treated with one cycle having a median survival time of 54 months, two cycles 39 months and a median survival time of 9 months in patients who had three cycles. INTRODUCTION
increase in the number of drug-resistant phenotypic variants in a growing cell population. Thus appropriate preoperative chemotherapy should not only destroy cells made more sensitive by their kinetic alteration but also prevent cell proliferation and so prevent an increase in resistant cells. Our objectives were firstly to identify a means of achieving operability of inflammatory breast cancers rapidly without additional discomfort to the patient, and secondly to correlate the response rate with overall survival to determine whether response to IACT was a prognostic factor.
Locally advanced T3 and T4 breast cancers with lymph node involvement are generally no longer curable, with occult or even manifest dissemination being the rule. Surgery alone gives a high incidence of locoregional recurrence. Even though cure is not possible, it is important to achieve local control if only to improve quality of life.’ For patients with metastatic (and, therefore, incurable) breast cancer chemotherapy offers only palliation. Thus, any effects of treatment have to be minimal and can not be balanced by the prospect of cure, as in localized disease. According to Hall’ ‘If the disease is incurable the toxic effects of treatment are of major concern.’ As Tamrock noted, ‘When cure remains elusive, it is time to start treating the patient, not just the tumour.’ The two rationales for preoperative chemotherapy are the effects of primary tumour removal on the growth kinetics of metastases and the Goldie-Coldman hypothesesG The former suggests that noncurative reduction of tumour results in an increase in the proliferation of residual tumour cells whereas the Goldie-Coldman hypothesis suggests there is an
PATIENTS AND METHODS From May 1985 to May 1989 45 patients suffering from primary inflammatory breast cancer were entered in this Phase II trial. All breast carcinomas showed inflammatory features and fulfilled Haagensen’s criteria (erythema, diffuse oedema, single or multiple tumours in the breast).7 In all patients the axillary nodal status was clinically Nl or N2. Apart from clinical examination, pretherapeutic staging with chest radiography, liver sonography, bone scintigraphy, computer tomography (CT) of the thoracic wall, mammography and breast sonography was performed. Histological
Correspondence to: R. P. de Dycker M. D., Dept. of Gynecologic Oncology, Acad. Marienhospital-Altenessen, University of Essen, Hospitalstrasse 24,430O - Essen 12, F’RG 82
Regional induction chemotherapy
confirmation was obtained in all patients by means of incision biopsy. IACT was performed supraselectively using digital subtraction angiography. Each cycle consisted of two treatments; in the first, the catheter was inserted via the brachial or femoral artery into the lateral thoracic artery, and in the second, 1 1 days later into the internal mammary artery. The patient was immobilized for the 72 h of the infusion and received subcutaneous heparin as thrombosis prophylaxis (3 x 5 000 IU heparimday ) (4,8-l 1). 30 mg mitoxantrone (Novantrone, Lederle) was administered through each artery at a rate of 10 mg per 24h. A total of 60 mg/cycle mitoxantrone was given. A new cycle was started after 4 weeks if necessary.4.x,” The efficacy of the IACT was evaluated by the disappearance of the inflammatory features and by the regression of the tumour size evaluated by clinical and radiographic measurements. A modified radical mastectomy was performed 4 weeks after the last infusion of mitoxantrone. On mastectomy specimens detailed histological examination and determination of hormone receptor status was performed.J,8,y Postoperatively, all premenopausal patients were treated with 6 cycles of systemic chemotherapy (cyclophosphamide, methotrexate, 5fluorouracil) and postmenopausal women with tamoxifen 30 mg daily for a period of 2 years.“’
RESULTS After only one cycle of IACT all 45 inflammatory breast cancers responded with loss of the inflammatory features and obvious regression of the tumour by 4 weeks, with 66% of tumours becoming operable (Table 1). There was a regression of more than 50% in almost 75% of patients. We found no complete remissions but in only 9% of cases was there a minor response (~30%
I 6
83
Table 1 Study data of the 45 patients with inflammatory breast cancer number of patients
15
menopausal status premenopausal postmenopausal
Z-1 21
number of cycles one cycle two cycles three cycles
patients (r/F) 66% 2.5% 9%
response partial partial minor
patients (9:) 73.39 17.7% 8.8%
rate remission >50% remission <500/o response x308
reduction) (Table 1). The median follow-up of this group of 45 patients is 37.2 months and 22 patients have been followed for more than three years. 29% of our group of patients were still alive with a median survival time of 50 months (Fig. 1). There was a marked difference in median survival time between pre- and postmenopausal women. The group of patients treated with tamoxifen after surgery had a median survival time of 60 months whereas the chemotherapy group had a median survival time of only 39 months. Survival rate. remission rate and duration of remission are inadequate criteria for evaluation and comparison of new treatment modalities especially for palliative treatments in diseases such as metastatic breast cancer which are heterogeneous in their course and symptomatology. The most appropriate assessment of palliative therapy is the disease-free survival time or the time during which tumour growth can be controlled by a certain therapy namely the time to progression. In this group of patients we had a median time to progression of 24.4 months and 25% of all patients were totally disease-free after 6 years. The premenopausal patients had a median time to progression of 19 months and only 14% of the patients are disease-free after 6 years
I 12
Fig. l-Overall
in locally advanced breast cancer
survival rate after 6 years ~ all patients N= 45 ------ premenopausal patients N= 24 -_- postmenopausal patients N= 2 I
Months Fig. 2-Time to progression after 6 years all patients N= 45 ------ premenopausal patients N= 24 -_postmenopausal patients N= 21
50 10 g
3 2
/L
30-
/“’
20-
iz
$ ‘O- ,x’ 0
;I
YjX
‘x
‘L_ ,-o_c-g-o~~
*-*-Y-*_
Y-r
,x Y’
‘x
n
0
1
2 Number
3
of cycles
x
regressionr50’1.
-0-
regression
+-
regression
c30’I. 30-50’1.
Fig. 3-Response rate in correlation to the number of cycles in patients with inflammatory breast cancer
whereas the tamoxifen group had a median disease-free survival time of 30.4 months and 32% of the patients are alive without any symptoms of disease after 6 years
(Fig. 2). A correlation was seen between response to IACT and the overall survival in each group of patients. During the first treatment cycle 77% responded with a reduction in tumour volume of more than 50%, in the group treated with two cycles 50% responded and in patients receiving three cycles the response rates was ~30% (Fig. 3). The overall survival rate in these three groups of patients differed markedly - in the group of patients treated with one cycle we found a median survival time of 54 months and 30% of the patients were alive without any symptoms of disease. In the group treated with two cycles the overall survival rate was 40% but the median survival time was only 39 months. In the group of patients needing 3 cycles all patients died with a median survival time of only 9 months (Fig. 4). All patients treated with more than one cycle of preoperative IACT developed progressive disease with a median time to progression of 27.4 months in the group receiving 2
___ _-_---.
100, , I
ONE CYCLE TWO CYCLES THREE CYCLES
(N=30) [N=ll) ---(N=1 I .___.
I
80-
i .-.-
.-. -.
D :
s6o g 40 -
I I
I.-.-.-.
1
I I I.- ,.-
L_
20-
FigA-Overall survival rate after 6 years in correlation patients with one cycle ------ patients with 2 cycles - - - patients with 3 cycles
to the number of cycles
Regional induction chemotherapy ONE CYCLE
in locally advanced breast cancer
85
(1~30) -
TWOCYCLES lN=‘ll--THREE CYCLES (N= 4) ‘-.-
‘00 y-q+
,
I
6
12
I
‘8
1
L
I
I
30 Months
36
12
48
I
24
Fig. S-Time to progression after 6 years in correlation ~ patients with one cycle ------ patients with 2 cycles -.-.- patients with 3 cycles
cycles and 9 months in the group having 3 cycles. Although patients treated with 1 cycle showed the same median disease-free survival as patients treated with 2 cycles, 34% were alive without symptoms of disease at 6 years (Fig. 5). In all mastectomies, resection margins were histologically free of tumour and free of dermal Iymphatic infiltration. Tumour histology was assessed according to the Bloom and Richardson grading. We found 24 cases of grade III and 15 cases of grade II ductal carcinoma; the other tumours showed a lobular or mixed lobular histology. We confirmed the finding of Sainsbury et al” with the most extensive histological response to treatment being found in the patients with a grade III tumour. Histology revealed in most cases extensive necrosis in the centre of the tumour with dense infiltration of Iymphocytes and plasma cells in the periphery. Using the classification of Shimosato,‘3 the histological evaluation of the effect of chemotherapy showed a grade IIa/IIb response in 12/29 of the resected specimens. In no carcinoma could we diagnose complete histological remission. Toxicity of the treatment is shown in Table 2. Dosage reduction or neutropenia-induced delay in treatment was not seen in 128 courses. Local side effects such as catheter displacement, haematomas and failed cannulations were seen only in the initial phase of our study.
!
I
I
54
60
to the number of cycles
been a notable improvement in the reported 5-year survival rate (from 28%-55%).‘b.‘9” In 1985, we looked for a new treatment modality in the management of primary locally advanced mammary carcinomas. Conventional therapy with systemic chemotherapy and/or irradiation can cause significant side effectsI whereas IACT is well tolerated and side effects are few.“,8,9Local complications occurred in the early phase of
Table 2
Side effects and complications
Local side effects ‘g
Haematomas Extravasation Thrombosis Catheter displacement Vertebral artery symptoms Infections Pain Failed access Aortic aneurysm
1.6 3.’ 1.6 4.0 0.8 0.8 14.4 2.4 0.8
72 H INFUSIONS Feeling of warmth Pain Bleeding-necrosis Temperature rise Circulatory problems Nausea-loss of appetite Fainting
67.2 32.8 14.4 27.2 8.8 16.8 0.R
LONG TERM EFFECTS
DISCUSSION The diagnosis of ‘inflammatory mammary carcinoma’ is based on clinical features described by Haagensen for this rare type of breast turnour.’ This cancer has a very poor prognosis: almost all those affected die of distant metastases within 12-24 months.5.‘“‘8 With the development of cytostatic cancer treatment there has
Temperature/ fever Nausea-loss of appetite Alopecia Diarrhoea Weight loss Thrombosis Stomatitis Leucopaenia c 2500
8.8 16.8 I 7.6 5.6 4.0 5.6
16.8 Il.6 8.8 14.4 8.0
seen
our studies but are now seen infrequently. A rise in temperature was a common finding, possibly due to tumour lysis. The alopecia and stomatitis rates of 17.6% and 16.8% are lower than equivalent doses given by intravenous routes. Dose reduction and delays due to leucopenia were not seen. The benefits of the scheduling of IACT in this study are considerable. The interval between diagnosis and operation was shorter than in other reported series; 91% of the tumours becoming operable after only 8 weeks. Regression of more than 50% was noticed in almost 75% of tumours. Analysing the response rates after successive cycles it is clear that little further tumour regression is seen after 2 cycles of IACT and this technique should probably cease at this time. The median survival time of 60 months in the tamoxifen group and only 39 months in the chemotherapy group demonstrates the marked difference between pre- and postmenopausal women. This is also seen when the time to progression is studied. It is likely that this is due to a preponderence of better prognostic features (oestrogen receptor positive tumours with a low growth fraction) in the postmenopausal group. In inflammatory breast cancer the response to preoperative induction chemotherapy is a prognostic factor in its own right.“,‘3 In our group of patients there was a good correlation between response to IACT and overall survival after 6 years (Fig. 4). All patients who needed treatment with more than 2 cycles died and only patients who responded after one cycle had a worthwhile median survival time of 54 months. A similar correlation was noted with time to progression. These findings are important because T4 tumours have been considered to represent cancers which are no longer curable. For such tumours it is important to select a treatment modality that offers the optimal combination of inhibition of tumour growth and minimal disruption of the patient’s life.4~6,‘9,20,23 On the basis of our results, IACT of primary locally advanced breast cancer fulfils these criteria and can be regarded as an alternative to preoperative intravenous cytotoxic treatment with or without irradiation.4’8 It achieves local operability after two treatment cycles with a response rate of 9 1% and a tumour regression rate greater than 50% in almost 75% of all patients and offers realistic palliation for the patient providing good quality of life.
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Acknowledgement The assistance of Mr. Richard Sainsbury publication of this paper is acknowledged.
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Date received 30 August 199 1 Date accepted 17 October 1991