Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Voth et al:
  • Performed an extensive review of the literature and found 157 patients with DFSP with fibrosarcomatous transformation:
    • Local recurrence was significantly lower:
      • With margins ≥ 2 cm compared with those with undefined margins:
        • 20% vs. 39%, p=0.01
• A deep margin in the surgical management of DFSP is considere adequate:
  • If it remains intact because the deep layer of the muscular fascia acted as an anatomic boundary
• There are no data to suggest a benefit from radiation therapy:
  • If the margins are adequate:
    • Even in patients with close or unknown surgical margins:
      • The benefit is inconclusive
• Of the 33 patients reported by Voth et al who received adjuvant radiation therapy because of concerns related to the margins:
  • 12 (36.4%) still had local recurrences
  • Five (15.2%) developed metastases
  • Three (9%) had both
• Voth et al noted distant metastases:
  • In 21 of 157 patients (13.4%):
    • Which is higher than the less than 5% rate in ordinary DFSP
  • However, no data have shown benefit of adjuvant imatinib for DFSP:
    • Although the response rate among unresectable locally advanced or metastatic tumors approaches 50% in patients with the t(17;22) mutation
  • Imatinib therapy:
    • May be considered to downstage unresectable tumors or prior to re-excision for those with tumor-positive margins
  • Although doxorubicin is considered the single most active agent in soft tissue sarcoma:
    • There is no evidence of its efficacy in DFSP
• References:
  • DuBay D, Cimmino V, Lowe L, Johnson TM, Sondak VK. Low recurrence rate after surgery for dermatofibrosarcoma protuberans: a multidisciplinary approach from a single institution. Cancer. 2004;100:1008-1016.
  • Leahy M, Garcia Del Muro X, Reichardt P, et al. Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The Sarcoma treatment and Burden of Illness in North America and Europe (SABINE) study. Ann Oncol. 2012;23:2763-2770.
  • Rutkowski P, Dƒôbiec-Rychter M, Nowecki Z, et al. Treatment of advanced dermatofibrosarcoma protuberans with imatinib mesylate with or without surgical resection. J Eur Acad Dermatol Venereol. 2011;25:264-270.
  • Voth H, Landsberg J, Hinz T, et al. Management of dermatofibrosarcoma protuberans with fibrosarcomatous transformation: an evidence-based review of the literature. J Eur Acad Dermatol Venereol. 2011;25:1385-1391.

• Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastasis.
• Distant metastases occur in 2% to 23% of patients with differentiated thyroid cancer, and approximately 50% will die of disease within 5 years of diagnosis.
• Pulmonary metastases are the most common, followed by bone metastases.
• Patients with distant metastases, in general, have a poorer prognosis, but when metastases are small and radioiodine-avid, complete remission with 131I ablation is still possible in about 35% of the cases.
• Children and young adults less than 45 years with pulmonary micrometastases identified by 131I scanning, but not seen on plain radiographs, have the best prognosis.
• Distant micrometastases are best detected after total thyroidectomy and appropriate lymph node dissection of involved compartments.
• Older patients with multiple extrapulmonary metastases that are not radioiodine avid have the worst prognosis.
• Serum Tg levels and radioiodine scanning are the most sensitive indicators of persistent disease, although PET / CT may be useful in patients with negative radioiodine scans.
• Surgical resection of metastases and adjunct interventions such as arterial embolization, ethanol or radiofrequency ablation, and external radiation may be beneficial in patients with isolated metastases or may be used to minimize morbidity and improve quality of life.

• Historically, even thin melanomas were excised with very wide margins (3 to 5 cm):
  • Studies have demonstrated, however, that narrower margins are often associated with the same recurrence rates as wider margins
• The first randomized study involving surgical margins for melanomas less than 2 mm thick:
  • Was reported by the WHO Melanoma Group Trial Number 10:
• In an update of the study including 612 patients randomly assigned to a 1-cm or 3-cm margin of excision:
  • There were no local recurrences:
    • Among patients with primary melanomas thinner than 1 mm
  • There were four local recurrences among the 100 patients with melanomas 1 to 2 mm thick
    • All four occurred in patients with 1-cm margins
  • There was no significant difference in survival:
    • Between the 1- and 3-cm surgical margin groups
  • These results demonstrate that:
    • A 1-cm excision margin is safe for thin melanomas:
      • Less than 1 mm thick
• A multi-institutional prospective randomized trial from France (French Cooperative Group Trial):
  • Compared 2 cm and 5 cm excisional margins in 362 patients:
    • With melanomas less than 2 mm thick
  • There were no differences in local recurrence rate or survival between the two groups
• A randomized trial from Sweden (Swedish Melanoma Trial Group):
  • Compared 989 melanomas patients with lesions less than 2 mm thick excised with 2- and 5-cm margins
    • The results were similar
• In regard to thicker lesions:
  • A randomized clinical trial from the United Kingdom:
    • The United Kingdom Melanoma Study Group (UKMSG) Trial:
      • Compared 1- and 3-cm excisional margins in 900 patients with melanomas at least 2 mm thick
        • With a median follow-up time of 60 months:
          • A 1-cm margin was associated with a significantly increased risk of locoregional recurrence:
          • 37% vs. 32% for 3-cm margins
        • However, overall survival (OS) was similar in the two groups
• For intermediate thickness lesions:
  • A randomized prospective study conducted by the Intergroup Melanoma Committee:
    • Compared 2- and 4-cm radial margins of excision for 1- to 4-mm thickness melanomas
    • There was no difference in local recurrence rate between the two groups
    • 46% of patients in the 4-cm group required skin grafts:
      • Whereas only 11% of patients in the 2-cm group did (P < 0.001)
      • Of note, however, a trend for improved 10-year disease-specific survival was seen in 4-cm margins (77%) versus 2-cm margins (70%)
• A clinical trial directly comparing 1- and 2-cm margins for 1- to 2-mm melanomas:
  • Has not been performed
  • Based upon data from the WHO Melanoma Group Number 10 Trial and the Intergroup Melanoma Trial:
    • 2-cm margins are recommended when the anatomic location is favorable and primary closure can be achieved
    • Since there is no demonstrable survival advantage for a 2-cm margin over a 1-cm margin in 1- to 2-mm melanomas:
      • A 1-cm margin can be justified in cases in which a 2-cm margin is not easily achievable

• Historically, local recurrence with desmoplastic neurotropic melanoma (DNM):
  • Has been high
• In a retrospective analysis of 280 patients with DNM and desmoplastic melanoma:
  • Quinn et al found:
    • A significantly greater local recurrence rate:
      • Associated with margins of less than 1 cm compared with margins greater than 2 cm (P=0.001):
        • No significant benefit was found when excision margins of 1 to 2 cm and greater than 2 cm were compared:
          • Although the odds ratio for recurrence was 2:1 for the group with 1- to 2-cm margins compared with the group with greater than 2-cm margins
  • Chen et al:
    • Noted a 6% crude local recurrence rate in their surgery-alone group:
      • This excellent local control rate was achieved despite 27.7% of the tumors having a mitotic rate of 5 or more, 14.9% of tumors being ulcerated, and 40.5% of tumors having a Breslow depth greater than 4 mm
• In the series reported by Chen et al:
  • Four patients had DNM involving named nerves
  • All patients received adjuvant RT:
    • Covering the primary excision site and the involved nerve and its route to the base of the skull
  • Local control was achieved in these patients, although one patient died of metastatic disease
  • RT is important for these patients:
    • As recurrence extending beyond the base of the skull may not be surgically salvageable
• Strom et al:
  • Analyzed 277 patients with desmoplastic melanoma:
    • Of whom 113 (40.8%) received RT
  • They found two subsets of patients who seemed to gain no benefit from RT:
    • These groups were those with:
      • Negative resection margins
      • A non-head and neck tumor location
      • A Breslow thickness of ≤ 4 mm
      • No perineural invasion
    • A patient with a head and neck tumor location with perineural invasion (PNI):
      • RT would be indicated based on these data
• Guadagnolo et al:
  • Analyzed 130 patients with desmoplastic melanoma:
    • Of whom 55% received adjuvant RT
  • Although local control was not found to be significantly different among those with PNI versus those without:
    • 81% vs 88%, respectively; P=.52:
      • When local control outcomes were stratified by receipt of postoperative RT:
        • Patients with PNI who received RT had significantly better local control than those who did not:
          • 91% vs 63% at 10 years, respectively; P=.02
        • For those patients who clearly did not have PNI:
          • RT did not significantly improve local control:
            • 90% with RT vs 85% without RT at 10 years; P=.82
• References:
  • Chen JY, Hruby G, Scolyer RA, et al. Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 128 cases. Cancer. 2008;113:2770-2778.
  • Guadagnolo BA, Prieto V, Weber R, et al. The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. Cancer.2014;120:1361-1368
  • Quinn MJ, Crotty KA, Thompson JF, Coates AS, O’Brien CJ, McCarthy WH. Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer. 1998;83:1128-1135.
  • Strom T, Caudell JJ, Han D, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer. 2014;120:1369-1378.

• Inflammatory breast cancer (IBC):
  • Is a clinical diagnosis characterized by:
    • The rapid progression of an enlarged breast with skin changes including:
      • Redness, edema, and peau d’orange
• Skin punch biopsy:
  • Will demonstrate lymphovascular tumor emboli:
    • In approximately 75% of cases:
      • But the absence should not rule out a diagnosis
• Staging scans, including:
  • A CT chest / abdomen / pelvis
  • PET scan, and / or
  • Bone scan
    • Should be completed prior to initiating treatment
• Inflammatory breast cancer:
  • Is a clinical stage T4d
  • It is the most fatal form of breast cancer:
    • Accounting for 7% of all breast cancer deaths
  • Real-world observational data have demonstrated that inflammatory breast cancer:
    • Has significantly worse survival compared to other non-metastatic locally advanced and metastatic non-inflammatory breast cancers:
      • Despite this, 5-year survival of IBC patients has increased from 40% to 50% in the 1990’s to almost 70% in 2008
• Recent national and international guidelines for IBC recommend:
  • Full staging (PET / CT preferred over CT chest / abdomen / pelvis + bone scan) and bilateral breast and axillary nodal imaging:
    • Followed by neoadjuvant systemic therapy, modified radical mastectomy (including level I and II lymph node dissection), and radiation
    • Adjuvant targeted therapy and hormonal therapy should be considered in appropriate cases
  • Notably, lumpectomy is contraindicated, and breast reconstruction should be delayed
  • Multi-modal therapy for IBC has resulted in the best overall survival rates
• For HER2-negative breast cancers:
  • Preoperative chemotherapy regimens should include sequential doxorubicin and cyclophosphamide followed by a taxane to achieve the highest pathologic complete response rate
• For HER2-positive breast cancers, chemotherapy should be used with dual anti-HER2-directed therapy with pertuzumab and trastuzumab to achieve the best pathologic complete response rate

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Available with login at: https://subscriptions.nccn.org.

2. Fouad TM, Barrera AMG, Reuben JM, Lucci A, Woodward WA, Stauder MC, et al. Inflammatory breast cancer: a proposed conceptual shift in the UICC-AJCC TNM staging system. Lancet Oncol. 2017;18(4):e228-e232.

3. Ueno NT, Espinosa Fernandez JR, Cristofanilli M, Overmoyer B, Rea D, Berdichevski F, et al. International consensus on the clinical management of inflammatory breast cancer from the Morgan Welch Inflammatory Breast Cancer Research Program 10th Anniversary Conference. J Cancer. 2018;9(8):1437-1447.

4. Rueth NM, Lin HY, Bedrosian I, Shaitelman SF, Ueno NT, Shen Y, et al. Underuse of trimodality treatment affects survival for patients with inflammatory breast cancer: an analysis of treatment and survival trends from the National Cancer Database. J Clin Oncol. 2014;32(19):2018-2024.

• In the preoperative setting:
  • Chemotherapy is typically recommended to:
    • Improve breast cancer operability or downstage the axilla among medically fit patients
  • However, neoadjuvant endocrine therapy (NET):
    • Is a good option for post-menopausal women with ER+ breast cancers:
      • When aiming for improved candidacy for breast conservation or 
      • In patients in whom chemotherapy will not be safely tolerated
• Studies evaluating NET:
  • Have demonstrated similar rates of:
    • Clinical and radiographic response and breast conservation therapy (BCT):
      • To those reported from studies using neoadjuvant chemotherapy:
        • When neoadjuvant chemotherapy (4 cycles of doxorubicin and paclitaxel) was compared directly to NET (12 weeks of aromatase inhibitors; exemestane or anastrozole):
          • NET was associated with:
            • Comparable clinical response
            • Higher rates of breast conservation:
              • 33% vs. 24%
            • No difference in local recurrence at approximately 3 years
• Meta-analysis and clinical trial data:
  • Support use of aromatase inhibitors (letrozole or anastrozole) over tamoxifen, including:
    • Higher clinical and radiographic response rates:
      • 55% vs. 36%
    • Improved rates of BCT:
      • 45% versus 35%
• The ACOSOG Z1031 trial:
  • Demonstrated comparable effectiveness of exemestane, letrozole and anastrozole:
    • For 16 to 18 weeks before surgery
• NET requires a longer duration of treatment than preoperative chemotherapy and depends on the patient’s individual eligibility for breast conservation
• NET is typically recommended for 3 to 6 months prior to surgery:
  • However, extended treatment for up to 12 months:
    • Has been safe and is associated with a greater response to treatment
• Although tumor progression is rare on NET:
  • Continued surveillance is important for women with an intact primary breast tumor taking endocrine therapy:
    • Cancer growth would be an indication for surgery
• The majority of clinical trials for NET have focused on postmenopausal women:
  • In that younger patients often have higher-risk tumor biology and are likely candidates for chemotherapy:
    • Thus, data on the use of NET in premenopausal patients are limited to phase II trials and include:
      • Ovarian suppression plus aromatase-inhibitors (i.e., exemestane + goserelin)

References

1. Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007;110(2):244-254.

2. Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat. 2007;105(suppl 1):133-143.

3. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter trial. Ann Oncol. 2001;12(11):1527-1532.

4. Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23(22):5108-5116.

5. Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, et al. Comparison of Anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the pre-operative “arimidex” compared to tamoxifen (PROACT) trial. Cancer. 2006;106(10):2095-2103.

6. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM5-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol. 2011;29(17):2342-2349.

• Among women with operable breast cancers at the time of diagnosis:
  • Neoadjuvant chemotherapy (NAC) is increasingly used:
    • To gain information about the tumor’s response to treatment, with pathologic response rates correlating with long-term prognosis
• The most accepted definition of pathologic complete response (pCR) includes:
  • No residual invasive disease in the breast or sampled axillary nodes:
    • Although this definition varies, residual in situ disease does not affect the risk of distant recurrence
• Response to preoperative treatment:
  • Differs by tumor biology:
    • With hormone-receptor positive breast cancer patients having the lowest overall pCR rate
• For some women with residual disease, including those with HER2-positive and triple-negative breast cancers:
  • This allows for use of additional adjuvant therapy:
    • That improves cancer outcomes including receipt of:
      • TDM-1 (trastuzumab emtansine, KATHERINE Trial)
      • Xeloda (Capecitebine, CREATE-X Trial)
      • Eligibility for ongoing clinical trials
• Notably, recent changes to the American Joint Committee on Cancer Staging System includes:
  • Pathologic stage after neoadjuvant chemotherapy as part of the updated system
• When pCR is achieved in both the breast and axillary nodes:
  • Survival is driven by response to chemotherapy compared to initial presenting stage
• Choosing a NAC regimen depends on tumor biology:
  • In HER2-positive patients:
    • Chemotherapy should be combined with HER2-targeted therapies:
      • Taxane + carboplatin + trastuzumab, pertuzumab (TCHP)
  • For HER2-negative patients:
    • Anthracycline-based drugs including:
      • Doxorubicin and cyclophosphamide followed by a taxane
    • Higher risk HER2-negative breast cancers (node-positive hormone-receptor positive patients and triple-negative patients):
      • Typically receive anthracycline and taxane-based regimens with or without carboplatin
    • Notably, results from the CALGB 40603 trial suggested that for triple-negative breast cancer:
      • The addition of carboplatin to NAC:
        • Resulted in a 14% increase in eligibility for breast conservation

References

1. Fayanju OM, et al. The Clinical Significance of Breast-only and Node-only Pathologic Complete Response After Neoadjuvant Chemotherapy. Annals of Surgery. 2018; 268(4): 591-601.

2. von Minckwitz, G et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. NEJM. 2018; 380(7): 617-628.

3. Masuda N, et al. Adjuvant Capecitabine for Breast Cancer After Preoperative Chemotherapy. NEJM. 2017; 376:2147-59.

4. Golshan M, et al. Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates: surgical results from CALGB 40603 (Alliance). Annals of Surgery. 2015; Sep; 262(3):434-9.

• Neoadjuvant chemotherapy (NAC):
  • Refers to the delivery of systemic treatment prior to surgery
• Preoperative chemotherapy:
  • Was initially utilized in women with locally advanced or inflammatory cancers:
    • To improve operability
  • Among women with early-stage breast cancers:
    • The NSABP B-18 and B-27 randomized clinical trials:
      • Demonstrated no difference in disease-specific or overall survival:
        • Between those who received neoadjuvant versus adjuvant chemotherapy
    • Neoadjuvant chemotherapy:
      • Improved rates of breast conservation:
        • 68% versus 60%
• More recent observational dat:
  • Have demonstrated no increased risk in surgical complications:
    • Among women who underwent neoadjuvant chemotherapy
• NAC has more recently been used to:
  • Downstage the axilla in patients with biopsy-proven lymph node involvement:
    • With hopes to avoid completion lymphadenectomy and decrease the risk of lymphedema
• Additionally, NAC has been used in women with operable breast cancers:
  • To theoretically treat micrometastatic disease prior to local therapy
  • To allow assessment of the in vivo tumor response to certain chemotherapy regimens
• Notably, results from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis included patient-level data from 4,756 women enrolled in clinical trials 1983-2002:
  • Results demonstrated a higher risk of in-breast recurrence after neoadjuvant chemotherapy:
    • At 15 years, women treated with NAC had a:
      • 21% risk of local recurrence (vs. 16% in the surgery-first patients):
        • This was attributed to a higher rate of breast conservation:
          • But with no difference in distant recurrence or breast cancer-specific overall survival

References

1. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16(8): 2672-2685.

2. Boughey J, Peintinger F, Meric-Bernstam F, Perry AC, Hunt KK, Babiera GV, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg. 2006;244(3):464-470.

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomized trials. Lancet Oncol. 2018;19(1):27-39.

• In the SOFT / TEXT trials:
  • Premenopausal women:
    • Were given ovarian function suppression with adjuvant aromatase inhibitor or tamoxifen and outcomes were compared to tamoxifen alone for 5 years
• The SOFT / TEXT trials:
  • Showed a disease-free survival benefit of 2.1% and an overall survival benefit of 4.3% at 8 years:
    • With GnRH agonist and tamoxifen over tamoxifen alone in the cohort of women who had prior chemotherapy
• Tamoxifen alone is still an effective endocrine therapy and would be appropriate if patients choose not to use ovarian function suppression
• Raloxifene is a selective ER modulator similar to tamoxifen:
  • It is FDA-approved only for breast cancer risk reduction in post-menopausal women
• Oophorectomy alone is not as effective without additional endocrine therapy

References

1. Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. New Engl J Med. 2015;372(5):436-446.

2. Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Lang I, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137.

3. Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert review of anticancer therapy. 2009;9(1):51-60.

• Radiotherapy (RT) after breast-conserving surgery (BCS):
  • Is a standard treatment option for the management of DCIS
• Multifocal disease:
  • Two or more foci contained within a limited area and usually the same quadrant of the breast:
    • Is not necessarily a contraindication to BCT
  • The detrimental effect of multifocality seen in one study:
    • Was limited to women who did not receive radiotherapy:
  • Among women treated with breast-conserving surgery plus radiation:
    • There was no difference in 10-year local recurrence-free survival:
      • 80% v 87%; P = .35
• Patients requiring mastectomy for high grade DCIS with comedy necrosis:
  • May benefit from sentinel node biopsy
• In the NSABP-B24 study:
  • Only patients with hormone receptor positive DCIS benefited from adjuvant tamoxifen

References

1. Rakovitch E, Pignol JP, Hanna W, Narod S, Spayne J, Nofech-Mozes S, et al. Significance of multifocality in ductal carcinoma in situ: outcomes of women treated with breast-conserving therapy. J Clin Oncol. 2007;25(35):5591-5596.

2. Allred DC, Anderson SJ, Paik S, Wickerham DL, Nagtegaal ID, Swain SM, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30(12):1268-1273.