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• The role of radiation therapy in melanoma care continues to evolve:
  • Particularly in this emerging era of more effective systemic therapy
• Overall, it is not as commonly utilized in contemporary practice:
  • Compared to the era preceding the implementation of checkpoint blockade and targeted therapy
• Radiation therapy is sometimes deployed:
  • In effort to enhance outcomes for melanoma patients
• While local control is routinely achieved by primary tumor wide excision:
  • Adjuvant radiation therapy is sometimes used in the uncommon presentation of:
    • The potentially locally aggressive desmoplastic neurotropic melanoma subtype:
      • The use of radiation in this setting is supported by various retrospective studies and the current national consensus guidelines
  • Radiation therapy is also sometimes used when surgery is not possible or feasible
• Although adjuvant radiation therapy has historically been offered:
  • To patients with multiple involved or matted regional nodes or with extracapsular extension of regional lymphatic metastases:
    • Its role in this context continues to rapidly evolve, and if considered, treatment plans should be developed in the context of the multidisciplinary care of the patient
  • Indeed, adjuvant radiation in the prevention of nodal relapse in high-risk populations was recently studied in the ANZMTG trial:
    • That randomized 250 patients with palpable regional nodal disease and high risk of nodal recurrence after lymphadenectomy to either adjuvant radiation therapy or observation:
      • Although radiation therapy decreased nodal recurrence in the radiation arm:
        • 21% vs. 36%, P = .02
      • The additional therapy did not result in a significant difference in either overall or relapse-free survival
  • The role of radiation therapy in the setting of progressively improving systemic treatment options remains an area of active clinical investigation
  • At MD Anderson, radiation therapy is sometimes used in the adjuvant setting:
    • To reduce in-basin failure in high-risk patients following lymphadenectomy
  • It is also used for the palliation of local symptoms and to reduce risk of local recurrence after failure of first-line therapy
  • More recently, radiation therapy has also been deployed in a clinical trial of nodal radiation therapy after SLN biopsy:
    • For patients with high-risk SLN-positive melanoma who are scheduled to have immunotherapy without completion lymph node dissection (i.e., undergoing nodal observation with active surveillance) (NCT04594187)
• Future research goals include clinical trials to further define the role of adjuvant radiation therapy alone or in combination with systemic therapies
• Patients with multiple involved or matted regional nodes or with extracapsular extension of regional lymphatic metastases may be considered for adjuvant radiation therapy in the context of the multidisciplinary care of the patient with metastatic melanoma
• Summary:
• Radiation therapy (RT) is not a first-line treatment for primary cutaneous melanoma:
  • Which is optimally managed with surgical excision
• However, RT has a defined role in select clinical scenarios:
  • Adjuvant RT is most clearly indicated for desmoplastic melanoma with high-risk features, such as:
    • Breslow thickness > 4 mm
    • Clark level V
    • Extensive neurotropism / perineural invasion
    • Head and neck location
    • Narrow deep margin resection
• The American Academy of Dermatology recommends considering adjuvant RT in these cases to improve local control:
  • Though it does not impact distant metastasis or overall survival
• Multidisciplinary consultation:
  • Including a radiation oncologist, is advised to weigh risks and benefits
• Primary RT may be considered for:
  • Melanoma in situ
  • Llentigo maligna type (MIS, LM):
    • When complete surgical excision is not feasible:
      • This is more common outside the United States, and recurrence rates in retrospective series range from 0% to 17%:
        • The depth of penetration with superficial RT is a concern, and its use is uncommon in the US
• Palliative RT:
  • Is used for symptomatic control of unresectable locoregional or metastatic disease, including cutaneous, subcutaneous, or brain metastases:
    • To reduce morbidity and improve quality of life
• The role of RT in the adjuvant setting for high-risk, resected melanoma is less well defined in the era of effective systemic therapies:
  • Ongoing studies are evaluating its utility in combination with immunotherapy
• References:
  • Guidelines of Care for the Management of Primary Cutaneous Melanoma. Swetter SM, Tsao H, Bichakjian CK, et al. Journal of the American Academy of Dermatology. 2019;80(1):208-250. doi:10.1016/j.jaad.2018.08.055.
  • Radiation and Melanoma: Where Are We Now?. Bliley R, Avant A, Medina TM, Lanning RM. Current Oncology Reports. 2024;26(8):904-914. doi:10.1007/s11912-024-01557-y.
  • Radiotherapy in the Treatment of Subcutaneous Melanoma. Borzillo V, Muto P. Cancers. 2021;13(22):5859. doi:10.3390/cancers13225859.
  • The Evolving Role of Radiation Therapy in the Management of Malignant Melanoma. Khan N, Khan MK, Almasan A, Singh AD, Macklis R. International Journal of Radiation Oncology, Biology, Physics. 2011;80(3):645-54. doi:10.1016/j.ijrobp.2010.12.071.
  • Radiation Therapy in the Management of Malignant Melanoma. Mahadevan A, Patel VL, Dagoglu N. Oncology (Williston Park, N.Y.). 2015;29(10):743-51.

• The concept of intralesional therapy:
  • For locoregional in-transit disease (or more broadly speaking for other accessible metastases) in melanoma is not new
• A potential advantage of such a strategy:
  • Is that a direct targeted approach may be associated with limited systemic toxicity:
    • While at the same time promoting a favorable local immune response and potentially direct cytotoxic activity
• Historically, this approach has been considered for patients with:
  • Unresectable, multiple, or locally advanced locoregional disease:
    • As well as patients with accessible M1a disease
• T-VEC (talimogene laherparepvec):
  • Is the only currently FDA-approved intralesional agent
  • It leverages the role of:
    • Granulocyte macrophage colony stimulating (GM-CSF) injection and its theoretical contribution to antitumor immunity
  • The agent is an attenuated oncolytic herpes simplex virus:
    • That has been modified to express the GM-CSF gene and is also capable of selective replication in tumor cells
  • The antitumor effect is thought to be due to a combination of:
    • A direct oncolysis from the viral infection and lytic replication
    • As well as the induction of a systemic immune response
  • In a phase III trial reported by Andtbacka et al:
    • 436 patients were enrolled and randomized to T-VEC or GM-CSF (control)
    • All patients had unresectable, injectable stage III or IV melanoma with a limited visceral disease burden
    • T-VEC was administered by intralesional injections once every 2 weeks, while in the other arm GM-CSF was administered subcutaneously daily for 14 days in each 28-day cycle
    • The durable (defined as ≥ 6 months) response rate, the primary objective of the trial:
      • Was significantly increased in patients receiving T-VEC (16.3% vs. 2.1%), as was the overall response rate (26.4% vs. 5.7%)
    • Some antitumor effects were observed in approximately one-third of uninjected lesions and in slightly more than 10% of visceral sites
    • OS was not significantly different among the arms of the trial:
      • However, in subset analysis there appeared to be a survival advantage in patients with stage III or IV (M1a) disease:
        • 4-year OS 32% vs. 21%, HR 0.57, 95% CI 0.40 to 0.80
    • Treatment with T-VEC was well tolerated:
      • Commonly reported adverse events included fatigue, chills, pyrexia, and other systemic flu-like symptoms
    • Based on these positive clinical results, in 2015, T-VEC became the first intralesional therapy approved by the FDA for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery
    • Efforts have been made to build upon the success of ILI and intralesional therapy (T-VEC in particular)
    • Ariyan et al. examined the safety and efficacy of combining ipilimumab with ILI in patients with in-transit disease:
      • After administering combination therapy to 26 patients, they observed response rates of 85% at 3 months (62% CR) and progression-free survival (PFS) at 1 year of 57%
    • A recent positive phase II trial comparing T-VEC followed by surgery versus surgery alone in stage IIIB to IV(M1a) melanoma:
      • Demonstrated an improvement in 2-year recurrence-free survival from 16.5% among 74 patients in the surgery alone arm to 29.5% in the 76 patients included in the T-VEC followed by surgery arm

• The presence of clinically or microscopically detectable locoregional non-nodal disease can be broadly categorized into three groups:
  • Satellites
  • In-transit metastasis
  • Microsatellite disease
• Satellite / in-transit patterns of recurrence:
  • Are relatively unique to melanoma:
    • They can occur in 3% to 10% of melanoma cases
  • Although the molecular determinants and pathophysiology of in-transit disease are not fully understood:
    • They are likely an intralymphatic manifestation of melanoma metastases
  • Independent predictors of in-transit recurrence among patients who underwent sentinel node biopsy include:
    • Age older than 50 years
    • Lower-extremity primary tumor
    • Increasing tumor thickness
    • Ulceration
    • Nodal involvement
• Regional nodal metastases:
  • Can occur in about two-thirds of patients with in-transit disease:
    • If present, are associated with lower survival rates
• Reported predictors of distant metastasis among patients with in-transit recurrence include:
  • Positive SLN status
  • In-transit tumor size of at least 2 cm
  • Disease-free interval before in-transit recurrence of less than 12 months
• Approach to Treatment:
  • The treatment landscape for patients with locoregional non-nodal disease continues to evolve:
    • It warrants a multidisciplinary team approach
  • Treatment options include:
    • Surgery:
      • Particularly for patients with limited, resectable disease
      • If surgery is performed:
        • It is recommended that clear histologic margins be obtained as there is no clinical trial-informed data to support wider excision margins
        • Regional approaches
        • Intralesional therapy
        • Systemic therapy
• Systemic treatment approaches:
  • Have mostly supplanted regional-directed therapy for multifocal and / or unresectable disease
• Patients with in-transit metastases confined to a limb:
  • That are not amenable to standard surgical measures (e.g., patients with recurrent and / or multiple in-transit metastases and patients with large-burden in-transit disease) and have failed or are not candidates for systemic therapy:
    • Pose a unique treatment challenge
    • Importantly, amputation is rarely indicated
• Hyperthermic Isolated Limb Perfusion (HILP) and Isolated Limb Infusion (ILI):
  • Although infrequently employed as a component of the current melanoma treatment landscape:
    • Regional chemotherapy techniques such as isolated limb infusion (ILI) or hyperthermic isolated limb perfusion (HILP) have been employed to treat in-transit metastases
• Hyperthermic isolated limb perfusion (HILP) with melphalan:
  • Was initially used to treat in-transit metastases of the extremities in the mid-1950s
  • With this procedure, a formal lymph node dissection is performed:
    • That provides exposure to the critical vessels of interest
    • Subsequently, cannulae are inserted and the extremity is placed on an extracorporeal (oxygenated) bypass circuit after a tourniquet is applied:
      • Effectively isolating the limb from systemic circulation
  • Melphalan has been the most employed agent for use in HILP:
    • Overall response rates of 64% to 100%
    • Median complete response rates of 58% have been achieved
    • The median response duration in patients with a complete response:
      • Generally ranges from 9 to 19 months
  • Although HILP was a rational treatment option for patents with in-transit metastases:
    • The technique was also complex and invasive:
      • To address these challenges, the technique of minimally invasive ILI was developed
  • ILI is essentially a low-flow minimally invasive isolated limb perfusion performed via percutaneously inserted catheters, and without oxygenation of the circuit (Figure):
    • Using standard radiologic techniques, catheters are inserted percutaneously into the main artery and vein of the unaffected limb (or placed in the main artery and vein in the affected limb, i.e., brachial or popliteal artery and vein)
  • Under general anesthesia, after a pneumatic tourniquet is inflated proximally, cytotoxic agents (generally melphalan and actinomycin-D):
    • Are infused through the arterial catheter and “hand-circulated” with a syringe technique for 20 to 30 minutes:
      • Progressive hypoxia occurs because, in contrast to isolated limb perfusion, no oxygenator is used
      • The hypoxia and acidosis associated with ILI are therapeutically attractive because numerous cytotoxic agents, including melphalan, appear to damage tumor cells more effectively under hypoxic conditions:
        • Hypoxia and acidosis have been reported to increase the cytotoxic effects of melphalan in experimental models
  • Although the limb tissues are exposed to the cytotoxic agent for only a short period (up to 30 minutes), the procedure has been shown to yield response rates roughly like those observed after conventional HILP:
    • Overall response rates of 85%
    • Complete response rate of 41%
    • Partial response rate of 44%
  • A multi-institutional study by Beasley et al:
    • Revealed a 31% complete response rate and a 33% partial response rate
  • Because of the relative simplicity of the isolated infusion technique, it became a more attractive option for patients with prohibitive comorbidities or the elderly, and in general became more widely used than HILP

• Toxicity and Morbidity of HILP and ILI:
  • HILP and ILI can be associated with potentially significant regional adverse effects, including:
    • Myonecrosis
    • Nerve injury
    • Compartment syndrome
    • Arterial thrombosis:
      • Sometimes necessitating fasciotomy or rarely amputation
    • Systemic leak of melphalan can result in additional toxicities
  • Following ILI, regional adverse events appear to be similar to those reported after conventional HILP:
    • With 41% of patients experiencing grade II toxic effects and 53% experiencing grade III toxic effects
  • Both procedures require a high degree of technical expertise:
    • If considered in the context of a multidisciplinary team-based approach, the procedure (almost exclusively ILI, as HILP is mostly of historical significance) should be performed only in centers that have experience with the technique
  • Moreover, in the era of modern targeted and immunotherapies, these techniques are rarely employed

• Approximately 28 million women ages 40 to 76 in the United States have dense breasts:
  • This represents approximately 40% of all women
• Breast density:
  • Refers to the relative quantities of fat (radiolucent) versus epithelium and stroma (radiodense) in breast tissue
• Higher breast density:
  • Is associated with decreased mammographic sensitivity and increased breast cancer risk
• While there are no clinical guidelines for women with dense breasts:
  • The data support a discussion of this risk and consideration of additional screening
• Supplemental screening can be considered in this population:
  • Although there is no consensus on the optimal additional screening modality used for women with dense breast tissue:
    • Often ultrasound or contrast-enhanced mammography (or tomosynthesis if not part of patient’s standard screening regimen) are selected
• The American College of Radiology Imaging Network (ACRIN) 6666 trial:
  • Investigated screening breast ultrasound in women with dense breast tissue and at least one additional breast cancer risk factor:
    • Incremental detection rate:
      • Was four cancers per 1000 patients when screening ultrasound was added to mammography
• MRI has the highest incremental cancer detection rate:
  • Reported in the high-risk population to be 4 to 14 per 1000 women following a negative mammogram
  • The majority of MRI detected cancers:
    • 67% to 80% are invasive
  • This benefit, though, needs to be balanced with the false positive rates:
    • Which range from 14% to 38% at time of baseline MRI and 8% to 18% for subsequent MRI screening
  • Additionally, breast MRI requires intravenous gadolinium contrast and is an expensive test
  • The American Cancer Society reports there is insufficient evidence:
    • To recommend for or against MRI in women with heterogeneously or extremely dense breasts on mammography as their only risk factor
  • The Dutch DENSE trial:
    • Is currently investigating the value of MRI screening in this population, but these data are not yet available
• Optimal screening regimens for women with dense breasts require a thorough discussion with the patient regarding the risks and benefits of supplemental screening, including:
  • The potential for false positives, additional biopsies and increased cost
• Risk models will often help guide individual screening recommendations but even in the absence of family history, breast density may justify supplemental screening:
  • Insurance reimbursement is variable
• References:
  • Throckmorton AD, Rhodes DJ, Hughes KS, Degnim AC, Dickson-Witmer D. Dense breasts: what do our patients need to be told and why? Ann Surg Oncol. 2016;23(10):3119-3127.
  • Melnikow J, Fenton JJ, Whitlock EP, Miglioretti DL, Weyrich MS, Thompson JH, et al. Supplemental screening for breast cancer in women with dense breasts: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(4):268-278.
  • Berg WA, Zhang Z, Lehrer D, Jong RA, Pisano ED, Barr RG, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394-1404.
  • Mann RM, Kuhl CK, Moy L. Contrast-enhanced MRI for breast cancer screening. J Magn Reson Imaging. 2019;50(2):377-390.
  • Breast Cancer Screening With MRI in Women Aged 50-75 Years With Extremely Dense Breast Tissue: the DENSE Trial. ClinicalTrials.gov Identifier: NCT01315015. https://clinicaltrials.gov/ct2/show/NCT01315015 Accessed November 8, 2019.

• Patients with chest wall recurrence:
  • Are at high risk for concurrent systemic recurrences:
    • Therefore, obtaining systemic staging and receptor information on the recurrence should be the first consideration
  • Often, there may be extensive local regional involvement in several areas along the chest wall and in the nodal regions
• According to National Comprehensive Cancer Network guidelines:
  • Systemic staging generally consists of either a:
    • PET/ CT scan or a CT of the chest, abdomen, and pelvis, as well as a bone scan
• Surgical excision with negative margins followed by comprehensive chest wall and nodal radiotherapy:
  • May be indicated in the absence of widespread systemic disease
• This patient should be managed by a multidisciplinary team:
  • Including the surgeon, medical oncologists, radiologists, pathologists, and potentially a plastic surgeon
• Patients may or may not benefit from chemotherapy:
  • In the CALOR trial:
    • Chemotherapy was found to benefit patients with resected ER negative isolated locoregional recurrence:
      • But not ER positive isolated local regional recurrence
• References
  • Hirsch A, Sabel MS, Hayes DF. Management of locoregional recurrence of breast cancer after mastectomy. UpToDate website 2016. http://www.uptodate.com/contents/management-of-locoregional-recurrence-of-breast-cancer-after-mastectomy. Accessed September 21, 2019
  • NCCN Guidelines v.4.2018. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/recently_updated.aspx. Accessed September 21, 2019.
  • Wapnir I et al. JCO 4/10/18 vol 36 #11. P 1073-1079 Wapnir IL, Price KN, Anderson SJ, et al. Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast cancer: final analysis of the CALOR Trial. J Clin Oncol. 2018;36(11):1973-1079.

• The main goal of routine post-treatment follow-up is:
  • The early detection of local-regional recurrence
• For patients with locally recurrent breast cancer, that appears to be confined to the soft tissue of the chest wall, and no evidence of metastatic disease:
  • When possible, surgical resection of the tumor is the initial treatment of choice for most patients
• Following surgery:
  • The addition of radiation therapy appears to further decrease the risk of a subsequent local recurrence
• The addition of adjuvant systemic therapy:
  • Should be considered for patients who suffer local recurrence with more than minimal tumor burden
• References:
  • Aebi S, Wapnir I. Management of locoregional recurrences. In: Winchester D J, Winchester D P, Hudis C A, and Norton L eds. Breast Cancer 2nd ed. Hamilton, Canada: B C Deker, Inc; 2006:511-523.
  • Buchanan C L, Dorn P L, Fey J, et al. Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll of Surg. 2006;203:469-474.
  • Dahlstrøm K K, Andersson A P, Andersen M, Krag C. Wide local excision of recurrent breast cancer in the thoracic wall. Cancer. 1993;72:774-777.
  • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Available at http://www.nccn.org.

• Ipilimumab:
  • Is a humanized monoclonal antibody that blocks CTLA-4:
    • A key regulatory molecule of the immune system
  • The use of immune checkpoint blockade via monoclonal antibodies targeting anti-CTLA4 (ipilimumab; Yervoy):
    • Has been established as an effective treatment for stage IV disease since 2011
    • Although approved in the metastatic setting for some time:
      • The use of checkpoint blockade in the adjuvant setting has been more recently approved in stage III melanoma:
        • Based on a number of randomized phase III trials
      • The randomized phase III clinical trial EORTC 18071 compared high-dose ipilimumab (10 mg/kg) to placebo, administered every 3 weeks for four doses, then every 3 months for 3 years unless toxicity or relapse prevented its continuation:
        • It demonstrated both a decreased rate of recurrence and improved OS for patients in the ipilimumab arm, leading to the approval of adjuvant ipilimumab
        • Despite the survival benefits noted in this adjuvant setting, opponents of this approach remark on the toxicity and paradoxical increased dosing seen in the adjuvant setting compared to metastatic disease (the latter of which employs a dose of 3 mg/kg every 3 weeks × four doses)
        • The toxicity from ipilimumab in EORTC 18071 was significant: adverse events of any grade were noted in 98.7% of patients treated with ipilimumab, including 54.1% with grade 3 or 4 toxicity
        • The median number of ipilimumab doses was four
        • Furthermore, there were five treatment-related deaths in patients treated with ipilimumab (three due to colitis, one to myocarditis, and one to multiorgan failure associated with Guillain–Barré syndrome)
        • While treatment-related deaths may be encountered in any clinical trial, such events in the adjuvant setting raise caution; some argue whether the toxicity is worth the potential survival benefit
        • This is relevant since there is a fraction of patients who will never recur and therefore have no potential to benefit from any adjuvant therapy
      • Of course, the challenge is that it is currently not possible to know that information at the level of an individual patient:
        • Therefore, the ability to prospectively identify higher- and lower-risk patients with biomarkers remains an area of intense clinical interest, as is interest on additional targets and combination therapies
• Following the success and approval of CTLA-4 inhibition:
  • The study of programmed cell death protein-1 (PD-1) axis:
    • Which functions in the periphery to modulate T-cell responses, has produced success in a number of clinical trials
• PD-1 interacts with two ligands:
  • PD-L1 and PD-L2:
    • To dampen T-cell responses:
      • Physiologically functioning to limit autoimmunity
  • The inhibitory effect of PD-1 is accomplished through a dual mechanism of:
    • Promoting apoptosis in cytotoxic T-cells (programmed cell death, as the name implies) while simultaneously reducing apoptosis in regulatory T cells
  • PD-1 protein is upregulated on activated T cells:
    • Blockade of this molecule upregulates the cellular immune system’s antitumor activity
  • In a randomized, double-blind, phase III clinical trial (CheckMate 238) for patients with resected advanced melanoma, over 900 patients who underwent complete resection of stage IIIB, IIIC, or IV melanoma received either nivolumab (3 mg/kg every 2 weeks) or ipilimumab (10 mg/kg every 3 weeks × 4 doses and then every 12 weeks):
    • Toxicity (grade 3 or 4 adverse events) was reported in 14.4% of the patients in the nivolumab group versus 45.9% of patients in the ipilimumab group; moreover, two deaths (0.4%) were reported and noted to be related to toxic effects in the ipilimumab group
    • Weber et al. concluded that nivolumab resulted in:
      • Significantly longer RFS and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab
    • Based upon the results of CheckMate 238:
      • Nivolumab was approved for adjuvant use by the FDA in 2017
  • Another anti–PD-1 drug, pembrolizumab, was compared to placebo in the randomized, controlled, double-blind phase III EORTC 1325-MG/KEYNOTE-054 trial:
    • AJCC 7th edition stage IIIA (if stage IIIA, SLN deposit had to be >1 mm metastasis), IIIB, and IIIC completely resected patients were included:
      • RFS was 59.8% in the 514 patients receiving pembrolizumab versus 41.1% in the 505 patients on placebo after 42 months of follow-up (HR 0.59; 95% CI, 0.49 to 0.70) in the updated trial results published in 2021
      • Pembrolizumab was approved by the FDA for adjuvant use in stage III disease in 2019 after the initial trial results were released
  • Building on the success of pembrolizumab in the stage III adjuvant setting, the phase III randomized clinical trial KEYNOTE-716 trial studied adjuvant pembrolizumab versus placebo in resected stage IIB or IIC melanoma patients, all of whom had a negative SLN biopsy:
    • At the second interim analysis with a median follow-up of 18 months:
      • This study demonstrated a significant reduction in relapse-free survival and distant metastasis among patients receiving pembrolizumab in an overall cohort of 1,182 patients
    • These findings led to the recently expanded indication for the use of pembrolizumab in the stage IIB and IIC setting
• As the indications continue to expand for the use of checkpoint blockade, their utilization in the metastatic, adjuvant, and neoadjuvant setting must be considered in view of their side effect profile:
  • Adverse events become increasingly important to the surgical oncologist as immunotherapy is increasingly utilized in the adjuvant and neoadjuvant settings
• Multidisciplinary care is ultimately crucial to these decisions in weighing the risks of a particular side effect profile, its potential downstream effects, and the potential benefit of these therapies

• In general, local chest wall or nodal recurrences should be excised if feasible, and then possibly treated with systemic therapy
• The role of chemotherapy following complete excision of isolated locoregional recurrence:
  • Was examined in the CALOR trial with the final analyses of this trial:
    • Demonstrating a 10-year disease-free survival benefit:
      • For patients with the addition of chemotherapy in ER negative recurrences:
        • But no statistically significant benefit for ER positive recurrences
• Re-irradiation with or without hyperthermia has also been examined:
  • Vernon et al. included multiple prospective randomized trials comparing radiation alone (RT) versus hyperthermia (HT):
    • The local complete response was:
      • 59% in the combined group and 41% in the RT alone group
  • A large meta-analysis by Datta et al. combined 34 studies (8 two-arm, and 26 single-arm):
    • The complete response (CR) rate reported for the combined RT + HT for the two-arm studies was 60% vs. 38% for RT alone
• Concurrent chemotherapy with radiation therapy has also been evaluated, in particular with chemosensitizers such as capecitabine:
  • Zagar et al. report that a combination of mild hyperthermia with a thermally sensitive doxorubicin containing liposome was safe when treating for patients with chest wall recurrences of breast cancer
• References
  • Wapnir IL, Price KN, Anderson SJ, et al. Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast cancer: final analysis of the CALOR Trial. J Clin Oncol. 2018;36:1073-9.
  • Vernon CC, Hand JW, Field SB, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35(4):731-744.
  • Datta NR, Puric E, Klingbiel D, Gomez S, Bodis S. Hyperthermia and radiation therapy in locoregional recurrent breast cancers: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2016;94(5):1073-1087.
  • Zagar TM, Higgins KA, Miles EF, et al. Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy. Radiother Oncol. 2010;97(3):535-540.
  • Zagar TM, Oleson JR, Vujaskovic Z, et al. Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data. Int J Hyperthermia. 2010; 26(7): 612-617.
  • Zagar TM, Vujaskovic Z, Formenti S, et al. Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. Int J Hyperthermia. 2014 Aug; 30(5): 285-294.

• The initial test recommended in the evaluation of hypothyroidism is:
  • A serum TSH concentration if the patient has any of the signs or symptoms of a hypothyroid syndrome or any of the risk factors shown in table
• The measurement of a TSH:
  • Is a very sensitive and specific method to diagnose hypothyroidism
  • It is almost always elevated in primary hypothyroidism:
    • The TSH rise occurs before the decreases of serum T4 and / or T3 levels
  • However, measurement of TSH is not a good initial test for secondary hypothyroidism:
    • Thus should not be used to assess the thyroid status of a patient with known or suspected hypothalamic or pituitary disease, or in severe nonthyroidal illness
  • Serum TSH is also difficult to use when thyroid hormone levels are in flux
  • If thyroid hormone replacement is not initiated after thyroidectomy:
    • TSH rises to > 30 mIU/L within 22 days in 95% of individuals

• An algorithm for the evaluation of hypothyroidism in an individual with signs and / or symptoms suggestive of the disease is presented in Figure
• If the serum TSH is within the normal range:
  • The patient is biochemically euthyroid and no further evaluation is necessary
• If the TSH is > 10 mIU/L:
  • Thyroid hormone replacement should be initiated:
    • An exception is during recovery from an acute illness or in subacute thyroiditis:
      • When the TSH may be transiently elevated before its normalization
• If the TSH is elevated above the reference range but still < 10 mIU/L:
  • It is recommended that the TSH with an estimate of free T4 and a serum TPO Ab level:
    • Be repeated in 1 month
  • If the TSH is elevated on repeat assessment and the free T4 (or FT4I) is decreased:
    • It is recommended to start thyroid hormone replacement therapy for the treatment of overt hypothyroidism
• Measurement of total or free T3 levels is not indicated in the evaluation of hypothyroidism:
  • Because T3 levels are maintained within the reference range:
    • In mild to moderate hypothyroidism:
      • Due to increased conversion of T4 to T3:
        • Via the increased activity of 5′deiodinase

• Subclinical Hypothyroidism:
  • Subclinical hypothyroidism is defined as:
    • An elevated serum TSH concentration with a normal measure of free T4 (either as FT4 or FT4I)
  • Of the U.S. population over age 80 years:
    • Approximately 15% have a serum TSH level > 4.5 mIU/L:
      • Particularly among those with serum thyroid antibody positivity
  • The optimal management of subclinical hypothyroidism has been a matter of controversy:
    • Because the TSH will normalize in approximately one-third of adults over a 3- to 4-year period:
      • It is important to identify those who will have persistent disease and / or those who may benefit from thyroid hormone replacement
  • Some small, well-controlled studies:
    • Have suggested a benefit toward improved well-being and a reduction in cholesterol levels:
      • In subclinically hypothyroid individuals treated with thyroid hormone
    • The benefit of reducing cardiovascular risk is primarily seen in middle-aged patients:
      • With less improvement among older patients
  • In general, the decision to treat patients with subclinical hypothyroidism:
    • Depends on the presence of signs or symptoms of hypothyroidism, or the increased risk of progression to overt hypothyroidism:
      • As indicated by a positive risk factor, such as:
        • Sonographic evidence of thyroiditis
        • Elevated serum antithyroid antibody titers
        • The presence of other high-risk conditions such as:
          • Cardiovascular disease
          • Pregnancy
          • Infertility
  • If the individual is asymptomatic:
    • The most conservative approach is to follow the patient clinically and repeat the TSH in 6 to 12 months or earlier as directed by signs or symptoms (Figure)
    • It would also be reasonable to obtain additional data to determine the risk of progression to overt hypothyroidism, including:
      • Inquiring about a family history of autoimmune thyroid disease
      • Performing a thyroid ultrasound to assess for thyroiditis
      • Obtaining a serum TPO Ab titer
    • In one study, women with mild subclinical hypothyroidism and serum thyroid autoimmunity followed for 4 years:
      • Had a 5% per year risk of developing biochemical hypothyroidism
• Serum Thyroid Antibodies in Hypothyroidism:
  • Measurement of serum antithyroid antibodies in the differential diagnosis of primary hypothyroidism:
    • Should be interpreted in the context of the clinical findings
  • TPO Ab or TgAb is positive:
    • In most patients with autoimmune thyroiditis (Hashimoto’s thyroiditis)
      • It is not required but confirms the diagnosis:
        • Those with high titers are likely to progress more rapidly to overt hypothyroidism
  • Elevated serum TPO Ab and TgAb:
    • Can be detected after the release of thyroid antigens:
      • In patients with silent subacute thyroiditis:
        • Such as postpartum thyroiditis
• Thyroid Imaging in Hypothyroidism:
  • Thyroid ultrasound in Hashimoto’s demonstrates:
    • A characteristic irregular texture and is often associated with diffuse enlargement
  • Blood flow, as assessed by Doppler:
    • Is reduced in subacute thyroiditis:
      • But it is difficult to distinguish reduced flow from normal
  • Radionuclide imaging of the thyroid:
    • Is almost never helpful for the diagnosis of hypothyroidism
  • Thus thyroid ultrasound and / or radionuclide imaging:
    • Should be performed only to evaluate suspicious structural abnormalities:
      • Such as a palpable thyroid nodule in the hypothyroid patient
  • Although controversial, there is an epidemiologic association of:
    • Concurrently elevated serum TSH concentrations in thyroiditis with an increased risk of thyroid malignancy
  • It has been suggested that clinicians use sonography to evaluate patients with thyroiditis, Hashimoto’s thyroiditis, and Graves’ disease:
    • To detect thyroid nodules:
      • Which would then require biopsy based on ultrasound features
• Treatment of Hypothyroidism:
  • Hypothyroidism is treated with thyroid hormone replacement:
    • Usually in the form of oral T4 (levothyroxine)
  • In individuals with little or no endogenous thyroid hormone production:
    • The usual requirement is 1.6 mcg/kg/day
  • Because 80% of circulating T3 is derived from T4:
    • T4 monotherapy is adequate in most patients for thyroid hormone replacement
  • Some patients, however, have persistent symptoms of hypothyroidism while on biochemically adequate levothyroxine replacement and prefer the use of T4 / T3 combined products:
    • Such as desiccated thyroid
  • The American Thyroid Association guidelines;
    • State that there is a lack of high-quality controlled long-term outcome data:
      • To routinely support the use of desiccated thyroid extract, combination synthetic T4 / T3, or T3 monotherapy:
        • Over levothyroxine therapy
• In patients with primary hypothyroidism:
  • Levothyroxine dose adjustments should be done based on a serum TSH measured 4 to 6 weeks after initiating the medication:
    • Due to the long half-life of levothyroxine, which is 7 to 10 days
  • The goal of treatment is a serum TSH level around the middle of the normal range:
    • For otherwise healthy individuals with primary hypothyroidism
  • And to suppressed TSH or a TSH level at the low end of the normal range is targeted for most patients with differentiated thyroid cancer

• Patients with chest wall recurrence:
  • Are at high risk for:
    • Concurrent systemic recurrences:
      • Therefore, obtaining systemic staging and receptor information on the recurrence should be the first consideration
• Often, there may be extensive local regional involvement in several areas along the chest wall and in the nodal regions
• According to National Comprehensive Cancer Network guidelines:
  • Systemic staging generally consists of either a PET/CT scan or a CT of the chest, abdomen, and pelvis, as well as a bone scan
• Surgical excision with negative margins:
  • Followed by comprehensive chest wall and nodal radiotherapy may be indicated in the absence of widespread systemic disease
• These patients should be managed by a multidisciplinary team, including:
  • The surgical oncologist, medical oncologists, radiologists, pathologists, and potentially a plastic surgeon
• Patients may or may not benefit from chemotherapy:
  • In the CALOR trial:
    • Chemotherapy was found to benefit patients with resected ER negative isolated locoregional recurrence:
      • But not ER positive isolated local regional recurrence
• References
  • Hirsch A, Sabel MS, Hayes DF. Management of locoregional recurrence of breast cancer after mastectomy. UpToDate website 2016. http://www.uptodate.com/contents/management-of-locoregional-recurrence-of-breast-cancer-after-mastectomy. Accessed September 21, 2019
  • NCCN Guidelines v.4.2018. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/recently_updated.aspx. Accessed September 21, 2019.
  • Wapnir I et al. JCO 4/10/18 vol 36 #11. P 1073-1079 Wapnir IL, Price KN, Anderson SJ, et al. Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast cancer: final analysis of the CALOR Trial. J Clin Oncol. 2018;36(11):1973-1079.