Implementation of the Targeted Axillary Dissection Procedure in Clinically Node-Positive Breast Cancer: A Retrospective Analysis.

BACKGROUND: The targeted axillary dissection (TAD) procedure is used in clinically positive lymph node (cN+) breast cancer to assess whether pathological complete response (pCR) is achieved after neoadjuvant systemic therapy (NST) to decide on de-escalation of axillary lymph node dissection (ALND). In this study, we review the implementation of the TAD procedure in a large regional breast cancer center. METHODS: All TAD procedures between 2016 and 2022 were reviewed. The TAD procedure consists of marking pre-NST the largest suspected metastatic lymph node(s) using a radioactive I-125 seed. During surgery, the marked node was excised together with a sentinel node procedure. Axillary therapy (ALND, axillary radiotherapy, or nothing) recommendations were based on the amount of suspected positive axillary lymph nodes (ALNs < 4 or ≥ 4) pre-NST and if pCR was achieved after NST. RESULTS: A total of 312 TAD procedures were successfully performed in 309 patients. In 134 (43%) cases, pCR of the TAD lymph nodes were achieved. Per treatment protocol, 43 cases (14%) did not receive any axillary treatment, 218 cases (70%) received adjuvant axillary radiotherapy, and 51 cases (16%) underwent an ALND. During a median follow-up of 2.8 years, 46 patients (14%) developed recurrence, of which 11 patients (3.5%) had axillary recurrence. CONCLUSIONS: Introduction of the TAD procedure has resulted in a reduction of 84% of previously indicated ALNDs. Moreover, 18% of cases did not receive adjuvant axillary radiotherapy. These data show that implementation of de-escalation axillary treatment with the TAD procedure appeared to be successful.

Efficacy of Internet-Based Cognitive Behavioral Therapy for Treatment-Induced Menopausal Symptoms in Breast Cancer Survivors: Results of a Randomized Controlled Trial.

PURPOSE: We evaluated the effect of Internet-based cognitive behavioral therapy (iCBT), with or without therapist support, on the perceived impact of hot flushes and night sweats (HF/NS) and overall levels of menopausal symptoms (primary outcomes), sleep quality, HF/NS frequency, sexual functioning, psychological distress, and health-related quality of life in breast cancer survivors with treatment-induced menopausal symptoms. PATIENTS AND METHODS: We randomly assigned 254 breast cancer survivors to a therapist-guided or a self-managed iCBT group or to a waiting list control group. The 6-week iCBT program included psycho-education, behavior monitoring, and cognitive restructuring. Questionnaires were administered at baseline and at 10 weeks and 24 weeks postrandomization. We used mixed-effects models to compare the intervention groups with the control group over time. Significance was set at P < .01. An effect size (ES) of .20 was considered small, .50 moderate and clinically significant, and .80 large. RESULTS: Compared with the control group, the guided and self-managed iCBT groups reported a significant decrease in the perceived impact of HF/NS (ES, .63 and .56, respectively; both P < .001) and improvement in sleep quality (ES, .57 and .41; both P < .001). The guided group also reported significant improvement in overall levels of menopausal symptoms (ES, .33; P = .003), and NS frequency (ES, .64; P < .001). At longer-term follow-up (24 weeks), the effects remained significant, with a smaller ES for the guided group on perceived impact of HF/NS and sleep quality and for the self-managed group on overall levels of menopausal symptoms. Additional longer-term effects for both intervention groups were found for hot flush frequency. CONCLUSION: iCBT, with or without therapist support, has clinically significant, salutary effects on the perceived impact and frequency of HF/NS, overall levels of menopausal symptoms, and sleep quality.

Radioactive seed localization is the preferred technique in nonpalpable breast cancer compared with wire-guided localization and radioguided occult lesion localization.

OBJECTIVES: Three commonly used techniques for localization of nonpalpable breast cancer are radioactive seed localization (RSL), wire-guided localization (WGL) and radioguided occult lesion localization (ROLL). In this study, we analysed the surgical margins of these three techniques. METHODS: Women diagnosed with nonpalpable breast cancer undergoing breast-conserving surgery with one of the above-mentioned techniques were retrospectively included. The primary outcome parameter was tumour-free margin rate. Secondary outcomes were re-excision rate, recurrence of disease and volume of removed tissue. RESULTS: In total, 272 women were included in whom RSL (n=69), WGL (n=76) or ROLL (n=137) was performed. RSL showed a higher tumour-free margin rate [64 (92.8%)] compared with WGL [51 (67.1%)] and ROLL [113 (82.5%)] (P=0.001). In our multivariable analysis, RSL showed a higher tumour-free margin rate as well compared with WGL (P=0.036) and ROLL (P=0.049). Also, fewer re-excisions were encountered using RSL [5 (7.2%)] compared with WGL [13 (17.1%)] and ROLL [15 (10.9%)] (P=0.171). In 11 patients (WGL n=2, ROLL n=9), recurrence of disease occurred, despite a radical excision. The mean resection volumes were comparable within the three groups. CONCLUSION: RSL results in a higher tumour-free margin rate in nonpalpable breast tumours compared with WGL and ROLL. Therefore, we prefer using RSL in nonpalpable breast tumours.

Isolated limb perfusion for melanoma.

Isolated limb perfusion with high-dose chemotherapy is an accepted treatment modality to achieve locoregional control in advanced melanoma of the extremities. The drug of choice is melphalan. Tumor necrosis factor-alpha is frequently added to melphalan in bulky disease, and this combination may be an option for repeat perfusion for recurrent melanoma after a first perfusion. Results of perfusions performed with tissue temperatures between 37 degrees C and 38 degrees C seem to be equivalent to those of the perfusions performed under mild hyperthermic conditions. Perfusion cannot be recommended as an adjunct to wide local excision in patients who have primary melanoma. Adjuvant perfusion in repeatedly recurrent limb melanoma, however, may be of value because it lengthens the limb recurrence-free interval and decreases the number of lesions per recurrence significantly. Regional toxicity of perfusion should be mild when risk factors are taken into account.

Isolated limb perfusion in regional melanoma.

Adjuvant perfusion to excision of a primary melanoma cannot be recommended because of its limited effect. In patients who have frequently recur-ring resectable locoregional melanoma, perfusion may provide valuable loco-regional disease control by decreasing the number of recurrences and lesions per recurrence. Randomized studies are needed to further establish the role of perfusion as an adjuvant treatment for resectable recurrences of melanoma. Unresectable limb melanoma is the primary indication for perfusion. Better response rates tend to be seen when TNF-a is used in patients who have a high tumor load. Repeat perfusion is feasible, resulting in response rates similar to those of a first perfusion for locoregional melanoma. Older age itself is not a contraindication for perfusion. The long-term health-related quality of life of survivors of melanoma who underwent treatment with perfusion is comparable to that of their healthy peers in the general Dutch population.

Isolated limb perfusion for unresectable melanoma of the extremities.

HYPOTHESIS: In patients with truly unresectable melanoma of the extremities, results after isolated limb perfusion (ILP) are absent in the literature. Complete response rates are probably lower than the reported 54% for locoregional recurrent melanoma. In these patients, ILP with melphalan and tumor necrosis factor alpha (TNF-alpha) could be superior to ILP with melphalan alone. DESIGN: Retrospective analysis with a median follow-up period of 21 months (interquartile range, 9-40 months). SETTING: Two tertiary care cancer centers in the Netherlands. PATIENTS: We assessed all 130 consecutive patients who underwent ILP for unresectable melanoma of the extremities, performed between 1978 and 2001. Of these patients, 38% had stage IIIA melanoma and 45% had stage IIIAB melanoma according to criteria of the MD Anderson Cancer Center. Lesions were considered unresectable on the basis of their size, number, or localization. INTERVENTIONS: Forty ILPs were performed with melphalan, and 90 were done with TNF-alpha and melphalan. MAIN OUTCOME MEASURES: Response rate, disease-free survival, limb salvage rate, and overall survival. RESULTS: In 45% of the patients, a complete response was attained after ILP with melphalan (95% confidence interval, 29%-61%) compared with 59% after ILP with TNF-alpha and melphalan (95% confidence interval, 49%-69%; P = .14). The time to complete response was 3 months (interquartile range, 2-6 months) vs 2 months (interquartile range, 1-3 months; P = .01), respectively. The recurrence rate and median limb recurrence-free survival were not significantly different for both ILP types. The overall limb salvage rate was 96%. Overall 5-year survival was 29% (95% confidence interval, 20%-38%). The ILP type was not an independent prognostic factor for complete response, nor was limb recurrence-free survival, whereas stage IIIA was a favorable prognostic factor (P = .01 and P = .02, respectively). Favorable prognostic factors for improved survival were complete response (P<.001) and a tumor size of 3 cm or less (P = .01). CONCLUSIONS: In more than half of the patients with truly unresectable melanoma of the extremities, a complete response was obtained after ILP with melphalan with or without TNF-alpha. The ILP type was not an independent prognostic factor for complete response, limb recurrence-free survival, or overall survival.

Isolated limb perfusion: what is the evidence for its use?

BACKGROUND: This study was conducted to assess the best available evidence for the use of isolated limb perfusion. METHODS: Following the principles of Evidence-Based Medicine, we reviewed the best available evidence for isolated limb perfusion (ILP) for melanoma and soft tissue sarcoma (STS) of the limb. RESULTS: Adjuvant ILP with melphalan (M-ILP) to wide local excision cannot be recommended for patients with primary melanoma with a limited regional benefit and no increase in overall survival (level 1b evidence). Prophylactic M-ILP next to the excision of recurrent melanoma has resulted in a nonsignificant decrease in recurrence rate (33% to 50%), with a significantly longer recurrence-free interval (10 to 17 months), but no survival benefit (level 2b evidence). Therapeutic M-ILP, with or without tumor-necrosis factor alpha and interferon gamma (T(I)M-ILP), seems indicated in unresectable melanoma (level 3 to 4 evidence). In unresectable STS of the limbs, limb salvage can be obtained in 57% to 86% of patients with neoadjuvant T(I)M-ILP (level 3 evidence). A comparison of level 3 to 4 studies on ILP and other neoadjuvant treatment modalities for unresectable STS shows that ILP results in the highest limb salvage rate with the lowest complication rate. CONCLUSIONS: Based on level 3 to 4 evidence, ILP is indicated in unresectable locoregional (recurrent) melanoma and unresectable STS of the limbs. Level 1 and 2b evidence does show an effect of prophylactic ILP on micrometastatic disease in locoregional (recurrent) melanoma of the limb. ILP seems the most effective limb sparing, neoadjuvant treatment modality when compared with other neoadjuvant treatment options for unresectable STS of the limb (level 3 to 4 evidence), although randomized studies are lacking.

Isolated limb perfusion prolongs the limb recurrence-free interval after several episodes of excisional surgery for locoregional recurrent melanoma.

BACKGROUND: The influence of isolated limb perfusion (ILP) on the limb recurrence-free interval (LRFI) and the number of lesions per recurrence was studied for patients with frequently recurring regional in-transit metastases previously managed by excisional surgery. METHODS: All 43 patients who had their first ILP for a third or further limb recurrence were selected from our computer database of 451 patients who underwent therapeutic ILP for recurrent extremity melanoma in our centers. Eighteen patients had resectable and 25 had locally unresectable lesions at the time of ILP. The patients had a total of 269 intervals between treatment of their primary melanoma and last recurrence or last follow-up. Median follow-up was 35 months (interquartile range, 14-64 months). RESULTS: The median LRFI decreases over time from primary melanoma to the third or further recurrence for which ILP was performed (P < 0.001). The median LRFI is 4.7 times longer (95% confidence interval [CI], 2.8-7.9; P < 0.001) after ILP in comparison with the last interval before ILP. Patients with resectable lesions have a median LRFI that is 5.9 times longer (95% CI, 2.7-13; P < 0.001). In all patients, the number of lesions increases by 22% per recurrence number (95% CI, 10%-35%; P = 0.02). At the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6-4.5) mean number of lesions than do patients after ILP (P < 0.001). CONCLUSIONS: ILP lengthens the LRFI and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma. Therefore, ILP could be a valuable adjunct to excisional surgery for in-transit metastases in these patients whose LRFIs tend to shorten over time.

Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremities.

BACKGROUND: Since 1992, isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and melphalan has been used for the treatment of patients with unresectable soft tissue sarcomas of the extremities. The authors retrospectively studied the results of limb salvage surgery using TNFalpha-ILP at their institution. METHODS: From 1992 to 2001, 49 patients (mean age, 51 years; range, 14-85 years) underwent ILP for unresectable soft tissue sarcomas of the extremities. All patients received melphalan and TNFalpha (four patients also received interferon-gamma). The median follow-up was 26 months (range, from 2 days to 103 months). RESULTS: In 1 patient (2%) who died 2 days after undergoing ILP, response and acute limb toxicity could not be assessed. One patient (2%) attained a clinical complete response (2%), 23 patients (47%) attained a clinical partial response, 17 patients (35%) demonstrated no change, and 7 patients (14%) had tumor progression. Thirty-one patients (63%) underwent tumor resection. Histologic material also was available from eight amputations and three punctures/biopsies. Pathologic response was complete in 4 patients (8%), partial in 14 patients (29%), and no change was observed in 24 patients (49%). Final response, based on both clinical and pathologic assessment in which pathology was decisive, was complete in 4 patients (8%) and partial in 27 patients (55%), resulting in a final overall response rate of 63%. Local control with preservation of the limb was attained in 28 patients (57%). Four of 32 patients (13%) who had been rendered tumor free by ILP with or without undergoing resection and radiation therapy, developed a local recurrence. The 5-year disease specific survival rate was 48% for the 49 patients. Acute limb toxicity after ILP was a mild Grade 1-2 reaction in 35 patients (71%) patients, a Grade 3 reaction in 12 patients (25%), and a Grade 4 reaction in 1 patient (2%). Three major ILP-related complications were encountered, including arterial thrombosis in two patients and a fulminant Clostridial infection leading to death in one patient. There were no severe cardiovascular reactions after ILP. CONCLUSIONS: In patients with unresectable soft tissue sarcomas of the limbs who underwent ILP with TNFalpha and melphalan followed by resection of the tumor remnant when possible, a 63% overall tumor response rate and a 57% local control rate with limb preservation was achieved.

Long-term results of a double perfusion schedule using high dose hyperthermia and melphalan sequentially in extensive melanoma of the lower limb.

The aim of this study was to assess the results of an isolated limb perfusion (ILP) schedule with high dose hyperthermia (42-43 degrees C) and melphalan, applied sequentially in patients with advanced melanoma of the limbs. Seventeen patients with extensive recurrent or bulky melanoma of a limb were treated with hyperthermic femoral ILP (42-43 degrees C) without drugs followed by normothermic (37-38 degrees C) ILP with melphalan. Eleven patients (65%) had a complete response. Three patients (27%) had limb recurrences after 5, 6 and 18 months, respectively. The 5 year limb recurrence-free interval for patients with a complete response was 63%. Limb toxicity was mild; pressure-related blistering and transient sensory disturbances occurred after the hyperthermic ILP, and 88% of the patients had a grade II reaction (mild erythema and oedema) after the second ILP. This sequential ILP schedule resulted in a high complete response rate and a low limb-recurrence rate in patients with extensive, recurrent melanoma of the limbs at the cost of only mild toxicity. This regimen could be an alternative to ILP with tumour necrosis factor-alpha and melphalan.