- Email: [email protected]
Treatment of relapsed small cell lung cancer
Treatment
of Relapsed Pieter
Small
cell
despite
lung
cancer
a high
therapy.
For
pends
and
a good
the
after
at relapse
earlier in
temporary
Saunders
be brain,
palliation.
For of main
radiotherapy
of first-line
For the
patients more
Evidence
off with
than
3
of chemo-
therapy.
In case
non-cross-resistant
given.
For
symptomatic
radiotherapy
me-
usually
intrathoracic bronchus
relapse and/or
is a possibility
if not
superior given
gives and
seca-
as part
treatment.
Oncol28
[suf@
4):48-52.
Copyright
0 2001
by W/3.
Company.
MALL CELL lung cancer (SCLC) is considered to be one of the most chemosensitive solid tumors, with response rates to first-line chemotherapy of more than 80%.1 Therefore, combination chemotherapy is considered the standard treatment for all stages of SCLC. Currently, early radiotherapy is part of the treatment of limiteddisease SCLC as well.2 Despite this high response rate after first-line chemotherapy, the majority of patients with SCLC relapse, and the overall sure viva1 after relapse is 2 to 4 months.1 For most patients there is the need and wish for additional treatment to provide as much palliation as possible. Guidelines for treatment at relapse after an initial response are relatively scarce, both with respect to the role of second-line chemotherapy in general and in specific situations encountered in daily clinical practice. In this review, we discuss published results for treatment of relapsed SCLC in general and in specific situations when symptomatology at the site of relapse is the most important reason for additional therapy.
S
From the Department of Pulmonary Diseases, University Hospital, Vrije Uniuersiteit, Amsterdam, The Netherlands. Address reprint requests to Pieter E. Postmus, MD, PhD, Deof Pulmonary Diseases,UniversityHospital Vrije Uniuersiteit, Box 7057, Amsterdam, The Netherlands 1007 MB. Copyright 0 2001 by W.B. Saunders Company
partment
0093-7754/01/2802-0409$35.00/O doi:10.1053/s0nc.2001.25750 48
F. Smit
CHEMOTHERAPY de-
time
choice
as initial
so-called or
obstruction
val vein, Semin
same
should bone
at relapse
a relapse
treatment, is the
progression,
tastases
and
and Egbert
Lung Cancer
chemo-
treatment,
of progression. status
first-line
chemotherapy
vere
site
Cell
tumor
first-line
treatment
to first-line
performance
therapy
relapsing
after
patients,
response
months of
is a frequently of response
these
on the
therapy,
rate
E. Postmus
Small
The first question concerning second-line chemotherapy for a relapseor progressionof SCLC in this era of “evidence-basedmedicine” is: Is there a scientifically solid basis for it? Chemotherapy at relapse is usually considered as the treatment of choice for those involved in the treatment of SCLC. Most physicians will find it difficult to believe that a different approach might be asbeneficial for the patient. No prospective randomized trials addressingthis specific question have been performed. In fact, there is only one published study in which the effect of treatment on survival at relapsewasinvestigated. Spiro et a13randomized 610 patients between treatment with either four or eight cycles of first-line chemotherapy, and also randomized them to receive either second-line chemotherapy or symptomatic treatment only at diseaseprogression.First-line chemotherapy consisted of cyclophosphamide/vincristine/etoposide, and second-line therapy consisted of methotrexate/doxorubicin. Symptomatic treatment included radiotherapy for indications such as bone pain, cerebral metastases,superior vena caval obstruction, dyspnea,hemoptysis, or large airway obstruction. Analgesics or corticosteroids were administered as necessary. No cytotoxic chemotherapy wasgiven to patients receiving symptomatic treatment. The study was powered to detect a 10% difference in overall survival (from 20% to 30%) at 1 year. Of the four treatment arms, the short chemotherapy plus symptomatic treatment arm was inferior to the other three, which were equal in outcome. Subgroup analysis shows that there are two answersto the question of whether chemotherapy at relapseis beneficial. First, for those receiving short-term chemotherapy plus chemotherapy at relapseor progression,survival is significantly improved compared with patients receiving symptomatic treatment. Median survival was 20 versus 11 weeks, respectively (P < .OOl). On the other hand, for those receiving long-term chemotherapy, second-line chemotherapy does not significantly improve survival compared with symptomatic treatment (median survival of 15 and 12 weeks, respectively) (Table 1). Seminars
in Oncology,
Vol 28, No 2, Suppl 4 (April),
200 I: pp 48-52
TREATMENT
OF RELAPSED
Table
SMALL
CELL
I. Treatment
LUNG
49
CANCER
and Results MS From
MS From start First-Line Therapy Short
Start SecondNo. of Patients
Response Rate (%)
38 30
105 106
25.6 -
20” I I*
42
II4 112
18.7 -
I5 I2
W4
Line Ws)
i second-
line Short + BSC Long + secondline Long + BSC
38
Abbreviation: MS, median * P < .oo I. Data from Spiro et aL3
survival;
BSC, best supportive
care.
It is difficult to draw conclusions regarding the value of treatment at relapse from this study. For those receiving short-term chemotherapy, it is clearly beneficial; however, four cycles of chemotherapy is less than usually given, potentially resulting in undertreatment. This is supported by the shorter time to progression than for those receiving longer treatment. On the other hand, in the group receiving longer treatment, more resistance towards chemotherapy might have developed, making additional chemotherapy potentially less effective. Although not significantly different, the response rate with the second-line regimen in the long-term treatment group was lower than that of the short-term treatment group (18.7% e, 25.6%). The most important problem in this study is the methodology used to select patients for secondline chemotherapy, which was not in accordance with daily practice. For instance, patients considered unfit for chemotherapy because of poor performance status would be excluded in the latter situation, but were included in this study. In addition, the selection of second-line chemotherapy components was based on an assumed lack of cross-resistance, not on current knowledge related to time off therapy and initial response to first-line chemotherapy.’ Literature
single-agent studies included evaluations of new drugs against SCLC including etoposide, cisplatin, carboplatin, ifosfamide, cytarabine, and vindesine. The combination chemotherapy studies were usually aimed to evaluate the efficacy of a second-line regimen. The choice of drugs was based on presumed non-cross-resistance of the drugs towards those used in first-line regimen. Arguments for non-cross-resistance were based on differences in mechanism of action or in vitro studies of tumor models. Overall, the combination of cisplatin/etoposide was found to be superior, with higher response rates than were obtained with other combination regimens or with cisplatin or etoposide as single agents. However, cisplatin/etoposide was not a common first-line combination at that time, which might account for its favorable results as second-line treatment. Furthermore, in most studies before 1990, all patients selected for secondline treatment were included without considering therapeutic results of first-line therapy, Usually, first-line therapy was not reported in detail, including response to therapy, progression while on therapy or after achieving a good response, and time off therapy, as well as indicating other prognostic factors for achieving a response to secondline therapies.5 The only exceptions were four reports that dealt exclusively with patients progressing after achieving at least a partial response to first-line therapy.6-9 In these studies, described in Table 2, the efficacy of reinduction chemotherapy was evaluated. An important characteristic of the patients evaluated in three of these studies was the relatively short duration of the first-line treatment,
Table Time After First-Line Study Grant
et al5
No. of
(4
Patients
>I2
6
Batist et al6
>4.5 54.5
I9 I8
POWllUS et al’ Giaccone
>4.s 54.5
8 4
>4.s 54.5
5 9
Review
Andersen et a14 reviewed studies of second-line treatment of SCLC reported before 1990. This review included a mixture of combination chemotherapy regimens and single-agent studies. The
2. Reinduction
et aI*
Response Rate (%)
Response Duration 0-4
67 79
IO 7
44 50
4 6
50 80 II
3
50
POSTMUS
usually less than 6 months.?-” This had become standard at that time, based on a number of large randomized studies that showed that prolonged cytotoxic treatment had no effect on survival. The second review of second-line treatment, by Huisman et al,1° describes the studies after 1990. This review included a number of single-agent phase II studies in which the drugs oral etoposide (at prolonged schedules),11 vinorelbine,i2 docetaxel,i3 temposide, topotecan,15 irinotecan,i6 and paclitaxeli7 were evaluated. In a number of these studies, the details of the first-line therapy as well as the effects were included,11 and inclusion criteria for some were based on thisis-is The evaluation of a second-line regimen was performed in the same way in a number of studies, and aimed to find a clinically relevant degree of non-cross-resistance.igJ” Based on the results of these and some earlier studies,2iJ2 a number of conclusions were drawn that form the basis for the current guidelines for second-line chemotherapy and the evaluation of new drugs: (1) Sensitive patients (ie, those who had a response to first-line therapy and were relapsing or progressing after 3 or more months) should be treated with combination chemotherapy, which may be identical to first-line treatment. (2) Refractory patients who never responded to first-line treatment or responded but progressed during first-line therapy or within 3 months from the end of induction treatment should be treated with drugs that are non-crossresistant to the drugs used in first-line therapy. RADIOTHERAPY
Treatment of Primary Tumor Small cell lung cancer is one of the most radiosensitive solid tumors, and thoracic radiotherapy is
AND
currently part of standard treatment of patients with limited disease.Adding more radiotherapy for local relapse is usually impossiblebecauseof the risk of severesideeffects. For extensive disease,the role of radiotherapy in first-line treatment is less certain. For these patients, radiotherapy to the primary tumor at the time of relapsemight still be considered.This is especially relevant when symp? toms from the primary tumor such assuperior vena caval obstruction, dyspnea, hemoptysis, or large airway obstruction require palliation. In three retrospective studies, the effects of radiotherapy for an intrathoracic relapseof SCLC were evaluated (Table 3).“‘-25 Although a wide rangeof radiotherapy dosesand scheduleswere applied, the impres sion of the investigators wasthat better palliation wasachieved with doses2 40 Gy. For the majority of patients, this results in a responsewithin the radiated area. Whether survival was improved by this approach is questionable. Treatment
of Bone Metastases
If painful bone lesionsimpair the quality of life of the patient, SCLC does not differ from any other type of solid tumor. As is standard for all bone metastases,local radiotherapy usually results in improvement of symptomatology and is without doubt indicated in situations with tumor relapsein supporting parts of the skeleton, such as the long bones of the legs, vertebrae, and pelvis. Treatment of Brain Metastases Thirty percent to 40% of SCLC patients develop clinically overt central nervous system metastasesbefore death. For daily practice, it is important to keep in mind that brain metastasesof SCLC are signsof progressionof the primary disease.The development of brain metastasesis as-
‘, .L
)_,/
TabIe
g ,-,
: _.! : ,J ‘1.
3. ~Radiatherepy
for Relapse
of Small
Cell
Lung
Cancer
: No. Study
lhde Ochs Salazar
Type
of Study
et alZ3
Retrospective
et al*4
Retrospective
et aI25
Dose
21-51 40
Retrospective
bO(n
45-55
=
Abbreviations:
LD, limited
disease;
ED, extensive
II)
(n = 14)
38-42(n= disease.
of Patients (LDIED)
(Gy)
II)
SMIT
Response
Rate in
Radiation
Port
(%)
Median
Survival Cm4
23 (I 1112) 25 (8/ 17)
52 64
3 4
3 b (2719)
77
4
TREATMENT
OF RELAPSED
SMALL
CELL
LUNG
CANCER
sociated with considerable morbidity. It is obvious from many studies that SCLC patients with a central nervous system relapse have a poor prognosis with regard to survival (ie, 3 to 4.5 months). Despite this, palliation of these patients is often needed.26 Whole-brain radiotherapy has been in use for decades as standard treatment of these patients, and in combination with corticosteroids it results in improvement of symptoms and a better quality of life for some time. For the rare patient in a complete remission after chemotherapy or chemoradiotherapy with a sole relapse in the brain, the role of whole-brain radiotherapy has been evaluated in a phase II study with disappointing results.27 During the last decade, treatment of patients with a relapse in the brain after previous chemotherapy has been reported in a number of studies. Recently, in a randomized study, the intracranial response rate was shown to be much higher with combined chemoradiotherapy than with chemotherapy alone; however, no survival benefit was seen.28 The activity of carboplatin after failure of teniposide illustrates that brain metastases in patients pretreated with chemotherapy behaves in the same way as metastases at other sites29 Therefore, the same rules regarding chemotherapy at relapse as for chemotherapy for patients with relapse of SCLC after chemotherapy should be applied.
51
in trials testing new drugs or concepts. For specific sites such as intrathoracic tumor or brain metastases, radiotherapy alone should be considered for palliation or in combination with chemotherapy. REFERENCES 1. Camey therapy,
don, Martin 2. Gregor
Despite the limited overall improvement in the treatment of SCLC, with prospects of cure of about 25% among good performance status patients with limited disease, the majority of patients have a grim outcome. For many patients, relapse after an initial success must be anticipated. In this situation, additional treatment is often needed as part of palliation. The type of treatment depends on the general condition of the patient, initial treatment, and the presence of organ dysfunction such as hyperbilirubinemia or renal failure caused by nephrotoxic first-line therapy. If chemotherapy is still considered feasible, the rules are the same as those described for second-line treatment? retreatment with the induction regimen if a response was seen after first-line treatment and the treatment-free interval is more than 3 months; in all other situations, non-cross-resistant chemotherapy is indicated, or the patient should be included
Shepherd HH
FA: Treatment (ed):
of SCLC:
Textbook
of Lung
3. Spiro
SG,
Souhami
RL,
Geddes
Chemo-
Cancer.
Dunitz Ltd, 2000, pp 261-272 A, Sause WT: Treatment of SCLC:
in: Hansen HH (ed): Textbook of Lung Martin Dunitz Ltd, 2000, pp 251-259
radiotherapy,
Cancer.
DM,
Lon-
London,
et al: Duration
of
chemotherapy campaign trial. 4. Andersen
in small cell lung cancer: A cancer research Br J Cancer 59578-583, 1989 M, Kristjansen PE, Hansen HH: Seond-line
chemotherapy
in
17:427-436, 5. Grant
small
cell
1990 SC, Gralla
motherapy
trials
lung
RJ, Kris
in small-cell
cancel-. MG,
lung
Cancer
1970
treated
6. Batist G, Ihde of lung: Reinduction
DC,
A, et al: Small-cell after late relapse.
Med 98:472-474, 7. Postmus
PE,
1983 Berendsen
therapy. Em J Cancer Clin 8. Giaccone G, Ferrati chemotherapy
in
small
Van
Huisman
cell
lung
C, Postmus
refractory 8:1613-1617, 12.
Furuse
vinorelbine Japan Lung 169-172,
lung
K, Kubota in heavily Cancer
N,
et al:
in
Clin
chemotherapy
lung
cancer.
Cancer
G, et al: Second-line small
cell
lung
cancer.
1999 Strupp J, et al: Prolonged in patients with relapsed or
cancer:
A phase
K, Kawahara previously Vinorelbine
Em J Cancer
I: First-line
DH, Greco FA, of oral etoposide
small-cell 1990
The Oncol
carcinoma Ann Intern
Zandwijk
cancer.
PE, Giaccone
and its evaluation Rev 25:199-206,
11. Johnson administration
J Clin
Oncol 23:1409-1411, 1987 I’, Donadio M, et al: Reinduction
after relapse in small cell Pharmacol 21:45-48, 1988
chemotherapy Cancer Treat
che-
regimen in small cell lung response to short term chemo-
Oncol 23:1697x1699, 1987 9. Vincent M, Evans B, Smith rechallenge Chemother
patients.
HH,
Retreatment with the induction cancer relapsing after an initial
Rev
to 1990:
previously Zabell therapy
Treat
et al: Single-agent
cancer,
case for studies in 10:484-498, 1992
10.
CONCLUSIONS
DN,
in Hansen
II trial.
J Clin
M, et al: Phase
treated Study
Oncol
II study
of
small cell lung cancer. Group. Oncology 53:
1996
13. Smyth JF, Smith IE, Sessa C, et al: Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC. Eur J Cancer 30A:1058-1060, 1994 14. (VM26)
Tummarello D, Guidi F, Torresi U, as second-line treatment for small
Anticancer Res 15. Ardizzoni Topotecan, of small-cell
10:397-399, A, Hansen
a new active lung cancer:
1990 H,
Dombernowsky
Cooperative
P,
et
al:
drug in the second-line treatment A phase I1 study in patients with
refractory and sensitive disease. The for Research and Treatment of Cancer Group and New Drug Development Cancer 1997
et al: Teniposide cell lung cancer.
Group.
J Clin
European Organization Early Clinical Studies Office, and the Lung Oncol
15:2090-2096,
52
16. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10:1225,1229, 1992 17. Smit EF, Fokkema E, Biesma B, et al: A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 77:347-351, 1998 18. Von Pawel J, Schiller JH, Shepherd FA, et al: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for treatment of recurrent small-cell lung cancer. J Clin Oncol 17~657.667, 1999 19. Postmus PE, Smit EF, Kirkpatrick A, et al: Testing the possible noncross resistance of two equipotent combination chemotherapy regimens against small-cell lung cancer: A phase II study of the EORTC lung cancer cooperative group. Eur J Cancer 29A:204-207, 1993 20. Groen HJ, Fokkema E, Biesma B, et al: Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: A non-cross resistant schedule. J Clin Oncol 17:927-932, 1999 21. Giaccone G, Donadio M, Bonardi G, et al: Teniposide in the treatment of small-cell lung cancer: The influence of prior chemotherapy. J Clin Oncol 6:1264-1270, 1988 22. Giaccone G, Dalesio 0, McVie GJ, et al: Maintenance chemotherapy in small-cell lung cancer: Longterm results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11:1230-1240, 1993
POSTMUS
AND
SMIT
23. Ihde DC, Bilek FS, Cohen MH, et al: Response to thoracic radiotherapy in patients with small cell lung carcinoma of the lung after failure of combination chemotherapy. Radiology 132:443-446, 1979 24. Ochs JJ, Tester WJ, Cohen MH, et al: “Salvage” radiation therapy for intrathoracic small cell carcinoma of the lung progressing on combination chemotherapy. Cancer Treat Rep 67:1123-1126, 1983 25. Salazar OM, Yee GJ, Slawson RG: Radiation therapy for chest recurrences following induction chemotherapy in small cell lung-cancer. Int J Radiat Oncol Biol Phys 21:645-650, 1991 26. Postmus PE: Brain metastases from small cell lung cancer: Chemotherapy, radiotherapy or both? Semin Rad Oncol 569-73, 1995 27. Postmus PE, Haaxma-Reiche H, Gregor A, et al: Brainonly metastases of small cell lung cancer: Efficacy of whole brain radiotherapy. An EORTC phase II study. Radiother Oncol 46:29-32, 1998 28. Postmus PE, Haaxma-Reiche H, Smit EF, et al: Treatment of brain metastases of small-cell lung cancer: Comparing teniposide and teniposide with whole brain radiotherapy - A phase III study of the EORTC Lung Cancer Cooperative Group. J Clin Oncol l&3400-3408, 2000 29. Groen HJ, Smit EF, Haaxma-Reiche H, et al: Carboplatin as second line treatment for recurrent or progressive brain metastases from small cell lung cancer. Eur J Cancer 29A:16961699, 1993
of Relapsed Pieter
Small
cell
despite
lung
cancer
a high
therapy.
For
pends
and
a good
the
after
at relapse
earlier in
temporary
Saunders
be brain,
palliation.
For of main
radiotherapy
of first-line
For the
patients more
Evidence
off with
than
3
of chemo-
therapy.
In case
non-cross-resistant
given.
For
symptomatic
radiotherapy
me-
usually
intrathoracic bronchus
relapse and/or
is a possibility
if not
superior given
gives and
seca-
as part
treatment.
Oncol28
[suf@
4):48-52.
Copyright
0 2001
by W/3.
Company.
MALL CELL lung cancer (SCLC) is considered to be one of the most chemosensitive solid tumors, with response rates to first-line chemotherapy of more than 80%.1 Therefore, combination chemotherapy is considered the standard treatment for all stages of SCLC. Currently, early radiotherapy is part of the treatment of limiteddisease SCLC as well.2 Despite this high response rate after first-line chemotherapy, the majority of patients with SCLC relapse, and the overall sure viva1 after relapse is 2 to 4 months.1 For most patients there is the need and wish for additional treatment to provide as much palliation as possible. Guidelines for treatment at relapse after an initial response are relatively scarce, both with respect to the role of second-line chemotherapy in general and in specific situations encountered in daily clinical practice. In this review, we discuss published results for treatment of relapsed SCLC in general and in specific situations when symptomatology at the site of relapse is the most important reason for additional therapy.
S
From the Department of Pulmonary Diseases, University Hospital, Vrije Uniuersiteit, Amsterdam, The Netherlands. Address reprint requests to Pieter E. Postmus, MD, PhD, Deof Pulmonary Diseases,UniversityHospital Vrije Uniuersiteit, Box 7057, Amsterdam, The Netherlands 1007 MB. Copyright 0 2001 by W.B. Saunders Company
partment
0093-7754/01/2802-0409$35.00/O doi:10.1053/s0nc.2001.25750 48
F. Smit
CHEMOTHERAPY de-
time
choice
as initial
so-called or
obstruction
val vein, Semin
same
should bone
at relapse
a relapse
treatment, is the
progression,
tastases
and
and Egbert
Lung Cancer
chemo-
treatment,
of progression. status
first-line
chemotherapy
vere
site
Cell
tumor
first-line
treatment
to first-line
performance
therapy
relapsing
after
patients,
response
months of
is a frequently of response
these
on the
therapy,
rate
E. Postmus
Small
The first question concerning second-line chemotherapy for a relapseor progressionof SCLC in this era of “evidence-basedmedicine” is: Is there a scientifically solid basis for it? Chemotherapy at relapse is usually considered as the treatment of choice for those involved in the treatment of SCLC. Most physicians will find it difficult to believe that a different approach might be asbeneficial for the patient. No prospective randomized trials addressingthis specific question have been performed. In fact, there is only one published study in which the effect of treatment on survival at relapsewasinvestigated. Spiro et a13randomized 610 patients between treatment with either four or eight cycles of first-line chemotherapy, and also randomized them to receive either second-line chemotherapy or symptomatic treatment only at diseaseprogression.First-line chemotherapy consisted of cyclophosphamide/vincristine/etoposide, and second-line therapy consisted of methotrexate/doxorubicin. Symptomatic treatment included radiotherapy for indications such as bone pain, cerebral metastases,superior vena caval obstruction, dyspnea,hemoptysis, or large airway obstruction. Analgesics or corticosteroids were administered as necessary. No cytotoxic chemotherapy wasgiven to patients receiving symptomatic treatment. The study was powered to detect a 10% difference in overall survival (from 20% to 30%) at 1 year. Of the four treatment arms, the short chemotherapy plus symptomatic treatment arm was inferior to the other three, which were equal in outcome. Subgroup analysis shows that there are two answersto the question of whether chemotherapy at relapseis beneficial. First, for those receiving short-term chemotherapy plus chemotherapy at relapseor progression,survival is significantly improved compared with patients receiving symptomatic treatment. Median survival was 20 versus 11 weeks, respectively (P < .OOl). On the other hand, for those receiving long-term chemotherapy, second-line chemotherapy does not significantly improve survival compared with symptomatic treatment (median survival of 15 and 12 weeks, respectively) (Table 1). Seminars
in Oncology,
Vol 28, No 2, Suppl 4 (April),
200 I: pp 48-52
TREATMENT
OF RELAPSED
Table
SMALL
CELL
I. Treatment
LUNG
49
CANCER
and Results MS From
MS From start First-Line Therapy Short
Start SecondNo. of Patients
Response Rate (%)
38 30
105 106
25.6 -
20” I I*
42
II4 112
18.7 -
I5 I2
W4
Line Ws)
i second-
line Short + BSC Long + secondline Long + BSC
38
Abbreviation: MS, median * P < .oo I. Data from Spiro et aL3
survival;
BSC, best supportive
care.
It is difficult to draw conclusions regarding the value of treatment at relapse from this study. For those receiving short-term chemotherapy, it is clearly beneficial; however, four cycles of chemotherapy is less than usually given, potentially resulting in undertreatment. This is supported by the shorter time to progression than for those receiving longer treatment. On the other hand, in the group receiving longer treatment, more resistance towards chemotherapy might have developed, making additional chemotherapy potentially less effective. Although not significantly different, the response rate with the second-line regimen in the long-term treatment group was lower than that of the short-term treatment group (18.7% e, 25.6%). The most important problem in this study is the methodology used to select patients for secondline chemotherapy, which was not in accordance with daily practice. For instance, patients considered unfit for chemotherapy because of poor performance status would be excluded in the latter situation, but were included in this study. In addition, the selection of second-line chemotherapy components was based on an assumed lack of cross-resistance, not on current knowledge related to time off therapy and initial response to first-line chemotherapy.’ Literature
single-agent studies included evaluations of new drugs against SCLC including etoposide, cisplatin, carboplatin, ifosfamide, cytarabine, and vindesine. The combination chemotherapy studies were usually aimed to evaluate the efficacy of a second-line regimen. The choice of drugs was based on presumed non-cross-resistance of the drugs towards those used in first-line regimen. Arguments for non-cross-resistance were based on differences in mechanism of action or in vitro studies of tumor models. Overall, the combination of cisplatin/etoposide was found to be superior, with higher response rates than were obtained with other combination regimens or with cisplatin or etoposide as single agents. However, cisplatin/etoposide was not a common first-line combination at that time, which might account for its favorable results as second-line treatment. Furthermore, in most studies before 1990, all patients selected for secondline treatment were included without considering therapeutic results of first-line therapy, Usually, first-line therapy was not reported in detail, including response to therapy, progression while on therapy or after achieving a good response, and time off therapy, as well as indicating other prognostic factors for achieving a response to secondline therapies.5 The only exceptions were four reports that dealt exclusively with patients progressing after achieving at least a partial response to first-line therapy.6-9 In these studies, described in Table 2, the efficacy of reinduction chemotherapy was evaluated. An important characteristic of the patients evaluated in three of these studies was the relatively short duration of the first-line treatment,
Table Time After First-Line Study Grant
et al5
No. of
(4
Patients
>I2
6
Batist et al6
>4.5 54.5
I9 I8
POWllUS et al’ Giaccone
>4.s 54.5
8 4
>4.s 54.5
5 9
Review
Andersen et a14 reviewed studies of second-line treatment of SCLC reported before 1990. This review included a mixture of combination chemotherapy regimens and single-agent studies. The
2. Reinduction
et aI*
Response Rate (%)
Response Duration 0-4
67 79
IO 7
44 50
4 6
50 80 II
3
50
POSTMUS
usually less than 6 months.?-” This had become standard at that time, based on a number of large randomized studies that showed that prolonged cytotoxic treatment had no effect on survival. The second review of second-line treatment, by Huisman et al,1° describes the studies after 1990. This review included a number of single-agent phase II studies in which the drugs oral etoposide (at prolonged schedules),11 vinorelbine,i2 docetaxel,i3 temposide, topotecan,15 irinotecan,i6 and paclitaxeli7 were evaluated. In a number of these studies, the details of the first-line therapy as well as the effects were included,11 and inclusion criteria for some were based on thisis-is The evaluation of a second-line regimen was performed in the same way in a number of studies, and aimed to find a clinically relevant degree of non-cross-resistance.igJ” Based on the results of these and some earlier studies,2iJ2 a number of conclusions were drawn that form the basis for the current guidelines for second-line chemotherapy and the evaluation of new drugs: (1) Sensitive patients (ie, those who had a response to first-line therapy and were relapsing or progressing after 3 or more months) should be treated with combination chemotherapy, which may be identical to first-line treatment. (2) Refractory patients who never responded to first-line treatment or responded but progressed during first-line therapy or within 3 months from the end of induction treatment should be treated with drugs that are non-crossresistant to the drugs used in first-line therapy. RADIOTHERAPY
Treatment of Primary Tumor Small cell lung cancer is one of the most radiosensitive solid tumors, and thoracic radiotherapy is
AND
currently part of standard treatment of patients with limited disease.Adding more radiotherapy for local relapse is usually impossiblebecauseof the risk of severesideeffects. For extensive disease,the role of radiotherapy in first-line treatment is less certain. For these patients, radiotherapy to the primary tumor at the time of relapsemight still be considered.This is especially relevant when symp? toms from the primary tumor such assuperior vena caval obstruction, dyspnea, hemoptysis, or large airway obstruction require palliation. In three retrospective studies, the effects of radiotherapy for an intrathoracic relapseof SCLC were evaluated (Table 3).“‘-25 Although a wide rangeof radiotherapy dosesand scheduleswere applied, the impres sion of the investigators wasthat better palliation wasachieved with doses2 40 Gy. For the majority of patients, this results in a responsewithin the radiated area. Whether survival was improved by this approach is questionable. Treatment
of Bone Metastases
If painful bone lesionsimpair the quality of life of the patient, SCLC does not differ from any other type of solid tumor. As is standard for all bone metastases,local radiotherapy usually results in improvement of symptomatology and is without doubt indicated in situations with tumor relapsein supporting parts of the skeleton, such as the long bones of the legs, vertebrae, and pelvis. Treatment of Brain Metastases Thirty percent to 40% of SCLC patients develop clinically overt central nervous system metastasesbefore death. For daily practice, it is important to keep in mind that brain metastasesof SCLC are signsof progressionof the primary disease.The development of brain metastasesis as-
‘, .L
)_,/
TabIe
g ,-,
: _.! : ,J ‘1.
3. ~Radiatherepy
for Relapse
of Small
Cell
Lung
Cancer
: No. Study
lhde Ochs Salazar
Type
of Study
et alZ3
Retrospective
et al*4
Retrospective
et aI25
Dose
21-51 40
Retrospective
bO(n
45-55
=
Abbreviations:
LD, limited
disease;
ED, extensive
II)
(n = 14)
38-42(n= disease.
of Patients (LDIED)
(Gy)
II)
SMIT
Response
Rate in
Radiation
Port
(%)
Median
Survival Cm4
23 (I 1112) 25 (8/ 17)
52 64
3 4
3 b (2719)
77
4
TREATMENT
OF RELAPSED
SMALL
CELL
LUNG
CANCER
sociated with considerable morbidity. It is obvious from many studies that SCLC patients with a central nervous system relapse have a poor prognosis with regard to survival (ie, 3 to 4.5 months). Despite this, palliation of these patients is often needed.26 Whole-brain radiotherapy has been in use for decades as standard treatment of these patients, and in combination with corticosteroids it results in improvement of symptoms and a better quality of life for some time. For the rare patient in a complete remission after chemotherapy or chemoradiotherapy with a sole relapse in the brain, the role of whole-brain radiotherapy has been evaluated in a phase II study with disappointing results.27 During the last decade, treatment of patients with a relapse in the brain after previous chemotherapy has been reported in a number of studies. Recently, in a randomized study, the intracranial response rate was shown to be much higher with combined chemoradiotherapy than with chemotherapy alone; however, no survival benefit was seen.28 The activity of carboplatin after failure of teniposide illustrates that brain metastases in patients pretreated with chemotherapy behaves in the same way as metastases at other sites29 Therefore, the same rules regarding chemotherapy at relapse as for chemotherapy for patients with relapse of SCLC after chemotherapy should be applied.
51
in trials testing new drugs or concepts. For specific sites such as intrathoracic tumor or brain metastases, radiotherapy alone should be considered for palliation or in combination with chemotherapy. REFERENCES 1. Camey therapy,
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