Professor Evgeni V. Khmelevsky, professor Georgiy A. Panshin, professor Vladimir D. Chkhikvadze, Roman V. Kolesnikov, professor Vladimir K. Bozhenko, professor Natalia Yurievna Dobrovolskaya, Yulia Anatolievna Ponkratova

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

Peculiarities of development and risk factors of post-mastectomy isolated and disseminated local-regional recurrence

Introduction

In spite of evident complication and intensification of modern programs of breast cancer treatment, local and regional recurrences negatively influence disease prognosis, quality of life of patients, and total cost of treatment. These reasons keep up constant interest in this problem.

Recurrence of breast cancer traditionally means renewal of tumor growth in the same half of the thoracic wall or regional lymph nodes zones independent of the duration after the end of radical treatment. Recurrences are divided into local and regional. In addition, according to the growth status, they can also be solitary or multiple, nodular or diffusive (or lymphangitic or infiltrative).

The onset of isolated relapse more often ends with dissemination of the tumor. Nevertheless, this fact is not an evidence for the increase in the metastatic potential of relapsed tumor, when compared with primary tumor. Moreover, the idea that relapse is not the source but only the marker of distant metastasis is more reasonable, and relapse itself indicates the high malignant status of primary tumor [1]. Furthermore, it is not yet clear regarding the factors that indicate certainty of dissemination after recurrence and the importance of neoadjuvant and adjuvant radiation and chemo-hormonal therapy as additional treatment among these factors. The purpose of this study is to specify the prognostic factors for isolated and disseminated (accompanied with dissemination at the moment of detection) post-mastectomy relapses of breast cancer.

Materials and Methods

Multifactorial analysis of 10-year risk of local-regional progression was conducted in 444 patients with stage I–III_B breast cancer treated at Russian Scientific Centre of Roeutgeno-radiology during 1990–1997. Treatment programs included mastectomy, different variants of neoadjuvant and adjuvant chemo- and hormonal therapy, and radiation therapy. Among these patients, 155 (338%) had operation after 1–4 courses of neoadjuvant chemotherapy, 170 (37.6%) had preoperative radiation therapy, and 121 (26.4%) had postoperative radiation therapy. Furthermore, 199 (43.3%) patients had adjuvant chemotherapy and 189 (41.2%) had hormonal therapy, and 58 patients (12.6%) had Madden’s mastectomy only.

Single-dose (7.5 Gy, 120 patients) and hypofractionated (25 Gy in five fractions, 50 patients) preoperative radiation of the affected breast and axillary zone was administered a day before or directly on the day of operation.

During postoperative period, if axillary lymph nodes were affected or if primary tumor had centromedial localization, supraclavicular and parasternal zones of the affected side were irradiated with a dose 44–50 Gy in 22–25 fractions. Radiation of regional zones was administered along with radiation of thoracic wall if more than three axillary lymphatic nodes were affected. In most cases (337 patients – 84.9%), radiation and/or surgical treatment were combined with any variant of chemo-hormonal therapy.

A total of 1–4 standard courses CMF or CAF or 4-week course of CMFVP were used as neoadjuvant chemotherapy, while adjuvant therapy included 6 courses CMF or antiestrogenic therapy (46% among them were administered for 2–5 years, while all the others were administered for less than 2 years).

Some characteristics of the patients are presented in Table 1.

Table 1. Classification of 444 breast cancer patients according to some prognostic factors

Criteria		Number of patients
		Abs	%
Age (years)	≤40	64	12,5
	41–69	363	81,7
	≥70	17	5,8
Menstrual status	reproductive	213	48
	menopause	231	52
Histological form	ductae	339	76,4
	lobular	55	12,4
	special forms	24	5,4
	non-detected	26	5,9
pT	pT1	170	38,3
	pT2	234	52,7
	pT3	24	5,4
	pT4	16	3,6
pN	pN0	191	43
	pN1	135	30,4
	pN2	92	20,7
	pN3	26	5,9
Stage of therapeutic pathomorphosis *	non-rated	141	31,8
	absent	181	59,7**
	1 stage	27	8,9**
	2 stage	53	17,5**
	3 stage	39	12,9**
	4 stage	3	1,0**

* Therapeutic pathomorphosis is rated when the preoperative (including single one) irradiation and/or neoadjuvant chemotherapy was conducted.

** From 303 patients with rated pathamorphosis

The received data were analyzed using software package “STATISTICS 6.0”. Besides the parameters presented in Table 1, the size of primary tumor, its growth status (single-noded, multicentric, diffusive), invasion of lymphatic vessels, variants of neoadjuvant and adjuvant therapy, time of recurrence onset, its localization, type of growth, and maximum size of relapsed node were also taken into account for multifactorial regression and clustering analysis (receptor status of tumor was not routinely evaluated in the indicated time period).

For studying the influence of treatment methods on local recurrence rate, all patients were divided into three prognostic groups according to initial prevalence of primary tumor (Table 2).

Table 2. Division of patients according to local progression risk.

Risk group	Disease state	Number of patients
Low risk	pT1–2N0	183 (41%)
Intermediate risk	pT1–2N1, pT3N0	133 (30%)
High risk	pT1–2N2–3, pT3N1-3, pT4N0-3	128 (29%)
Total		444 (100%)

The following stages were combined into prognostic groups of regional recurrence:

I–II_A – Group of low risk

II_B–III_B – Group of high risk.

The median follow-up was 156.3 months.

Results

A total of 60 cases (13.5%) of local and/or regional progression were noted during the observation period. Local recurrences were diagnosed in 56 patients (12.6%), regional recurrences in 4 patients (0.9%), and their combination in 12 cases (2.7%). Regional recurrences included 11 cases of axillary (2.5%), 6 cases of parasternal (1.4%), and 1 case (0.2%) of Rotter’s lymph node involvement.

Eighty percent of recurrences (48 of 60) had nodal type of growth (including multinodal growth in 25 cases – 46.2%), while the rest 20% had lymphangitic-type growth. There were 28 isolated (6.1%) and 32 (7.2%) disseminated (that appeared after or simultaneously with distant metastases) recurrences. The probability of combination of local-regional relapse and distant metastases was significantly correlated with the type of recurrence growth: In the case of single relapsed node, it was only 18.8%; in the case of multinodal type, it was 65.5%; and in the case of lymphangitic type, it was 72.7% (for both the latter cases, p<0.02). However, the average size of relapsed node in the case of isolated and disseminated recurrence did not differ considerably: 20.5±13.4 and 21.9±15.1 mm, respectively (p>0.05).

Subsequent appearance of regional recurrences were insignificant, when compared with local recurrences: In two-third of the cases, regional recurrence occurred after 3 years (including all parasternal ones), whereas 60% of local recurrences occurred in the first 3 years. Moreover, the time of recurrence onset was not significantly correlated to the initial regional prevalence: 50% of relapses in pN_0-1 cases were diagnosed during the first 3 years, and that in pN_2-3 were diagnosed during the first 1.5 years. Also, during the first year, we observed one-third (31.3%) of all the disseminated and one-fifth (21.4%) of all the isolated recurrences (p>0.05).

The correlation of local-regional progression rate with some prognostic factors is presented in Table 3.

Table 3. Dependence of local-regional progression on some characteristics of patients and parameters of primary tumor

Indication		Recurrence rate (%)	Correlation
Age	≤ 40 years	9.4	No
	41–69 years	13.1
	≥70 years	11.8
Menstrual status	reproductive	11.7	No
	menopause	13.4
Histological form	ductal	14.5*	Yes p<0.05
	lobular	7.3
	special form	0.0*
	not indicated	11.5
pT	pT1	11.8	No
	pT2	13.2
	pT3	16.7
	pT4	6.3
pN	pN0	5.2*	Yes p<0.02
	pN1	14.6*
	pN2	20.8*
	pN3	22.8
Multicentric	no	12.2	No
	yes	17.1
Lymph vessels invasion	no	11.8*	Yes p<0.03
	yes	31.6*
Degree of therapeutic pathomorphosis	not studied	14.9	No
	is absent	8.5
	1 degree	14.8
	2 degree	17.0
	3 degree	10.3
	4 degree	0.0

The most important factors of recurrence prognosis were found to be lymphatic vessels invasion and regional prevalence of primary tumor. Multicentricity had no effect on local progression, but it was significantly correlated to regional recurrences rate: 2.0% in the absence of and 8.6% in the presence of multicentric growth of primary tumor (p=0.048). Dependence of recurrence rate from initial regional prevalence was similar for isolated and disseminated cases: The initial average number of affected lymph nodes was 3.1±0.5 and 4.7±0.8, respectively (p>0.05), whereas patients without recurrence had significantly less number of affected lymph nodes, (2.2±0.2; p<0.01).

The rate and nature of local breast cancer recurrences in different risk groups are presented in Table 4.

Table 4. Rate and nature of local breast cancer recurrences in different risk groups

Risk group of the local recurrence	Nature of recurrence
	Isolated (%)	Disseminated (%)	In total (%)
Low (n=183)	2.7	2.7	5.4*
Intermediate (n=133)	7.6	6.9	14.5*
High (n=128)	9.9	14.5	24.4*

*p<0.02

There were no considerable differences in the rate of disseminated and isolated local recurrences within each risk group (p>0.05), whereas the differences between the groups were statistically significant. Furthermore, the time of recurrence onset and median size of relapsed node did not differ noticeably in the risk groups. At the same time, lymphangitic type of recurrence developed significantly more often in the high risk group of patients: 28.6% versus 11.1% in intermediate risk and 0% in low risk group (p<0.05).

The rate of regional recurrence differed significantly between the two groups of risks: 1.6% (3/182) in the low-risk group and 5.0% (13/262) in the high-risk group (p<0.05). However, distribution of isolated and disseminated recurrence rate within these groups was the same as in the case of local progression.

The correlation between radiation therapy variants and local progression risk in different risk groups is presented in Table 5.

Table 5. Risk of local progression in dependence of radiation therapy variant and risk group

Risk group	Variant of radiation therapy	Tumor prevalence		Recurrence rate (%)	Reliability of differences (p)
		Average size of the tumor (mm)	Average number of the affected lymph nodes
Low	PreORTh^1	25.6±1.0	-	11.0*
	PostORTh (reg)^2	25.4±1.6	-	2.0
	MM^4	20.9±1.2*	-	1.7*	<0.04
Intermediate	PreORT	28.5±1.7	1.6±0.8	10.5
	PostORT (reg)	26.3±2.1	1.7±0.1	21.1
	PostORT (th.w+reg.)^3	26.5±3.0	1.8±0.1	12.1	>0.05
High	PreORT	35.9±3.3	6.6±0.5	27.5*
	PostORTh (reg)	32.9±3.9	6.2±0.9	40.0*
	PostORT (th.w+reg.)	41.3±3.2*	6.6±0.5	14.1*	<0.03

¹Pre ORT – Preoperative radiation therapy

²Post ORT (reg) – Postoperative radiation therapy of regional zones only

³Post ORT (th.w+reg.) – Postoperative radiation therapy of thoracic wall and regional zones

⁴MM – Madden’s mastectomy only

* Reliable differences (p<0.05) within limits of this risk group

The most effective reduction of post-mastectomy local recurrence rate was detected in the case of postoperative irradiation of thoracic wall and regional zones. Preoperational irradiation was reliably less effective for both the low- and high-risk groups. Irradiation of regional zone alone could not be absolutely justified when the risk of recurrence was medium and high, and was not reasonable for low-risk group. Moreover, in the low-risk group, the best results were achieved after surgery only, although the primary size of tumor was reliably less and patients were more aged.

Analysis of regional recurrence rate in the high-risk group (analysis was impossible for the low-risk group because of minimum number of patients) also demonstrated preference of postoperative wide-field radiation (with inclusion of thoracic wall and regional zones in the exposure region). Use of this program resulted in 1.0% of axillary-subclavicular recurrence vs. 1.9% in the case of postoperative irradiation of regional zones only and 5.4% in the case of preoperative irradiation (for the last case, p<0.05). Recurrence rate in parasternal zone did not correlate with the radiation method and appeared to be from 1.1 to 2.9%.

Neoadjuvant chemotherapy noticeably, but not statistically significantly, reduced the frequency of recurrence from 5.7% to 0% (p>0.05) in the low-risk group; however, it did not influence the treatment results in other groups.

Neither the quality nor the number of courses of adjuvant chemotherapy influenced the frequency and type of local-regional recurrences, including correlation between isolated and disseminated recurrences. At the same time, duration of antiestrogenic therapy positively influenced the local-regional progression if it lasted for more than 3 years: The reduction in the local recurrence rate reduced twice to 6.3% vs. 13.4 and 20.4% among patients taking Tamoxifen for less than 3 years (p<0.05) and less than 1 year (p=0.07), respectively.

Multifactorial regression analysis demonstrated statistically valid correlation of local recurrences only in the risk group (p<0.04), invasion of lymph vessels (p<0.04), and number of affected lymph nodes (p<0.05). At the same time, independent prognostic factors of isolated and disseminated recurrences differed. The rate of the former correlated to the risk group only, while that of the latter ones correlated positively to the number of affected axillary lymph nodes (p=0.047) and negatively to preoperational irradiation (p=0.02).

Discussion

In the literature, noticeable differences in post-mastectomy recurrences rates have been explained as the different initial prevalence of tumor process and duration of observation (Table 6).

Table 6. Rate of post-mastectomy local-regional recurrences according to literature database

Author, year of publication	No. of Patients	Disease state	Duration of observation	Recurrences rate
				All (isol. + dissem.	Only isol.
Gaffney P. et al., 1997[16]	140	I–III	5 years		9.0
Dunst J. et al., 2001[3]	959	I–III	10 years		13.6
Hehr T. et al., 2004[17]	287	I–III	5 years	15.0	9.0
Broun S. et al., 2005[18]	4703	I–III	5,2 years	9.5
Yadav B. et al., 2007[7]	688	I–III	67 months	8.5
Private data	444	I–III	156 months	13.5	6.1
Truong P. et al., 2005[4]	1505	T1-2N0	10 years	7.8
Private data	183	T1-2N0	156 months	5.4	2.7
Cheng J. et al., 2002[2]	110	T1-2N1	4 years	16.1	8.0
Fodor J. et al., 2003[6]	249	T1-2N1	189 months	12.0	8.0
Strancl H. et al., 2004[19]	183	T1-3N1	44 months		7.7
Truong P. et al., 2007[4]	821	T1-2N1	10 years	28.6	12.7
Private data	133	T1-2N1	156 months	16.7	8.4
Aksu G. et al., 2007[12]	156	T3-4N0	27 months	10.9
Chang D et al., 2007[20]	63	N3 (>9n)	15 years		13.0
Overgard M. et al., 2007[10]	1152	N2-3	15 years		10.0
Private data	128	IIIA–IIIB	156 months	25.2	9.9

According to the majority of authors, the basic prognostic factor of local-regional progression in breast cancer is the regional prevalence of tumor process, including the number of affected lymph nodes and lymphovascular invasion [2, 3, 4]. The latter factor, together with the size of primary tumor, has fundamental importance in the case of intact axillar lymph nodes [5]. On the other hand, importance of primary tumor grade (Grade 3) and age (<35–40 years) are not often indicated [2, 6, 4, 7]. At the same time, nowadays, more and more information are being collected about the influence of ER/PR/HER2 status [2, 4, 7, 8] and genes expression profiles [9].

Postoperative radiation therapy (among other additional treatment methods) is the only method considered to be an independent positive prognostic factor for patients with affected lymph nodes [7, 10]. Even patients with complete histologic regression achieved after neoadjuvant chemotherapy have been reported to have better local-regional control after standard additional postoperative irradiation [11]. However, this positive effect has been registered only for Stage-III patients, and not Stage-II patients.

The results of our study confirm that the number of affected lymph nodes and lymphovascular invasion are independent prognostic factors for local-regional control. Furthermore, it is reasonable to divide the patients into three risk groups of local progression, because the influence of this factor is notable for isolated and disseminated recurrence rate. Positive influence of postoperative radiation therapy has been detected in patients with low and high recurrence risk, but in the latter case, only if regional zones are irradiated along with thoracic wall. It must be noted that optimization of irradiated tissue volume and equivalent doses (in diapason of 40–50 Gy) is a necessary condition for achieving the required effect [12, 13]. Furthermore, we did not obtain any data about preoperative irradiation as an independent negative prognostic factor for disseminated recurrence rate. Although we will not discuss the possible mechanism of this fact in detail, the phenomenon of “adaptive response” [14] and analogical influence of single and large-fractional preoperative irradiation on dissemination processes must be mentioned [15].

Nevertheless, preoperative radiation therapy, in contrast to postoperational radiation therapy, cannot be considered as an adequate method for the prevention of local-regional progression in the case of resectable breast cancer. The effects of neoadjuvant chemotherapy and adjuvant hormonal therapy, which demonstrate either a tendency of increased effectiveness in the low-risk group (chemotherapy) or significant effect within the frame of unifactorial analysis (hormonal therapy if it is used for less than 3 years), will be specified in future research works.

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