Radiation Oncology/Breast/Recurrence

Patterns of failure
General:
 *  Joint Center for Radiation Therapy (JCRT) (1968-85) - PMID 2033433, 1991 &mdash; "Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma." Recht A et al. J Clin Oncol. 1991 Jun;9(6):988-96.
 * Retrospective. 1624 pts. Stage I-II treated with breast conserving therapy. Median f/u 77 months.
 * Regional nodal failure was first site of failure in 2.3%.
 * For pts undergoing axillary dissection and RT to the breast only: Axillary failure was 2.1% for those who were node negative and 2.1% for those with 1-3 positive nodes. Supraclavicular recurrence in 1.9% (N0) and 0% (1-3 LN).
 * For cN0 pts without axillary dissection treated with breast + axilla RT: Axillary failure 0.8% and supraclavicular failure 0.3%.
 * Salvage after failure: only 47% of pts achieved control after treatment for a nodal relapse.

Supraclavicular

 * Germany (1978-88) - PMID 8276654, 1994 &mdash; "The prognostic significance of the supraclavicular lymph node metastases in breast cancer patients." Kiricuta IC et al. Int J Radiat Oncol Biol Phys. 1994 Jan 15;28(2):387-93.
 * Retrospective. 21 pts with supraclav metastasis at diagnosis and 38 pts who developed supraclav mets after therapy. Compared with 20 pts with M1 disease at diagnosis and 278 pts who later developed distant mets.
 * Survival of pts with supraclav mets was similar to those with M1 disease. 2-yr and 5-yr OS was 52% and 34% with SCLV at diagnosis vs 50% and 16% with M1 disease at diagnosis.

After mastectomy:
 * PMID 3002595, 1986 &mdash; "The significance of supraclavicular fossa node recurrence after radical mastectomy." Fentiman IS et al. Cancer 1986 Mar 1;57(5):908-10.
 * 35 pts. Survival intermediate between single nodule and multiple nodule groups.

Prediction

 * 2006 NSABP PMID 16720680 -- Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer. (Paik S, J Clin Oncol. 2006 May 23; [Epub ahead of print])
 * Prospective PCR gene-assay of 21 genes (RS score). Used 651 tissue blocks from NSABP-20 patients. 227 tamoxifen, 424 tamoxifen + chemotherapy. Patients ranked "low", "intermediate", or "high" for distant recurrence risk
 * High RS score: large benefit from chemotherapy, absolute decrease in 10-year recurrence rate 28%
 * Intermediate RS score: unclear benefit
 * Low RS score: no benefit from chemotherapy, absolute decrease in 10-year recurrence rate -1.1%
 * Conclusion: The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.


 * 2004 NSABP PMID 15591335 -- A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. (Paik S, N Engl J Med. 2004 Dec 30;351(27):2817-26. Epub 2004 Dec 10.)
 * Prospective PCR gene-assay of 21 genes (RS score). Used 668 tissue blocks from NSABP-14 patients. BCA node-negative, on tamoxifen. Patients ranked "low", "intermediate", or "high" for distant recurrence risk
 * Patient proportions: low 51%, intermediate 22%, high 27%
 * 10-year recurrence rate: low 7%, intermediate 14%, high 30% (recurrence score independently predictive)
 * Conclusion: The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor-positive breast cancer.

Treatment

 * Limited data available
 * Probably reasonable to re-treat with 45-50 Gy, or if hyperthermia with 30-35 Gy

General:
 * Multi-Institutional; 2008 (1993-2005) PMID 17869019 -- "Multi-institutional review of repeat irradiation of chest wall and breast for recurrent breast cancer." (Wahl AO, Int J Radiat Oncol Biol Phys. 2008 Feb 1;70(2):477-84. Epub 2007 Sep 14.)
 * Retrospective. 8 institutions. 81 patients treated with repeat RT for breast/CW recurrence. Median dose first RT 60 Gy. Median dose second RT 48 Gy. Median interval 3.2 years. Most pts treated to the chest wall. Concurrent HT 54%, concurrent chemo 54%. Median F/U 1 years
 * 54 of 81 pts (or 2/3) had gross disease present.
 * Outcome: CR 57%; no variable predictive, but trend for hyperthermia benefit (67% vs. 39%, p=0.08). 1-yr local DFS 66% (median LDFS 31 m); DFS 53% for those with gross disease, 100% for no gross disease.
 * Toxicity: Late Grade 3/4 5%
 * Conclusion: Repeat RT to CW is feasible, acceptable toxicity, and encouraging response rates


 * Germany; 2002 (1987-96) - PMID 12153940 &mdash; "Radiotherapy in the treatment of locoregional relapses of breast cancer." Schuck A et al. Br J Radiol. 2002 Aug;75(896):663-9.
 * 5-yr OS 43%. Chest wall recurrences associated with improved survival.

Salvage Breast Conservation
There is a scant amount of published information on treatment of IBTR with salvage breast conserving surgery as opposed to salvage mastectomy, but SBCS is feasible in selected patients. There does not appear to be a loss of survival to those treated with SBCS, but they are at risk for continued local recurrences.


 * Yale; 2005 ( PMID 16199315 -- "Ipsilateral breast tumor recurrence after breast conservation therapy: outcomes of salvage mastectomy vs. salvage breast-conserving surgery and prognostic factors for salvage breast preservation." (Alpert TE, Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):845-51.)
 * Retrospective. 146 pts with IBTR after BCS+RT. Of these, 30 refused mastectomy and opted for salvage breast-conserving surgery (SBCS); the other 116 underwent salvage mastectomy (SM). Of SM pts, 28 pts had multicentric disease (known prior to surgery by mammogram or PE).
 * Median f/u 13.8 yrs. OS 64.5% at 10 yrs overall (SM, 65.7%; SBCS, 58.0; NS). No difference in rate of DM (30%) between groups. Local recurrence: 19% (SBCS) vs 4% (SM).
 * Half of pts with BRCA1/2 mutations had multicentric disease at time of mastectomy.
 * Conclusion: Long-term survival is possible after IBTR. Salvage mastectomy represents the standard of care, but SBCS appears feasible in select pts (favorable biology). Survival does not appear to be compromised by SBCS. There does not appear to be a Pts with BRCA1/2 mutations are less appropriate for SBCS. Pts treated with SBCS are at continued risk for subsequent IBTR.


 * Marseille (France); 1988 (1963-86) PMID 3129175 Full text -- "Results of wide excision for mammary recurrence after breast-conserving therapy." (Kurtz JM, Cancer. 1988 May 15;61(10):1969-72.)
 * Retrospective. 118 pts treated with BCS+RT for breast cancer developed local recurrence. Of these, 52 pts with recurrences < 2cm (with no skin changes and no signs of rapid growth) were selected for salvage breast conserving surgery with wedge resection (+/- axillary dissection). 96% of these recurrences were near the original tumor (true recurrence).
 * Median 6 yrs. OS 79% at 5 yrs, 64% at 10 yrs (from date of 2nd surgery). DM in 27%. Freedom from breast recurrence 78%
 * Second local or regional recurrence in 23% (12 of 52; 10 - breast alone; 1 breast + nodes; 1 nodes only) at median interval 36 months. 10 of 12 second recurrences were operable
 * In 10 of 18 pts undergoing axillary dissection, positive nodes found.
 * Conclusion: wedge resection of small in-breast recurrence results in acceptable alternative to salvage mastectomy.

Supraclavicular node recurrence

 * MDACC; 2011 (1975-1994) PMID 21168284 -- "Long-term outcomes in patients with isolated supraclavicular nodal recurrence after mastectomy and doxorubicin-based chemotherapy for breast cancer." (Reddy JP, Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1453-7.)
 * 47 pts (treated prospectively on clinical trials) developed SCLV recurrence with or without other locoregional recurrence (but no DM). Compared outcomes with pts who had LRR not involving SCLV lymph nodes.
 * 3-yr DM-free survival 40% (SCLV) vs 54% (non-SCLV); OS 49% vs 69%; both SS.
 * Isolated SCLV recurrence: 23 pts had isolated SCLV recurrence. Overall survival was similar to those with isolated CW recurrence. 5-yr OS 25%.
 * Conclusion: "Although breast cancer recurrence with SCV involvement carries a high risk of distant metastasis and death, among women with recurrence limited to the SCV alone, overall survival after isolated SCV recurrence can be long (25% >5 years)."


 * Italy - PMID 16446058, 2006 (1995-2002)"Prospective multicenter study of combined treatment with chemotherapy and radiotherapy in breast cancer women with the rare clinical scenario of ipsilateral supraclavicular node recurrence without distant metastases." Pergolizzi S et al. Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):25-32.
 * Prospective, non-randomized. 44 pts. Treated with doxorubicin or taxol based chemo x 6 courses and RT to 60 Gy to "involved field." RT given between 3rd and 4th cycles of chemo.
 * Overall response 94.9%. Median TTF 28 months and MS 40 months. 5-yr OS 35% and DFS 20%.


 * Netherlands, 2003 (1984-94) - PMID 12833449 &mdash; "Detection, treatment, and outcome of isolated supraclavicular recurrence in 42 patients with invasive breast carcinoma." Van der Sangen MJ et al. Cancer. 2003 Jul 1;98(1):11-7.
 * 42 pts with isolated SCLV failure after axillary dissection. Treated with various modalities
 * CR achieved in 83%, but of these 34% developed a second SCLV relapse. 5-yr OS (based on date of sclv recurrence) was 38%.

Hyperthermia

 * ''Please also see the main hyperthermia page


 * Duke (1994-2001) -- RT +/- hyperthermia
 * Randomized. 109 patients with superficial tumors (<= 3cm depth); breast 65%, H&N 13%, melanoma 10%. Tumors had to be "heatable" on initial HT. Arm 1) RT alone vs. Arm 2) RT + HT. Hyperthermia to >43C x1 hour, 2x/week. RT dose 30-60 Gy if previous RT, otherwise 60-70 Gy in 1.8-2.0 Gy/fx
 * 2005 PMID 15860867 -- "Randomized trial of hyperthermia and radiation for superficial tumors." (Jones EL, J Clin Oncol. 2005 May 1;23(13):3079-85.)
 * Outcome: CR RT 42% vs. RT+HT 66% (SS). Patients with prior RT had most benefit (68% vs. 23%, SS)
 * Toxicity: Well tolerated, 1 Grade III thermal burn
 * Conclusion: Significant local control benefit for HT


 * International Collaborative Hyperthermia Group (1988-1991) -- combined results from 5 PIII trials
 * Randomized. 5 trials merged due to slow accrual, closed early after benefit. 306 patients. Advanced primary or recurrent BCA; 50% active disease outside treatment area. Could have had prior RT. Trials: Dutch Hyperthermia Group (DHG), Medical Research Council (MRC BrI and BrR), European Society of Hyperthermic Oncology (ESHO), and Princes Margaret (PMH). Target hyperthermia 43C. RT given in various fractions.
 * 1996 PMID 8690639 -- "Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group." (Vernon CC, Int J Radiat Oncol Biol Phys. 1996 Jul 1;35(4):731-44.)
 * Outcome: CR RT 41% vs. RT+HT 59% (SS); greatest effect in recurrent lesions in previous RT, where re-irradiation dose was low. 2-year OS ~40% (NS), 74% patients progressed outside HT area during follow-up
 * Conclusion: Combined result demonstrated efficacy of hyperthermia as adjunct to RT for treatment of recurrence


 * Wisconsin; 1991 (1981-1989) PMID 2000551 -- "Hyperthermia and irradiation for locally recurrent previously irradiated breast cancer." (Phromratanapongse P, Strahlenther Onkol. 1991 Feb;167(2):93-7.)
 * Retrospective. 44 patients, locally recurrent previously RT BCA. RT mean 30 Gy (16-56). Hyperthermia goal 43 C for 60 min.
 * Outcome: CR 41%, PR 23%, NR 36%; small tumor s(<= 6cm2) significantly better CR 65% vs. 26%); higher thermal dose (> 50 tumor-minutes at 42.5C) better 53% vs. 14%
 * Conclusion: Higher thermal doses and smaller tumors associated with more favorable response


 * Henry Ford; 1989 (1984-1987) PMID 2642537 -- "Local superficial hyperthermia in combination with low-dose radiation therapy for palliation of locally recurrent breast carcinoma." (Dragovic J, J Clin Oncol. 1989 Jan;7(1):30-5.)
 * Retrospective. 30 patients with locally recurrent BCA (28 prior RT, median dose 50 Gy). RT 32/8 given BIW 4 Gy/fx. HT immediately after RT, goal 43 C for 60 minutes
 * Outcome: CR 57%, PR 36%. Long-term local control 80%. Lesions <5 cm significantly more likely to respond
 * Toxicity: 30% persistent non-healing ulcer (in 80% associated with persistent tumor)
 * Conclusion: Palliative RT + hyperthermia in previously treated CW has value

Systemic therapy

 * CALOR Trial (Chemotherapy as Adjuvant for LOcally Recurrent Breast Cancer; IBCSG 27-02 / BIG 1-02 / NSABP B-37) (closed 2010)
 * 2012 Abstract: San Antonio Breast Cancer Symposium (Dec 2012), Abstract #S3-2. "Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: The CALOR trial" (Aebi S).
 * Trial schema Slide presentation Press Release
 * Locoregional recurrence of breast cancer, radically resected (R0 or R1) +/- RT. Can involve breast, chest wall / scar, axillary nodes, IM nodes. No SCLV involvement. Pts randomized to: chemotherapy or observation.
 * Both arms can receive hormonal therapy and/or HER2-directed therapy.
 * RT recommended in all pts. Mandatory for pts with positive margins.
 * Closed early with 162 pts, no interim analysis. (Original sample size 977 pts).
 * Over 50% of original recurrences were in-breast recurrences (IBTR).
 * 5-yr DFS 69% (chemo) vs 57% (no chemo).
 * ER+: DFS 70% vs69%. ER-: 67% vs 35%.
 * 5-yr OS 88% vs 76% (SS).
 * ER+: OS 94% vs 80% (NS). ER-: 79% vs 69% (NS)
 * Conclusion: adjuvant chemotherapy improved DFS and OS. The data are strongest for patients with ER-negative recurrences. Longer follow-up is necessary for pts with ER+ recurrences.