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Long-term survivors in stage IV melanoma: a regional population-based study in France

European Journal of Dermatology. Volume 19, Number 1, 38-43, January-February 2009, Clincial report

DOI : 10.1684/ejd.2008.0569

Summary

Author(s) : Tatiana Tchen, Fabienne Léonard, Christian Derancourt, Géraldine Perceau, Céline Goutorbe, Ziad Reguiaï, Philippe Bernard, Florent Grange , Department of Dermatology, Hôpital Robert Debré, Avenue du Général Koenig, Reims 51100, France, Department of Dermatologie, Hôpital Pierre Zobda Quitman, BP 632, 97261 Fort de France Cedex, Martinique.

Summary : We aimed to better characterize exceptional cases of long survivors (LSs) among patients with stage IV melanoma. We performed a comprehensive regional investigation in the Champagne-Ardenne region, France. During the period 1994-2003, 316 patients died of melanoma whereas 10 patients diagnosed with distant metastases had a subsequent survival time > 4 years. These 10 LSs were characterized by a long delay (median: 58 months) prior to distant metastases and by frequent subsequent complete remissions (CRs). Eighteen episodes of CRs, lasting 3-139 months (mean: 26.4), were documented in 9 patients, for single or multiple tumors, for metastases of any site and with any treatment, even including spontaneous CRs. Four of 8 evaluable patients had clinical and/or biological features of auto-immunity. At 31 March 2007, 3 patients had died of melanoma and 1 of a chemo-induced leukaemia. The median survival time was 65 months (range: 52-139). These data suggest that long survival in stage IV melanoma might depend less on the site of metastases and specific therapies than on the patients themselves and their spontaneous antitumor control.

Keywords : long-term survivors, stage IV melanoma

ARTICLE

Auteur(s) : Tatiana Tchen¹, Fabienne Léonard¹, Christian Derancourt^1,2, Géraldine Perceau¹, Céline Goutorbe¹, Ziad Reguiaï¹, Philippe Bernard¹, Florent Grange Florent Grange¹

¹Department of Dermatology, Hôpital Robert Debré, Avenue du Général Koenig, Reims 51100, France
²Department of Dermatologie, Hôpital Pierre Zobda Quitman, BP 632, 97261 Fort de France Cedex, Martinique

accepté le 12 Août 2008

Stage IV melanoma was defined in the 6th edition of the American Joint Committee on Cancer (AJCC) by the presence of distant metastases [1]. The prognosis is poor, with a median survival time of 6 to 8 months [2]. However, there are rare cases of patients with unusual long-term survival. These patients, referred to as long survivors (LSs), have been reported in studies with various designs. Most reports derive from phase 2 clinical trials [3-7], in which investigators often base their arguments on a few LSs to emphasize the possible efficacy of assessed therapies. However, such hypotheses have rarely been confirmed in randomized trials and the role of specific therapies in long-term survival remains uncertain. In observational studies of a large number of patients with stage IV melanoma, 10 patients out of 635 (1.6%) [8], 5 out of 153 (3.3%) [9], and 10 out of 503 (2%) [10] were found to be alive 5 years after entering stage IV.

Lastly, survival analyses using the Kaplan-Meier method were performed in reference center-based large series of patients with stage IV melanoma. These studies reported survival rates of 8% at 1 year [11], 11% at 2 years [12] and 6 to 7% at 5 years [2, 13]. In one of the larger studies to date, Balch et al. evaluated the 5-year survival rate of 1158 patients with stage IV melanoma at around 10%. In this study, the site of distant metastases and the lactic dehydrogenase level were found to have significant value in predicting survival.

Although these earlier studies provide different evaluations of the proportion of LSs among patients with stage IV melanoma referred to reference centers, details of the clinical histories of these exceptional cases are often lacking and few studies have been performed on a population basis. Our aim was to identify LSs among patients with stage IV melanoma living in a defined geographic region over a specific period of time, to evaluate their clinical history, spontaneous evolution and responses to various therapies, and to find out their possible clinical and biological characteristics.

Materials and methods

Geographical setting

The study was performed in the French region of Champagne-Ardenne, which covers 25,606 km² and has 1.4 million inhabitants. This region comprises 59 dermatologists, 1 university hospital and 1 regional cancer center. Most patients with metastatic melanoma are referred to the dermatology department of the university hospital (Reims), but some of them may be referred to the regional cancer center or to non-university hospitals.

The crude incidence of melanoma in Champagne-Ardenne was punctually estimated at around 13/100,000 in 1998 [14] but more accurate and long-term assessments are not available due to the absence of cancer registries. Data on mortality, however are available through exhaustive reviewing of death certificates (Center of Epidemiology on Medical Causes of death, Inserm) [15]. Between 1 January 1994 and 31 December 2003, 316 deaths related to melanoma were reported in the Champagne-Ardenne region, in 170 male and 146 female patients, respectively. Our aim was i) to identify patients in this region who had developed a stage IV disease during this 10-year period and had a subsequent survival time of 4 years or longer, and ii) to study their characteristics, clinical history and outcome.

Pre-selection and inclusion

Eligible cases were first screened using a survey of private and hospital dermatologists working in the region or in nearby surroundings. All of them were asked in two mail surveys, in April 2006 and May 2007, to report anonymously any patient with distant metastases of melanoma diagnosed since 1 January 1994, who had a subsequent unusual, prolonged survival time. Oncologists at the regional cancer center were also questioned. In addition, a database of patients with stage IV melanoma identified in the department of dermatology of the regional university hospital (Robert Debré Hospital, Reims) was reviewed. When patients with stage IV melanoma diagnosed in the study region were identified as possible long survivors, their clinical data, pathological reports and imaging studies were reviewed in detail. Those who satisfied the following criteria were included in this report:

1) Visceral and/or distant metastases of melanoma (AJCC stage IV) occurring within the study period irrespective of previous history.
2) Clinical evidence or histological confirmation of distant metastases.
3) Survival time of 4 years or longer after diagnosis of stage IV disease.

Patients with uncertain stage IV melanoma and/or suspicion of distant metastases on imaging studies without histological assessment were excluded.

Data collection

The following data were anonymously collected using standardized data forms: age; sex; characteristics of the primary melanoma and initial surgical and adjuvant therapies; occurrence of regional/stage III disease with site of metastases and therapies; date of entering stage IV, number and location of metastases; and further clinical history. Clinical data recorded during stage IV disease included successive therapies, remissions, recurrences with number and sites of metastases, occurrence of vitiligo, final status at 31 March 2007 and date and cause of death.

Complete remissions (CRs) were defined by the absence of any detectable disease on clinical examination and appropriate imaging studies (most often Computed Tomography (CT) scans), lasting for at least 3 months. In addition, patients alive in June 2006 were investigated for biological features of auto-immunity, i.e. antithyroid, anticardiolipin and antinuclear antibodies. Blood samples were tested by enzyme-linked immunosorbent assays. A positive result was defined as a titration of greater than 1/100 for antinuclear antibodies, > 150 UI/mL for antithyroid antibodies, > 15 U GPL for Ig G anticardiolipin antibodies.

Follow-up and statistical analysis

All patients were followed until death or until 31 March 2007. Survival times until death or censoring (31 March 2007) were calculated from first melanoma diagnosis, and from diagnosis of stage IV disease. Means and medians were calculated using Microsoft Excel.

Results

Ten patients met the inclusion criteria. Five were primarily notified by hospital dermatologists, 2 by private dermatologists, and 3 were identified both by private and hospital dermatologists. Eight were followed at the regional university hospital of Reims and 2 at a private clinic. None was followed at the regional cancer center or at non-university hospitals.

These 10 LSs represent 3.5% of the 316 patients who died of melanoma in the Champagne-Ardenne region during the 10-year study period.

We first present the detailed clinical history of 3 patients and then summarize the data in the entire series (tables 1 and 2).

Case reports

Patient 1: a 72-year-old woman underwent amputation of the right thumb for an achromic melanoma associated with satellite metastases. A CT-scan evaluation revealed a hepatic nodule 2 cm in diameter, suggestive of an isolated metastasis in the segment III of the liver. A hepatic needle aspiration showed a proliferation of tumor cells of various sizes with hyperchromatic and irregular nuclei and a positive HMB45 staining. A hepatic lobectomy was therefore proposed, but only performed two months later. Surprisingly, the histological analysis only revealed a cicatricial tissue with fibrosis, small lymphocytes, and numerous macrophages containing abundant melanin as assessed by Fontana staining. Tumor cells were not present and Protein S100 and HMB45 immunostainings were negative. Further regular CT-scan examinations were negative, until two pulmonary nodules of < 5 mm in diameter were reported 2 years later by the radiologist as possibly due to melanoma. They spontaneously disappeared, however, without any treatment within 18 months. The patient was alive without evidence of disease 80 months after stage IV diagnosis.

Patient 4: a 62-year-old woman was treated for a thick nodular melanoma of the right leg with regional lymph node metastases. She successively underwent an excision of the primary tumor, two regimens of cisplatin and dacarbazin and a complete lymph node dissection. She presented with a contra-lateral dissemination 18 months later, including a tumor of the left buttock, and metastases of iliac lymph nodes and the iliac bone. A treatment with 9 infusions of fotemustin and/or dacarbazin followed by radiotherapy resulted in a slow regression of all detectable disease within 10 months, as she developed a progressive vitiligo. She was alive without evidence of disease 60 months after the diagnosis of stage IV disease.

Patient 6: a 45-year-old man with no known history of melanoma underwent two pulmonary lobectomies at 4 months’ interval for isolated tumors of both lungs. The diagnosis of carcinoma and sarcoma were discussed on histological examination, without definitive conclusion. He presented 1 year later with acute abdominal pains due to intra-abdominal metastases. A large surgical resection was performed, including duodenopancreatectomy, splenectomy, cholecystectomy and total colectomy. Immunohistochemical examination revealed duodenal and multiple latero-aortic lymph node metastases of melanoma. A comprehensive immunohistochemical review of previous lung tumors also concluded to melanoma, with Protein S100 and HMB45 positive tumor cells identical to those observed in the duodenum and nodes. Further regular clinical and CT-scan examinations were negative for 3 years, when small pulmonary and abdominal images were reported by the radiologist to be suggestive of lung and node metastases, before they spontaneously disappeared within 3 months. The patient received 3 infusions of dacarbazin at this time. He was alive without detectable disease 41 months after the diagnosis of lung tumors.
Table 1 Clinical history and outcome in 10 long-term survivors with stage IV melanoma

Patient	Age at diagnosis of stage IV	Sex	Primary melanoma^a	Time from melanoma diagnosis to stage IV (months)	Previous nodal/stage III disease	Sites of metastases at stage IV diagnosis	Further sites of metastases	Successive therapies	Auto-immunity	Last status	Survival time (months) since stage IV diagnosis
1	72	F	ALM, achromic, thumb	2	No	Liver (1)	Lung (3)		Ac antinuclear Ac anticardiolipin	CR	80
2	70	M	LMM, 5 mm, head	66	No	Intestin (1)	Skin (2) Bone (multiple) Lung (multiple) Brain (multiple) Intestine (1)	S + Chem + RT + IF + IL-2	ND	Dm	54
3	40	F	Nodular, 4.6 mm, ulcerated, forearm	105	No	Brain (1)		S + Chem	ND	Dother	139
4	61	F	Nodular, 4 mm, leg	6	Yes	Muscle (1) Bone (1) Lymph node (1)		Chem + RT	Vitiligo	CR	60
5	36	F	Nodular, 7 mm, head	133	Yes	Liver (1)	Brain (1) Liver (multiple) Skin (multiple)	S + Chem + RT + dendritic cells	ND	Dm	52
6	45	M	Unknown primary	0	No	Lung (2)	Intestin (1) Lymph node (multiple) Lung (multiple)	S + Chem	Absence	CR	70
7	69	F	Nodular, 4.85 mm, leg	28	Yes	Skin (2)	Lung (multiple) Skin (multiple) Liver (multiple) Brain (multiple)	S + Chem + dendritic cells	ND	Dm	77
8	54	M	SSM, 1.32 mm, trunk	192	Yes	Lung (4)	Lung (multiple) Liver (multiple) Bone (multiple) Skin (multiple)	S + Chem + vaccination	Ac antinuclear Ac antithyroglobulin Ac antimicrosomal	M+	70
9	57	M	ALM, 6 mm, foot	35	Yes	Lung (multiple)		Chem	ND	Dother	47
10	52	F	ALM, 1.8 mm, thumb	58	No	Lung (1)	Adrenal gland (1)	S	Ac anticardiolipin	CR	55

^anumber in mm refers to Bresloww thickness.

Table 2 Complete remissions (CR) in 10 long-term survivors with stage IV melanoma

Patient	Complete remission (CR)	Site of regressive metastases	Treatment before remission	Duration of CR (months)
1	CR1	Liver	No treatment	24
	CR2	Lung (uncertain)	No treatment	36
2	CR1	Intestin	S+Chem (DTIC + Eldesin)+IF	5
	CR2	Skin	S	10
	CR3	Bone	Chem (Fote + Cisplatin)+RT	11
	CR4	Pancreas	S+Chem (Fote + DTIC+Eldesin)	14
3	CR1	Brain	S+Chem (Fote)	139
4	CR1	Bone	RT+Chem (DTIC + Fote)	44
		Lymph node
		Muscle
5	CR1	Liver	S+chem (Fote)	3
	CR2	Brain	RT+Chem (DTIC + Fote)	28
6	CR1	Lung	S	11
	CR2	Intestin	S	34
		Lymph node
	CR3	Lung	No treatment	19
		Lymph node
7	CR1	Skin	S	21
	CR2	Lung	Chem (DTIC)	18
8	CR1	Lung	S	6
9	No CR
10	CR1	Lung	S	45
	CR2	Adrenal gland	S	7

Data in the entire series

Patients were four males and six females, aged from 36 to 72 years (mean: 56; median: 52) at the diagnosis of stage IV melanoma. Nine patients had been treated for a primary melanoma 2 to 192 months (median: 58; mean: 69.4) before the occurrence of distant metastases. The mean Breslow thickness of the primary melanoma was 4.3 mm. Two patients had satellite metastases at primary diagnosis and 3 had nodal regional metastases at first diagnosis. The AJCC stage at diagnosis was Ib, IIb, IIc, IIIb and IIIc in 2, 1, 1, 3 and 2 cases, respectively. Overall, regional lymph node metastases occurred in 5 patients 6 to 133 months (median: 27; mean: 42.2) before evolution into stage IV. The other 5 patients evolved directly from local stage to distant metastases (4 cases) or entered their disease with visceral metastases (Patient 6).

Sites and number of metastases at stage IV diagnosis are shown in table 1. Histological confirmation of distant metastases was obtained in all cases except in patient 4, who had clinical evidence of dissemination. All but 1 patient had only 1 metastatic site. Five patients had a single detectable metastasis and 5 had multiple ones. The AJCC stage IV at diagnosis was M1a, M1b and M1c in 1, 4 and 5 cases respectively. Initial therapies after diagnosis of stage IV disease were surgery; surgery and chemotherapy; surgery, chemotherapy and interferon; chemotherapy alone; and chemotherapy and radiotherapy in 4, 2, 1, 1 and 1 cases, respectively. Further metastatic sites and therapies during the course of the disease are summarized in table 1.

Patient 9 never achieved a CR and had a stable disease under maintenance chemotherapy until he died of acute leukaemia 55 months after diagnosis of lung metastases. The other 9 patients had 1 to 4 (median: 2) apparent CRs during the course of their disease. A total of 18 probable CRs was documented in the entire series (table 2). CRs occurred for single metastasis in 8 cases and for multiple metastases in 10 cases. Sites of regressive metastases included the lung (6), liver (2), skin (2), small intestine (2), bones (2), pancreas (1), brain (2), lymph nodes (3), muscles (1) and adrenal gland (1).

Treatments leading to CRs were of any type, including surgery alone (7 cases); surgery and chemotherapy (3 cases); surgery, chemotherapy and interferon (1 case); chemotherapy alone (1 case); radiotherapy and chemotherapy (2 cases); and radiotherapy alone (1 case). Three apparent CRs occurred spontaneously. Patient 1 had a spontaneous regression of a histologically confirmed hepatic metastasis. The last 2 spontaneous CRs (patients 1 and 6) remain uncertain because they only concerned small suspicious images detected on systematic CT-scans without histological confirmation. The duration of CRs varied from 3 months to 139 months (mean: 26.4).

Three patients developed another cancer after the diagnosis of stage IV melanoma. Patient 9 died of a possibly chemo-induced acute leukaemia, after having received a total of 10 infusions of dacarbazine and 16 infusions of fotemustin. Patient 7 was treated for breast cancer but finally died of melanoma. Patient 3 had a lung epidermoid carcinoma and achieved a CR of both malignancies but finally died of a heart attack 11.5 years after stage IV melanoma diagnosis.

At the end point on 31 March 2007, 4 patients were alive without disease, 1 had a progressive disease, 3 had died of melanoma and 2 had died of other causes. The survival time from the diagnosis of stage IV disease varied from 52 to 139 months (mean: 70.4; median: 65). The survival time from the first diagnosis of melanoma varied from 66 to 262 months (mean: 132.9; median: 109).

Results of auto-immune investigation are shown in table 1. Overall, 4 of 8 patients still alive in June 2006 had clinical or biological features of auto-immunity.

Discussion

Few patients with stage IV melanoma have prolonged survival. During a 10-year study period in a region covering 1.4 million inhabitants, we identified 10 patients with a survival time of 4 years or longer. Within the same period, 316 patients died of melanoma. This ratio of 3.5% is similar to that observed in most clinical trials in stage IV melanoma with a long follow-up time [8-10], but lower than the 5 to 10% observed in some retrospective series [11-13]. This may be explained by the strict inclusion criteria in the present study, since only patients with clinical evidence or histological confirmation of distant metastases were included, or by selection biases in reference center-based retrospective series. In addition, our study did not rely on a prospective registration of all melanoma cases, so that some LSs might have been unknown despite a comprehensive retrospective investigation in the study area.

Few reports have focused on characteristics and clinical history of LSs [9, 10, 12]. Eton et al. [12] described 36 patients with survival greater than 2 years, 10 of whom had exclusive extravisceral metastases. He found that LSs were more frequently female patients, and were characterized by frequent nodal, cutaneous or single visceral metastases, complete surgical resections and achievement of complete remissions. Ahmann et al. [10] described 10 patients with a survival of more than 5 years among 503 patients included in 25 clinical trials. Only 3 of these 10 patients had experienced a complete response to chemotherapies investigated within these trials, suggesting that long-term survival may have been independent of these therapies.

Our patients were characterized by a long delay from the primary tumor to distant metastases and by the frequent occurrence of prolonged CRs, which even included spontaneous regressions. The mean delay of nearly 70 months to stage IV disease was much longer than the 3 years generally observed in the natural course of progressive melanoma [11].

CRs frequently concerned single or lung metastases, but were also observed for multiple tumors and metastases of any site, including the liver, brain, pancreas and bones (table 2). These CRs most often followed exclusive or combined surgery, but were also achieved after any kind of treatment, including chemotherapy, radiotherapy and interferon. We also observed spontaneous regressions. While this was histologically documented in only one case, our data suggest that LSs may have small visceral metastases that do not increase in size and may even eventually disappear as a result of spontaneous immune control. However, only exceptional cases of spontaneous regression of visceral metastases have been reported to date [16].

All these data on a population basis suggest that unusual prolonged survival in a small minority of patients with stage IV melanoma might depend less on treatment choices or location of metastases than on the patients themselves and their spontaneous antitumor control. A long free interval between the diagnosis of primary melanoma and distant metastases may reflect a slow tumoral kinetic, secondary to a state of relative equilibrium between tumor cells and immune regulatory cells. The long delay between the occurrence of regional nodal metastases, and progression to stage IV, and the long duration of CRs observed in our patients, may result from the same persistent immune control.

Several investigators have demonstrated that melanoma is an immunogenic tumor [17]. Both cellular and humoral immune responses to melanoma-associated antigens have been observed.

Therefore, immunotherapy with various cancer vaccines or adoptive immunotherapy have been evaluated at different stages of the disease [18-21]. In stage IV, prolonged survival was mainly observed when vaccines were used following complete resection of metastases (Hsuech [22] and Tagawa [23]), which suggests a better efficacy of this approach in the context of slowly growing tumors.

It has also been demonstrated that vitiligo is associated with an improved prognosis in melanoma patients of different stages. In stage IV, a recent prospective study showed that, among patients treated with interleukin 2 as maintenance therapy, those who developed vitiligo had a longer survival than those without vitiligo [24]. In this context, vitiligo could be an auto-immune response to melanoma-associated antigens shared by normal melanocytes and melanoma cells. Other auto-immune reactions have been suspected to be associated with a favorable prognosis in melanoma. Gogas et al. [25] found a significant association between the development of auto-immune manifestations (including vitiligo, and/or antinuclear, anticardiolipin and antithyroid antibodies) and improved overall and relapse-free survival in patients treated with adjuvant high-dose interferon for stage II and III melanoma. In a recent study of 283 patients in stage IV, Vercambre-Darras et al. [26] identified 15 LSs (5.3%) who were still alive more than 3 years after stage IV diagnosis. Among 10 of these patients who were investigated for the presence of auto-antibodies, 5 (50%) had antithyroid antibodies, as compared to 10% in a control group of non-LS/stage IV patients. The authors suggested that spontaneous auto-immunity in stage IV melanoma could be linked to a better anti-tumor control and a longer survival. In our series, 4 of 8 patients still alive in June 2006 had clinical or biological features of auto-immunity, as defined by Gogas et al. [25] Despite the absence of a control group, this result seems in accordance with these recent hypotheses. Our population-based clinical study suggests that long survival in stage IV melanoma probably depends on a prolonged equilibrium between disseminated tumor cells and the host antitumor response. Although we (and others) have observed persistent complete responses for up to 10 years following stage IV diagnosis [14], an escapement to anti-tumor control eventually occurs in many cases, with faster proliferation, poorer responses to therapies and death long after diagnosis. Further genetic and immunological studies and specific clinical trials in these rare long-survivor patients could lead to a better comprehension of the disease and to the development of new immunological therapies.

Acknowledgements

Conflict of interest: none. Financial support: none.

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