Cancer Treahzent
Reviews
(1990)
17,427-436
Second-line lung cancer
chemotherapy
Mette
Paul
Andersen,
in small
E. G. Kristjansen
Department of Oncology, Rigshospitalet,
and Heine
Blegdamsvej
cell
H. Hansen*
9, 2100 Copenhagen, Denmark
Introduction One of the key problems of small cell lung cancer (SCLC) treatment is to overcome the emergence of drug-resistant relapses. The strikingly different single agent activity in previously untreated patients compared with pretreated patients, as observed with, for example, teniposide, etoposide and carboplatin, illustrates the clinical problem with pleiotropic drug resistance. On the one hand, it is unknown whether the observed lower response rate of chemotherapy given secondarily to patients who have achieved prior remission is a specific effect of the primary chemotherapy or whether on the other it is a general quality ab initio of a SCLC tumor after suppression or elimination of its most sensitive clones (42). Secondary resistance, defined as lack of response to the agent(s) in adequate dosage(s), may thus be an effect of a facilitated growth of primarily resistant subpopulations or an acquired resistance. The latter may be mutational or related to an over-expression of MDR-genes and other metabolical events such as altered levels of enzymes (3). At present it is unclear to what degree drug resistance should be anticipated when deciding which drugs to choose for second-line chemotherapy, if they are clinically indicated at all.
Methodology In order to elucidate some of these problems, the literature on second-line chemotherapy in SCLC for the period 1979-1989 was reviewed, including 35 reports (26 articles and 9 abstracts) comprising 987 patients. Second-line chemotherapy was defined as chemotherapy administered at relapse during or after chemotherapy or to patients refractory to first-line chemotherapy, irrespective of whether or not there had been an interval without treatment. The reports concerned Phase II type studies, with relatively few patients. There were no randomized trials. The studies were compiled in three groups according to type of second-line therapy:
*Address
correspondence
0305-7372/90/040427
to Heine
H. Hansen. 0
+ 10 $03.00/0 427
1990 Academic
Press Limited
428
II III
M.
ANDERSEN
ET
AL.
I Reinduction, with the same combination as initially given (Table 1); Cisplatin and/or VP-16 with or without other agents (Table 2(a)-(c)); Other assumed non-cross-resistant agents (Table 3).
Response data, including duration of response when available, were extracted from each paper together with patient and study characteristics. For each group both crude cumulated response rates and median response rates were calculated and compared. In the cumulated response rate, the responding patients were pooled to obtain an average response rate in the groups independent of the number of patients in the individual trials. The median expresses the typical response rate in the trials. As patients were originally treated and described very differently, a further detailed cumulative description is not feasible, nor would a thorough evaluation of prognostic variables be meaningful on the basis of this material.
Results The results from the studies reviewed are summarized in Tables 1-3, each table referring to one group of second-line chemotherapy. In addition, the three tables are summed up in Table 4. Information was frequently incomplete with regard to duration of response on first-line therapy and length of any drug-free interval. The latter was only reported in about one third of the reports. In group I, this interval ranged from 2-30 months. The first-line combinations consisted of various conventional drug combinations. Information about additional thoracic irradiation was reported for about half of the patients, of whom 55% were irradiated. Before the start of second-line chemotherapy, the stage of disease was reported in 60% of the patients, of whom 30% had local disease (LD) and 70% had extensive disease (ED). Based on the available information, the three groups are comparable with regard to sex, performance status, age distribution, and the limited/extensive stage ratio before the start of second-line chemotherapy. Type and duration of the primary response were unknown for the majority of patients in the three groups, except for the patients who were given reinduction therapy. The cumulated secondary response rate was 30% (275/987), and 5% (49/987) obtained a complete remission (CR). The response rates obtained with the combination of cisplatin (P) and VP-16 (E) or reinduction chemotherapy were 45% and 64%, respectively, as compared to rates < 20% in regimes consisting of supposedly non-cross-resistant agents or PE not given in combination. In 23 of the studies (55% of the patients) the duration of response was reported. The longest median duration of response was 10 months.
Discussion Relapses are likely to represent the emergence of resistant clones, but other reasons should also be considered. After a short-term response the cause of relapse may be unperturbed regrowth of sensitive clones, while late relapses may represent sensitive de nova tumor clones. The toxicity rather than the efficacy defines the maximum dosages in cytostatic therapy.
1.
Reinduction
NR
59
63
50
Age”
1
NR
2
2
Performance (W.H.O.)” before 2nd line
4/g
14123 2+4
6+
o+
17
10
2+2
‘W 2113
Response (CR+ PR)
LD/ED before 2nd line
46
62
67
67
(“4)
Response
6
6
3
10
Duration of response” (months)
CAE VAC VAC/PE
CAE
JE J
VACE VAC VACE
HexaPr,
Reinduction
Reinduction
Reinduction
Reinduction
Chemotherapyb ~-.1st line 2nd line
Ar, Ara-C; B, BCNU; C, Cyclophosphamide; P, Cisplatin; Cc, CCNU; Ca, Carbazilquinone; E, Etoposide, VP-16; H, I, Ifosfamide; J, JM-8, carboplatin; L, Lomustine; M, Methotrexate; Mi, Mitomycin-C; Ni, Nitrosourea; Na, N-acetylcysteine; Vindesine; NR, not reported; $, non-SCLC included. reported after Karnofsky’s scale, these are converted into W.H.O. scale (all tables).
NR
13
71
NR
13/Z
15
37
412
Male/ female
6
NO. of patients
*Median. bAbbreviatiom: A, Adriamycin; methylmelamine; hd, high dose; Procarbazine; V, Vincristine; Vd, In cases where performance are
Total:
Postmus 1987 (36) Giaccone 1987 (15)
Batist 1983 (2) Vincent 1988 (41)
Reference
Table
tz
E
z
F
5
2
z
5
E
2
E
E
h z n
3
s
2.
Group
No. of patients
Chahinian 1984 (5) Hino 1988 (21)
Lam 1988 (24) Lopez 1985 (27)
Evans 1984 (10) Figoli 1988 (13)
Tinsley 1983 (40) Osoba 1981 (3)
NR
NR
17
16/14
30
13
NR
NR
NR
59
NR
60
NR
27
20
60
2519
62
34
16/S
22
58
NR
2118
NR
NR
62
57121
15
1
NR
NR
NR
NR
2
NR
NR
2
2
NR
NR
NR
64
NR
NR
agents
Age”
Performance (W.H.O.)’ before 2nd line
54
Male/ female
therapy
or without other IO/2
II second-lime
(a) Cisplatin and VP-16 with Frytak12 1987 (14) Matsui 8 1988 (28) 8 LoPa (1982 (26) Evans 78 1985 (11) Porter 29 1985 (35)
Reference
Table
NR
NR
6/24
NR
11/16
9125
2120
718
NR
24154
NR
l/7
3/g
LD/ED before 2nd line
2
0+3
2+6
0+8
2+9
0+15
2+8
0+7
15
6+37
If4
1+7
4+5
Response (CR+ PR)
12
23
27
40
41
44
45
47
52
55
63
75
75
Response (%)
NR
4%
3
591
2,5-5
NR
4+
NR
3
4,5
4+
NR
NR
Duration of response” (months)
-
NR
CMV VAC evt. + CMCc VAC CMV CAMPr/EBH VAC CAE CAMCc VAC VAC CVPrL CAML CAMCc
VAC+/-Cc MPr E+/-VAC HPr hdC 50% excl. NR
VACE VAC+/-PNi PE (62%) NR (32%) NR
1st line
E
PE
PEMiH
PE
PE
PE
PE
PE
PE
PE
PE
PE
bdPE
PEC
2nd line
Chemotherapyb
8
3
E!
B
%
F
other
d Median. b For abbreviations
see Table
1.
NR
32
103
NR
17
Total:
NR
22
32/O
Chiuten 1986 (6) Greco 1979 (17) Hino 1988 (21)
or without
agents
NR
38
199
18/4
61/18
79
22
1212
NR
agents,
32
with
other
2217
14
46
with or without
342
29
Niederle 1984 (30)
(c) Cisplatin
Total:
Tempera 1981 (39) Harper 1982 (18)
1979 (17) Evans 1984 (10) Wolff 1986 (43)
GPXO
(b) VP-16
Total:
Batist 1986 (1)
excluding
excluding
NR
NR
57
56
VP-16
NR
54
NR
54
NR
cisplatin
56
NR NR
NR
3/19
12/20
NR
NR
NR
o/14
NR
12117
2
2
2
NR
NR
NR
2
0+3
1+3
2t4
O+l
0+1
0+4
O+l
o+ 13
0+3
6
18
18
19
3
5
5
7
28
10
NR
3,5
635
NR
NR
VACEH
VAC E I CcEM VACE
VAC CcMPr CA CB
NR
8
VAC CMV CVPr CMCc
VAC+/-?
VAC
CMCc VAPr CMCc/VAPr
NR
2
4
3-l
P PCs
P
PVd
PVd
E
E
E
E
EPrH
PE
(33)
(23)
(25)
(31)
(22)
(37)
(4)
(29)
(38)
(34)
(7)
3.
Other
*Median. ’ For abbreviations
Total:
Cohen 1982 Poplin 1982 Shepherd 1987 Nierderle 1982 Cantwell 1988 Rave2 1988 JOSS 1982 Osborne 1987 Loehrer 1986 JOSS 1984 Petruska 1981
Reference
Table
see Table
272
12
25
18
15
13
43
48
23
29
29
17
of patients
NO.
assumed
1.
NR
2213
NR
817
13/o
4013
NR
23/O
2118
2019
17/o
Male/ female
non-cross-resistant
62,5
60
NR
59
62
NR
NR
NR
57
60
54
Age”
agents
NR
1
NR
1
2
1
NR
NR
2
1
1
Performance (W.H.O.)” before 2nd line
NR
7/18
NR
‘39
7/6
14129
NR
10/13
8121
812 1
5112
LD/ED before 2nd line
o+o
O+l
0+1
I+0
O+l
0+4
3+6
2+4
3+5
5+4
4+6
Response (CR+PR)
0
4
6
7
8
9
19
26
28
31
59
Response (%)
NR
3.7
NR
2,5
2
NR
NR
NR
NR
3-7,5
5,6+
Duration of response” (months)
VAC
NR
NR
hdC
NR
EVd+/-P
VAE
CC
VAC+/-IE
EJ
PE
CAE
Vd
HVd
INa
Ar
MiHVd
VAC
I
EMCc
VAC
CcMPrV
VAPr
Chemotherapyb ~ 1st line 2nd line
CMCc
___
k
t? Y
z E
3 ;
SECOND-LINE Table
Group
4.
Summary
of Tables
2nd line chemotherapy
L(a)
PE + / - other Reinduction
II(b)
E+ /excl. P+ / excl. Other
II(c) III
A Cumulated. h Only reported
CHEMOTHERAPY
other agents, P other agents, E agents
LUNG
433
CANCER
l-3 NO.
agents
IN
NO.
of trials
patykts
144
342 71
5
199
4
103
Response (CR + PR)”
18+112 lOf33 (+ 17)” 0+20 3+10
Response rate range (%)
Response rate median (%)
Cumulated response rates (%)
46-67 l&75
45 64
43 61
3-28
5
10
6-19
18
15
o-59
9
18
(+2)” I1
272
18+32
as response.
Thus, even very effective combinations are not per se optimal with regard to cell kill. Accordingly, there may be sensitive cells left in the tumor after an apparently optimal treatment with chemotherapy. If, on the other hand, the composition of the tumor has changed during treatment to consist of a majority of resistant clones, continued therapy aimed at only a small sensitive fraction of tumor cells is not likely to produce clinical responses. The genetic concept (16) stating that the risk of developing resistance by mutations is a function of tumor mass and age has provided a useful theoretical working model with regard to avoidance of secondary resistance. By adapting these considerations in the clinic, the impact of cross-resistance has been emphasized, although attempts directed against it, the non-cross-resistant alternating combination chemotherapy, has so far demonstrated only modest superiority to continuous therapy [8, 9, 12, 20, 32(a)]. The poor results of the attempted non-cross-resistant second-line therapy support the view that failure to identify real cross-resistant agents is the reason for the lack of success. Whether the patients benefit from second-line chemotherapy in terms ofimproved survival and/or quality of life is not quite clear. In a recent trial (19), 610 evaluable patients with SCLC, were primarily randomized between four and eight cycles of chemotherapy and in a second randomization at relapse between second-line chemotherapy and symptomatic treatment alone. The only treatment strategy associated with significantly worse survival was short-term (i.e. four cycles) initial chemotherapy followed by symptomatic treatment at relapse. Thus, the short duration of the initial chemotherapy may be the reason for the survival benefit of additional chemotherapy. To elucidate these problems future Phase III trials in SCLC should include an evaluation of relapse treatment, preferentially by a second randomization. The stratification of patients included in such second-line evaluations should contain information on the duration of the primary response. With the current therapeutic potentials, second-line therapy should be evaluated primarily by its palliative quality rather than by response rates as the prospect of cure seems to be minimal in relapsed patients. Considering the above-mentioned limitations and the retrospective nature ofthis review, one may cautiously conclude that the attempted non-cross-resistant approach (not including VP-16 and cisplatin, PE) produced the poorest results. The PE combination and reinduction were superior with regard to response rate (Table 4). The seemingly super-
434
M.
ANDERSEN
ET
AL.
additive effect of etoposide and cisplatin, as apparent when examining Table 4, corroborates earlier reports on the synergism of the two drugs (35). The superiority of reinduction therapy in this analysis, compared with other combinations, may be a consequence of the selection ofpatients with proven response potentials. Obviously, no patient in this group was a non-responder during primary treatment, thereby constituting a potential bias. In addition, all patients in this group, by definition had a drug-free interval. However, the results demonstrate that in a particular subgroup of candidates for second-line chemotherapy, i.e. responders with a subsequent pause in the chemotherapy, rechallenge with the original combination was effective in more than 50% with a median duration of response up to 10 months.
Summary
The literature on second-line chemotherapy in small cell lung cancer (SCLC) for the period 1979-1989 is reviewed. The reports consisted mainly of Phase II type studies and comprised a total of 987 patients with relatively few patients per study. The information was frequently incomplete with regard to duration of response on first-line chemotherapy, length of any drug-free interval and duration of response on second-line chemotherapy. The overall second-line response rate was 30%, but only 5% were complete responses (CR), The response rates obtained by the combination of cisplatinum (P) and VP-16 (E) or reinduction therapy were 45% and 64% (medians), respectively. These rates were superior to regimens consisting of supposedly non-cross-resistant agents. With P and E not given in combination, the response rates were less than 20%.
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SECOND-LINE
CHEMOTHERAPY
IN
LUNG
CANCER
435
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ANDERSEN
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31. Osborne, R. J., Clark, P. I., Slevin, M. L. & Wrigley, P. F. M. (1987) High-dose cytarabine in small cell lung cancer. Cancer Treat. Rep. 71: 417-418. 32. Osoba, D., Evans, W. K. & Feld, R. (1981) VP-16 and cisplatinum combination chemotherapy for relapse in small cell lung cancer. Am. Sm. Clin. Oncol. Abstracts, C-633. 32a. Bsterlind, K., Pedersen, A. G., Vindelw, L., SBrenson, S., Hansen, M., Dombernowsky, P. & Hansen, H. H. (1986) Alternating or continuous chemotherapy of extensive stage small cell lung cancer. Results of a controlled trial on 204 patients. Lung Cancer 2: 127-128. 33. Petruska, P., Luedke, D., Luedke, S., Gallagher, N. & Broun, G. (1981) Phase II study of vindesine in refractory small cell carcinoma of lung. Am. Sot. Clin. Oncol. Abstracts, C-653. 34. Poplin, E. A., Aisner, J., van Echo, D. A., Whitacre, M. & Wiernik, P. H. (1982) CCNU, vincristine, methotrexate, and procarbazine treatment of relapsed small cell lung carcinoma. Cancer Treat. Rep. 66: 1557-1559. 35. Porter, L. L., Johnson, D. H., Hainsworth, J. D., Hande, K. R. & Greco, F. A. (1985) Cisplatin and etoposide combination chemotherapy for refractory small cell carcinoma of the lung. Cancer Treat. Rep. 69: 479-481. 36. Postmus, P. E., Berendsen, H. H., van Zandwijk, N., Splinter, T. A. W., Burghouts, J. T. M. & Bakker, W. (1987) Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur. J. Cancer Clin. Oncol. 23: 1409-1411. 37. Ravez, P., Sculier, J. P., Klastersky, I., Libert, P., Vandermoten, G., Michel, J., Brohee, D., Thiriaux, J., Dabouis, G., Themelin, L. & Mommen, P. (1988) Cyclophosphamide, adriamycin and vincristine (CAVi): an ineffective second-line regimen for small cell lung cancer. Lung Cancer 4 (Suppl.): Abstract 6.1.12. 38. Shepherd, F. A., Evans, W. K., MacCormick, R., Feld, R. & Yau, J. C. (1987) Cyclophosphamide, doxorubicin and vincristine in etoposideand cisplatin-resistant small cell lung cancer. Cancer Treat. Rep. 71: 941-944. 39. Tempero, M., Kessinger, A. & Lemon, H. M. (1981) VP-16-213 therapy in patients with small-cell carcinoma of the lung after failure on combination chemotherapy. Cancer Clin. Trials 4: 155-157. 40. Tinsley, R., Comis, R., DiFino, S., Ginsberg, S., Gullo, J., Hickes, R., Poiesz, B., Rudolph, A., Issell, B. & Lee, F. (1983) Potential clinical synergy observed in the treatment of small cell lung cancer (SCLC) with cisplatin (P) and VP-16-213 (V). Am. Sac. Clin. Oncol. Abstracts, C-772. 41. Vincent, M., Evans, B. & Smith, I. (1988) First-line chemotherapy rechallenge after relapse in small cell lung cancer. Cancer Chemother. Pharmacol. 21: 4548. 42. Vindelw, L. (1985) Cell kinetics, tumor heterogeneity and antineoplastic treatment ofsmall cell carcinoma of the lung. Clin. Oncol. 4: 45-57. 43. Wolff, S. N., Birch, R., Sarma, P. & Greco, F. A. (1986) Randomized dose-response evaluation of etoposide in small cell carcinoma of the lung. Cancer Treat. Rep. 70: 583-587.
Reviews
(1990)
17,427-436
Second-line lung cancer
chemotherapy
Mette
Paul
Andersen,
in small
E. G. Kristjansen
Department of Oncology, Rigshospitalet,
and Heine
Blegdamsvej
cell
H. Hansen*
9, 2100 Copenhagen, Denmark
Introduction One of the key problems of small cell lung cancer (SCLC) treatment is to overcome the emergence of drug-resistant relapses. The strikingly different single agent activity in previously untreated patients compared with pretreated patients, as observed with, for example, teniposide, etoposide and carboplatin, illustrates the clinical problem with pleiotropic drug resistance. On the one hand, it is unknown whether the observed lower response rate of chemotherapy given secondarily to patients who have achieved prior remission is a specific effect of the primary chemotherapy or whether on the other it is a general quality ab initio of a SCLC tumor after suppression or elimination of its most sensitive clones (42). Secondary resistance, defined as lack of response to the agent(s) in adequate dosage(s), may thus be an effect of a facilitated growth of primarily resistant subpopulations or an acquired resistance. The latter may be mutational or related to an over-expression of MDR-genes and other metabolical events such as altered levels of enzymes (3). At present it is unclear to what degree drug resistance should be anticipated when deciding which drugs to choose for second-line chemotherapy, if they are clinically indicated at all.
Methodology In order to elucidate some of these problems, the literature on second-line chemotherapy in SCLC for the period 1979-1989 was reviewed, including 35 reports (26 articles and 9 abstracts) comprising 987 patients. Second-line chemotherapy was defined as chemotherapy administered at relapse during or after chemotherapy or to patients refractory to first-line chemotherapy, irrespective of whether or not there had been an interval without treatment. The reports concerned Phase II type studies, with relatively few patients. There were no randomized trials. The studies were compiled in three groups according to type of second-line therapy:
*Address
correspondence
0305-7372/90/040427
to Heine
H. Hansen. 0
+ 10 $03.00/0 427
1990 Academic
Press Limited
428
II III
M.
ANDERSEN
ET
AL.
I Reinduction, with the same combination as initially given (Table 1); Cisplatin and/or VP-16 with or without other agents (Table 2(a)-(c)); Other assumed non-cross-resistant agents (Table 3).
Response data, including duration of response when available, were extracted from each paper together with patient and study characteristics. For each group both crude cumulated response rates and median response rates were calculated and compared. In the cumulated response rate, the responding patients were pooled to obtain an average response rate in the groups independent of the number of patients in the individual trials. The median expresses the typical response rate in the trials. As patients were originally treated and described very differently, a further detailed cumulative description is not feasible, nor would a thorough evaluation of prognostic variables be meaningful on the basis of this material.
Results The results from the studies reviewed are summarized in Tables 1-3, each table referring to one group of second-line chemotherapy. In addition, the three tables are summed up in Table 4. Information was frequently incomplete with regard to duration of response on first-line therapy and length of any drug-free interval. The latter was only reported in about one third of the reports. In group I, this interval ranged from 2-30 months. The first-line combinations consisted of various conventional drug combinations. Information about additional thoracic irradiation was reported for about half of the patients, of whom 55% were irradiated. Before the start of second-line chemotherapy, the stage of disease was reported in 60% of the patients, of whom 30% had local disease (LD) and 70% had extensive disease (ED). Based on the available information, the three groups are comparable with regard to sex, performance status, age distribution, and the limited/extensive stage ratio before the start of second-line chemotherapy. Type and duration of the primary response were unknown for the majority of patients in the three groups, except for the patients who were given reinduction therapy. The cumulated secondary response rate was 30% (275/987), and 5% (49/987) obtained a complete remission (CR). The response rates obtained with the combination of cisplatin (P) and VP-16 (E) or reinduction chemotherapy were 45% and 64%, respectively, as compared to rates < 20% in regimes consisting of supposedly non-cross-resistant agents or PE not given in combination. In 23 of the studies (55% of the patients) the duration of response was reported. The longest median duration of response was 10 months.
Discussion Relapses are likely to represent the emergence of resistant clones, but other reasons should also be considered. After a short-term response the cause of relapse may be unperturbed regrowth of sensitive clones, while late relapses may represent sensitive de nova tumor clones. The toxicity rather than the efficacy defines the maximum dosages in cytostatic therapy.
1.
Reinduction
NR
59
63
50
Age”
1
NR
2
2
Performance (W.H.O.)” before 2nd line
4/g
14123 2+4
6+
o+
17
10
2+2
‘W 2113
Response (CR+ PR)
LD/ED before 2nd line
46
62
67
67
(“4)
Response
6
6
3
10
Duration of response” (months)
CAE VAC VAC/PE
CAE
JE J
VACE VAC VACE
HexaPr,
Reinduction
Reinduction
Reinduction
Reinduction
Chemotherapyb ~-.1st line 2nd line
Ar, Ara-C; B, BCNU; C, Cyclophosphamide; P, Cisplatin; Cc, CCNU; Ca, Carbazilquinone; E, Etoposide, VP-16; H, I, Ifosfamide; J, JM-8, carboplatin; L, Lomustine; M, Methotrexate; Mi, Mitomycin-C; Ni, Nitrosourea; Na, N-acetylcysteine; Vindesine; NR, not reported; $, non-SCLC included. reported after Karnofsky’s scale, these are converted into W.H.O. scale (all tables).
NR
13
71
NR
13/Z
15
37
412
Male/ female
6
NO. of patients
*Median. bAbbreviatiom: A, Adriamycin; methylmelamine; hd, high dose; Procarbazine; V, Vincristine; Vd, In cases where performance are
Total:
Postmus 1987 (36) Giaccone 1987 (15)
Batist 1983 (2) Vincent 1988 (41)
Reference
Table
tz
E
z
F
5
2
z
5
E
2
E
E
h z n
3
s
2.
Group
No. of patients
Chahinian 1984 (5) Hino 1988 (21)
Lam 1988 (24) Lopez 1985 (27)
Evans 1984 (10) Figoli 1988 (13)
Tinsley 1983 (40) Osoba 1981 (3)
NR
NR
17
16/14
30
13
NR
NR
NR
59
NR
60
NR
27
20
60
2519
62
34
16/S
22
58
NR
2118
NR
NR
62
57121
15
1
NR
NR
NR
NR
2
NR
NR
2
2
NR
NR
NR
64
NR
NR
agents
Age”
Performance (W.H.O.)’ before 2nd line
54
Male/ female
therapy
or without other IO/2
II second-lime
(a) Cisplatin and VP-16 with Frytak12 1987 (14) Matsui 8 1988 (28) 8 LoPa (1982 (26) Evans 78 1985 (11) Porter 29 1985 (35)
Reference
Table
NR
NR
6/24
NR
11/16
9125
2120
718
NR
24154
NR
l/7
3/g
LD/ED before 2nd line
2
0+3
2+6
0+8
2+9
0+15
2+8
0+7
15
6+37
If4
1+7
4+5
Response (CR+ PR)
12
23
27
40
41
44
45
47
52
55
63
75
75
Response (%)
NR
4%
3
591
2,5-5
NR
4+
NR
3
4,5
4+
NR
NR
Duration of response” (months)
-
NR
CMV VAC evt. + CMCc VAC CMV CAMPr/EBH VAC CAE CAMCc VAC VAC CVPrL CAML CAMCc
VAC+/-Cc MPr E+/-VAC HPr hdC 50% excl. NR
VACE VAC+/-PNi PE (62%) NR (32%) NR
1st line
E
PE
PEMiH
PE
PE
PE
PE
PE
PE
PE
PE
PE
bdPE
PEC
2nd line
Chemotherapyb
8
3
E!
B
%
F
other
d Median. b For abbreviations
see Table
1.
NR
32
103
NR
17
Total:
NR
22
32/O
Chiuten 1986 (6) Greco 1979 (17) Hino 1988 (21)
or without
agents
NR
38
199
18/4
61/18
79
22
1212
NR
agents,
32
with
other
2217
14
46
with or without
342
29
Niederle 1984 (30)
(c) Cisplatin
Total:
Tempera 1981 (39) Harper 1982 (18)
1979 (17) Evans 1984 (10) Wolff 1986 (43)
GPXO
(b) VP-16
Total:
Batist 1986 (1)
excluding
excluding
NR
NR
57
56
VP-16
NR
54
NR
54
NR
cisplatin
56
NR NR
NR
3/19
12/20
NR
NR
NR
o/14
NR
12117
2
2
2
NR
NR
NR
2
0+3
1+3
2t4
O+l
0+1
0+4
O+l
o+ 13
0+3
6
18
18
19
3
5
5
7
28
10
NR
3,5
635
NR
NR
VACEH
VAC E I CcEM VACE
VAC CcMPr CA CB
NR
8
VAC CMV CVPr CMCc
VAC+/-?
VAC
CMCc VAPr CMCc/VAPr
NR
2
4
3-l
P PCs
P
PVd
PVd
E
E
E
E
EPrH
PE
(33)
(23)
(25)
(31)
(22)
(37)
(4)
(29)
(38)
(34)
(7)
3.
Other
*Median. ’ For abbreviations
Total:
Cohen 1982 Poplin 1982 Shepherd 1987 Nierderle 1982 Cantwell 1988 Rave2 1988 JOSS 1982 Osborne 1987 Loehrer 1986 JOSS 1984 Petruska 1981
Reference
Table
see Table
272
12
25
18
15
13
43
48
23
29
29
17
of patients
NO.
assumed
1.
NR
2213
NR
817
13/o
4013
NR
23/O
2118
2019
17/o
Male/ female
non-cross-resistant
62,5
60
NR
59
62
NR
NR
NR
57
60
54
Age”
agents
NR
1
NR
1
2
1
NR
NR
2
1
1
Performance (W.H.O.)” before 2nd line
NR
7/18
NR
‘39
7/6
14129
NR
10/13
8121
812 1
5112
LD/ED before 2nd line
o+o
O+l
0+1
I+0
O+l
0+4
3+6
2+4
3+5
5+4
4+6
Response (CR+PR)
0
4
6
7
8
9
19
26
28
31
59
Response (%)
NR
3.7
NR
2,5
2
NR
NR
NR
NR
3-7,5
5,6+
Duration of response” (months)
VAC
NR
NR
hdC
NR
EVd+/-P
VAE
CC
VAC+/-IE
EJ
PE
CAE
Vd
HVd
INa
Ar
MiHVd
VAC
I
EMCc
VAC
CcMPrV
VAPr
Chemotherapyb ~ 1st line 2nd line
CMCc
___
k
t? Y
z E
3 ;
SECOND-LINE Table
Group
4.
Summary
of Tables
2nd line chemotherapy
L(a)
PE + / - other Reinduction
II(b)
E+ /excl. P+ / excl. Other
II(c) III
A Cumulated. h Only reported
CHEMOTHERAPY
other agents, P other agents, E agents
LUNG
433
CANCER
l-3 NO.
agents
IN
NO.
of trials
patykts
144
342 71
5
199
4
103
Response (CR + PR)”
18+112 lOf33 (+ 17)” 0+20 3+10
Response rate range (%)
Response rate median (%)
Cumulated response rates (%)
46-67 l&75
45 64
43 61
3-28
5
10
6-19
18
15
o-59
9
18
(+2)” I1
272
18+32
as response.
Thus, even very effective combinations are not per se optimal with regard to cell kill. Accordingly, there may be sensitive cells left in the tumor after an apparently optimal treatment with chemotherapy. If, on the other hand, the composition of the tumor has changed during treatment to consist of a majority of resistant clones, continued therapy aimed at only a small sensitive fraction of tumor cells is not likely to produce clinical responses. The genetic concept (16) stating that the risk of developing resistance by mutations is a function of tumor mass and age has provided a useful theoretical working model with regard to avoidance of secondary resistance. By adapting these considerations in the clinic, the impact of cross-resistance has been emphasized, although attempts directed against it, the non-cross-resistant alternating combination chemotherapy, has so far demonstrated only modest superiority to continuous therapy [8, 9, 12, 20, 32(a)]. The poor results of the attempted non-cross-resistant second-line therapy support the view that failure to identify real cross-resistant agents is the reason for the lack of success. Whether the patients benefit from second-line chemotherapy in terms ofimproved survival and/or quality of life is not quite clear. In a recent trial (19), 610 evaluable patients with SCLC, were primarily randomized between four and eight cycles of chemotherapy and in a second randomization at relapse between second-line chemotherapy and symptomatic treatment alone. The only treatment strategy associated with significantly worse survival was short-term (i.e. four cycles) initial chemotherapy followed by symptomatic treatment at relapse. Thus, the short duration of the initial chemotherapy may be the reason for the survival benefit of additional chemotherapy. To elucidate these problems future Phase III trials in SCLC should include an evaluation of relapse treatment, preferentially by a second randomization. The stratification of patients included in such second-line evaluations should contain information on the duration of the primary response. With the current therapeutic potentials, second-line therapy should be evaluated primarily by its palliative quality rather than by response rates as the prospect of cure seems to be minimal in relapsed patients. Considering the above-mentioned limitations and the retrospective nature ofthis review, one may cautiously conclude that the attempted non-cross-resistant approach (not including VP-16 and cisplatin, PE) produced the poorest results. The PE combination and reinduction were superior with regard to response rate (Table 4). The seemingly super-
434
M.
ANDERSEN
ET
AL.
additive effect of etoposide and cisplatin, as apparent when examining Table 4, corroborates earlier reports on the synergism of the two drugs (35). The superiority of reinduction therapy in this analysis, compared with other combinations, may be a consequence of the selection ofpatients with proven response potentials. Obviously, no patient in this group was a non-responder during primary treatment, thereby constituting a potential bias. In addition, all patients in this group, by definition had a drug-free interval. However, the results demonstrate that in a particular subgroup of candidates for second-line chemotherapy, i.e. responders with a subsequent pause in the chemotherapy, rechallenge with the original combination was effective in more than 50% with a median duration of response up to 10 months.
Summary
The literature on second-line chemotherapy in small cell lung cancer (SCLC) for the period 1979-1989 is reviewed. The reports consisted mainly of Phase II type studies and comprised a total of 987 patients with relatively few patients per study. The information was frequently incomplete with regard to duration of response on first-line chemotherapy, length of any drug-free interval and duration of response on second-line chemotherapy. The overall second-line response rate was 30%, but only 5% were complete responses (CR), The response rates obtained by the combination of cisplatinum (P) and VP-16 (E) or reinduction therapy were 45% and 64% (medians), respectively. These rates were superior to regimens consisting of supposedly non-cross-resistant agents. With P and E not given in combination, the response rates were less than 20%.
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CHEMOTHERAPY
IN
LUNG
CANCER
435
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ANDERSEN
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