ARTICLE
Chemotherapy for cutaneous malignant melanoma has proved moderately efficient,
with a response rate of 20 to 30%, whereas immunotherapy with INF-alpha 2a
or IL-2, a more recent approach, has shown response rates of around only
15%. In fact, immunomodulators and chemotherapeutic agents act by different
mechanisms, the former stimulating immune cells (notably cytotoxic T cells,
NK cells and macrophages) [1, 2] and the latter producing direct anti-tumor
action. It is thus conceivable that a combination of the two could have
a synergistic effect. In this context, we performed a multicenter study
to assess the efficacy of SC, low-dose IL-2, INF-alpha and cisplatin in patients
with metastatic malignant melanoma. Moreover, we sought to show that SC
IL-2 could provide results comparable to those obtained intravenously,
but with fewer adverse affects, thereby allowing ambulatory treatment
and a greater respect for the quality of life of patients.
Patients and methods
Thirty-three patients (20 men and 13 women; mean age 49.4 years, range
22-66) with confirmed, measurable metastases of malignant melanoma were
included in a multicenter study associating four French hospital centers
(Montpellier, Nantes, Nîmes, and Villejuif).
The inclusion criteria were age less than 70 years, a Karnofsky index
over 80%, life expectancy of more than 3 months, no chemo- or radiotherapy
within the 4 weeks prior to inclusion (adjuvant INF-alpha treatment within
the 6 preceding months was acceptable if patients showed no signs of disease
progression), and a biological profile leukocytes > 3,500, platelets
> 100,000, hematocrit > 30%, and serum bilirubin and creatinine
< 1.25 times the upper limit of normal. All patients gave their informed
consent to take part in the study.
The exclusion criteria included the presence of brain metastases, epilepsy,
autoimmune diseases, dysthyroidism or uncontrolled cardiac conditions,
a history of allograft and previous cancers (except basal cell carcinomas
and treated, in situ cervical cancers), previous treatment with
IL-2, cisplatin or INF-alpha for curative purposes, and seropositivity for
human immunodeficiency virus and hepatitis B virus.
Induction treatment (Table I)
consisted of two cycles with a 3-week interval, associating cisplatin
100 mg/m2 in a 30-min, intravenous infusion at day 0 of each
cycle; INF-alpha-2a (Roféron* Roche, France) 3 million units per
day by SC injection, 3 times per week without interruption; and IL-2 (Proleukinalpha
Chiron, France) 9 million units per day by SC injection, from day 3 to
7 and day 10 to 14 of each cycle (i.e. 10 injections per cycle).
This ambulatory treatment required only one day of hospitalization for
the cisplatin infusion. The SC injections of INF-alpha and IL-2 were administered
by a nurse at the patient's home.
Maintenance therapy for responding or stabilized patients was initiated
two weeks after the last IL-2 injection of the second induction cycle
and was conducted every 4 weeks according to the same treatment schedule
for a maximum of 10 months. A first clinical and radiological evaluation
was performed after the two induction cycles and then before each maintenance
course.
The response criteria used during the different evaluations were the
following: complete response (CR), disappearance of any known lesion for
a period of more than 4 weeks in the absence of any new lesions; partial
response (PR), a reduction of at least 50% in tumor size in the absence
of any new lesions or progression of preexisting lesions; stable disease
(S), a reduction of less than 50% in tumor size or an increase of less
than 25% in the absence of any new lesions; and progressive disease (P),
an increase of at least 25% in tumor size or the appearance of new lesions.
The modalities of maintenance treatment were as follows: a patient showing
CR at the end of the second induction cycle received a single maintenance
course; a patient showing PR or S after induction treatment received a
maintenance course which was repeated if improvement was observed (up
to a maximum of 4 maintenance courses); and a patient showing P at the
end of induction treatment or during maintenance treatment was removed
from the protocol.
The length of CR or PR was determined from the date of the first observation
of CR to the date at which a further change was noted.
Adverse clinical or biological effects of treatment were assessed monthly
according to the WHO toxicity scale.
Results
The characteristics of the 33 patients included in the study are summarized
in Table II. Primary melanoma
involved the trunk in 42.4% of cases, the lower limbs in 21.2%, the head
or neck in 15.1% and was not localized in 21.2%. All patients were in
good general condition (Karnofsky index above 80%). Metastases were mainly
nodal (54.5%), pulmonary (51.5%), cutaneous (36.4%) and hepatic (30.3%).
Several organs were generally involved (72.7% of cases), with two (45.4%),
three (24.2%) or four (3%) target organs. For 27 patients (81.8%), chemotherapy
constituted first-line treatment. Only 6 patients had already been treated
by chemotherapy, and 12 patients had received adjuvant therapy (Table
II).
The rate of overall response was 24.2% (3 CR and 5 PR) at 2 months (i.e.
at the end of induction treatment) and 30.3% (3 CR and 7 PR) at the end
of the first course of maintenance therapy. CR corresponded to the disappearance
of nodal metastases in 2 cases and to the regression of nodal and cutaneous
metastases in one case. These complete remissions were maintained for
respectively 2.2 and 7 months (followed respectively by pulmonary, pulmonary-nodal
and nodal recurrences) in two patients, the third patient continuing to
be in remission (14+). Five of the 7 patients showing PR maintained
their response to the last follow-up, with a mean period of 8.4 months
(6+, 6+, 8+, 8+, 14+).
The other two patients had a further progression of their disease after
1 and 3 months of follow-up.
Adverse effects were observed in 28 patients (84.8%) but were most often
minor ones (grade 1 or 2) such as pseudoflu syndrome, pain at the injection
site with local swelling and erythema or gastrointestinal disorders. Grade
3 adverse effects mainly involved asthenia, vomiting, and grade 4 thrombopenia
and leucopenia which were always reversible after stopping treatment with
IL-2 and INF-alpha with a maximum of 21.2% toxic effects, as reported in Table
III. Treatment was discontinued in only 3 cases because of toxicity
(1 hepatic cytolysis, 2 thrombopenia), and a fourth patient requested
that his treatment be stopped because of severe asthenia. No hospitalization
were required for treatment-related toxicities.
Among the 7 patients with grade 3 asthenia, only one patient requested
a discontinuation of treatment. For the other patients, treatment was
continued. For the patients with fever, pain, vomiting and grade 3 diarrhea,
a symptomatic treatment was given and the treatment was continued.
Grade 3 hypotension disappeared after only a short interruption of treatment.
No dobutamine perfusions were performed. Central nervous system involvement
included a depressive syndrome and one hypoacousia which did not necessitate
stopping treatment.
Leukopenia were treated with G-colony-stimulating factor (G-CSF).
Discussion
Metastatic malignant melanoma is difficult to treat and responds poorly
to chemotherapy. Dacarbazine, with a response rate of 14 to 25%, is considered
as the reference drug for chemotherapy.
Our study showed the efficacy and good tolerance of an ambulatory treatment
associating cisplatin monochemotherapy and SC administration of IL-2 and
INF-alpha. Our results showed an overall response rate of 30.3%, with toxic
effects most often limited to grades 1 and 2 on the WHO scale. No hospitalisation
was necessary, side effects disappearing after a short interruption of
the treatment. A cost benefit analysis was not performed for this study.
However, it is important to point out the fact that it is an ambulatory
treatment avoiding intensive care which is often more expensive.
IL-2 was chosen for this indication essentially on the basis of its
immunomodulatory effect [1]. This cytokine induces the proliferation of
cytotoxic T-lymphocyte clones [2] and also increases the antitumor effects
of macrophages through induction of interferon-gamma [3]. Moreover, it
can induce cellular reactivity against tumor target cells by activating
a subpopulation of NK mononuclear cells and this effect would be greater
in vitro with low doses of interleukin-2 [4-6]. However, the first
clinical trials with intravenous (IV) IL-2 in metastatic melanomas showed
an overall response rate of only 10 to 20%, with severe toxicity problems
(notably hematologic, hepatic and cardiac) and sometimes a threat to survival
[7-10].
Concerning IFN-alpha, several studies published since 1978 have assessed
its moderate efficacy in metastatic melanoma [11]. The mechanism of action
of this glycoprotein is based on three effects: immunomodulation, induction
of tumor cell differentiation and inhibition of tumor proliferation [11].
INF-alpha administered subcutaneously has allowed response rates of 15 to
20% to be obtained [11, 12].
Studies in vitro and in animals have suggested that INF-alpha and
IL-2 have a synergistic action on tumor cell lines [13-15]. This effect
is probably mediated by an increase in the number and activity of NK cells
and the presence of a CD 8+ cytotoxic infiltrate at the tumor
site. However, clinical trials have not always shown this synergistic
action. In fact, one study by the IL-2 Working Group investigating the
superiority of IL-2+ INF-alpha over IL-2 alone obtained response rates of
only 10 and 5% respectively [16]. Other studies using the IL-2+ INF-alpha
association found an overall response rate of only 6.6% (5 responders
out of 75 patients) [17-21].
These immunomodulatory treatments have been
combined with conventional chemotherapy in an effort to optimize the treatment
of metastatic melanoma through the synergistic effect of chemotherapy
and immunomodulatory treatment on tumor cells. Thus, the association of
dacarbazine and INF-alpha proved more efficient than dacarbazine alone [22].
When cisplatin was administered alone at doses equal to or less than 100
mg/m2, the response rate was less than 15% [23], whereas cisplatin
+ INF-alpha gave a response rate of 24% in a non-controlled study of 42 patients
[24], and cisplatin + IV IL-2 a response rate of 37% in a study of 27
patients [25].
Studies involving an association of IL-2, INF-alpha and polychemotherapy
seem to provide even better results (response rates of 35 to 83%) [26-30],
confirming the synergy between chemotherapy and biotherapy. However, it
is difficult to compare these studies because of the multiplicity of protocols
(choice of substances, posology, dose frequency and administration route)
and the low number of participants. Yet some findings are obvious: the
toxicity of cisplatin is related to the use of high doses [27], higher
cisplatin doses and an increase in the number of drugs do not seem to
improve the response rate or the rate of complete remission [27], and
the use of the venous route for IL-2 is a source of adverse and sometimes
severe effects requiring careful surveillance in suitable care units.
Thus, Khayat et al. [27], who evaluated an association of IV cisplatin
(100 mg/m2), SC INF-alpha-2a and IV IL-2, found an overall response
rate of 53.8% (5 CR and 16 PR in 39 patients), but with severe adverse
effects: a drop in systolic blood pressure below 80 mmHg (requiring the
use of filling solutions or vasopressors) for nearly all patients, central
nervous system (CNS) disorders in 4, Staphylococcus aureus septicemia
in 2, pulmonary edema in 2 and myocarditis in 1.
The toxicity of IL-2 IV has led some authors to use the SC route in
protocols associating chemotherapy and biotherapy. In fact, preliminary
studies have shown that SC IL-2 induces immunological alterations similar
to those of IV IL-2, but with fewer side effects, allowing ambulatory
treatment [31-33].
The association of dacarbazine, SC INF-alpha and SC IL-2 in ambulatory treatment
produced a response rate of 26.2% after two induction cycles, with adverse
effects most often limited to grades 1 and 2 and an absence of grade 4
toxicity [34]. Likewise, Atzpodien et al. reported two protocols
for polychemotherapy associated with SC biotherapy which confirmed the
good tolerance of this route as well as its efficacy, i.e. response
rates of 35 and 55% respectively for dacarbazine-carboplatin-SC IL-2-SC
INF and dacarbazine-cisplatin-carmustine-SC tamoxifen-SC IL-2-SC INF [26].
Comparison of the results of our study with those of Khayat et al.
[27] (IV cisplatin-IV IL-2-SC INF-alpha) and Atzpodien et al. [26]
(two protocols for polychemotherapy associated with SC INF-alpha and IL-2)
is instructive (Table IV).
The therapeutic responses concerned similar, classically responsive targets
(nodal and cutaneous metastases). Although our results were less promising
for overall response rates, the figures are similar in the four studies
for the rate of complete remission (ranging from 7.5 to 12.8%). The length
of the response period with the protocols of Atzpodien et al. [26]
(mean maintenance therapy for CR of + 19 and 11+ months) raises
the question of the efficacy of dacarbazine combined with cisplatin in
prolonging periods of remission.
However this phenomen is not confirmed by Khayat's study, with a duration
of response of only 5.5 months. At the moment, no study in the literature
has really demonstrated the role of DTIC in the prolongation of response,
even in combined therapy.
CONCLUSION
Our study confirmed the better tolerance of SC IL-2 compared to IV IL-2,
allowing ambulatory treatment of patients. It confirms that the association
of cisplatin with IL-2 and INF-alpha gives better results than monotherapy
with either of these substances.
REFERENCES
1. Oldham RK. Biological response modifiers program workshop: in vivo
effects of IL-2. J Biol Response Modif 1984; 3: 455-532.
2. Cheever MH, Greenberg PD, Fefer A, Gillis S. Augmentation of anti-tumor
therapeutic efficacy of long-term cultured T lymphocytes by in vivo
administration of purified interleukin-2. J Exp Med 1982; 155:
968-80.
3. Zhang SR, Urias PE, Twilley TH, Talmadge JE, Herberman RB, Wiltrorut
RH. Augmentation of liver-associated NK activity and macrophage-mediated
cytotoxicity following administration of biological response modifiers.
Cancer Immunol Immunother1986; 21: 19-25.
4. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated
killer cell phenomenon: lysis of natural killer-resistant fresh solid
tumour cells by interleukin-2 activated autologous human peripheral blood
lymphocytes. J Exp Med 1982; 155: 1823-41.
5. Lafreniere R, Rosenberg SA. Adoptive immunotherapy of murine hepatic
metastases with lymphokine activated killer (LAK) cells and recombinant
interleukin-2 (rIL-2) can mediate the regression of both immunogenic and
non-immunogenic sarcomas and adenocarcinoma. J Immunol 1985; 135:
4273-80.
6. Mazumder A, Rosenberg SA. Successful immunotherapy of natural killer-resistant
established pulmonary melanoma metastases by the intravenous adoptive
transfer of syngenic lymphocytes activated in vitro by interleukin-2.
J Exp Med 1984; 159: 495-507.
7. Rosenberg SA, Yang JC, Topalian SL. Treatment of 283 consecutive
patients with metastatic melanoma or renal cell cancer using high-dose
bolus interleukin-2. JAMA 1994; 27: 907-13.
8. Vlasveld LT, Horenblas S, Hekman A. Phase II study of intermittent
continuous infusion of low-dose recombinant interleukin-2 in advanced
melanoma and renal cell cancer. Ann Oncol 1994; 5: 179-81.
9. Gutwald JG, Groth W, Mahrle G. Peritumoral injections of interleukin-2
induce tumour regression in metastatic malignant melanoma. Br J Dermatol
1994; 130: 541-2.
10. Antineoplastic agents and immunosuppressants. In : Reynolds JEF,
editors. Martindale: The extra pharmacopoeia. London: The Pharmaceutical
Press 1994: 446.
11. Dréno B. Advances in the treatment of melanoma. Oxford
Clinical Communications: Oxford 1995.
12. Agarwala SS, Kirkwood JM. Interferons in the therapy of solid tumors.
Oncol 1994; 51: 129-36.
13. Brunda MJ, Bellantoni D, Sulich V. In vivo antitumor activity
of combinations of interferon alpha and interleukin-2 in a murine model.
Correlation of efficacy with the induction of cytotoxic cells resembling
natural killer cells. Int J Cancer 1987; 40: 365-71.
14. Cameron RB, McIntosh JK, Rosenberg SA. Synergistic antitumor effects
of combination immunotherapy with recombinant interleukin-2 and recombinant
hybrid alpha-interferon in the treatment of established murine hepatic
metastases. Cancer Res 1988; 48: 5810-7.
15. Ligo M, Sakurai J, Tamura T. In vivo antitumor activity of
multiple injections of recombinant interleukin-2 alone and in combination
with three different types of recombinant interferons, on various syngeneic
murine tumors. Cancer Res 1988; 48: 260-4.
16. Kirkwood JM. Systemic therapy of melanoma. Curr Opin Oncol
1994; 6: 204-11.
17. Tamura T, Sasaki T, Shinkai T. Phase I study of combination therapy
with interleukin-2 and beta-interferon in patients with advanced malignancy.
Cancer Res 1989; 49: 730.
18. Talpaz M. IL-2 + interferon alpha in melanoma. Satellite Symposium:
Use of INF in malignant melanoma, Venice, 16 October 1989.
19. Whitehead RP, Figlin R, Citron ML. A phase II study of concomitant
recombinant human interleukin-2 (IL-2) and recombinant interferon-alpha
2a in patients with disseminated malignant melanoma. Proc Am Soc Clin
Oncol 1990; 9: 281.
20. Zinzani PL, Clark JW, Wanebo HJ. Continuous intravenous infusion
interleukin-2 and interferon-alpha therapy for melanoma with in vitro
studies of combination cytokines for melanoma. Proc Am Soc Clin Oncol
1990; 9: 279.
21. Atzpodien J, Korfer A, Franks CR. Home therapy with recombinant
interleukin-2 and interferon 2b in advanced malignancies. Lancet
1990; 335: 1509-12.
22. Falkson CI, Falkson G, Falkson HC. Improved results with the addition
of interferon-alpha 2b to dacarbazine in the treatment of patients with
metastatic malignant melanoma. J Clin Oncol 1991; 9: 1403-8.
23. AL Sarraf M, Flether W, Orski N. Cisplatin hydration with and without
mannitol diuresis in refractory disseminated malignant melanoma. A SWOG
study. Cancer Treatment Rep 1992; 66: 31-5.
24. Margolin KA, Doroshow JH, Akman SA. Phase II trial of cisplatin
and interferon-alpha in advanced malignant melanoma. J Clin Oncol
1992; 10: 1574-8.
25. Demchak PA, Mier JW, Robert NJ. Interleukin-2 and high-dose cisplatin
in patients with metastatic melanoma: a pilot study. J Clin Oncol
1991; 9: 1821-30.
26. Atzpodien J, Lopez Hanninen E, Kirchner H, Franzke A, Korfer A,
Volkenandt M, et al. Chemoimmunotherapy of advanced malignant melanoma:
sequential administration of subcutaneous interleukin-2 and interferon-alpha
after intravenous dacarbazine and carboplatin or intravenous dacarbazine,
cisplatin, carmustine and tamoxifen. Eur J Cancer 1995; 31A: 876-81.
27. Khayat D, Borel C, Tourani JM, Benhammouda A, Antoine E, Rixe O,
et al. Sequential chemoimmunotherapy with cisplatin, interleukin-2,
and interferon-alfa 2a for metastatic melanoma. J Clin Oncol 1993;
11: 2173-80.
28. Hamblin TJ, Davies B, Sadullah B. A phase 2 study of the treatment
of metastatic malignant melanoma with a combination of dacarbazine, cisplatin,
interleukin-2 and interferon-alpha. Proc Am Soc Clin Oncol 1991;
10: 294.
29. Legha S Plager C, Ring S. A phase II study of biochemotherapy using
interleukin-2 + interferon-alpha 2a in combination with cisplatin, vinblastine
and DTIC in patients with metastatic melanoma. Proc Am Soc Clin Oncol
1992; 11: 343.
30. Richards JM. Sequential chemoimmunotherapy for metastatic melanoma.
Semin Oncol 1991; 18: 91-5.
31. Atzpodien J, Kirchner H. The out-patient use of recombinant human
interleukin-2 and interferon-alpha 2b in advanced malignancies. Eur
J Cancer 1991; 27 (suppl. 4) 588-92.
32. Rosso R, Sertoli MR, Queirolo P. An out-patient phase I study of
subcutaneous interleukin-2 and intramuscular interferon-alpha 2a combination
in advanced malignancies. Ann Oncol 1992; 3: 559-63.
33. Leahy MG, Pitfield D, Popert S. Phase I study comparing continuous
infusion of recombinant interleukin-2 by subcutaneous or intravenous administration.
Eur J Cancer 1992; 28: 1049-51.
34. Dréno B, Cupissol D, Joly P, Sassolas B, Bonneterre T, Tourani
JM. Ambulatory treatment of metastatic melanoma associating subcutaneous
dacarbazine, interferon-alpha and interleukin-2. J Eur Acad Dermatol
Venereol 1995; 4: 248-53.
|
Printable version
