Rationale for complete metastasectomy in patients with stage IV metastatic melanoma

Patients with stage IV melanoma have usually been treated with systemic therapies; however, the overall survival for patients with this approach is disappointing. A complete surgical resection of metastatic disease to stage IV sites offers the best chance to maximize survival. This review article will present data supporting the position that if a complete metastasectomy is technically feasible, then surgery should be strongly considered the first option for properly selected patients with stage IV melanoma.     

Metastasectomy for recurrent stage IV melanoma.

BACKGROUND AND OBJECTIVES: Many patients undergoing complete surgical resection of distant metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IV) develop recurrent disease. We examined whether a second metastasectomy could prolong the survival of patients with recurrent stage IV melanoma. DESIGN AND PATIENTS: Retrospective review of our 8,750-patient melanoma database identified 211 patients who were rendered clinically free of disease by surgical resection of stage IV metastases during the 24-year study period (January 1971 through December 1995). Our study population comprised the 131 patients who developed recurrent stage IV disease and were followed for at least 24 months or until death. RESULTS: The median disease-free interval prior to recurrent stage IV disease was 8 months (range 0.6-91.8 months). There were 131 tumor-involved anatomic sites; the median number was one (range 1-3). Of these sites, 71 (54.2%) were soft tissue, 35 (26.7%) were pulmonary, 28 (21.4%) were gastrointestinal, 23 (17.6%) were cerebral, 13 (9.9%) were skeletal, and 2 (1.5%) were gynecologic. Median survival following treatment for recurrent stage IV melanoma was 18.2 months after complete metastasectomy, compared with 12.5 months or 5.9 months after a palliative surgical procedure or nonsurgical management, respectively. The 5-year survival rate was 20.0% (8/40) for patients in the complete surgical metastasectomy group, compared with 7.0% (3/43) and 2.1% (1/48) for those in the palliative surgical and nonsurgical groups, respectively. By multivariate analysis, the two most important prognostic factors for survival following diagnosis of recurrent stage IV melanoma were a prolonged disease-free interval to recurrence (P = 0.0001) and complete surgical metastasectomy of the recurrence (P = 0.0001). CONCLUSIONS: Metastasectomy can prolong the survival of patients with recurrent stage IV melanoma if all clinically evident tumor can be resected.     

Surgical management of distant metastases

Although the location of metastases is of prognostic importance in stage IV melanoma, as seen in the revised AJCC staging classification system and other studies, certain guiding principles apply to patients who have any stage IV disease. Close follow-up of any patient who has melanoma may identify surgically resectable metastatic disease, although this method is controversial. Components of this monitoring may include careful questioning to determine symptoms, such as cough, abdominal pain, or headaches; physical examination for evidence of skin, soft tissue, and lymph node metastases; and screening tools, such as radiographs and laboratory tests. Identifying patients who have metastatic disease at the earliest stage possible is crucial for surgical resection to be an option. Patients should also be thoughtfully evaluated for the possibility of a complete surgical re-section. Complete metastectomy, regardless of the anatomic site, confers survival advantages not seen with other treatment modalities. This aggressive surgical approach should be tempered with the knowledge that incomplete resections put patients at increased risk without any proven survival benefit, and should be reserved only for palliation of symptoms.Systemic adjuvant therapies for stage IV melanoma are evolving, but do not yet confer the survival advantage of complete surgical resection. Until novel drug therapies show efficacy and significantly prolong survival in patients who have stage IV disease, careful consideration should be given to a complete metastectomy if technically feasible.     

A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430

BACKGROUND:

On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting.

METHODS:

Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death.

RESULTS:

Seventy‐seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow‐up of 5 years, the median relapse‐free survival was 5 months (95% CI, 3‐7 months) whereas median overall survival was 21 months (95% CI, 16‐34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively.

CONCLUSIONS:

In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse‐free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy. Cancer 2011;. © 2011 American Cancer Society.     

Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with Stage IV melanoma

BACKGROUND: Metastatic melanoma carries a poor prognosis, with a median survival of 7-9 months. Surgical resection of metastatic disease has been advocated to improve survival. Immunotherapy after metastasectomy may further improve the outcome for high-risk resected disease. METHODS: Charts from patients treated on institutional vaccine trials were analyzed. Patients with American Joint Committee on Cancer (AJCC) Stage IV melanoma who underwent surgical resection of metastatic sites followed by treatment on a peptide vaccine trial were eligible for this study. Survival was calculated from the date of enrollment on the clinical trial. RESULTS: Forty-one patients met inclusion criteria. The median age was 56.5 years, with approximately equal numbers of men and women. The ECOG performance status was 0 in all patients. Approximately 46% of patients underwent resection of visceral metastases before vaccine. The median follow-up was 5.6 years. The median overall survival was 3.8 years. CONCLUSIONS: In selected patients with AJCC Stage IV melanoma, resection of metastatic disease followed by vaccine therapy can result in long-term survival.     

Adjuvant treatment with vindesine in comparison to observation alone in patients with metastasized melanoma after complete metastasectomy: a randomized multicenter trial of the German Dermatologic Cooperative Oncology Group

To evaluate the efficacy and safety of vindesine in patients with metastatic melanoma after complete metastasectomy. One hundred and forty-two patients with metastatic spread to regional sites, lymph nodes, and distant sites after complete metastasectomy were randomized to receive either treatment with vindesine for 2 years or observation alone. Vindesine 3 mg/m intravenously was administered biweekly for the first 26 weeks following 3-week intervals for an additional 26 weeks and thereafter every 4 weeks for 52 weeks. One hundred and thirty-nine patients were eligible for intent-to-treat analysis. Median follow-up time was 46 months. Median recurrence free survival was 7.9 months in the vindesine group and 7.6 months in the observational group (P=0.40). Three-year overall survival rate was 54.9% (37 patients) for patients receiving vindesine in comparison to 43.6% (31 patients) in the observation arm (P=0.07). No grade IV toxicity was observed. The two major side effects in the vindesine group were alopecia and peripheral neuropathy. Ten patients went off treatment because of grade III toxicity. Adjuvant treatment with vindesine did not significantly prolong disease free or overall survival in high-risk melanoma patients. Thus, this randomized trial did not confirm earlier reports of beneficial effects of adjuvant vindesine and can therefore not be recommended.     

Skin tests predict survival after autologous tumor cell vaccination in metastatic melanoma: Experience in 81 patients

Background:Currently there is no standard adjuvant treatmentfollowing surgical resection of metastatic melanoma. We investigated whethersurgery followed by autologous tumor cell-BCG vaccination was beneficial formalignant melanoma patients. In this study we focus on the prognostic valueof DTH response following vaccination therapy. Patients and methods:Eighty-one patients with AJCC stage III andIV melanoma were selected. Whenever feasible, radical metastasectomy wasperformed. ASI was initiated by the administration of three weeklyintra-cutaneous vaccinations with 10⁷ irradiated autologous tumorcells, starting four weeks after surgery. Depending on the size of DTHresponse to the first three injections, subsequent vaccinations were planned.The first two vaccines also contained 10⁷ BCG organisms as animmune stimulatory adjuvant. Results:Induration as well as erythema correlated strongly withsurvival (P< 0.0001 and P= 0.0004). After radicalmetastasectomy in stage III melanoma patients a five-year survival of48% was observed. In stage IV disease, a five-year survival of34% was seen, after radical surgery had been performed. Whenmacroscopic disease was present at start of vaccination treatment, no clinicalresponses occurred. Apart from transient skin ulceration at the site ofBCG-containing vaccinations, no serious side effects were observed. Conclusions:This study shows that large-scale preparation ofautologous melanoma cell vaccines is feasible, while vaccination results inDTH responses that correlate significantly with survival. ASI seemed to bebeneficial in stage III and stage IV melanoma when given in the adjuvantsetting, while causing only very mild side effects.     

Can surgeons improve survival in stage IV melanoma?

Successful systemic management of stage IV melanoma continues to be elusive because of the paucity of effective therapies. This has fueled the continued interest in surgical resection. Several single-institution studies and a current, large, multi-institutional phase III trial have demonstrated a survival benefit for patients who underwent surgical resection for melanoma metastases. Incorporating these results into new approaches using multimodality treatment may enhance survival in patients with stage IV melanoma.     

Metastasectomy for limited metastases from soft tissue sarcoma

Opinion statement The development of metastatic soft tissue sarcoma (American Joint Committee on Cancer stage IV) is associated with a poor prognosis. Surgical resection of isolated solitary or multiple metastases is the only curative treatment; all other forms of treatment are considered palliative. As with all surgical procedures, patient selection is important to maximize the clinical benefit of metastasectomy and to minimize the risk for treatment-related morbidity. Over the past decade, nonresectional ablative approaches have been developed to manage visceral metastatic disease. These ablative procedures include cryosurgery, radiofrequency tumor ablation, and alcohol injection. All such procedures are considered investigational; outcome should be compared to that achievable with traditional surgical metastasectomy. The optimal sequence of treatments and role for perioperative (combined with metastasectomy) chemotherapy are unknown. Given the potential curative nature of metastasectomy, all patients with metastatic soft tissue sarcoma should be evaluated for the possibility of surgical resection. Patients with good performance status who have radiographically resectable disease should be considered for metastasectomy.     

A role for hepatic metastasectomy in stage IV melanoma and breast cancer: reestablishing the surgical modality

Historically, liver-related metastases associated with melanoma or breast cancer have portended a poor prognosis. Many affected patients are not considered for surgical resection based on the extent and multifocal nature of their disease. For this patient population, treatment includes systemic and/or regional therapy, local destruction (ablation/radiation), and embolization. Despite the best therapeutic regimens, prognosis remains poor. Advances in surgical technique and postoperative care have led to a resurgence in the use of metastasectomy, most notably seen in patients with colorectal-related liver metastases. With the potential for therapeutic durability and a small chance of cure, surgical resection may offer improved survival compared to other therapeutic modalities. This review summarizes the existing literature that addresses the topic of metastasectomy in patients with melanoma and breast cancer.     

Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor.

PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m(2) was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival. RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P <.001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction). CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.     

Debulking surgery in advanced melanoma

In general, patients with stage IV melanoma have poor survival. However, there are subsets of stage IV melanoma patients who are candidates for surgical debulking. There is a growing body of retrospective evidence about clinicians being able to better select patients who may benefit from surgical resection in isolated stage IV disease. In addition, palliative-type resections may improve quality of life in selected cases. In this article, we discuss how recent advances in effective systemic therapies for melanoma may impact the clinical use of debulking surgery in melanoma patients. We also review the available literature about the rationale, risks, benefits and selection of patients for these procedures.     

Laparoscopic surgery for melanoma metastases to the adrenal gland

The probability of developing cutaneous melanoma is now predicted to be one in 55 for males and one in 88 for females. Although melanoma is relatively uncommon compared with other malignancies such as breast (one in seven) or prostate cancer (one in six), the incidence is growing at an alarming rate. The development of novel strategies for the management of advanced disease will become even more urgent and require continued and controlled investigations over the next 10 years. Surgery is effective for the palliation of isolated resectable metastases. However, most patients with Stage IV melanoma have widespread disease and are not cured by metastasectomy. For the few individuals with isolated adrenal metastases from melanoma, complete resection appears to confer a survival advantage. New data are emerging about the efficacy and outcome of laparoscopic adrenalectomy for malignant lesions. However, the natural history of laparoscopic surgery for these lesions is still unknown. The indications for and limitations of laparoscopic adrenalectomy for metastatic melanoma are discussed.     

Laparoscopic surgery for melanoma metastases to the adrenal gland

The probability of developing cutaneous melanoma is now predicted to be one in 55 for males and one in 88 for females. Although melanoma is relatively uncommon compared with other malignancies such as breast (one in seven) or prostate cancer (one in six), the incidence is growing at an alarming rate. The development of novel strategies for the management of advanced disease will become even more urgent and require continued and controlled investigations over the next 10 years. Surgery is effective for the palliation of isolated resectable metastases. However, most patients with Stage IV melanoma have widespread disease and are not cured by metastasectomy. For the few individuals with isolated adrenal metastases from melanoma, complete resection appears to confer a survival advantage. New data are emerging about the efficacy and outcome of laparoscopic adrenalectomy for malignant lesions. However, the natural history of laparoscopic surgery for these lesions is still unknown. The indications for and limitations of laparoscopic adrenalectomy for metastatic melanoma are discussed.     

Effect of Surgery at Primary and Metastatic Sites in Patients With Stage IV Breast Cancer

BackgroundThere is no clear evidence of a survival benefit of resection of the primary tumor, or distant site resection (metastasectomy) in patients with stage IV breast cancer.Patients and MethodsThis retrospective analysis of stage IV breast cancer using the National Cancer Database. To evaluate variables associated with surgery at the primary site, we used univariate analyses followed by multivariate logistic regression. Consequently, we evaluated the impact of lumpectomy, mastectomy or metastasectomy on survival by conducting multivariate Cox regression survival analyses on the following groups: all stage IV patients; a subset of those with only one metastatic site; and another subset with metastasis to multiple distant sites.ResultsA total of 54,871 stage IV breast cancer patients were included in this analysis. Variables associated with the use of surgery at the primary were: age, race, Charlson/Deyo score, insurance and facility type, involved breast quadrant, receptor status, N stage, extent of metastasis, and year of diagnosis. Survival analysis showed that both lumpectomy (median overall survival [OS], 45 months) and mastectomy (median OS, 44 months) were associated with better OS compared to no surgery (median OS, 22 months). The statistical effect was larger in the subgroup with metastasis to one site, but still significant in the subgroup with multiple metastatic sites. Distant site resection also yielded a survival benefit.ConclusionIn patients with metastasis to only one site, metastasectomy was associated with better OS when that site was the liver, lung, or brain.     

Survival after surgical resection of isolated pulmonary metastases from malignant melanoma.

BACKGROUND: The overall prognosis for patients with metastatic malignant melanoma remains poor. However, careful staging and identification of patients with limited metastatic disease offers the opportunity for surgical salvage and improved survival for selected patients. METHODS: We reviewed the experience over the last 17 years at our institute with isolated pulmonary metastasectomy in 86 patients with advanced malignant melanoma. RESULTS: Our data demonstrate an overall median time to relapse of approximately 8.4 months and a median survival of 35 months. The 5-year survival rate is estimated at 33%, and 16% remain continuously free of disease after a median follow-up of 35 months. Resection of properly staged and evaluated patients with limited pulmonary metastases appears to convey a significant survival benefit. Patients with a single metastasis fare best. CONCLUSIONS: These encouraging results offer a rationale for the careful follow-up of resected patients. One third of all relapses will be limited and additional surgery contributes to their overall survival.     

Lung metastases from melanoma: when is surgical treatment warranted?

Surgical treatment of lung metastases from melanoma is highly controversial as the expected outcome is much poorer than for other primary tumours and a reliable system for selecting patients is lacking. This study evaluated the long-term results of lung metastasectomy for melanoma, with the aim of defining a subset of patients with better prognosis. By reviewing the data of the International Registry of Lung Metastases (IRLM), we identified 328 patients who underwent lung metastasectomy for melanoma in the period 1945-1995. Survival was calculated by Kaplan-Meier estimate, using log-rank test and Cox regression model for statistical analysis. After complete pulmonary metastasectomy (282 patients) the 5- and 10-year survival was 22% and 16%, respectively. In this group of patients, a time to pulmonary metastases (TPM) shorter than 36 months or the presence of multiple metastases were independent unfavourable prognostic factors. There were no long-term survivors after incomplete resection (46 patients, P< 0.01). Using the IRLM grouping system, patients without risk factors (TPM > 36 months and single lesion) experienced the best survival (29% at 5 years), followed by those with one risk factor only (20% at 5 years). On the other hand, those with two risk factors or incomplete resection showed a significantly poorer survival (7% and 0% at 5 years). Surgery plays an important role in carefully selected cases of pulmonary metastatic melanoma. The prognostic grouping system proposed by the International Registry of Lung Metastases provides a simple and effective method for improving the selection of surgical candidates.     

Significance of tumor recurrence before pulmonary metastasis in pulmonary metastasectomy for soft tissue sarcoma

Background

Resection for pulmonary metastasis from soft tissue sarcomas is an accepted method for treatment, but it is still debatable which patients will benefit from surgical intervention. To find an entity of patients benefiting from pulmonary metastasectomy, we reviewed our institutional experience.

Methods

Between 1990 and 2007, 23 patients with pulmonary metastases from soft tissue sarcomas underwent complete pulmonary resection. All patients had obtained locoregional control of their primary tumors. Various perioperative variables were investigated retrospectively to confirm the role of pulmonary metastasectomy and to identify possible prognostic factors for survival after metastasectomy.

Results

Overall survival rate after metastasectomy was 43% and 29% at 5 and 10 years, respectively. Disease-free survival rate was 9% at 1 year after pulmonary resection. On multivariate analysis, no tumor recurrence (neither locoregional recurrence nor extrapulmonary metastasis) before pulmonary metastasis provided a significantly favorable overall survival (P = 0.038). In addition, repeat metastasectomy for recurrent pulmonary metastasis also provided a favorable overall survival (P = 0.041).

Conclusions

Our data suggested that patients most likely to benefit from pulmonary metastasectomy for soft tissue sarcoma have no tumor recurrence before pulmonary metastasis. Furthermore, patients with repeat metastasectomy for recurrent pulmonary metastasis also presented a significantly longer survival.     

The role interferon-alpha in malignant melanoma remains to be defined

Interferon-alpha (IFNalpha) is a pleiotropic cytokine with various direct and indirect inflammatory response modulating activities. Some of these activities may have direct or indirect antitumour effects. For such a wide range of biological activities, the dose for optimal biological activity may differ greatly from the maximally tolerated dose as different effects are mediated by different concentrations of IFNalpha. Because of its immunomodulatory effects, it has been extensively studied in melanoma patients. Little antitumour activity has been demonstrated in metastatic stage IV melanoma, with overall response rates of 10-15%, which were not dose-related. Yet, IFNalpha has been widely studied in the adjuvant setting for stage II and III disease. Many trials have been underpowered, have used very heterogeneously mixed patient populations, a wide variety of doses and treatment schedules, and have suffered from early and unplanned analyses. Mature data are still pending in some 3000 patients of the overall approximately 6000 patients that participated in the adjuvant trials. A meta-analysis has demonstrated a similar impact on relapse-free survival across various dose ranges of IFNalpha, but no significant impact on overall survival (OS). In light of the lack of impact on OS and the considerable to serious dose-dependent toxicity of IFNalpha, we do not have a clearly dose- and schedule-defined role for IFNalpha in the adjuvant setting and have no evidence for a benefit of IFNalpha in stage IV melanoma. For the adjuvant setting, the main question: efficacy of very toxic high dose therapy versus efficacy of non-toxic long-term treatment will be answered by the mature data from the large US-Intergroup high-dose and EORTC intermediate-dose and long-term maintenance therapy trials.