Treatment for metastatic malignant melanoma: Old drugs and new strategies

1. Single agent chemotherapy 

Chemotherapeutic agents are cytotoxic anticancer drugs that impair cell division, resulting in the death of rapidly dividing cells. They are widely used in the treatment of malignancies; however, melanoma is resistant to many forms of traditional chemotherapy. A large number of clinical trials have tested different single drug-like alkylating agents, nitrosureas, vinca alkaloids, platinum drugs, taxanes, topoisomerase inhibitors, and anthracyclines (Table 1), but few have shown an objective response rate (<20%) or an increase in progression-free and overall survival rates [2], [3], [4]. In 1975, dacarbazine (DTIC) became the first US Food and Drug Administration (FDA) approved chemotherapeutic agent for the treatment of metastatic melanoma. The response rates with dacarbazine were 15–25%, with median response durations of 5–6 months, but less than 5% of complete responses. Long-term follow-up of patients treated with DTIC alone shows that less than 2% of the patients could survive for 6 years [5], [6].

Table 1. Single drugs and their activity in metastatic malignant melanoma.

	Drugs	Abbreviation	No. of Pts	Dose	Overall response	Refs.
	Dacarbazine	DTIC	1,868	250mg/m2/day×5 d	15–25%	[6]
	Temozolomide	TMZ	305	150–200mg/m2/day×5 d	14%	[7], [9]
	Carmustine,	BCNU	122	75–110mg/m2	13–18%	[10]
	Semustine	MET-CCNU	347	130mg/m2	16	[10]
	Fotemustine	FTMU	153	100mg/m2/week×3 w	20–25%	[11]
	Cisplatin	CDDP	114	60–150mg/m2	15%	[14]
	Carboplatin	CBDCA	30	400mg/m2 I.V. every 4 weeks	19%	[15]
	Vindezine	VDS	273	3mg/m2 slow I.V. (7–14 day intervals)	14	[18]
	Vinblastine	VLB	62	6–8mg/m2 slow I.V. 1/week	13	[18]
	Docetaxel	TXT	43	100mg/m2 I.V. every 21 days	14	[19]
	Paclitaxel	TXL	34	125–275mg/m2	15	[21]
	Tamoxifen	TAM	172	20mg/day orally	7 (4–13)	[23]

Another related agent, temozolomide (TMZ), an orally available analog of DTIC, demonstrated efficacy in the treatment of variety of solid tumors with the advantage of central nervous system penetration. Temozolomide activity as single agent in metastatic malignant melanoma has been tested in several clinical studies [7], [8], [9]. A randomized phase III trial comparing TMZ to DTIC on 305 patients with advanced melanoma demonstrated the non-inferiority of TMZ as compared to DTIC in terms of objective response rate and overall survival, but a statistically significant increase in progression-free survival (1.9 months vs 1.5 months) was observed [8]. Despite these poor outcomes, TMZ was very well tolerated and showed an advantage in terms of improvement in the quality of life resulting in a large use of TMZ for the treatment of metastatic melanoma.

2. Multi-drug combinations 

The disappointing results with single agent chemotherapy led to the evaluation of multi-drug combinations regimens in the 1980s in efforts to improve outcome and enhance response rates in patients with metastatic disease. A listing of major randomized studies evaluating DTIC vs drug combination is summarized in Table 2. Initial combinations added nitrosourea, vinka alkaloids, or platinum compounds to DTIC. The majority of those trials have failed to demonstrate any significant benefit for chemotherapy combination when compared with DTIC, except for a slight increase in response rates [24], [25], [26]. More aggressive multi-agent combinations such as BHD (BCNU, hydroxyurea, and DTIC) and BOLD (bleomycin, vincristine, CCNU, and DTIC) were used and resulted in higher response rates but there was no survival advantage. Legha et al. [27] conducted a phase II study based on the association of cisplatinum, vinblastine and dacarbazine (CVD); they obtained a response rate of 40% including 4% of complete response. However, in a randomized trial on 150 patients comparing CVD to DTIC, the response rate was higher in the CVD arm as compared to the DTIC arm (19% vs 14%), without any differences in either response duration or survival but increased toxicity has been observed [28].

Table 2. Key randomized studies evaluating dacarbazine (DTIC) vs drug combination.

	Control arm dacarbazine dose/schedule	Study arm drugs (dose/schedule)	No. of randomised patients	Overall response (%)	Overall survival (months)	Study by
	2mg/kg/day (I.V.)×10 days	Carmustine 150mg/m2 (I.V.)+vincristine 2mg/m2 (I.V.) on day 1 only	50	22 vs 25	NA	Bellet et al. [103]
	250mg/m2 (I.V.) on days 1–5 every 3 weeks	Cisplatin 20mg/m2/day for 4 days starting on day 2+vinblastine 1.6mg/m2/day×5 days+dacarbazine 800mg/m2 (I.V.) on day 1	104	11 vs 24	5 vs 6	Buzaid et al. [28]
	1000mg/m2 bid short I.V. infusion every 3 weeks	Tamoxifen 10mg twice daily by mouth 1 week before chemotherapy+carmustine 150mg/m2 on day 1+dacarbazine 220mg/m2 (I.V.)+cisplatin 25mg/m2/days 1–3	240	10.2 vs 18.5	6.3 vs 7.7	Chapman et al. [104]
	250mg/m2 (I.V.) for 4 days every 3 weeks	Dacarbazine 250mg/m2 (I.V.) days 1–4 every 3 weeks+detorubicin 120mg/m2 I.V. every 3 weeks	51	15 vs 36	5 vs 6	Chauvergne et al. [105]
	1200mg/m2 day 1 every 3 weeks	Carmustine 150mg/m2 (I.V.) on day 1+cisplatin 25mg/m2 (I.V.)/day on days 1–3+dacarbazine 220mg/m2 (I.V.)/day on days 1–3+tamoxifen 160mg orally/day×7 days prior to chemotherapy. Treatment cycles repeated every 28 days, BCNU every 2 cycles	60	6 vs 26	7 vs 9	Chiarion Sileni et al. [106]
	2.5mg/m2 (I.V.) injection on days 1–4 every 4 weeks	Dacarbazine 2.5mg/m2 (I.V.) by means of bolus injection on days 1–4 every 4 weeks+corynebacterium parvum 7mg (IM) 1 week before starting DTIC and at 4-week intervals thereafter	49	22 vs 27	5 vs 5	Clunie et al. [107]
	250mg/m2 on days 1–5 every 3 weeks	Dacarbazine 250mg/m2 (I.V.)×5 days, every 3-weeks+tamoxifen 20mg/m2 orally daily	117	12 vs 28	11.8 vs 7.25	Cocconi et al. [31]
	200mg/m2 (I.V.) for 5 days repeated every 3 weeks	P.O. Methyl-CCNU 200mg/m2 once every 6 weeks Dacarbazine 150mg/m2 (I.V.)×5 days/3 weeks+P.O. methyl-CCNU 130mg/m21/6 weeks	415	15 vs 15 15 vs 14	4.0 vs 4.2 4.0 vs 4.0	Costanza et al. [108]
	250mg/m2 (I.V.) on days 1–5 every 3 weeks	Dacarbazine 250mg/m2 (I.V.)/day on days 1–5+epirubicin 90mg/m2 on day 1 every 3 weeks	42	9 vs 21	NA	Lopez et al. [109]
	250mg/m2 (I.V.) on days 1–10 every 4 weeks	Vinblastine 6mg/m2/day (I.V.) on days 1–2+24-h infusion of bleomycin 15units/m2 from days 1–5+cisplatin 50mg/m2 1h (I.V.) infusion on day 5. After four courses, vinblastine and cisplatin were given alone. Courses repeated on a cycle of 4 weeks	77	14 vs 10	4.1 vs 3.42	Luikart et al. [110]
	300mg/m2/day×6 days every month days.	Dacarbazine 100mg/m2/8h×6 days every month days Carmustine 150mg/m2+vincristine 2mg/m2 every 30 days	120	32 vs 29 32 vs 24	8.5 vs 8.4 8.5 vs 6.5	Moon et al. [111]
	250mg/m2/day (I.V.) for 5 days every 4 weeks	Dacarbazine 250mg/m2/day (I.V.)×5 days every 4 weeks+vindesine 3mg/m2/week	119	18 vs 25	4.1 vs 5.7	Ringborg et al. [112]
	220mg/m2 on days 1–3, q 21 days	Dacarbazine 220mg/m2 on day 1–3+carboplatine AUC 5, day 1, q 21 days	148	11.7 vs 21.3	7 vs 9	Babovic et al. [113]
	200mg/m2/day (I.V.) for 5 days every 28 days	Arm 2: (I.V.) IFN-α 15MU/m2/day days 1–5×3 weeks, then (SC) 10MU/m2 3×/week+dacarbazine 200mg/m2 daily (IV) days 1–5 starting on day 22, every 28 days Arm 3: orally tamoxifen 20mg/day starting day 1+dacarbazine 200mg/m2/day (I.V.) days 1–5 every 28 days Arm 4: (IV) IFN-α 15MU/m2/day days 1–5×3 weeks, then (SC) 10MU/m2 3×/week+orally tamoxifen 20mg/day starting day 1+dacarbazine 200mg/m2/day (I.V.) days 1–5/28 days	280	15 vs 21 15 vs 18 15 vs 19	9.99 vs 9.33 9.99 vs 7.97 9.99 vs 9.54	Falkson et al. [35]
	800mg/m2 (I.V.) on days 1 and 21	Dacarbazine 800mg/m2 (I.V.) days 1 and 21+daily (IM) INF-α 3MIU at days 1–3, 6MlU days 4–6, and 9MIU daily thereafter. Started concomitantly Dacarbazine 800mg/m2 (I.V.) days 1 and 21+(IM) INF-α 3MIU 3×/week. Started concomitantly	266	20 vs 28 20 vs 23	11 vs 13 11 vs 11	Bajetta et al. [114]
	800mg/m2 (I.V.) every 3 weeks	Dacarbazine (I.V.) escalating dose 200mg/m2, 400mg/m2, 800mg/m2/3 weeks; S.C. IFN-α starting at 3MU/day on days 1–3, 9MU/day on days 4–70, then 9MU 3×/week	170	17 vs 21	7.36 vs 6.27	Thomson et al. [115]

Abbreviation: NA, not available; IFN-α, interferon-alpha.

Preclinical models have supported the idea that high-dose TAM synergized with cisplatin and reversed multi-drug resistance (MDR) [29]. Non-randomized trials of combination chemotherapy that included TAM have produced provocative results attributed to TAM. In a phase II study, Lattanzi et al. [30] reported their experience with the addition of TAM to the three-drug combination regimen of cisplatin, BCNU and DTIC (the Dartmouth regimen); it showed high response rates (55%) with a 20% complete response Since then several randomized clinical trials have been conducted to confirm the therapeutic benefit of TAM in combination with chemotherapy.

Cocconi et al. [31] published a small phase III trial demonstrating an improvement of response (28% vs 12%, p=.03) and survival (48 weeks vs 29 weeks, p=.02) with the addition of tamoxifen to dacarbazine compared to dacarbazine alone. McClay et al. [32], [33] reported a significant reduction in the objective response rate when tamoxifen was omitted from the Dartmouth regimen. However, two large randomized trials with low and high-dose tamoxifen in combination with either dacarbazine alone or the Dartmouth regimen failed to demonstrate an advantage to the addition of tamoxifen [34], [35].

One of the more unexpected developments in recent years is the reported efficacy of the combination of paclitaxel and carboplatin in the treatment of metastatic melanoma. Although originally tested in two small phase II clinical trials and deemed not sufficiently clinically active, recent evidence suggests that the combination of paclitaxel and carboplatin may be worth further consideration [36].

In a meta-analysis comparing two or three-drugs combination regimens with DTIC alone, Huncharek et al. [37] concluded that there was no advantage for the combination in terms of response or survival. Since survival was not improved by the use of single or combination chemotherapy for metastatic melanoma, treatment decisions remain controversial, and quality of life and toxicity issues from treatment assume greater importance.

3. What about immunotherapies? 

The relationship between melanoma and the immune system has been recognized for decades. Case reports of spontaneous tumor regression in patients with metastatic melanoma have suggested that immunotherapy might have a higher impact on the outcome of metastatic melanoma than in other cancers. This has led to intensive studies of immune-based treatment strategies with biologic response modifiers (cytokines) especially interleukin-2 and interferon-α witch have important roles in both adjuvant therapy and treatment of metastatic melanoma [38].

4. Interferon-alpha (IFN-α) 

Several studies have demonstrated that IFN-α has antiproliferative and immunomodulatory effects, including the inhibition of angiogenesis [39], the increase of major histocompatability complex class I antigen expression and the infiltration of CD4+ T cells into melanomas [40]. In a metastatic situation, single agent IFN-α showed approximately 15% of responses with less than 5% of complete response rates and median response duration between 6 and 9 months with a maximum of 12 months for the best studies [41]. These response rates, while encouraging, were not significant enough to lead to its widespread use in the treatment of metastatic melanoma. However, observations that patients with non-visceral disease were more likely to respond suggested that the use of IFN-α may demonstrated a grater impact in patients with micrometastasis [41], [42].

5. Interleukin-2 

Initially, IL-2, a natural product secreted by CD4+ T lymphocytes, was described as a T cell growth factor, which plays a central role in immune regulation. However, IL-2 can also modulate immunological effects by stimulating HLA-restricted or non-restricted cytotoxic cell, activate natural killer cells, B lymphocytes, macrophages and induce lymphokine-activated killer cells in vitro as well as the production of other cytokines [43]. In initial clinical studies, a bolus I.V. infusion of high-dose IL-2 (600.000–720.000IU/kg every 8h on days 1–5 and 15–19) was administered to treat stage IV melanoma. It produced overall response rates in 15–20% of patients with complete responses in 4–6% [44], [45], [46], [47], [48], [49]. Based on the ability of this IL-2 regimen to produce durable responses in a meaningful proportion of patients, the Food and Drug Administration approved high-dose IL-2 therapy for the treatment of patients with unresectable metastatic melanoma in January 1998 and is currently included in the NCCN guidelines for advanced melanoma.

The associated toxicity has been the problem with high-dose IL-2 therapy [44], [45], [48], [49]. This led to the question of whether low-dose IL-2 could be effective in treating stage IV melanoma with fewer side effects than high-dose IL-2. In 25 patients with metastatic renal cell carcinoma or melanoma, Tagliaferri et al. [50] administered low-dose subcutaneous IL-2 (1MIU every 8h for 5 days, followed by a 9-day rest period, for at least six courses). They reported a 33% response rate for renal cell carcinoma but no major responses for metastatic melanoma. The effective dose range administered by intravenous or subcutaneous route is 9–20MIU/m2/day for 4 days. Intermediate-and high-dose continuous infusion schedules (18×106IU/day for 5 days) remain common treatments in Europe and result in comparable objective responses (15–20%) as high-dose bolus IL-2 [51]. Chang and Rosenberg [52] reviewed the results of 371 patients with metastatic melanoma treated with high-dose bolus IL-2 and showed that patients with visceral metastases were less likely to have a response to IL-2 than those with cutaneous or subcutaneous metastases. In a recent systematic review, Petrella et al. [53] suggest that patients with a good performance status (ECOG 0–1), a normal lactate dehydrogenase level, less than three organs involved or cutaneous and/or subcutaneous metastases, have the highest probability of responding and achieving a durable complete response. This carefully selected group of patients should be considered for treatment with high-dose IL-2. This toxic, inpatient regimen is not appropriate for patients with significant comorbidities or compromised performance status and, therefore, is offered to relatively few patients.

Another approach to circumvent the immunomodulatory effects of IL-2 has been to test cytokines that may be more purely immunostimulatory. Clinical trials that involve IL-4 and IL-6 have been disappointing. Investigations with. IL-12 [54], [55], [56] GM-CSF [57] and IL-18 [58], [59] have been more promising. Although sporadic clinical benefits have been reported for some of these agents, none has shown consistent evidence of efficacy. Finally, the experience with tumor necrosis factor-α has been used successfully only in isolated limb perfusion for in transit melanoma of the limbs [60].

6. Combination of IFN-α and IL-2 

Encouraged by the results of the high-dose IL-2 data, efforts have been made to combine IL-2 with IFN-α. This association did not seem to achieve better results (median response rate of 18% with three complete response) than if these agents were given alone [61], [62], [63]. By contrast, in a small randomized phase III trial comparing continuous infusion IL-2 plus interferon vs continuous infusion decrescendo IL-2 plus interferon, Keilholtz et al. [64], demonstrated improved response rates and reduced toxicity with decrescendo dosing. This is now the standard dosing schedule for incorporation of IL-2 in biochemotherapy regimens in Europe. After preclinical data suggesting that histamine enhances the antitumor response of IL-2 [65], additional clinical trials investigated the addition of histamine dihydrochloride (HDC, Celpene) to low-dose IL-2 on an outpatient basis. In a phase III trial, in which 305 patients with advanced metastatic melanoma were randomized to IL-2 (9MIU/m2 bid SC on days 1–2 of weeks 1 and 3, and 2MIU/m2 bid SC on days 1–5 of weeks 2 and 4) with or without histamine (1.0mg bid SC days 1–5, weeks 1–4), the overall survival reported was not different between the two arms. However, the subgroup of patients with liver metastases demonstrated significant improvement in survival with IL-2/histamine compared with IL-2 alone [22]. A confirmatory phase III trial focusing only on patients with liver metastasis failed to confirm this result. Middleton et al [66] evaluated the safety and efficacy of combining IL-2, INF-α2b and histamine dihydrochloride vs dacarbazine in 241 patients with stage IV melanoma. They showed that treatment with HDC/IL-2/IFN was safely administered on an outpatient basis without any improvement on the response rate and overall survival seen with DTIC.

In summary, the results seen with immunotherapy are not better than those with chemotherapy. However a positive trend for complete response rates and the possibility of maintained remissions after immunotherapy seem to argue in favor of this treatment modality for further developments.

7. Moving on to biochemotherapy 

Because chemotherapy and cytokines have different and perhaps synergistic mechanisms of action and in order to improve response rates and durable remissions, several teams including our group developed in the early 1990s the concept of biochemotherapy, a combination of chemotherapy and biologic response modifiers [67], [68], [69], [70], [71], [72], [73], [74]. A listing of major randomized studies of biochemotherapy is summarized in Table 3.

Table 3. Randomized studies evaluating biochemotherapy.

	Trial regimen	No. of randomized patients	Overall response (%)	Overall survival (months)	Study by
	Arm A: CDDP (20mg/m2/day)+VLB (1.2mg/m2/day, days 1–4)+DTIC (800mg/m2 day 1 only)	201	11	8.7	Atkins et al. [116]
	Arm B: Same scheme+cont. I.V. IL-2 (9MIU/m2/day, days 1–4)+sc IFN-α (5MIU/m2/day, days 1–5, 8, 10, 12). Cycles repeated at 21-d intervals for a maximum of four cycles	204	17	8.4
	Arm A: CDDP (35mg/m2 days 1–3)+BCNU (150mg/m2 at day 1 cycles 1 and 3 only)+DTIC (220mg/m2 days 1–3)+oral TAM (20mg/m2 daily)	60	34.3	13	Atzpodien et al. [117]
	Arm B: Same scheme+S.C. IL-2 (10MIU/m2 days 3–5, week 4); 5MIU/m2 days 1, 3, 5, week 5)+S.C. IFN-α (5MIU/m2, day 1, week 4; days 1, 3, 5, week 5)	64	29.9	12
	Arm A: CDDP (30mg/m2 days 1–3)+VDS (2.5mg/m2 on day 1)+250mg/m2 days 1–3)	75	21	12	Bajetta et al. [118]
	Arm B: Same scheme+S.C. IFN-α2b (5MU/m2/day days 1–5)+S.C. IL-2 (9MIU/day days 1–5 and 8–15, every 3 weeks treatment repeated every 21 days×6 cycles	76	23	11
	Arm A: CDDP (100mg/m2+IL-2 (18MIU/m2 on days 3–6 and 17–21) after 3-day rest period	57	16	10.4	Dorval et al. [119]
	Arm B: Same scheme+S.C. IFN-α (9MIU/m2 3× a week) during IL-2 administration	60	25	10.9
	Arm A: CDDP (20mg/m2 days 1–4 and 22–25)+VLB (2mg/m2 days 1–4 and 22–25)+DTIC (800mg/m2 on days 1 and 22)	92	25	9.5	Eton et al. [76]
	Arm B: Same regimen except VLB dose 1.5mg/m2+24-h C.I. IL-2 (9MIU/m2 days 5–8, 17–20 and 26–29)+S.C. IFN-α2b (5MU/m2 days 5–9, 17–21 and 26–30)	91	48	11.8
	Arm A: DTIC (850mg/m2 every 28 days)+IFN-α2a/b (3MIU/m2 twice day 1, 1/day days 2–5; 5MIU/m2 3× a week from weeks 2–4)	144	18.1	11	Hauschild et al. [120]
	ARM B: Same regimen+I.V. IL-2 (4.5MIU/m2×3h day 3; 9MIU/m2 days 3–4; S.C. 4.5MIU/m2 days 4–7)	137	16.1	11
	Arm A: Decrescendo regimen on days 3–8 of H.D. IL-2 (18MIU/m2/6h, 18MIU/m2/12h, 18MIU/m2/24h and 4.5MIU/m2/24h×3)+S.C. IFN-α (10MU/m2 days 1–5)	66	18	9	Keilholz et al. [64]
	Arm B: Same regimen+CDDP100mg/m2 on day 1	60	35	9
	Arm A: CDDP 30mg/m2 on days 1–3+DTIC 250mg/m2+S.C. IFN-α2b 10MU/m2 days 1–5	180	23	9	Keilholz et al. [121]
	Arm B: Same regimen+decrescendo regimen H.D. I.V. IL-2 on days 5–10 (18MIU/m2/6h, 18MIU/m2/12h, 18MIU/m2/24h, andMIU/m2 for 3× 24h)	183	21	9
	Arm A: I.V. CDDP (75mg/m2)+I.V. DTIC (800mg/m2)+optionally I.V. BCNU (100mg/m2 at day 1)	89	20.2	9.5	Ridolfi et al. [122]
	Arm B: Same regimen+S.C. IL-2 (4.5MIU/m2 days 3–5 and days 8–12)+I.M. IFN-α2b (3MIU days 3 and 5 and thereafter 3×/week. Treatment repeated every 21 days×6 cycles	87	25.3	11
	Arm A: Orally TAM (40mg day 1, 10mg days 2–29)+CDDP (25mg/m2 I.V. over 30m+DTIC 220mg/m2 I.V. over 1h at days 2–4 and 23–25)	52	27	15.8	Rosenberg et al. [123]
	Arm B: Same regimen+S.C. IFN-α2b (6MIU/m2 days 5 and 26×4)+IL-2 (7.2MIU/15min every 8h)	50	44	10.7

Abbreviation: DTIC, dacarbazine; IFN-α, interferon-alpha; IL-2, interleukin 2, BCNU, carmustine; CDDP, cisplatin; TAM, tamoxifen VLB, vinblastine; VDS, vindezine; S.C., subcutaneous, I.V., intravenously; I.M., intramuscularly; H.D., high-dose; C.I., continuous infusion.

Dacarbazine/IFN-α combinations are one of the most evaluated combinations in metastatic malignant melanoma. In a randomized phase II trial, Falkson et al. [75] reported that the association of IFN-α to dacarbazine resulted in an encouraging response rate (53% vs 20% for dacarbazine alone) and a higher duration of response (8.9 months vs 2.5 months) but IFN significantly increased the toxicity. However, a follow-up of a large randomized trial demonstrated no benefit for the addition of IFN to dacarbazine and significantly more severe toxic events occurred with treatments that contained IFN [35]. As with IFN-α, dacarbazine/IL-2 combination was also tested in melanoma but no clinical benefit was demonstrated for this association [37].

The other approaches of biochemotherapy have involved either sequential chemotherapy (cisplatin, vinblastine, and dacarbazine, CVD) followed by biologic response modifiers (continuous infusion of 9MIU/m2 of IL-2+IFN-α) because of concern of toxicity if all the drugs were given simultaneously or concurrent chemoimmunotherapy. Both approaches have produced promising results with overall response rates between 40% and 60% and a long-term remission rate of about 9%. The sequential approach was compared to chemotherapy alone in a randomized trial conducted at the MD Anderson Cancer Center. Although response rate and time to progression were improved in the sequential biochemotherapy group, the survival difference was at borderline significance and toxicity was very high [76]. In an effort to maintain IL-2 dose intensity and decrease toxicity, Legha et al. [77] developed the first concurrent biochemotherapy regimen. The “Legha” regimen combined cisplatin, vinblastine, and dacarbazine (CVD) chemotherapy with continuous infusion IL-2 (9MU/m2/day×4 days) and 5 days of subcutaneous INF-α (5MU/m2/day) at 21-day intervals. The results were encouraging with an overall response rate of 64%, a complete response rate of 21%, a median survival of 12 months, and a 2-year survival rate of 10%. Efficacy was comparable to the sequential regimen with significantly lower toxicity. In a phase II trial of poor prognosis stage IV patients, the same total dose of IL-2 reported by Legha was given but in a front-loading decrescendo schedule (18MU/m2 on day 1, 9MU/m2 on day 2, and 4.5MU/m2 on days 3 and 4); the results indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate or median survival in patients with poor prognosis metastatic melanoma [73].

The recent results of the largest phase III trial (ECOG/Intergroup E3695 trial) and most definitive test for biochemotherapy comparing concurrent CVD-Bio to CVD alone showed that biochemotherapy produced slightly higher response rates and significantly longer median progression-free survival than CVD alone, but once again failed to show any improvement in either overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent biochemotherapy regimen cannot be recommended for patients with metastatic melanoma [78].

Recently, two meta-analysis [79], [80] from 18 randomized trials on more than 2625 patients showed an increase of objective response rates in patients treated by biochemotherapy as compared to chemotherapy. Nevertheless, the impact of these increased response rates was not translated into a survival benefit. Additionally, an increase of hematological and non-hematological toxicities in people treated with biochemotherapy was observed.

Patients who achieve remission after intensive biochemotherapy regimens relapsed after a median time to progression lower than 6 months. In an attempt to maintain these remissions and prevent rapid disease progression, one strategy has been the use of maintenance biotherapy after “induction” biochemotherapy. In a pilot study, 33 patients with metastatic melanoma who achieved a partial response or stable disease to induction biochemotherapy were treated with chronic S.C. low-dose IL-2 and granulocyte macrophage–colony stimulating factor (GMCSF) along with pulses of decrescendo continuous infusion IL-2; objective complete responses were observed in a small group of patients who achieved a partial response to biochemotherapy. Overall survival was prolonged compared with matched historical controls not treated with maintenance therapy [81]. The conclusion from that and from all randomized trials of biochemotherapy performed to date was that biochemotherapy should not be used routinely outside of a clinical trial. However, biochemotherapy may be useful in symptomatic patients with rapidly progressive disease to provide symptomatic relief if high-dose IL-2 is not an option.

8. Investigational and new agents 

A number of new agents and combination have entered clinical trials with promising results in melanoma and we will resume some of them; lenalidomide (initially known as CC-5013; ImiDS or Revlimid) is a thalidomide derivative designed to be more effective and less toxic. In a phase I trial, it was found to be well tolerated in patients with metastatic melanoma and to produce immune activation [82]. Two randomized phase III trials of lenalidomide in patients with metastatic melanoma who had failed first-line therapy were initiated. Both trials were negative; in the US, there was no difference in outcome between patients who received high-dose vs low-dose of lenalidomide and in Europe there was no difference in outcome between patients who received lenalidomide and those who received placebo. On the basis of this information, thalidomide has been combined with temozolomide chemotherapy in patients with melanoma. Hwu et al. [83], [84], in a single-center study involving patients with stage IV melanoma with or without brain metastases reported response rates as high as 30% for the thalidomide and temozolomide combination. However, the SO508 trial has not confirmed these encouraging results with a response rate of 14%, and all the responses were partial [85].

The renewed interest in taxanes for the treatment of melanoma has resulted in a number of novel taxanes such as ABI-007 which is an albumin-bound nanoparticle formulation of paclitaxel with an improved therapeutic index. ABI-007 has been tested in a phase II trial in 37 previously treated and chemotherapy-naive patients with metastatic melanoma and produced more than 30% of overall response rate [86].

Another agent of interest that has shown promises is Sorafenib (BAY 43-9006) a small molecule, multi-tyrosine kinase inhibitor with in vitro activity against BRAF, which is in advanced clinical trials for metastatic melanoma therapy. Sorafenib is orally available and has been shown to be well tolerated in phase I trials [87], [88]. In a phase II randomized discontinuation trial, 39 patients with metastatic melanoma were treated with Sorafenib at 400mg bid orally. The drug was well tolerated with a 3% partial response, 16% of stable disease and a median progression-free survival of 2.8 months [89]. These disappointing results with single agent provided the rationale for combining sorafenib with cytotoxic chemotherapy. The first trial to test this concept in 35 metastatic melanoma patients was a large phase I/II trial of carboplatin, paclitaxel, and sorafenib. The preliminary results showed 27% of PR and 58% of SD observed mainly in patients with skin, subcutaneous, lymph node metastases (stage M1a) and a limited number of previous therapies but the antitumor activity was independent of b-raf mutational status [90]. These results were encouraging and provided the necessary evidence to launch a phase III trial investigating the efficacy of paclitaxel plus carboplatin with or without sorafenib but it did not show any benefit in terms of PFS or objective responses as second-line treatment in patients with advanced melanoma [91].

To determine if a more tolerable chemotherapy regimen could be substituted for carboplatin and paclitaxel with similar results, a phase II trial evaluating the combination of DTIC and sorafenib or temozolomide and sorafenib have been undertaken. The combination of DTIC and sorafenib was tested in a phase II open-label, first-line, uncontrolled study as well as a phase II randomized placebo-controlled study in patients with unresectable stage III or IV melanoma. In the uncontrolled phase II study, sorafenib and DTIC were well tolerated and showed a promising efficacy (10% PR and 41% SD) with a median PFS and OS of (14 and 41 weeks). These data are encouraging, compared with DTIC alone which achieved a response rate of 7.5% and a PFS time of 6 weeks) [92]. Results from a placebo-controlled study support a better efficacy trend in terms of objective responses and PFS compared with DTIC alone in advanced melanoma. The median PFS times were 21.1 weeks vs 11.7 weeks for sorafenib in combination with DTIC compared with DTIC plus placebo, respectively [93].

Preliminary results of the phase II trial of temozolomide and sorafenib confirmed the phase I/II experience with carboplatin, paclitaxel, and sorafenib, as observed response rates and progression-free survival were improved compared to previously reported outcomes for temozolomide alone but this combination is especially promising in patients with brain metastases, for which limited therapeutic options are available [94].

RAD-001 (everolimus) is an oral inhibitor of mTOR. mTOR is a serine threonine kinase that effectively regulates the production of VEGF, cell growth and proliferation. In a phase II study with RAD-001 [95], after the first planned interim analysis in 20 patients, there were no objective responses but 35% had stable disease. While the results of this study are negative, a subset of patients appeared to have slight benefit.

The anti Bcl-2 antisense (Oblimersen) is another agent tested in metastatic melanoma [96]. In a large phase III trial of Bcl-2 antisense in combination with dacarbazine compared with dacarbazine alone there was an increase in response rate (13.5% vs 7.5%) and a small improvement in PFS (2.6 months vs 1.6 months) but no significant improvement in overall survival. The subset of patients who seemed to benefit had a normal or low lactate dehydrogenase [97]. These data support the idea that Bcl-2 antisense has at least modest activity when it is combined with DTIC and justify further studies of this compound and similar strategies to overcome drug resistance in metastatic melanoma.

MEDI-522 is a humanized monoclonal antibody directed against the αVβ3 integrin, is highly expressed in melanomas and is associated with tumor growth. In a phase II trial, 112 patients with metastatic melanoma were randomized to either MEDI-522 alone or MEDI-522 with dacarbazine chemotherapy. MEDI-522 with or without DTIC generally was well tolerated and active. Although a few patients receiving MEDI-522 and dacarbazine exhibited tumor responses, no objective responses with MEDI-522 alone occurred. Progression-free survival was short in both arms but better in the combination arm. Most unexpected was the finding that patients treated with MEDI-522 alone had a median survival longer (>12 months) than the combined arm. These results remain to be determined and might be related to a selection bias or a delayed effect of the therapy on survival alone [98]. Those results provided the impetus to evaluate single agent MEDI-522 in a confirmatory phase III trial in patients with metastatic melanoma.

Last but certainly not least, another noteworthy agent is a monoclonal antibody anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4). This antibody had the effects of “taking the brakes off” the immune system thereby causing enhancement of the patient's immune responses to the tumor [99]. Currently, there are two fully human anti-CTLA-4 monoclonal antibodies undergoing advanced testing. A very small difference between the two products exists. Ipilimumab (BMS/Medarex) is an IgG1 isotype and fixes the complement and tremelimumab (Pfizer) is an IgG2 isotype and does not fix the complement. Ipilimumab has been evaluated in three phase II studies. One of the studies [100] did not meet its primary end point, which was to rule out a best objective response rate of less than 10%. Nevertheless, other data from the three studies suggested a clear dose–response effect and a unique pattern of responses [100], [101], [102]. These data are particularly important when we compared the usual median overall survival (6–9 months) to a 1-year survival rate of 25–35% for patients with stage 3 or 4 metastatic melanoma. A phase 3 trial of melanoma comparing dacarbazine alone with combination ipilimumab and dacarbazine is currently in progress.

In summary, the first generation of targeted therapies opened new possibilities for the treatment of metastatic melanoma, however to date no targeted therapy has yielded promise as a single agent. While the response rate is low, this class of agents appears to induce a proliferative arrest in cancer growth, stabilizing the disease over time. Added to this, the relatively favorable side-effect profile and the ease of administration (oral) make them attractive agents for combination chemotherapy.

9. Take home message 

Metastatic melanoma has remained refractory to systemic treatment for decades. It is hoped that the therapeutic strategies for the patients with metastatic melanoma is entering a new era of exploration in the hope of identifying better therapies. To date, there are no markers that can help to evaluate which patients will or will not respond to any of the treatments available. Nevertheless, we are still faced with the need to make choices for care today. We should first consider participation in a clinical trial for appropriate patients. When there are limited sites of metastases and the clinical situation permits it, a surgical approach (metastatectomy) is offered. This approach is based on case series, which suggest that a subset of patients who undergo metastatectomy have a prolonged survival. For younger patients with good cardiopulmonary, renal, and liver function, single agent high-dose IL-2 therapy is considered. For older patients, and those with slow growing disease, single agent chemotherapy with DTIC, FTMU, or TMZ is reasonable. If there is a rapid progression of disease and significant cancer-related symptoms, the use of combination chemotherapy or biochemotherapy is considered. Once a first-line therapy has failed, secondary treatments can be considered. Again, participation in a clinical trial is reasonable including use of new agents in phase I trials.

In conclusion, the treatment of patients with advanced melanoma remains disappointing. Single agent or combination chemotherapy or new agents or biologic response modifiers alone have not resulted in response rates of durable remissions that are high enough to affect median survival. Despite encouraging data from phase II trials, no agent or regimen has yet shown improvement in overall survival in phase III trials. There is an urgent need for more effective single agents and to develop new innovative treatment options, which, either alone or in combination, will achieve more significant impact on this disease. Many current opportunities exist for improving the treatment of patients with melanoma, including novel immunotherapy approaches, molecularly targeted and antiangiogenic therapies, and efforts to select treatments for patients based on tumor and host molecular and genetic features. In particular, efforts should focus on enhancing the individual treatment strategies and defining the subsets of patients and tumors most likely to benefit. Clinical trials are actively evaluating novel molecules. Combinations of these new agents will likely be necessary to progress in the treatment of the disease.

Conflict of interest 

The authors declare no conflict of interest with this paper is to be disclosed.

Reviewers 

Prof. Alexander M.M. Eggermont, University Hospital Rotterdam, Department of Surgical Oncology, 301 Groene Hilledijk, NL-3075 EA Rotterdam, Netherlands.

Prof. Olivier Michielin & Dr. Roger Stupp, University of Lausanne/CHUV, CH-1011 Lausanne, Switzerland.