Professor Evgeni V. Khmelevsky, professor Georgiy A. Panshin, professor Natalia Y. Dobrovolskaya, Yulia A. Ponkratova

Radiology department, Russian Scientific Centre of Roentgeno-radiology, Moscow, Russia

Dose reduction of postmastectomy irradiation in treatment of locally advanced breast cancer

Introduction

Anticancer activity (in local control) of radiation following mastectomy has been known since the middle of XX century.[1] Nevertheless several randomized trials of EBCTCG[2] in 2005 studied role of postmastectomy radiation in adjuvant treatment and revealed not only 14,8% reduction of local recurrence risk in patients with 4 and more metastatic lymph nodes (median follow-up 5 years) but also 2,3% reduction of cancer-specific mortality (70,3% vs 68,0%) and 1,7% reduction of overall (72,4% vs 70,8%) mortality (median follow-up 15 years). Unfortunately this positive effect can be leveled by increasing of mortality due to postradiation complications which can be even more severe if chemotherapy and radiation combination is used. [3,4] G. Gagliardi et al. [5] in 1997 reported that risk of death caused by cardiovascular complications after radiation therapy of breast cancer vary from 2,1% to 12%; they also demonstrated that the risk is significantly minimized by reduction of dose cumulated by heart, this can be achieved by using 3D planning techniques, protective blocks and intensive radiation beam. Besides of these methods one more can be proposed - adequate reduction of equivalent dose, which is based on two preconditions:

1. improvement of dose homogeneity in radiated areas due to upgrade of modern technologies;

2. additive effect of modern neoadjuvant and adjuvant chemotherapy.

The letter method is being investigated in our Centre among patients with locally advanced breast cancer.

Material and methods

The study is pilot, retrospective and nonrandomized. It includes 211 patients with II-III stages of breast cancer treated with mastectomy and adjuvant radiation therapy in Russian Research Centre of Roentgeno-radiology in 1998-2004. Median follow-up was 104 months. All patients were divided into 2 groups (according to dose to chest wall):

1. 1 group –variant of normal-dose (50 Gy to chest wall) radiation therapy with/without chemotherapy (129 patients).

2. 2 group –variant of low-dose (40 Gy to chest wall) radiation therapy with/without chemotherapy (82 patients).

Dose to regional areas (46-50 Gy according to the number of metastatic lymphatic nodes) as well as neoadjuvant and adjuvant chemotherapy regimes were similar in both groups.

Median follow-up was 111 and 95 months for the 1 and 2 group respectively.

Treatment

As the first step of treatment 128 patients were given neoadjuvant chemotherapy with CMF or CAF regimens.

All the patients had undergone radical mastectomy (Madden - 203 (95,8%), Halsted– 2 (0,9%), simple mastectomy – 6 (2,8%).

As adjuvant treatment there were radiation treatment, chemotherapy if recommended (4-6 courses of CMF, CAF or taxane-based regimens) and hormonal therapy in case of positive receptor status (in premenopausal women – LHRH for 2 years or ovarioectomy with concurrent antiestrogens or aromatase inhibitors during 5 years; in postmenopausal women - antiestrogens or aromatase inhibitors during 5 years).

Radiation

Radiation treatment was performed with 1,2-6 Mev photons or high-energy electrons. In case of photon radiation special fixing capacity and some methods improving dose homogeneity in radiated volume were used. [6]

Statistics

Summary statistics were conducted on personal computer using electron table «Microsoft Exñel» and packet of programs «Statistica for Windows» v.6.0, StatSoft Inc (USA). Fisher and Student exact tests were used as base criteria. Survival analysis was estimated according to Kaplan-Meier method. Significance was defined as P value ≤0,05 . 95% confidence intervals and P values were calculated for each parameter in both groups.

Results

Frequency of several characteristics of patients’ condition, disease staging and treatment specialties in both groups is presented at the following Table 1.

Locoregional recurrence

Frequency of locoregional recurrence in 1 and 2 groups during all follow-up period was 6,2±2,1 % (8 patients) è 3,7±2,1% (3 patients) respectively. We have found no statistically significant differences between two groups (p=0,4). Mean time to relapse was 41 month (21-78 months) for the low-dose group and 21 months (9-34 months) for the normal-dose group, the difference is statistically significant (p=0,003). From 8 cases of locoregional recurrence in normal-dose group 4 were local (3,1%), 2 – regional (1,6%) and 2 – locoregional (1,6%); in low-dose group: 1 - local (1,1%), 1 – regional (1,1%) and 1 – locoregional (1,1%) (Fig.1).

All recurrences in the 1^st group occurred in patients who got any adjuvant chemotherapy, in the 2^nd group only one patient with relapse did not get it (so we could not reveal any statistical dependence between locoregional relapse and adjuvant chemotherapy, p=0,5). Adjuvant hormonal therapy also did not cause statistically important changes: only 2 from 8 relapses in normal-dose group occurred in patients who did not get adjuvant hormonal therapy (p=0,7) and all 3 relapses in low-dose group – in patients after it.

5-year frequency of locoregional recurrence was 6,2±2,1% and 2,4±1,7% for 1 è 2 groups respectively (ð=0,6).

Distant recurrence

Frequency of distant progression in 1 and 2 groups during all follow-up period was 34,6±4,2% (45 patients) è 19,5±4,4% (16 patients). Low-dose radiation had

statistically significant benefit (ð<0,05). Mean time to distant metastases had occurred was 23 month (1-100 months) for the low-dose group and 30 months (3-92 months) for the normal-dose group, the difference is not statistically significant (p=0,7).

5-year frequency of distant recurrence was 31±4,1% è 18,3±4,3% for 1 è 2 groups respectively (ð<0,05).

Statistically significant decrease of distant progression frequency in 2^nd group was more likely caused by lager number of patients with intact lymph nodes (26,5% in low-dose vs 17,1% in normal-dose group).

Frequency of any organs and tissues involvement in metastatic process did not differ significantly between the groups. Patients from the 1^st group had metastases to liver in 55,6%, to bones – 48,4%, to lungs and pleura – 17,8%, brain – 4,4%, nonregional lymphnodes and soft tissue – 20%. The same positions in the 2^nd group were 23,5%, 53%, 29,4%, 11,8%, 14,3% respectively.

We have found no statistically significant influence of adjuvant chemo- and hormonal therapy on distant recurrence frequency (ð=0,5).

Progression-free survival

There are no statistically significant difference in progression-free survival (PFS) between the two groups (Fig.2).

5-year PFS was 61,6±6,4% in the low-dose and 53,5±5,4% in the normal-dose group.

PFS occurred to be in reverse relation to disease stage (table 2).

There were no statistical difference in PFS between the groups depending on patients’ age, number on regional lymphnodes involved and using of adjuvant chemo- and hormonal therapy.

Overall survival

Overall survival was not differ statistically between the two groups (ð=0,8) (Fig.3).5-year OS was 72,2±6,3% in the low-dose and 65,3±5,6% in the normal-dose group. We did not noted any statistical differences between the groups according to the variant of adjuvant drug treatment.

5-year cancer-specific survival was similar for the normal-dose and low-dose groups: 78,2±4,8% and 79,7±6,1% respectively.

Late cardial dysfunctions

To evaluate the rate of late cardial dysfunction in the groups we used method of pairs. From the whole number of patients we selected 2 groups of 20 women:

1st group - low-dose radiation treatment,

2^nd group - normal-dose radiation treatment.

As the criteria for the forming groups we used (from more to less significance):

· Localisation of the tumor (left only)

· Patient’s age

· Severity of cardial pathology before treatment

· Impairment of cardac function during the course of treatment

· Anthracyclines in neoadjuvant and adjuvant chemotherapy

· Comorbidities: thyreoid disfunction, diabetes mellitus, obesity.

As a criteria of cardiovascular system statement only data from ECG was used. ECG is a routinely procedure before and in the course of treatment as well as at least annually during follow-up period. We considered cardiopathies both first revealed during the treatment (as early complications) and during follow-up period (as late complications – at least 1 year after start of treatment).

Late cardiac impairment on ECG occurred in 55±11,1% and 75±9,7% of patients from low-dose and normal-dose group. We did not get statistical difference, but strong tendency to more favourable results in low-dose radiation can not be ignored.

Discussion

Results of our work correlate to data from randomized studies estimated the influence of adjuvant radiation therapy on progression-free and overall survival of patients with locally advanced breast cancer (Table 3).

So, frequency of locoregional relapse in our study was 3,7% and 6,2% for low-dose and normal-dose variants of radiation, in other studies – 7-15% [7, 8, 9,10, 11, 12, 13, 14, 15]. The difference is likely to be explained by fewer number of patients and shorter follow-up period in this work. 5-year progression-free survival also corresponds to world statistic data: 64% and 44% for the 1^st and 2^nd groups in our study and 48-69% according to foreign authors. [9,10, 11, 13,15]

5-year cancer-specific survival in both groups was 50% and 69,7%, 5-year overall survival – 65,3% and 72,2% for normal-dose and low-dose groups respectively. These results are not at variance with data from several studies of EBCTCG in 2005 where cancer-specific and overall survival accounted 70,3% and 72,4%.[2].

Data about cardiotoxicity after postmastectomy radiation vary significantly among different authors: from 1% to 54% [16, 17, 18, 19, 20].

According to study conducted earlier in our Center frequency of late cardiac dysfunctions registered on ECG estimated as 36,6±3,7%. In case of cumulative dose on chest area less than 40 Gr or right-side tumors changes on ECG were registered in 24%; and in case of left-side tumors – 32%. In the group of patients who received cumulative dose on chest area more than 40 Gr changes on ECG occurred in 36% and 50% in case of right-side and left-side tumor respectively [21, 22, 23].

Preliminary results of this study confirm influence of cumulative dose on frequency of cardiopathies: late cardiac dysfunctions were registered with ECG in 55% in low-dose group and 75% in normal-dose group (both in case of left-side tumors).

Summarizing all afore-sited data, it can be concluded that all results of this method of complex treatment including low-dose postmastectomy chest irradiation are comparable with other researchers’ data, who used standard radiation therapy. Nowadays one of the most important way of oncology development is treatment individualization. According to this one of the main problem in radiation therapy of breast cancer is development of methods of individual dose selection resulting in standard level of local control and minimum of side effects. Our study is continued now as a randomized research in order to solve afore-mentioned problem.

Table I. Characteristic of some prognostic factors

Categories	Normo-dose RT (1 group) Abs (%)	Low-dose RT (2 group) Abs (%)	ð
Years · < 40 · 41-50 · 51-60 · 61-70 · > 71	11 (8,5±2,5) 48 (37,2±4,3) 39 (30,2±4,0) 26 (20,2±3,5) 5 (3,9±1.7)	6 (7,3±2,9) 23 (28,1±5,0) 24 (29,3±5,0) 29 (35,4±5,3) 0	ð<0,05
Local tumor (stage Ò) · 1 · 2 · 3 · 4	7 (5,4±2,0) 51 (39,5±4,3) 32 (24,8±7,6) 39 (30,2±4,0)	5 (6,1±2,6) 37 (45,1±5,5) 24 (29,3±5,0) 16 (19,5±4,4)
Regional lymph nodes (pN) · 0 · 1 · 2 · 3	22 (17,1±3,3) 19 (14,7±3,1) 69 (53,5±4,4) 19 (14,7±3,1)	21 (25,6±4,8) 14 (17,1±4,2) 36 (43,9±5,5) 11(13,4±5,5)
Stage · IIA · IIB · IIIA · IIIB · IIIC	6 (4,7±1,9) 14 (10,9±2,7) 50 (38,8±4,3) 36 (27,9±3,9) 19 (14,7±3,1)	4 (4,9±2,4) 16 (19,5±4,4) 37 (45,1±5,5) 13 (15,9±4,0) 11 (13,4±3,8)	ð<0,05
Drug treatment in perioperation period · Neoadjuvant CT · Adjuvant CT · Adjuvant hormonal therapy	86 (66,73±4,1) 113 (87,6±3,0) 100 (77,5±6,8)	42 (51,2±5,5) 66 (80,5±4,4) 66 (80,5±4,4)
Morphology · Ductal · Lobular · Ductal+Lobular · Special forms · N/A	81 (62,8±4,2) 22 (17,1±3,3) 3 (2,3) ±1,3 5 (4,0±1,7) 12 (9,3±2,6)	57 (64,0±5,3) 18 (20,2±4,4) 1 (1,1±1,1) 2 (2,2±1,6) 13 (14,7±3,9)
Hormonosensitivity · Sensitive · Nonsensitive · N/A	58 (77,3±4,8)* 17 (22,7±4,8)* 54 (41,8±4,3)	58 (81,7±4,6)* 13 (18,3±4,6)* 11 (13,4±3,8)

* of the examined ones.

Table II. Dependance of 5-year PFS on disease stage in the 1^st and 2^nd groups

Stage RT	IIb (%)	IIIa (%)	IIIb (%)	IIIc (%)
Normal-dose RT	60,7±18,4	49±7,9	37,8±9,6	17,1±10,6
Low-dose RT	58,5±17,2	65,6±9,4	65,1±18,7	40,8±18,0

Table III. Effectiveness of postmastectomy radiation therapy (according to literature data)

Authors, year	Number of patients	Decease stage	Median follow-up	Local relupse	Distant relapse	5-year PFS	5-year OS	Cancer-specific survival
Dunst J et al., 2001[7]	959	I-III	10 years	13,6%			70,5 %
Hehr T.et al., 2004[8]	287	I-III	5 years	15,5%		61%	70%
Yadav B.et al.,2007[9]	688	I-III	67 mon	8,5%	18,7%	69%	81%
Fodor J.et al., 2003[10]	249	T1-2N1	189 mon	12%		57% (15- year)	52% (15- year)
Chang D. et al., 2007[11]	63	N3	15 years	13%		46%	57%
Wang SL. Et al., 2009[12]	874 (<65 ëåò)	IIb-IIIc	47 mon	0% -IIb 7,2% - IIIc			87% - IIb 79,2% - IIIc
Overgaard M. et al., 1997[13]	852	II-III	10 years	9%		48% (10- year)
Huang EH et al., 2004[14]	542	>IIb	10 years	11%			54%(10- year)	58%(10- year)
Zhang YJ. et al., 2009[15]	217	T1-2N1	69 mon	14,8%		81,8%	90,2%
Our results (normal-dose RT)	129	IIb-IIIc	111 mon	6,2%	34,6%	43,8%	65,3%	78,2%
Our results (low-dose RT)	82	IIb-IIIc	95 mon	3,7%	19,5%	64,0%	72,2%	79,7%

Fig.1. Frequency of locoregional recurrence in 1 and 2 groups

Fig.2. Progression-free survival in the 1^st and 2^nd groups (p>0,05)

Fig.3. Overall survival in the 1^st and 2^nd groups (p>0,05)

Conclusion

There are no statistically significant differences in local control, overall and relapse-free survival rates of traditional normal-dose and low-dose variants of postmastectomy chest-wall irradiation. This method of dose-reduced postmastectomy chest-wall irradiation in compliance with modern systemic treatment allows to decline risk of cardiotoxicity with the maintenance of the treatment effectiveness achieved by using traditional method.

Clinical Practice Points

Anticancer activity in local control of radiation following mastectomy has been known since the middle of XX century. Then in 2005 several randomized trials of EBCTCG revealed also reduction of cancer-specific mortality overall mortality. Unfortunately this positive effect in survival can be leveled by increasing of mortality due to postradiation complications. G. Gagliardi et al. in 1997 reported that risk of death caused by cardiovascular complications after radiation therapy of breast cancer is significantly minimized by reduction of dose cumulated by heart.

In our study we proposed method of dose reduction on chest-wall area (40Gr in 20 fr) which is based on precondition of additive effect of modern neoadjuvant and adjuvant chemotherapy. We got no statistically significant differences in local control, overall and relapse-free survival rates of traditional normal-dose (50Gr in 20 fr) and low-dose (40Gr) variants of postmastectomy chest-wall irradiation, but strong tendency to more favourable results according to cardiotoxicity in low-dose radiation. One of the main problem in radiation therapy of breast cancer is development of methods of individual dose selection resulting in standard level of local control and minimum of side effects. We suppose that method of dose-reduced postmastectomy chest-wall irradiation in compliance with modern systemic treatment allows to decline risk of cardiotoxicity with the maintenance of the treatment effectiveness achieved by using traditional method.

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