Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma

Morton, Donald L.; Ollila, David W.; Hsueh, Eddy C.; Essner, Richard; Gupta, Rishab K.

doi:10.3322/canjclin.49.2.101

Cited by 86 publications

(35 citation statements)

References 64 publications

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“…Instead, its therapeutic effects depend on the ability of its tumor-associated antigens to induce immune responses against cross-reactive antigens on the patient's autologous tumor cells. 19 Thus, patients who do not develop cell-mediated immunity and/or antibody responses cannot derive any benefit from a therapeutic vaccine. A patient's pretreatment tumor burden is of critical importance because the latency period for the induction of a maximum immune response is 8 to 16 weeks, during which the melanoma metastases are growing with an average doubling time of 30 to 40 days and likely to overwhelm the immune response generated by the vaccine.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Survival of Patients Receiving Active Immunotherapy With Canvaxin Therapeutic Polyvalent Vaccine After Complete Resection of Melanoma Metastatic to Regional Lymph Nodes

et al. 2002

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ObjectiveTo determine whether adjuvant postoperative active specific immunotherapy with a therapeutic polyvalent vaccine (PV) called Canvaxin can prolong survival following complete resection of melanoma metastatic to regional nodes (American Joint Committee on Cancer [AJCC] stage III melanoma). Summary Background DataDespite complete lymphadenectomy, 5-year overall survival (OS) for patients with melanoma metastatic to regional lymph nodes is only 20% to 50%, depending on the number of tumor-involved nodes. In 1984, the authors began phase II trials of Canvaxin PV as postsurgical adjuvant therapy for AJCC stage III melanoma. MethodsPatients who received PV between 1984 and 1998 were compared with patients who did not receive PV postsurgical therapy between 1971 and 1998. The seven covariates recently defined by the AJCC Melanoma Staging Committee (number of metastatic nodes, palpable status, ulceration, age, primary site, pT stage, and gender) were included by Cox regression in a multivariate model of OS. A computerized program matched PV and non-PV patients by these covariates. ResultsOf 2,602 patients who underwent complete lymphadenectomy for AJCC stage III melanoma with regional nodal metastases and were followed up by the same team of oncologists between 1971 and 1998, 935 received PV and 1,667 did not.Median OS and 5-year OS were significantly higher in PV than non-PV patients (56.4 vs. 31.9 months and 49% vs. 37%, respectively; P ϭ .0001). When the non-PV patients were matched by the four most significant covariates, 447 matched pairs were formed between patients seen before or after January 1, 1985, and the OS was not different between the two time periods (P ϭ .789). However, when the PV patients were matched with non-PV patients by six covariates forming 739 pairs, the PV patients survived longer (P ϭ .0001). Detailed analysis of the 1,505 patients who were seen or who began vaccine therapy within 4 months after lymphadenectomy, and who had more complete data on the seven prognostic covariates showed that median OS and 5-year OS were higher in 445 PV patients than in 1,060 non-PV patients: 70.4 versus 31 months and 52% versus 37%, respectively (P ϭ .0001). Multivariate Cox regression analysis identified six significant prognostic factors: number of metastatic nodes, size of metastatic nodes, pT stage, ulceration, age, and PV therapy. PV therapy reduced the relative risk of death to 0.64 (95% confidence interval, 0.55-0.76) (P ϭ .0001); sex and site of primary were of borderline significance. ConclusionsThis large single-institution study independently confirmed the significance of prognostic covariates in the new AJCC staging system. By using modern statistical methods that controlled for all known prognostic factors, it also demonstrated PV's ability to significantly enhance OS. A multicenter phase III randomized trial is underway to validate the efficacy of PV as a postsurgical adjuvant.

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Section: Discussionmentioning

confidence: 99%

Prolonged Survival of Patients Receiving Active Immunotherapy With Canvaxin Therapeutic Polyvalent Vaccine After Complete Resection of Melanoma Metastatic to Regional Lymph Nodes

et al. 2002

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“…This may be one explanation for why metastases are initially evident at only one or two sites early in the process. Future metastases may actually be arising from the initial metastatic site, propagating the metastatic process and hastening the patient's demise [13].…”

Section: Site-specific Metastasismentioning

confidence: 99%

The role of surgery in treatment of stage IV melanoma

Young

Martinez

Essner

2006

Journal of Surgical Oncology

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The prognosis for patients with melanoma has not improved over the last 30 years. So far, almost without exception, clinical trials conducted with single or multiple agent chemotherapy, biological therapy (interferon-alpha, interleukin-2), and biochemotherapy have failed to demonstrate consistent survival benefit. Without effective alternate treatments, surgery must be considered the primary treatment of melanoma, independent of disease stage. Although surgery is clearly favored as the treatment of localized melanoma, consensus opinion and clinician preference become divided once melanoma progresses beyond its primary site. Many physicians will adopt an attitude of resignation and hesitancy when treating metastatic melanoma. As a result, patients with advanced disease are often treated with medications that produce little survival or palliative benefit at the expense of significant toxicity. Numerous studies have demonstrated clear and durable survival advantages for patients undergoing complete resection of metastatic melanoma. Further, surgical resection can produce an immediate decrease in tumor burden with minimal morbidity and mortality at a reasonable cost.

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“…Of the skin cancers, melanoma is the most lethal by far, responsible for six of every seven deaths caused by skin cancer (1,2). When detected early, patients with melanoma can be cured by surgical excision (3). Although metastatic melanoma may respond to chemotherapy or radiation therapy, the long term outcome for these patients is poor (1, 4 -6).…”

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confidence: 99%

“…Dendritic cells (DCs) 3 are the most potent APCs, highly specialized to prime T cell-dependent Ag-specific immune responses (14 -17). Unlike other APCs, DCs can present Ags to naive and memory T cells (18).…”

mentioning

confidence: 99%

Host Absence of CCR5 Potentiates Dendritic Cell Vaccination

Ng-Cashin

Kuhns

Burkett

et al. 2003

The Journal of Immunology

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Previous work has shown that dendritic cells (DCs) express specific chemokine receptors that allow for coordinated movement in vivo. To test the in vivo relevance of this, we used a murine melanoma system and knockout mice to investigate the function of the chemokine receptor CCR5 and its ligands, CCR ligand (CCL)3 and CCL5. We found that the lack of CCR5 in the host mouse resulted in delayed tumor growth, but this effect was overcome at a higher tumor load. With the administration of tumor charged DCs, CCR5−/− mice that had previously been injected with tumor were completely protected from tumor. This effect was dependent on the dose of tumor cells and the expression of CCR5 on the DC and its absence in the host. In contrast, the loss of the CCR5 ligand, CCL3, led to an early delay in tumor growth that did not persist, while the absence of the CCR5 ligand, CCL5, had no effect. Blocking the activity of CCR5 in the host may represent a new strategy for enhancing the activity of a therapeutic melanoma DC vaccine.

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Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma

Cited by 86 publications

References 64 publications

Prolonged Survival of Patients Receiving Active Immunotherapy With Canvaxin Therapeutic Polyvalent Vaccine After Complete Resection of Melanoma Metastatic to Regional Lymph Nodes

Prolonged Survival of Patients Receiving Active Immunotherapy With Canvaxin Therapeutic Polyvalent Vaccine After Complete Resection of Melanoma Metastatic to Regional Lymph Nodes

The role of surgery in treatment of stage IV melanoma

Host Absence of CCR5 Potentiates Dendritic Cell Vaccination

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