Partial breast irradiation as second conservative treatment for local breast cancer recurrence

Jean-Michel Hannoun-Levi IJROBP 2004;60:1385

Mastectomy is the treatment of reference for local relapse after breast cancer (BC). The aim of this study was to document the feasibility and the results of associating lumpectomy with partial breast irradiation by interstitial brachytherapy (IB) as local treatment for an isolated ipsilateral BC local recurrence (LR). Between 1975 and 1996 at Marseille and Nice Cancer Institutes, 4026 patients received lumpectomy and radiotherapy (RT) (50–80 Gy) for a localized breast cancer of which 473 presented a LR. Among these patients, 69 (14.6%) received a second lumpectomy followed by IB, which delivered 30 Gy (Nice, n = 24) or 45–50 Gy (Marseille, n = 45) with 3 to 8 192Ir wires in 1 or 2 planes on the 85% isodose.

Median age at LR was 58.2 years, median follow-up since primary BC was 10 years, and median follow-up after the second conservative treatment was 50.2 months (range, 2–139 months). Immediate tolerance was good in all cases. Grade 2 to 3 long-term complications (LTC) according to IB dose were 0%, 28%, and 32%, respectively, for 30 Gy, 45 to 46 Gy, and 50 Gy (p = 0.01). Grade 2 to 3 LTC according to total dose were 4% and 30%, respectively, for total doses (initial RT plus IB) ≤ 100 Gy or >100 Gy (p = 0.008). Logistic regression showed that the only factor associated with Grade 2 to 3 complications was higher IB doses (p = 0.01). We noted 11 second LRs (LR2), 10 distant metastases (DM), and 5 specific deaths. LR2 occurred either in the tumor bed (50.8%) or close to the tumor bed (34.3%) or in another quadrant (14.9%). Kaplan-Meier 5-year freedom from (FF) LR2 (FFLR2), FFDM, and DFS were 77.4%, 86.7%, and 68.9%, respectively.

Overall 5-year survival (OS) was 91.8%. Univariate analysis showed the following factors associated with a higher FFLR2: (1) number of wires used for IB (3–4 vs. 5–8 wires, p = 0.006), (2) IB doses (30–45 Gy vs. 46–60 Gy, p = 0.05), (3) number of planes (1 vs. 2, p = 0.05), (4) interval between primary breast cancer and LR (< 36 months vs. ≥36 months, p = 0.06). Multivariate analysis showed two factors associated with better local control: (1) number of wires (5–8 wires, p = 0.013) and (2) interval between primary breast cancer and LR ≥36 months (p = 0.039). The multivariate analysis showed two factors associated with better FFDM: (1) absence of initial axilla involvement (p = 0.019) and (2) relapse in a different location (p = 0.04). These two factors were also associated with a higher OS.

Conclusion

Our experience showed that second conservative treatments for local relapse were feasible and gave results comparable to standard mastectomy. We recommend delivering IB doses of at least 46 Gy in 2 planes when initial radiotherapy delivered 50 Gy. The study gives enough information to encourage a Phase III trial that compares radical mastectomy to conservative procedures for localized breast cancer recurrences.

Discussion

Until now, the standard treatment of LR after conservative radiosurgical breast therapy remains total mastectomy. In studies of salvage mastectomy after breast tumor recurrence, median local tumor control rates of 67% (range, 52–95%) have been reported. Could the data obtained after mastectomy and lumpectomy for primary breast cancer treatment in terms of psychological adjustment, quality of life, sexuality, and body image be transposed to cases of ipsilateral local recurrence treatment? In other words, could a woman who experienced breast conservative treatment for the primary occurrence benefit from a second conservative treatment for a small, local breast cancer recurrence?

Kurtz advocated second conservative treatments with lumpectomy alone and obtained second local recurrence rates of 36%. Similar results were provided by Dalberg and more recently by Komoike . Notably, in the studies that used lumpectomy for LR, without adjuvant radiation therapy, the second local recurrence rate ranged from 30% to 36% and was very similar to that obtained in cases of primary conservative treatments without irradiation.

Whereas second radiation therapy was used in the treatment of head and neck, lung, or rectal cancer recurrences, several studies that used a second radiosurgical approach for ipsilateral breast cancer recurrence were published. The radiation technique applied was either external beam or brachytherapy, both of which were focused on the tumor recurrence bed. The study published by Mullen and recently updated by Deutsch presented a technique of external radiation that delivered 50 Gy in 25 fractions over 5 weeks via electrons beam of appropriate energy . The authors provided a local recurrence rate of 10.2% without Grade 3 to 4 complication. In a study by Kurtz , 11 of 50 patients received additional radiation after excision for in-breast tumor recurrence outside the primary tumor site. Seven of these 11 patients received 20 to 30 Gy of radiation via electron beams, and 4 received 50 Gy via interstitial brachytherapy. Four of the 11 patients had a second breast tumor recurrence, but the study could not determine whether those recurrences were caused by the chosen radiation regimen. Interstitial brachytherapy with either low dose rate (LDR), pulse dose rate (PDR), or high dose rate (HDR)has been used as adjuvant radiation therapy after lumpectomy for ipsilateral breast cancer recurrence. Guix treated 41 patients with, after conservative surgery, an HDR brachytherapy protocol that delivered a total dose of 30 Gy in 3-Gy per fraction twice a day over 5 days. In this case, the total dose was less important than the dose delivered with interstitial HDR brachytherapy protocol used for partial breast irradiation for primary tumor. However, the authors presented a high local control rate of 90% without Grade 3 to 4 complications. Maulard treated 38 patients who experienced local tumor recurrences with LDR brachytherapy. In this study, a subgroup of 15 patients was treated with limited tumor resection and 30-Gy postoperative brachytherapy. The other 23 patients underwent exclusive split-course brachytherapy with 60 to 70 Gy. Although the patients treated after surgery for only microscopic disease would be expected to have better local tumor control compared with the patients treated for gross disease with split course brachytherapy, such was not the case. The patients treated for gross disease had a better local control (83%), compared with a local control rate of 74% for those patients treated for a microscopic disease. Resch treated 17 patients who had small recurrent breast carcinomas after initially undergoing breast-conserving therapy (lumpectomy plus postoperative radiation therapy) . Local recurrence was treated with tumor excision and PDR brachytherapy. Eight patients underwent a combination of PDR brachytherapy (total dose range, 12.5 to 28.0 Gy) and external-beam radiation therapy (total dose range, 12 to 30 Gy). Nine patients underwent radiation therapy with 40.2-Gy to 50.0-Gy PDR brachytherapy only. Twelve of 17 patients had no local tumor at a median follow-up time of 59 months. Four women (29.4%) treated with combined external-beam radiation therapy and brachytherapy had secondary local tumor recurrences treated by mastectomy. Despite having undergone radiation therapy previously, patients had side effects limited to moderate (Grade 1–2) fibrosis. Taken together, the Kurtz , Maulard and Resch results provide significant data for a clear relationship between local control rate and applied total radiation dose. In our study as well, we observed significantly more second local recurrences in the group of patients treated with 30 Gy compared with the patients treated with 50 Gy (43.8% vs. 5.3%). Nevertheless, this difference in term of second local control was not correlated with a better overall survival for patients receiving a higher radiation dose (74% vs. 77%). However, the dose has to be delivered through an interstitial brachytherapy implant placed according to the ICRU report #58 recommendations Indeed, if the number of implanted wires is not sufficient to cover the CTV, an increase of the prescribed dose is unacceptable because of the concomitant increase of hyperdosage volumes and risk of late complications. In such a case, other needles or planes must be implanted to properly cover the CTV.

The Grade 2 to 3 complication rate was higher in cases of higher radiation exposure (8% vs. 11%), in accord with previous published data. One reason for no more than 10% Grade 2 to 3 complications, although the cumulative dose is higher than 100 Gy, is because of the very small volume irradiated. This “high dose in small volume” principle allows delivery of a very high dose through brachytherapy or intraoperative electron-beam radiation therapy with an acceptable late toxicity.

In the present study, the disease-free interval between primary and local recurrence treatment could be considered as a prognostic factor for a second local recurrence with a 36-month cutoff (63.6% vs. 83.3%, p = 0.063). Kurtz analyzed the results of wide excision for 50 selected ipsilateral breast cancer recurrences after standard radiosurgical conservative treatment. Cox multivariate analysis of 18 parameters indicated that only disease-free interval and resection margins significantly influenced local control. Five-year local control was 92% for recurrences after 5 years vs. 49% for shorter intervals and 73% for negative vs. 36% for positive or indeterminate margins. However, other authors did not consider the disease-free interval between primary and LR treatment as a prognostic factor for second local recurrence but rather as a predicted factor for distant metastasis. According to the difference in terms of prognosis between early and late ipsilateral breast recurrences, Huang analyzed 126 patients who experienced a local relapse after primary radiosurgical conservative treatments. The authors classified the ipsilateral breast recurrence as “true recurrence” (TR) if it was located within 3 cm of the primary tumor bed and was of the same pathologic subtype. All other ipsilateral breast recurrences were designated “new primary” (NP). Of the 126 patients, 48 (38%) were classified as NP and 78 (62%) were classified as TR. Mean time to disease recurrence was 7.3 years for NP vs. 5.6 years for TR (p = 0.0669). The patients with NP had improved 10-year rates of overall survival (NP 77% vs. TR 46%, p = 0.0002), cause-specific survival (NP 83% vs. TR 49%, p = 0.0001), and distant disease-free survival (NP 77% vs. TR 26%, p < 0.0001). Smith used a similar definition of primary and true recurrence that included flow cytometry modification from aneuploid to diploid and provided similar results. These researchers concluded that patients with NP had significantly better survival rates than those with TR and that distinguishing new breast carcinomas from local disease recurrences may have importance in therapeutic decisions and chemoprevention strategies.

In the present study, 85% of the LRs were located in or close to the primary tumor bed. Moreover, 67 patients (97%) developed an LR that presented similar pathologic characteristics compared with the primary. According to the criteria described above, we could consider at least 80% of the analyzed LRs to be TR and not NP. For LRs that appeared at a distance from the primary tumor bed (15%), in accord with the delay (>36 months) between LR and primary and even if they presented the similar pathologic features, we considered those recurrences as second primary or NP. The critical point for a patient who experiences an ipsilateral breast cancer recurrence after radiosurgical conservative treatment appears to be the prevention of distant metastatic disease, whereas the local treatment could be a second conservative treatment using a second radiosurgical procedure or a radical mastectomy, depending on the patient's wishes. Even if radical mastectomy remains the standard treatment for ipsilateral breast cancer recurrence after conservative treatment for the primary, the published data failed to consider salvage mastectomy as conferring a better second local control rate or a better overall survival compare with a second conservative treatment using partial mastectomy and a second course of radiation therapy. To compare the behavior of patients who present with a local breast cancer recurrence, treated with either salvage mastectomy or a second conservative procedure that included partial mastectomy and partial breast irradiation, a multicentric Phase III randomized trial that includes a high number of patients because of the small number of events (i.e., local recurrences) would be interesting to conduct. Such a trial should also take into account the impact of treatment on the sexuality and the body image of young and older patients