Sequential chemoimmunotherapy in the treatment of metastatic melanoma.

Sequential Chemoimmunotherapy in the Treatment of Metastatic Melanoma By Jon M. Richards, Nilesh Mehta, Kathleen Ramming, and Peter Skosey Purpose: A phase II study that alternates the sequence of chemotherapy (carmustine [BCNU], cisplatin [CDDP], and dacarbazine [DTIC]) and biologic therapy (interleukin-2 [IL-2] and interferon alfa-2a [alFN]) was performed to establish a safe and efficacious way to sequence these forms of treatment for metastatic melanoma. Patients and Methods: Patients who had measurable metastatic melanoma, a Karnofsky performance status of > 70, and no clinically significant cardiac or pulmonary dysfunction were eligible for entry onto this trial. Responses to treatment were assessed after a treatment cycle by two tumor evaluations at least 4 weeks apart. Results: Forty-two consecutive patients with metastatic melanoma were treated with this sequential chemoimmunotherapy. Transient thrombocytopenia and neutropenia were observed frequently, but neither hemorrhage nor infection occurred in any of the patients. Of the 42 patients, 10 achieved a complete response (24%), 14 achieved a partial response (33%), two achieved a

METASTATIC

MELANOMA has been resistant to many forms of therapy. Most single-agent chemotherapeutics provide only low response rates. Dacarbazine (DTIC), the most active single agent in the treatment of melanoma, can be expected to yield a 20% response rate, but has not been shown to alter survival.' Although most trials of combination chemotherapy for the treatment of metastatic melanoma clearly have not been superior to DTIC alone, the combination of carmustine

(BCNU), DTIC, cisplatin

(CDDP), and

tamoxifen (BCDT) originally described by DelPrete et a12 has produced significant antitumor responses in 24 approximately 50% of patients. -

Interleukin-2 (IL-2) has shown significant activity against melanoma. 5,6 Although the high response rate originally reported has not been confirmed, bolus IL-2 6 infusions can produce up to a 20% response rate. -8 Interferon alfa-2a (aIFN) also has shown activity against melanoma. Whether this is caused by enhanced natural-

minor response (5%), eight had stable disease (19%), and eight (19%) had progressive disease. The median time to disease progression for all patients was 7 months. The median survival for all patients entered onto the trial was 11.5 months. A vitiligo-like depigmentation was induced in many patients by this treatment. Conclusions: Cytotoxic chemotherapy can be administered safely immediately before or immediately after IL-2 and alFN. Sequential chemoimmunotherapy administered as previously described yields a response rate of more than 55%. The overall survival curve suggests that a proportion of patients may achieve a long-term benefit from this treatment. Also, cutaneous depigmentation induced by this treatment suggests that immune modulation may contribute to the antimelanoma effect of this treatment. J Clin Oncol 10:1338-1343. c 1992 by American Society of Clinical Oncology.

killer cell cytolytic (NKCC) activity, direct tumoricidal effect, enhanced tumor-cell antigenicity, or some other mechanism remains unclear. However, as a single agent, alFN produces only a 15% response rate, and these responses are often only at nonvisceral sites. 9 Combinations of IL-2 and aIFN have been evaluated for the treatment of melanoma, and in nonrandomized trials, the combination of these agents seems to be more active than either agent used alone. Rosenberg et al10 reported a 34% response rate when IL-2 and alIFN were administered every 8 hours. Because the toxicities associated with IL-2 and alFN generally are not shared by cytotoxic agents, we sought to evaluate the safety and efficacy of a combination of BCDT with IL-2 and alFN. The previously reported schedules of both the chemotherapy and biologic regimens were preserved and overlapped to evaluate the safety of IL-2 and IFN administration either before or after cytotoxic chemotherapy. PATIENTS AND METHODS

From the Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL. Submitted October 11, 1991; acceptedMarch 11, 1992. Supported in part by the Goldfine-Smilgoff Memorial Club and Hoffmann-LaRoche, Inc, Nutley, NJ. Address reprintrequests to Jon M. Richards,MD, PhD, University of Chicago, Section of Hematology/Oncology, Department of Medicine, 5841 S Maryland,Box 420, Chicago,IL 60637. ©1992 by American Society of Clinical Oncology. 0732-183X/92/1008-0020$3.00/0

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Patients All patients entered onto this investigational review boardapproved trial had biopsy-proven metastatic melanoma and had signed informed consent before therapy. Additional eligibility criteria included: an age older than 18 years, a Karnofsky performance status of more than 60, the presence of bidimensionally measurable disease, and the ability to give informed consent. Ineligibility criteria included: clinically significant pulmonary or cardiac dysfunction, serum creatinine level of more than 2.0 mg/dL, prothrombin time of more than 1.5 times control, platelet

Journalof Clinical Oncology, Vol 10, No 8 (August), 1992: pp 1338-1343

Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

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CHEMOIMMUNOTHERAPY FOR MELANOMA

minutes every 8 hours; aIFN (6 mU/m 2) was administered as a daily subcutaneous injection. When administered during part A of the treatment cycle, IL-2 administration began at 8 AM on the fourth day of the cycle and continued for 15 doses. aIFN was administered at 4 PM on days 4 to 8. During part B of the treatment cycle, IL-2 and aIFN administration was completed before chemotherapy. In this part of the cycle, IL-2 administration and cIFN administration began at 4 PM on day 17 of the treatment cycle. IL-2 was continued for 15 doses, and aIFN was administered daily for 5 days.

Table 1. Patient Characteristics (N = 42)

Age (years) Median Range Kamofsky performance status Median Range Male:female ratio Prior therapy Radiation Chemotherapy Biologic None Sites of disease Lung Visceral soft tissue Lymphatic Liver Subcutaneous

50 22-73 90 70-100 22:20 11 12 14 16

Dose Modification Provisions were not made for dose reduction, rather treatment was delayed for grade 3 toxicity (grade 4 myelosuppression) and terminated for grade 4 toxicities (except myelosuppression). When the observed toxicities had returned to grade 1 or less, treatment was resumed, but the missed doses were not administered. The toxicities that actually delayed treatment included: a serum creatinine level of more than 4.5 mg/dL, an absolute neutrophil count of less than 500/IpL, and a platelet count of less than 25,000/p•L.

28 17 15 14 13 4 3 3

Bone

Spleen Brain No. of metastatic sites One Two

Supportive Measures

11 12 12 7

Three Four or more

NOTE. Six patients did not complete one treatment cycle. count of less than 100,000/CiL, absolute neutrophil count of less than 1,500/p.L, major surgery within 3 weeks, radiotherapy or chemotherapy within 4 weeks (6 weeks for nitrosoureas), or requirement of systemic steroids for intercurrent illness. Characteristics of the 42 patients entered onto this trial are listed in Table 1. Treatment Chemotherapy. Except for tamoxifen, all therapy was administered only in the hospital, but patients were not treated in an intensive care unit. The treatment plan is illustrated in Fig 1. BCNU (150 mg/m 2) was administered as a 1-hour intravenous (IV) infusion on day 1 that began in the evening. DTIC (220 mg/m 2) and CDDP (25 mg/m 2) each were administered as 2-hour IV infusions on days 1 to 3 and 22 to 25. Tamoxifen (10 mg) was administered orally twice daily for 6 weeks and began on day 1. Biologics. The biologic agents IL-2 and aIFN were provided by Hoffmann-LaRoche, Inc (Nutley, NJ). IL-2 (1.5 x 106 U/m 2 or 3.9 x 106 IU/m2) was administered as an IV bolus infusion for 15

Patients routinely received oral acetaminophen 650 mg every 4 hours and IV cimetidine 300 mg every 6 hours. Before chemotherapy administration, patients received IV metoclopramide (2 mg/ kg) and IV lorazepam (1 to 2 mg). Patients also were given prochlorperazine (10 mg) and lorazepam (1 to 2 mg) as needed for nausea and agitation, respectively. Fluids were not administered routinely for asymptomatic hypotension. Rather, IV saline was administered by bolus or continuous infusion when patients developed symptomatic orthostatic hypotension. Rigors were treated with IV meperidine (10 to 25 mg). Evaluations Within 2 weeks of the start of therapy, each patient underwent IV contrast-enhanced computed tomography (CT) scans of the brain, chest, abdomen, and pelvis. All patients older than 40 years of age underwent a cardiac stress test before therapy. The extent of melanoma was reevaluated by CT scan 2 to 3 weeks and 6 to 7 weeks after the completion of a cycle of therapy. The decision for re-treatment was left to the patient, providing that no disease progression was documented on the posttreatment CT scans. Complete blood cell (CBC) count, differential WBC count, platelet count, serum electrolytes, and serum creatinine level were determined every other day during hospitalization. A CBC count, which included differential WBC count and platelet count, was performed every other day between parts A and B of the treatment

Part A Day Agents Fig 1. Treatment schema. Doses and schedules for each agent are detailed in Patients and Methods. Tamoxifen (not shown) was administered twice daily (10 mg) for 6 weeks and began on day 1.

1 DTIC cDDP BCNU

2 DTIC cDDP

3 DTIC cDDP

17

18

19

IL-2 alFN

IL-2 alIFN

IL-2 alFN

4 IL-2 alFN

5 IL-2 alFN

6 IL-2 alFN

20

21

22

IL-2 aIFN

IL-2 alFN

7 IL-2 anFN

8 IL-2 alFN

Part B Day Agents

23

24

25

DTIC cDDP

DTIC cDDP

DTIC cDDP


1340

RICHARDS ET AL

cycle and twice per week after the completion of a treatment cycle until myelosuppression had resolved. When feasible, NKCC was determined by using peripheral-blood mononuclear cells (PBMC) that were obtained from patients before treatment, 2 days after part A, and 2 days after part B of each treatment cycle.11

Response Criteria Melanoma was quantified as the sum of the products of perpendicular diameters of marker lesions. All measurable lesions on CT scans were used as marker lesions, and up to 10 subcutaneous nodules were used as marker lesions. Responses were defined as follows: complete response (CR), disappearance of all measurable disease; partial response (PR), 50% or more reduction in measurable disease with no new lesions; minor response (MR), 25% to 50% reduction in measurable disease and no new lesions; stable disease (SD), less than 25% change in measurable disease and no new lesions; and progressive disease (PD), 25% or more increase in measurable disease or the appearance of new lesions. Responses must have been confirmed by two posttreatment evaluations.

RESULTS Tumor Response Six of 42 patients entered onto this protocol did not complete a cycle of treatment. Two patients refused to continue treatment because of fatigue. Two patients who had undergone previous autologous bone marrow transplantation, had prolonged myelosuppression that precluded completion of the treatment. One patient required surgery for an ischemic bowel (no melanoma found), and one patient required radiotherapy for bone metastases. Of the 36 patients who completed one cycle of treatment, responses were as follows: CR, one; PR, 23; MR, one; SD, six; and PD, five. The objective response rate among these 36 patients was 69%. All 25 patients who responded were offered, and chose to receive, a second cycle of therapy. After the second cycle of therapy, nine PRs had achieved CRs and one PR had her remaining subcutaneous nodule removed and became a surgical CR. All other PRs were observed without further treatment. The only MR had a CR in skin and developed profound calcification of hepatic hypodensities that her hepatic disease was no longer measurable. This patient remains progression-free at 11.5 months without any additional therapy. Of the eight patients with SD after the first cycle of therapy, three were ineligible or refused further treatment. In two patients, the remaining disease was removed surgically. Three patients with SD received a second cycle of therapy. Two patients subsequently progressed in the brain at 4 months and 6 months. One patient was allowed a third cycle of treatment and remains stable at 9 months. None of the patients with SD achieved a better response with subsequent treatment cycles.

Twenty of 34 (59%) assessable patients responded to this treatment, and eight (24%) achieved a CR from this therapy alone. Patients have been reevaluated by CT scan every 6 to 8 weeks without any additional therapy. Three of the 20 responders have had disease progression at 5, 8, and 10 months; the median duration of response has not been reached. Among CRs, the median duration of response was more than 9 months, and among PRs, which included the one MR, it was more than 7 months. Survival may be influenced favorably by response to this treatment. Although a longer follow-up is necessary to define better this advantage, the life-table survival curve shown in Fig 2 suggests a tail in the survival curve. Median survival among nonresponders was 8.4 months. The median survival for the entire study population was 10.3 months. Among the 16 previously untreated patients, three achieved a CR and five achieved a PR after two cycles of therapy. It remains unclear if prior therapy significantly alters the efficacy of this treatment. Toxicity of Treatment Generally, treatment-related toxicity was not dramatically different than that expected from the toxicities of the individual agents used. The entire treatment cycle required hospitalization for 17 days. Patients were hospitalized for a median of 18 days. The most significant clinical toxicity of therapy was fatigue, and this could not be correlated with the initial performance status or age. Some patients were able to return to work 2 days after they were discharged from the hospital, ^ ^/

I.vv

0.75 0

S0.50 a. 0.25

0 0

3

6

9

12

15

18

Months Fig 2. Patient survival on the chemoimmunotherapy regimen. Kaplan-Meier method plot of survival. The first 42 patients who were treated are shown as labeled on the graph. Censored points are indicated as vertical lines on graph.


1341


whereas other patients required more than 1 week to recover from the treatment. All patients reported nausea, and 95% of patients had at least one episode of emesis during the first treatment cycle. Nausea and emesis were treated effectively with prochlorperazine, metoclopramide, and/or lorazepam. Most patients developed a fever (temperature > 390 C) and experienced chills during the administration of IL-2 and aIFN. All but one patient developed rigors at least once during the first treatment cycle. Rigors were abrogated effectively with IV meperidine. Blood pressure (BP) decreased in all patients who received IL-2 and alIFN. The mean arterial BP decreased more than 10% in all patients, but decreased more than 20% in only five (12%) patients. Pressors were not used in any of the patients, but IV saline was administered to seven (17%) patients for symptomatic orthostatic changes in BP. Some patients developed transient thrombocytopenia in association with IL-2 and IFN administration. All patients developed a delayed thrombocytopenia at 4 to 7 weeks, which is consistent with the effect of BCNU. The median nadir in the platelet count during the first course of therapy was 52,000/ L (range, 8,000 to 130,000/ pL). A decrease in the platelet count occurred early (Fig 3). In most cases, thrombocytopenia was not a significant problem, but prolonged thrombocytopenia was observed in three heavily pretreated patients. Platelet transfusions were administered to three patients for platelet counts of less than 20,000/ pL. Two of these patients were refractory to platelet transfusions and were found to have multiple antiplatelet antibodies, even though they had never been transfused previously. 450

(n ILJ

300

F_

225

-J

Absolute neutrophil counts frequently were decreased during this treatment. The median nadir of the absolute neutrophil count during the first cycle of therapy was 1,535/ipL (range, 150 to 3,450). No infections were documented during these nadirs, and no patients were treated for neutropenic fever. The serum creatinine level was increased in association with IL-2 administration. The median increase in the serum creatinine level was 0.5 mg/dL (range, 0 to 12.4), but this effect was completely reversible. Autoimmune Toxicities During the second cycle of therapy, two patients developed antibody-positive idiopathic thrombocytopenic purpura (ITP), and one patient developed autoimmune hemolytic anemia. Both cases of ITP resolved within 10 days without the use of steroids. The Coombs'positive hemolytic anemia resolved in 2 weeks, but multiple RBC antibodies, which included anti-E, anti-c, and anti-SD, remained. Of particular interest were two unanticipated toxicities, vitiligo and telogenic hair loss, which is similar to that found in alopecia areata. Of the 36 patients who completed at least one cycle of therapy, 22 (61%) exhibited vitiligo-like depigmentation. Vitiligo has been persistent, although not progressive in most cases. Of the 22 patients who developed vitiligo on this sequential therapy, 17 (77%) had objective tumor regression, which included the one MR, after one cycle of therapy and the remaining five patients had SD at the end of one treatment cycle. Fourteen patients had not developed vitiligo by 8 weeks. Among these patients, only three (21%) had achieved a PR by the end of the first treatment cycle, and three had PD. Two additional nonvitiliginous patients developed PD before the second cycle of therapy could be administered. Vitiligo-like depigmentation is correlated positively with tumor regression (P < .005). Immunologic Changes

-J I_

150

0

2 1

4 3

6 5

8 7

10 9

12 11

14 13

16 15

17

DAY Fig 3. The effect of treatment on platelet counts. Rapid decline in platelet counts, (0); the mean and error bars represent 1 SE. The number of values (N) for each mean varies from 12 to 42.

NKCC in PBMC was assessed in only a few of the first 42 patients. In all patients tested (five), NKCC in PBMC was increased on day 10 to 11 relative to pretreatment activity. Additionally, NKCC in PBMC on day 24 to 25 was increased relative to pretreatment activity. No significant correlation of NKCC with treatment outcome could be identified. The rebound lymphocytosis that occurs after IL-2 administration was not observed in this trial. Of 72 cycles of therapy initiated in these 42 patients, the mean percent increase in absolute lymphocyte count (ALC)


1342

RICHARDS ET AL

was 34% (SD ±+48). The median day of this peak in ALC was 14. Neither the increase in ALC nor the day of this peak correlated with response. DISCUSSION This was a phase II evaluation of a combination of chemotherapy (BCDT) with IL-2 and aIFN. One objective of this study was to determine the safety and tolerability of IL-2 and aIFN that was given before and after chemotherapy. With the exception of one patient who required surgery for an ischemic bowel, none of the patients in this trial required intensive care unit management; a median of only one additional hospital day was needed to complete the first cycle of therapy. Thus, based on the limited need for acute care, the treatment described is tolerable. The in-hospital care of the patients who were treated on this trial was directed largely at nausea control, elevated temperature reduction, hydration maintainence, and rigors treatment. The commonly used supportive interventions that required hospitalization included IV antiemetics, cooling blankets, IV fluids, and IV meperidine. Thus, although this treatment generally is well tolerated, we would not consider it suitable for outpatient administration. The response rate observed with this treatment is not clearly higher than that reportedly achieved with chemotherapy (BCDT) alone (Richard et al, in preparation 1991).6,7 However, when the treatment reported here is used, the durability of these responses, the higher proportion of CRs (24%), and the indication of a tail on the survival curve (Fig 3) suggest that this treatment approach may have an impact on the survival of some patients with metastatic melanoma. Clearly, a longer follow-up is required to assess any potential survival advantage. The mechanism by which IL-2 and alIFN may enhance BCDT may depend on the initial tumoral effect of BCDT. It is not unreasonable to expect that the overall response rate of the treatment combination may not be dramatically more than the chemotherapy alone. Patient selection was not a factor in favor of prolonged patient survival in this trial. Factors that have been identified previously as poor prognostic indicators of survival include: visceral versus nonvisceral metastases and multiple versus solitary sites of metastases. 12 Seventy-four percent of the patients in this trial had multiple sites of metastatic disease, and 88% had visceral metastases. Only two (5%) patients in this trial had only one type of nonvisceral metastatic disease. Addition-

ally, most patients in this trial (62%) had undergone prior unsuccessful therapy. Thus, with the exception of a median performance status of 90, this group of patients had poor prognostic indicators for survival. Two explanations for the apparently encouraging responses observed with this treatment are obvious. Because the response of melanoma to biologic agents such as IL-2 and aIFN may be related to tumor burden, reduction of tumor burden with chemotherapy may improve the efficacy of IL-2 and aIFN. Alternatively, the immunosuppressive effects of chemotherapy may produce a tumor-tolerant host and allow melanoma to readily recover after effective chemotherapy alone. The administration of IL-2 and aIFN may accelerate the recovery of immunocompetence, and, thereby, may prevent the rapid recurrence of melanoma that often is observed after chemotherapy. However, none of these explanations predicts the autoimmune sequelae that is observed after this combination therapy. Vitiligo, which may be the result of autoimmune destruction of melanocytes, often is associated with other autoimmune disorders. 13,14 The relationship between vitiligo and melanoma is intriguing because the association of vitiligo with prolonged survival with melanoma has been described. 15 The possibility that the sequential chemoimmunotherapy described induced an immunologically mediated destruction of malignant melanocytes through recognition of melanoma-associated antigens that also were present on some normal or dysplastic melanocytes is an appealing hypothesis. Notably, depigmentation has not been reported after BCDT chemotherapy alone (D. Berd, personal observation and personal communication, May 1991) or after treatment with IL-2, aIFN, or IL-2 and aIFN. Thus it would seem that vitiligo and depigmentation are phenomena manifested by the combination of agents rather than by any of the individual components. The depigmentation that is observed is the result of melanocyte destruction. Biopsy specimens of depigmented skin have been examined with AgNO 3-staining to detect melanin and by transmission electron microscopy to confirm the absence of melanocytes in the depigmented areas. Lymphocytes are not observed at the sites of depigmentation. Because melanocytes transfer melanin to keratinocytes, which may not be sloughed for weeks, recognition of depigmentation may occur long after melanocyte destruction. Additionally, the diffuse erythroderma that usually are present during IL-2 administration may obscure recognition of the local inflammation during melanocyte destruction.


1343


If immunologic functions are altered by this treatment, these alterations may not be restricted to melanoma and melanocytes. The occurrence of two cases of transient, antibody-positive thrombocytopenia, which preceded administration of any blood products, suggests that regulatory networks that attenuate autoimmune reactions may have been disrupted generally by the treatment described. Thus, melanocyte destruction may not be the only autoimmune manifestation of sequential chemoimmunotherapy. Although vitiligo has not been reported previously in association with any treatment for melanoma, hypothyroidism has been reported in clinical trials that use IL-2 alone.1 6 These studies also have reported the presence of antibodies, which is consistent with an autoimmune etiology of the hypothyroidism. Although we identified

hypothyroidism clinically in only one patient, it is possible that subclinical hypothyroidism was present in some patients. Subsequent patients will be evaluated for this and other markers of autoimmune disorders. Because an autologous tumor is not available routinely in our patients, studies currently are underway to evaluate the major histocompatibility complex-restricted cytotoxicity of the patients' lymphocytes before and after chemoimmunotherapy by using HLA-Amatched human melanoma lines.' 7 Preliminary studies have demonstrated that a low level of major histocompatibility complex-restricted, T-cell receptor-mediated cytotoxicity in fresh PBMC develops after this treatment. The principles outlined in this combination should be evaluated in other chemotherapy-responsive human malignancies that have high failure rates.

REFERENCES 1. Balch CM, Houghton A, Peters L: Cutaneous melanoma, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 3. Philadelphia, PA, Lippincott, 1989, pp 1499-1542 2. Richards JM, Gilewski TA, Ramming K, et al: Effective chemotherapy for melanoma after treatment with interleukin-2. Cancer 69:427-429, 1992 3. DelPrete SA, Maurer LH, O'Donnell J, et al: Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep 68:1403-1405, 1984 4. McClay EF, Mastrangelo MJ: Systemic chemotherapy for melanoma. Semin Oncol 15:569-577, 1988 5. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492, 1986 6. Richards JM: Therapeutic uses of interleukin-2 and lymphokine-activated killer (LAK) cells. Blood 3:110-119, 1989 7. Parkinson DR, Abrams J, Wiernik PH, et al: Interleukin-2 therapy in patients with metastatic malignant melanoma: A phase II study. J Clin Oncol 8:1650-1656, 1990 8. Dutcher DP, Gaynor ER, Boldt DH, et al: A phase II study of high-dose continuous infusion interleukin-2 with lymphokineactivated killer cells in patients with metastatic melanoma. J Clin Oncol 9:641-648, 1991 9. Mastrangelo MJ, Schultz S, Kane M, et al: Newer immunologic approaches to the treatment of patients with melanoma. Semin Oncol 15:589-594, 1988

10. Rosenberg SA, Lotze MT, Yang JC, et al: Combination therapy with interleukin-2 and alpha interferon for the treatment of patients with advanced cancer. J Clin Oncol 7:1863-1874, 1989 11. Richards JM, Barker E, Latta J, et al: Phase I study of weekly 24-hour infusion of recombinant human interleukin-2. J Natl Cancer Inst 80:1325-1328, 1988 12. Balch CM, Soong SJ, Murad TM, et al: A multifactorial analysis of melanoma. IV. Diagnostic factors in 200 melanoma patients with distant metastases (Stage III). J Clin Oncol 1:126134, 1983 13. Naughton GK, Eisinger M, Bystryn JC: Antibodies to normal human melanocytes in vitiligo. J Exp Med 158:246-251, 1983 14. Norris DA, Kissinger RM, Naughton GK, et al: Evidence for immunologic mechanisms in human vitiligo: Patients' sera induce damage to human melanocytes in vitro by complement-mediated damage and antibody-dependent cellular cytotoxicity. J Invest Dermatol 90:783-789, 1988 15. Nordlund JJ, Kirkwood JM, Forget BM, et al: Vitiligo in patients with metastatic melanoma: A good prognostic sign. J Am Acad Derm 9:689-696, 1984 16. Pichert G, Jost LM, Zobeli L, et al: Thyroiditis after treatment with interleukin-2 and interferon-alpha-2a. Br J Cancer 62:100-104, 1990 17. Darrow TL, Slingluff CL, Seigler HF: The role of HLA class I antigens in recognition of melanoma cells by tumor-specific cytotoxic T lymphocytes. J Immunol 142:3329-3335, 1990


Sequential chemotherapy and immunotherapy for the treatment of metastatic melanoma.

Letter: Chemoimmunotherapy of malignant melanoma.

Chemoimmunotherapy in disseminated melanoma and colorectal carcinoma.

Monocytopoiesis in malignant melanoma: untreated, during immunotherapy and chemoimmunotherapy.

Immune checkpoint inhibitors in the treatment of metastatic melanoma.

[Systemic treatment of distant metastatic malignant melanoma].

Dabrafenib in the treatment of metastatic or unresectable melanoma.

Fotemustine--an advance in the treatment of metastatic malignant melanoma.

Adjuvant treatment in stage I and II malignant melanoma: a randomized trial between chemoimmunotherapy and immunotherapy.

[New treatment options for metastatic melanoma].

Vemurafenib for the treatment of BRAF mutant metastatic melanoma.

The scope of nanoparticle therapies for future metastatic melanoma treatment.

cisplatin and interleukin-2 in metastatic melanoma: immunological effects of therapy.

Pembrolizumab: First in Class for Treatment of Metastatic Melanoma.

Treatment options for metastatic melanoma in solid organ transplant recipients.

Therapeutic Advances and Treatment Options in Metastatic Melanoma.

Treatment patterns in patients with metastatic melanoma: a retrospective analysis.

First-line treatment of metastatic melanoma: role of nivolumab.

Treatment of Regional Metastatic Melanoma of Unknown Primary Origin.

Metastatic melanoma - a review of current and future treatment options.

Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.

Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen.

Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program.

The role of MEK inhibitors in the treatment of metastatic melanoma.