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Clinical status of diagnosis and therapy of malignant melanoma
0883-2897/89 $3.00 + 0.00 Copyright Q 1989 Pergamon Press plc
Nwl. Med. Viol. Vol. 16, No. 6, pp. 621.-624, 1989 Iw. J. Radiat. Appl. Instrum. Part B Printed in Great Britain. All rights reserved
Clinical Status of Diagnosis and Therapy of Malignant Melanoma F. BELLI,
M. SANTINAMI, M. T. BALDINI, and N. CASCINELLI
Division
A. TESTORI,
A. MA10
of Surgical Oncology “B”, National Cancer Institute, Milan, Italy
Malignant melanoma, as well-known, is a neoplasia characterized by an impressive degree of malignancy. Its biological behaviour includes rapid spreading of the disease to the regional nodes by means of the lymphatic system or to many distant sites through the general circulation. The peculiarity of the disease is confirmed by some clinico-biological aspects as the possibility for the neoplastic cells to diffuse along the lymphatic drainage of the region, generating in the anatomic area included between the site of origin of primary and the regional nodes, the so called “in transit” recurrences. These occurrences are not only clinical curiosities but represent well defined aspects of a complex disease influencing clinical staging, therapeutic decisions and prognostic evaluation (Karakousis et al., 1980). On the basis of these items a correct staging for this disease could be postulated as indicated in Table 1. Any clinical decision or therapeutic procedures must be therefore carefully evaluated and correlated with the diffusion of the disease, realizing that today this tumor represents a difficult problem requesting a multidisciplinary diagnostic and therapeutical approach. From a diagnostic point of view in the first stages, corresponding to a regional diffusion of the disease, an appropriate clinical examination represents today the best means for diagnosis. An experienced clinician should not have great difficulties in detecting primaries or suspected lesions that must be removed in toto for histological examination following correct oncological criteria. The current diffusion of information on melanoma through the mass media and the institution of many peripheral specialized public structures, as well as the overcoming of ancient prejudices, have led to a more appropriate and earlier diagnosis in many cases, and these are the principal reason for the improved prognosis of patients in recent years. A very interesting prospective seems to be offered by the introduction of computerized imaging techniques that utilize the differences on the chromatic
aspects of the different lesions. This will be a very useful diagnostic means in the near future especially for less skilled clinicians, or in doubtful cases (Cascinelli et al., 1987). But at present the clinical examination remains the principal and safest tool in the detection of primaries as well in the study of regional lymph nodes. But if the accuracy of a clinical exploration is excellent in the laterocervical and inguinal nodal sites, a correct evaluation of the axillary status is most difficult and is inaccurate in at least 3040% of cases. On the other hand, until recently, there were no reliable radiological examinations (or the classic lymphography) able to solve the most difficult or doubtful situations. In this direction an important improvement has been achieved, as demonstrated by an ongoing prospective study started at the National Cancer Institute of Milan0 (NCI), with the immunoscintigraphy of axillary nodes. In fact the test has demonstrated a sensitivity greater than 80% and a specificity of 100% (Buraggi, ef al., 1986). A correct definition of the nodal status represents a central point in the management of these patients. In fact the presence of lymph nodal recurrences are considered an adverse prognostic element in the natural history of these cases (Cascinelli et al., 1984). Also lymph node involvement is considered the unique indication, in our opinion, for removing regional lymph nodes in patients affected by malignant melanoma. Regional lymphoadenectomy in these patients is one of the more hotly debated subjects in surgical oncology, but a randomized study performed at NC1 has demonstrated no differences in the survival rate of patients submitted to either elective node dissection or therapeutic node dissection (Veronesi et al., 1977, 1980, 1982). Therefore an exact knowledge of the presence or absence of metastatic disease in the nodes of the region markedly influences the therapeutic decision, and the utility represented by the use of monoclonal antibodies must be stressed. Also, in cases of distant recurrences this scintigraphic technique has demonstrated an undoubtful 621
F. BELLSeral.
622 Table
I. Clinical staging of cutaneous melanoma (M.
D. Anderson
classification)
1
Evidence of primary without nodal or “in transit” metastases
Stage II
Evidence of “in transit” mctastases in the peritumoral area
Stage IllA
Evidence of “in transit” recurrences between the area of origin of primary and the regiohal nodes
stage 1116
Regional nodal involvement without presenceof “in transit” metastaxs
Stage
Stage IllAB
Synchronous stage IIIA plus Stage IllB
Stage IV
Evidence of distant visceral, cutaneous and/or not regional nodal recurrences
usefulness in the detection of metastatic nodes in different areas without site toxicity, general effects or personal distress (Larson, 1985; Buraggi et al., 1985, 1984; Cascinelli ef al., 1988). Up to now a correct staging of these advanced cases was done following “symptomatic” criteria and performing specific examinations which were guided by the principal clinical findings and symptoms in the individual patient. Immunoscintigraphy with monoclonal antibodies presents limits of accuracy mainly related to the dimension of the lesion, the qualitative and quantitative expression of the tumor associated antigens on the cell surface and the radioactive background; despite these facts, this exam represents an important step in staging these advanced cases and offers an absolute specificity which is greater than other radiological exams and of enormous interest for therapeutic prospectives. Concerning the therapeutic approach to melanoma surgery remains actually the main and safer tool of care in these cases, especially in patients with regional disease (Veronesi and Cascinelli, 1988). The principal aim of the surgeon is to remove all the neoplastic tissue following well established oncological criteria both at the primary site (where the cutaneous, subcutaneous and the fascial plane must be removed “en block” remaining at an appropriate distance from the edge of the lesion) (Cascinelli et al., 1980; Elder et al., 1983; Breslow and Macht, 1977) and at the regional nodal locations (where all the lymphatic tissue of the area is dissected and taken off) (Balch, 1980; Furtner et al., 1975). When an operation at this level is well performed for regional metastases, the estimated 5 year survival rate of these patients is calculated at about 33-35%. A specific mention must be made of the treatment followed in the presence of the above mentioned “in transit” metastases with or without regional nodal involvement (Roses et al., 1983). In these cases the best results have been reached through the technique of the hyperthermic perfusion of antineoplastic drugs in extracorporeal circulation. The technique consists of the isolation of the main distribution vessels of the affected limb, which are opened and cannulated with two silastic catheters. These are then connected with an extracorporeal machine receiving blood from
venous lines, which after an appropriate oxygenation, reinjects the same blood through the arterious line into the limb. A system completely isolated from the general circulation is created and into it, without risks of general effects, high concentrations of drugs are introduced, and by a special heat-exchanger the temperature of blood and of the involved tissues are elevated up to 40-41”C (hyperthermic effect). This method of treatment is based on three basic principles: hyperthermia to which neoplastic cells are more sensitive than normal cells, a high drug dose approximately ten time greater than the dosage that can be administered through the general route, and a synergic action between hyperthermia and some drugs resulting in a considerable increased drug action (Rochlin and Smart, 1965; Sugarbacker and McBride, 1976; Davis et al., 1976; Stehlin et al., 1975). But, with the exception of the consistent and persistent regression obtained in these regional metastases with this peculiar type of chemotherapy, the systemic injection of drugs has not reached positive goals. Many clinical trials in the past years have clearly demonstrated the uselessness of any complementary treatment and also for therapeutical purposes the mean response rate obtained (evaluated both as complete and partial regression) is not greater than 28-30%. The inefficacy of medical therapy in these advanced patients and the knowledge of the importance of the immunological factors in the natural history of this cancer, confirmed by experimental and clinical evidence (Cascinelli et al., 1987), has stimulated many investigators to test different types of immunological means in the control of the disease. In the past years a multitude of clinical studies have been started using a great number of putative immunostimulating agents such as BCG, levamisol, cell membrane fractions, polynucleotides injected through different routes with no relevant results. In the most recent period a more appropriate approach has utilized the interferons for systemic or regional injection, but with these products also, in spite of the experimental and biological data, the clinical experience has been much more discouraging than expected. At the moment one of the most stimulating projects is represented by the adoptive immunotherapy by means of cytotoxic cells associated with IL-2. This treatment consists of the activation and cloning through a highly purified and specific growth factor (IL-2) of a cytotoxic lymphoid cell line taken from the selected patient, and then reinjected into the same patient along with IL-2 to maintain the viability of the cells as long as possible. The technique, which is extremely fascinating from a theoretical point of view, has achieved, as reported in the literature and in our experience, some clinical
Diagnosis and therapy of malignant melanoma
many consistent toxic effects which often force the discontinuation of the programmed schedule of therapy after some days of treatment (Marolda et al., 1987; Atkins et al., 1986; Rosenberg et al., 1985, 1986, 1987; Rosenstein et al., 1986; Thurman et al., 1986). In spite of this we believe that the immunotherapy of melanoma represents a fundamental approach in the treatment of this disease. In this regard the monoclonal antibodies, because of their high specificity, their demonstrated lack of toxicity after repeated injection and the possibility of their use both as direct cytotoxic factors and carriers of other molecules, constitute one of the most intriguing prospectives of therapy of this threatening cancer. results but at the same time produces
References Atkins, M. B.: Gould, J. A.; Allegretta, M.; Li, J. J.; Dempsey, R. A.; Rudders, R. A.; Parkinson, D. R.; Reichlin, S; Mier, J. W. Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J. Clin. Oncol. 4:138&1391; 1986. Balch, C. M. Surgical management of regional lymph nodes in cutaneous melanoma. J. Am. Acad. Dermafol. 3:511; 1980.
Breslow, A.; Macht, S. D. Optimal size of resection margin for thin cutaneous melanoma. Surg. Gynecol. Obstef. 145:691-692; 1977. Buraggi, G. L.; Callegaro, L.; Turrin, A.; Cascinelli, N.; Attili, A.; Emanuelli, H. ef al. Immunocintigraphy with ‘231,*mTc, and “‘In-1abelled F(ab’), fragments of monoclonal antibodies to a human high molecular weightmelanoma associated antigen. J. Nucl. All. Sci. 28:283-295; 1984. Buraggi, G. L.; Callegaro, L.; Mariani, G.; Turrin, A.; Cascinelh, N.; Attih, A. et al. Imaging with ‘311-labelled monoclonal antibodies to a high weight-melanoma associated antigen: efficacy of whole Ig and its Fab2 fragments. Cancer Res. 45:3378-3387; 1985. Buraggi, G. L.; Turrin, A.; Cascinelli, N.; Attili, A.; Gasoarini. M.: Calleearo. L.: Ferrone. S.: Sereani. E.; Bombardieri, E.; Beyli, F. Radioimmunodeteciion of melanoma: preliminary results of a prospective study. Int. J. Biol. Markers
1:47-54;
1986.
Cascinelli, N.; Van der Esch, E. P.; Breslow, A.; Morabito, A.: Bufalini. R. Stane I melanoma of the skin: the problem of resection margins. Eur. J. Cancer 16:1079-1085;
1980.
Cascinelli, N.; Vaglini, M.; Nava, M.; Santinami, M.; Marolda, R.; Rovini, D.; Clemente, C.; Bufalino, R.; Morabito, A. Prognosis of skin melanoma with regional node metastases (Stage II). J. Surg. Oncol. 25:24&247; 1984. Cascinelli, N.; Ferrario, M.; Tonelli, T.; Leo, E. A possible new tool for clinical diagnosis of melanoma: the computer. J. Am. Acad. Dermutol. 16:361-367; 1987. Cascinelli, N.; Bajetta, E.; Santinami, M.; Buzzoni, R.; Balch, C. M., Peter, H., Bernengo, M. G. Adjuvant therapy: has it a role? In: Veronesi, U.; Cascinelli, N.; Santinami, M., editors. Curuneous Melanoma-Srurus of Knowledge and Future Perspertive. London: Academic Press; 1987:563-575. Cascinelli, N.; Attili, A.; Belli, F.; Buraggi, G. L.; Turrin, A.; Gasparini, M.; Terno, G.; Vaglini, M. Anti-melanoma monoclonal antibody 225-288: evaluation of toxicity in man. Tumori 74:35-40; 1988. Davis, C. D.; Ivins, J. C.; Some, E. H. Mayo Clinic experience with isolated perfusion for invasive malignant
623
of the extremities. In: Melanomas: Basic Properties and Clinical Behavior, Vol. 11. Proc. 9th Int. Pigment Cell Conf., Houston, Texas, 1975. New York:
melanoma
S. Karger; 1976; 379. Elder, D. E.; Guerry, D. P. IV; Heiberger, R. M.; La Rossa, D.; Goldman, L. I.; Clark, W. H.; Thompson, C. J.; Matozzo, I.; Van Horn, M. Optimal resection margin for cutaneous malignant melanoma. Plusr. Reconsrr. Surg. 71:6&72; 1983. Fortner, J. G.; Schottenfeld, D.; MacLean, B. J. En bloc resection of primary melanoma with regional lymph node dissection. Arch. Surg. 110:674; 1975. Karakousis, C. P.; Choe, K. J.; Holyoke, E. D. Biologic behavior and treatment of in transit metastasis of melanoma. Surg. Gynecol. Obstet. 150:29; 1980. Krementz, E. T. Regional perfusion. Current sophistication, what next? Cancer 57:41&432; 1986. Larson, S. M. Radiolabeled monoclonal anti-tumor antibodies in diagnosis and therapy. J. Nucl. Med. 26:538-545; 1985. Marolda, R.; Belli, F.; Prada, A.; Villani, F.; GambacortiPasserini, C., Galazka, A.; Permiani, G.; Cascinelh. N. A phase I study of recombinant interleukin 2 in melanoma patients. Toxicity and clinical effects. Tumori 73:575-584; 1987.
Rochlin, D. B., Smart, C. R. Treatment of malignant melanoma by regional perfusion, Cancer 18:I5441 550; 1965. Rosenberg, S. A.; Lotze, M. T.; Mum, L. M.; Leitma, S.; Chang, A. E.; Ettinghausen, S. E.; Matory, Y. L.; Skibber, J. M.; Shiloni, E.; Vetto, Y. L.; Seipp, A.; Simpson, C.; Reichert, C. L. Observation on the systemic administration of autologous lymphokine activated killer cells and recombinant interleukin 2 to patients with metastatic cancer. N. Enal. J. Med. 313:1485-1492: 1985. Rosenberg, S. A:; Mule, J. J.; Shu, S.; Spiess, P.; Schwartz, S. Systemic administration of recombinant interleukin 2 leads to regression of established tumors in mice. J. Exp. Med. 161:1169-l 188; 1985. Rosenberg, S. A.; Lotze, M. T.; Muul, L. M.; Leitman, S.; Chang, A. E.; Vetto, J. T.; Seipp, C.; Simpson, C. A new approach to the therapy of cancer based on the systemic administration of autologous lymphokine activated killer cells and recombinant interleukin 2. Surgery 100:262-271; 1986. Rosenberg, S. A.; Lotze, M. T.; Muul, L. M.; Chang, A. E.; Avis, F. P.; Leilman, S.; Lineham, W. M.; Robertson, C. N.; Lee, R. E.; Rubin, J. T.; Seipp, C. A.; Simpson, C. G.; White, D. E. A progress report on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and interleukin-2 or high dose interleukin-2 alone. N. Engl. J. Med. 316:889-897; 1987. Rosenstein, M.; Ettinghausen, S. E.; Rosenberg, S. A. Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin-2. J. Immunol. 137~173551742;1986. Roses, D. F.; Harris, M. N.; Rigel, D.; Carrey, Z.; Friedman, R.; Kopf, A. W. Local and in-transit metastases following definitive excision for primary cutaneous malignant melanoma. Ann. Surg. 198:65-69; 1983. Schraffordt Koops, H.; Beekhuis, H.; Oldhoff, J.; Oosterhuis, J. W.; Van der Ploeg, E.; Vermey, A. Local recurrence and survival in patients with (Clark level IV/V and over 1.5 mm. thickness) stage I malignant melanoma of the extremities after regional perfusion. Cancer 48: 1952; 1981.
Stehlin, J. S. Jr; Giovanella, B. C.; Delpolyi, P. D.; Muenz, L. R.; Anderson, R. F. Results of hyperthermic perfusion for melanoma of the extremities. Surg. Gynecol. Obstef. 140:339-348;
1975.
Sugarbacker, E. V.; McBride, C. M. Survival and regional disease control after isolation perfusion for invasive Stage I melanoma of the extremities. Cancer 37:188-198; 1976.
624
F. BELLIet al.
Thurman, G. B.; Malvish, A. E.; Rossio, J. L.; Schlik, E.; Orozaki, K.; Talmadge, J. E.; Procopio, A. D. G.; Ortaldo, J. R.; Ruscetti F. W.; Stevenson, H. C.; Cannon, G. B.; Iyan, S.; Herberman, R. B. Comparative evaluation of multiple lymphoid and recombinant human interleukin-2 preparations. J. Bid\. Response Mod. 5:85-107; 1986. Veronesi, U.; Adamus, J.; Bandiera, D. C.; Brennhovd, I. 0.; Caceres, E.; Cascinelli, N. et al. Inefficacy of immediate node dissection in stage I melanoma of the limbs. N. Engl. J. Med. 297~627; 1977.
Veronesi, U.; Cascinelli, N. Surgical treatment of malignant melanoma of the skin. World J. Surg. 3:279-288; 1979.
Veronesi, U.; Adamus, J.; Bandiera, D. C.; Brennhovd, I. 0.; Caceres, E.; Cascinelli, N. et al. Stage I melanoma of the limbs: immediate versus delayed node dissection. Tumori 66373;
1980.
Veronesi, U.; Adams, J.; Bandiera, D. C.; Brennhovd, I. 0.; Caceres, E.; Cascinelli, N. et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 49:2420; 1982.
Nwl. Med. Viol. Vol. 16, No. 6, pp. 621.-624, 1989 Iw. J. Radiat. Appl. Instrum. Part B Printed in Great Britain. All rights reserved
Clinical Status of Diagnosis and Therapy of Malignant Melanoma F. BELLI,
M. SANTINAMI, M. T. BALDINI, and N. CASCINELLI
Division
A. TESTORI,
A. MA10
of Surgical Oncology “B”, National Cancer Institute, Milan, Italy
Malignant melanoma, as well-known, is a neoplasia characterized by an impressive degree of malignancy. Its biological behaviour includes rapid spreading of the disease to the regional nodes by means of the lymphatic system or to many distant sites through the general circulation. The peculiarity of the disease is confirmed by some clinico-biological aspects as the possibility for the neoplastic cells to diffuse along the lymphatic drainage of the region, generating in the anatomic area included between the site of origin of primary and the regional nodes, the so called “in transit” recurrences. These occurrences are not only clinical curiosities but represent well defined aspects of a complex disease influencing clinical staging, therapeutic decisions and prognostic evaluation (Karakousis et al., 1980). On the basis of these items a correct staging for this disease could be postulated as indicated in Table 1. Any clinical decision or therapeutic procedures must be therefore carefully evaluated and correlated with the diffusion of the disease, realizing that today this tumor represents a difficult problem requesting a multidisciplinary diagnostic and therapeutical approach. From a diagnostic point of view in the first stages, corresponding to a regional diffusion of the disease, an appropriate clinical examination represents today the best means for diagnosis. An experienced clinician should not have great difficulties in detecting primaries or suspected lesions that must be removed in toto for histological examination following correct oncological criteria. The current diffusion of information on melanoma through the mass media and the institution of many peripheral specialized public structures, as well as the overcoming of ancient prejudices, have led to a more appropriate and earlier diagnosis in many cases, and these are the principal reason for the improved prognosis of patients in recent years. A very interesting prospective seems to be offered by the introduction of computerized imaging techniques that utilize the differences on the chromatic
aspects of the different lesions. This will be a very useful diagnostic means in the near future especially for less skilled clinicians, or in doubtful cases (Cascinelli et al., 1987). But at present the clinical examination remains the principal and safest tool in the detection of primaries as well in the study of regional lymph nodes. But if the accuracy of a clinical exploration is excellent in the laterocervical and inguinal nodal sites, a correct evaluation of the axillary status is most difficult and is inaccurate in at least 3040% of cases. On the other hand, until recently, there were no reliable radiological examinations (or the classic lymphography) able to solve the most difficult or doubtful situations. In this direction an important improvement has been achieved, as demonstrated by an ongoing prospective study started at the National Cancer Institute of Milan0 (NCI), with the immunoscintigraphy of axillary nodes. In fact the test has demonstrated a sensitivity greater than 80% and a specificity of 100% (Buraggi, ef al., 1986). A correct definition of the nodal status represents a central point in the management of these patients. In fact the presence of lymph nodal recurrences are considered an adverse prognostic element in the natural history of these cases (Cascinelli et al., 1984). Also lymph node involvement is considered the unique indication, in our opinion, for removing regional lymph nodes in patients affected by malignant melanoma. Regional lymphoadenectomy in these patients is one of the more hotly debated subjects in surgical oncology, but a randomized study performed at NC1 has demonstrated no differences in the survival rate of patients submitted to either elective node dissection or therapeutic node dissection (Veronesi et al., 1977, 1980, 1982). Therefore an exact knowledge of the presence or absence of metastatic disease in the nodes of the region markedly influences the therapeutic decision, and the utility represented by the use of monoclonal antibodies must be stressed. Also, in cases of distant recurrences this scintigraphic technique has demonstrated an undoubtful 621
F. BELLSeral.
622 Table
I. Clinical staging of cutaneous melanoma (M.
D. Anderson
classification)
1
Evidence of primary without nodal or “in transit” metastases
Stage II
Evidence of “in transit” mctastases in the peritumoral area
Stage IllA
Evidence of “in transit” recurrences between the area of origin of primary and the regiohal nodes
stage 1116
Regional nodal involvement without presenceof “in transit” metastaxs
Stage
Stage IllAB
Synchronous stage IIIA plus Stage IllB
Stage IV
Evidence of distant visceral, cutaneous and/or not regional nodal recurrences
usefulness in the detection of metastatic nodes in different areas without site toxicity, general effects or personal distress (Larson, 1985; Buraggi et al., 1985, 1984; Cascinelli ef al., 1988). Up to now a correct staging of these advanced cases was done following “symptomatic” criteria and performing specific examinations which were guided by the principal clinical findings and symptoms in the individual patient. Immunoscintigraphy with monoclonal antibodies presents limits of accuracy mainly related to the dimension of the lesion, the qualitative and quantitative expression of the tumor associated antigens on the cell surface and the radioactive background; despite these facts, this exam represents an important step in staging these advanced cases and offers an absolute specificity which is greater than other radiological exams and of enormous interest for therapeutic prospectives. Concerning the therapeutic approach to melanoma surgery remains actually the main and safer tool of care in these cases, especially in patients with regional disease (Veronesi and Cascinelli, 1988). The principal aim of the surgeon is to remove all the neoplastic tissue following well established oncological criteria both at the primary site (where the cutaneous, subcutaneous and the fascial plane must be removed “en block” remaining at an appropriate distance from the edge of the lesion) (Cascinelli et al., 1980; Elder et al., 1983; Breslow and Macht, 1977) and at the regional nodal locations (where all the lymphatic tissue of the area is dissected and taken off) (Balch, 1980; Furtner et al., 1975). When an operation at this level is well performed for regional metastases, the estimated 5 year survival rate of these patients is calculated at about 33-35%. A specific mention must be made of the treatment followed in the presence of the above mentioned “in transit” metastases with or without regional nodal involvement (Roses et al., 1983). In these cases the best results have been reached through the technique of the hyperthermic perfusion of antineoplastic drugs in extracorporeal circulation. The technique consists of the isolation of the main distribution vessels of the affected limb, which are opened and cannulated with two silastic catheters. These are then connected with an extracorporeal machine receiving blood from
venous lines, which after an appropriate oxygenation, reinjects the same blood through the arterious line into the limb. A system completely isolated from the general circulation is created and into it, without risks of general effects, high concentrations of drugs are introduced, and by a special heat-exchanger the temperature of blood and of the involved tissues are elevated up to 40-41”C (hyperthermic effect). This method of treatment is based on three basic principles: hyperthermia to which neoplastic cells are more sensitive than normal cells, a high drug dose approximately ten time greater than the dosage that can be administered through the general route, and a synergic action between hyperthermia and some drugs resulting in a considerable increased drug action (Rochlin and Smart, 1965; Sugarbacker and McBride, 1976; Davis et al., 1976; Stehlin et al., 1975). But, with the exception of the consistent and persistent regression obtained in these regional metastases with this peculiar type of chemotherapy, the systemic injection of drugs has not reached positive goals. Many clinical trials in the past years have clearly demonstrated the uselessness of any complementary treatment and also for therapeutical purposes the mean response rate obtained (evaluated both as complete and partial regression) is not greater than 28-30%. The inefficacy of medical therapy in these advanced patients and the knowledge of the importance of the immunological factors in the natural history of this cancer, confirmed by experimental and clinical evidence (Cascinelli et al., 1987), has stimulated many investigators to test different types of immunological means in the control of the disease. In the past years a multitude of clinical studies have been started using a great number of putative immunostimulating agents such as BCG, levamisol, cell membrane fractions, polynucleotides injected through different routes with no relevant results. In the most recent period a more appropriate approach has utilized the interferons for systemic or regional injection, but with these products also, in spite of the experimental and biological data, the clinical experience has been much more discouraging than expected. At the moment one of the most stimulating projects is represented by the adoptive immunotherapy by means of cytotoxic cells associated with IL-2. This treatment consists of the activation and cloning through a highly purified and specific growth factor (IL-2) of a cytotoxic lymphoid cell line taken from the selected patient, and then reinjected into the same patient along with IL-2 to maintain the viability of the cells as long as possible. The technique, which is extremely fascinating from a theoretical point of view, has achieved, as reported in the literature and in our experience, some clinical
Diagnosis and therapy of malignant melanoma
many consistent toxic effects which often force the discontinuation of the programmed schedule of therapy after some days of treatment (Marolda et al., 1987; Atkins et al., 1986; Rosenberg et al., 1985, 1986, 1987; Rosenstein et al., 1986; Thurman et al., 1986). In spite of this we believe that the immunotherapy of melanoma represents a fundamental approach in the treatment of this disease. In this regard the monoclonal antibodies, because of their high specificity, their demonstrated lack of toxicity after repeated injection and the possibility of their use both as direct cytotoxic factors and carriers of other molecules, constitute one of the most intriguing prospectives of therapy of this threatening cancer. results but at the same time produces
References Atkins, M. B.: Gould, J. A.; Allegretta, M.; Li, J. J.; Dempsey, R. A.; Rudders, R. A.; Parkinson, D. R.; Reichlin, S; Mier, J. W. Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J. Clin. Oncol. 4:138&1391; 1986. Balch, C. M. Surgical management of regional lymph nodes in cutaneous melanoma. J. Am. Acad. Dermafol. 3:511; 1980.
Breslow, A.; Macht, S. D. Optimal size of resection margin for thin cutaneous melanoma. Surg. Gynecol. Obstef. 145:691-692; 1977. Buraggi, G. L.; Callegaro, L.; Turrin, A.; Cascinelli, N.; Attili, A.; Emanuelli, H. ef al. Immunocintigraphy with ‘231,*mTc, and “‘In-1abelled F(ab’), fragments of monoclonal antibodies to a human high molecular weightmelanoma associated antigen. J. Nucl. All. Sci. 28:283-295; 1984. Buraggi, G. L.; Callegaro, L.; Mariani, G.; Turrin, A.; Cascinelh, N.; Attih, A. et al. Imaging with ‘311-labelled monoclonal antibodies to a high weight-melanoma associated antigen: efficacy of whole Ig and its Fab2 fragments. Cancer Res. 45:3378-3387; 1985. Buraggi, G. L.; Turrin, A.; Cascinelli, N.; Attili, A.; Gasoarini. M.: Calleearo. L.: Ferrone. S.: Sereani. E.; Bombardieri, E.; Beyli, F. Radioimmunodeteciion of melanoma: preliminary results of a prospective study. Int. J. Biol. Markers
1:47-54;
1986.
Cascinelli, N.; Van der Esch, E. P.; Breslow, A.; Morabito, A.: Bufalini. R. Stane I melanoma of the skin: the problem of resection margins. Eur. J. Cancer 16:1079-1085;
1980.
Cascinelli, N.; Vaglini, M.; Nava, M.; Santinami, M.; Marolda, R.; Rovini, D.; Clemente, C.; Bufalino, R.; Morabito, A. Prognosis of skin melanoma with regional node metastases (Stage II). J. Surg. Oncol. 25:24&247; 1984. Cascinelli, N.; Ferrario, M.; Tonelli, T.; Leo, E. A possible new tool for clinical diagnosis of melanoma: the computer. J. Am. Acad. Dermutol. 16:361-367; 1987. Cascinelli, N.; Bajetta, E.; Santinami, M.; Buzzoni, R.; Balch, C. M., Peter, H., Bernengo, M. G. Adjuvant therapy: has it a role? In: Veronesi, U.; Cascinelli, N.; Santinami, M., editors. Curuneous Melanoma-Srurus of Knowledge and Future Perspertive. London: Academic Press; 1987:563-575. Cascinelli, N.; Attili, A.; Belli, F.; Buraggi, G. L.; Turrin, A.; Gasparini, M.; Terno, G.; Vaglini, M. Anti-melanoma monoclonal antibody 225-288: evaluation of toxicity in man. Tumori 74:35-40; 1988. Davis, C. D.; Ivins, J. C.; Some, E. H. Mayo Clinic experience with isolated perfusion for invasive malignant
623
of the extremities. In: Melanomas: Basic Properties and Clinical Behavior, Vol. 11. Proc. 9th Int. Pigment Cell Conf., Houston, Texas, 1975. New York:
melanoma
S. Karger; 1976; 379. Elder, D. E.; Guerry, D. P. IV; Heiberger, R. M.; La Rossa, D.; Goldman, L. I.; Clark, W. H.; Thompson, C. J.; Matozzo, I.; Van Horn, M. Optimal resection margin for cutaneous malignant melanoma. Plusr. Reconsrr. Surg. 71:6&72; 1983. Fortner, J. G.; Schottenfeld, D.; MacLean, B. J. En bloc resection of primary melanoma with regional lymph node dissection. Arch. Surg. 110:674; 1975. Karakousis, C. P.; Choe, K. J.; Holyoke, E. D. Biologic behavior and treatment of in transit metastasis of melanoma. Surg. Gynecol. Obstet. 150:29; 1980. Krementz, E. T. Regional perfusion. Current sophistication, what next? Cancer 57:41&432; 1986. Larson, S. M. Radiolabeled monoclonal anti-tumor antibodies in diagnosis and therapy. J. Nucl. Med. 26:538-545; 1985. Marolda, R.; Belli, F.; Prada, A.; Villani, F.; GambacortiPasserini, C., Galazka, A.; Permiani, G.; Cascinelh. N. A phase I study of recombinant interleukin 2 in melanoma patients. Toxicity and clinical effects. Tumori 73:575-584; 1987.
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