University of Groningen
Evolving treatment of locoregional metastatic melanoma
Faut, Marloes
DOI:
10.33612/diss.93011206
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Publication date:
2019
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Faut, M. (2019). Evolving treatment of locoregional metastatic melanoma. University of Groningen.
https://doi.org/10.33612/diss.93011206
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The first part of this thesis focuses on the result of the surgical treatment of metastatic melanoma in the past and present. In chapter two, three and four, the outcome of surgically treated metastatic melanoma patients is described and predictors for recurrence and survival are analyzed. Before the introduction of new systemic therapies, surgical treatment was the golden standard for stage III melanoma. It can offer a cure for patients in 30-80% of the cases, depending on tumor burden. For stage IV melanoma, surgery is the golden standard in case of limited resectable disease. In this patient group, 5-year overall survival can be up to 40%.
The second part of this thesis focuses on the current and future multidisciplinary approach in melanoma care. Results of surgical treatment combined with novel systemic therapies are described. The availability of these novel treatment strategies causes new treatment dilemmas and challenges for the surgeon treating metastatic melanoma.
Surgical treatment of metastatic melanoma
Much has been written about sentinel node positive patients and their prognostic value. It is well established that sentinel node positivity is a risk factor for recurrence. There is less knowledge on those patients with a seemingly favorable prognosis (negative SLNB) who suffer a recurrence during follow-up. In chapter two the risk factors for recurrence in the latter group are described. A retrospective analysis was performed on SLNB’s performed in 668 patients. Recurrence rates were 53.2% in SLNB positive and 17.9% in SLNB negative patients. Male sex, increasing age, melanoma located in the head & neck region, nodular melanoma and the presence of ulceration were variables associated with overall recurrence in SN negative patients. In SN negative patients with a nodular melanoma, the recurrence rate was 29.7%, if ulceration was also present in the primary melanoma, the recurrence rate increased to 43.1 %. Multivariate cox regression analysis revealed melanoma located on the head & neck, trunk and upper extremity to be associated with immediate distant recurrence in SN negative melanoma patients as well as increasing Breslow thickness. The absence of mitosis is protective for immediate distant recurrence in
those of sentinel node positive patients. Perhaps, the latter patient group should be considered for inclusion in adjuvant systemic therapy trials, as was the case for positive sentinel lymph node biopsy melanoma patients.
An inguinal lymph node dissection (ILND) is a surgical procedure with a high rate of postoperative complications and short- and long-term morbidity. Minimizing the extent of the dissection in order to minimize postoperative complications and morbidity, is subject to debate. Whether a combined ilioinguinal dissection is imperative in case of superficial nodal involvement, is not clear. Chapter three aims to find predicting factors for pelvic nodal involvement prior to the ILND, in order to clarify the previously mentioned discussion. A total of 226 ILND’s in 223 patients were analyzed. In patients with micrometastatic disease, 15.7% had pelvic nodal involvement. In patients with macrometastatic disease this was 28.2%. During the median follow-up of 26.1 months, 60.1% of patients experienced a recurrence. Multivariate logistic regression revealed the presence of more than four positive superficial nodes to be associated with the occurrence of deep nodal involvement. None of the basic patient or tumor characteristics were associated with the occurrence of deep pelvic nodal involvement. Leaving clinicians unable to predict pelvic nodal involvement prior to the ILND.
In stage III melanoma patients, regional lymph node dissection used to be standard treatment after a positive SLNB and still is standard surgical therapy in case of clinically palpable lymph nodes. Unfortunately, over the previous decades, lymph node dissection of the inguinal region (ILND) has been associated with high rates of wound complications, including wound infection, seroma and wound necrosis in half of the patients. In chapter four the different peri- and postoperative protocol adjustments over the years were evaluated with regard to their influence on wound complications after an ILND. A total of 244 ILND’s in 239 patients, were analysed. The majority of patients (95%) underwent a combined superficial and deep ILND. Overall, one or more wound complications occurred in 51.2% of the patients. Wound infection was the most frequent (29.8%). Over the years different peri- and postoperative protocol adjustments were made: prophylactic antibiotics in the CLND group had no impact on the incidence of wound complications nor on the incidence
of postoperative wound infections. The institution of a door movement protocol in 2007 did not lead to a reduction in wound infections. There was no difference in the occurrence of wound complications between the different perioperative care protocol groups. Multivariate analysis revealed increasing age to be associated with the occurrence of wound complications. BMI>30 was independently associated with the occurrence of wound infections. As the present results show, none of the instituted changes in a 30-year experience with ILND, were able to reduce the occurrence of postoperative wound complications. However, we learned that bed rest ,and with that, hospital stay, can be reduced without negative influence on the occurrence of wound complications. When taking into account the negative influence of higher age and obesity, and the expected increase of elderly and obese patients in the future, changing the surgical procedure to a minimally invasive technique might be a promising method to reduce wound complications after ILND’s.
In chapter five our first experience with a minimal invasive videoscopic inguinofemoral lymph node dissection (V-IFL) is analysed. Twenty-four V-IFL’s where performed at a median age of 61 years. With a median lymph node harvest of 9 lymph nodes, the V-IFL met the required quality demands. In 14 patients (58.3%) at least one postoperative complication occurred. The most frequent postoperative complication was seroma (45.8%), followed by wound infection (29.2%). Of all the complications 91.3% were grade I or II and none of these complications required surgical intervention. Taking the learning curve into account, complication rates are expected to reduce in the future as well as operation time. Therefore the V-IFL seems a valuable alternative to a conventional open inguinofemoral lymph node dissection.
The multidisciplinary treatment of metastatic melanoma
In stage III melanoma it is well established that a R0 resection is essential to improve loco regional disease control and prognosis. In cases where stage III melanoma is deemed irresectable, due to unacceptable mutilation or expected loss of function postoperatively, patients are generally treated in a similar fashion as stage IV melanoma patients. Approximately 50% of cutaneous melanomas harbor a
Using BRAF-inhibitors in a neo-adjuvant fashion to reduce tumor size , paving the way for a radical surgical resection, is a logical next step.
Chapter six describes outcome in six irresectable stage III melanoma patients treated with BRAF inhibition in a neo-adjuvant setting. Treated between January 2012 and December 2015. Five of six patients had low grade side effects of BRAF-inhibitor treatment. An R0 resection was achieved in five patients. Median postoperative hospital stay was six days. The 30-day postoperative period was uncomplicated in four patients. In five resected specimens, vital tumor tissue was found. Three patients had a recurrence after neo-adjuvant BRAF-inhibitor treatment followed by resection. These results show that neo-adjuvant BRAF-inhibitor treatment in irresectable stage III melanoma patients is feasible with acceptable side effects, low complication rate and minimal hospital stay. The possibility of disease progression and the concurrent loss of a surgical window during BRAF-inhibitor treatment challenges the timing of surgery.
As is apparent from this thesis, the treatment of metastatic cutaneous melanoma has evolved to a multidisciplinary approach where multiple clinicians from different disciplines cooperate to improve the outcomes of treatment.
With a clear reduction in morbidity and overtreatment in patients with no evidence of nodal disease, the development of the SLNB concept in by Donald Morton was the first of more to come in improving patients outcome in melanoma. It has led to an improved staging of cutaneous melanoma. The MSLT II trial, which succeeded the MSLT I trial was designed to find out whether a completion lymph node dissection improves survival compared to nodal observation with ultrasonography. This showed that “wait and see” does not deteriorates survival. The MSLT II trial showed that surgeons sometimes can take a step back to prevent unnecessary morbidity in patients.
With the introduction of new systemic treatment options and concurrent different treatment sequences, a close collaboration is needed between the different disciplines involved in melanoma treatment.
The primary subject of discussion is no longer whether to perform a lymph node dissection. New topics such as whether a patient should receive neo-adjuvant systemic therapy prior to surgery are now the subject of debate. Metastatic melanoma comes with a widespread variety of clinical presentations and adherent treatment dilemma’s. With the ongoing advancements and availability of systemic treatment options for metastatic melanoma, the role of surgery has changed. It is still a central part of melanoma treatment, but no longer the only or last resort.
