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Chemotherapy versus best supportive care for extensive small cell lung cancer

  1. Marta Pelayo Alvarez1,*,
  2. Virginie Westeel2,
  3. Marcela Cortés-Jofré3,
  4. Xavier Bonfill Cosp4

Editorial Group: Cochrane Lung Cancer Group

Published Online: 27 NOV 2013

Assessed as up-to-date: 17 OCT 2013

DOI: 10.1002/14651858.CD001990.pub3


How to Cite

Pelayo Alvarez M, Westeel V, Cortés-Jofré M, Bonfill Cosp X. Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD001990. DOI: 10.1002/14651858.CD001990.pub3.

Author Information

  1. 1

    Conselleria Valenciana, Atención Primaria Área 11, Valencia, Spain

  2. 2

    University Hospital of Besançon, Thoracic Oncology, Besançon, France

  3. 3

    Programa Doctorado en Ciencias Médicas, Universidad de La Frontera, Facultad de Medicina, Universidad Católica de la SS. Concepción, Concepción, VIII, Chile

  4. 4

    CIBER Epidemiología y Salud Pública (CIBERESP), Spain - Universitat Autònoma de Barcelona, Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Catalonia, Spain

*Marta Pelayo Alvarez, Atención Primaria Área 11, Conselleria Valenciana, Valencia, Spain. MPelayo@Hospital-Ribera.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 27 NOV 2013

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Characteristics of included studies [ordered by study ID]
Ciuleanu 2010

MethodsRandomised controlled trial


ParticipantsRandomised 401 patients, extensive disease refractory or in progression within 6 months of first-line chemotherapy

Evaluable 321, 84% male, median age 85 years, 88% Caucasian, 85% performance status 0-1, 15% performance status 2


InterventionsArm A (n=133): BSC

Arm B (n=268): picoplatin IV 150 mg/m2 every 3 weeks median cycles 3 (1-15)


OutcomesMedian survival

Median survival in two subgroups (patients who did not received chemotherapy post-study, patients who were refractory or relapsed within 45 days of first-line chemotherapy)

Progression-free survival

Time to progression

Toxicity

Follow-up until death


NotesStudy published in abstract with complementary data on the Pharmaceutical website, without attrition data, tumour response, randomisation method. Sponsor: Poniard Pharmaceuticals

Uncertain/high risk of bias


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThere is no information data. Mentioned as multi-centre and probably randomisation made centrally. Patients randomly assigned 2:1

Allocation concealment (selection bias)Unclear riskThere is no information provided

Blinding of participants and personnel (performance bias)
Survival
Low riskNo information provided. Probably unblinded, but to determine survival it is probably not biased

Blinding of participants and personnel (performance bias)
Toxicity, tumour response, quality of life
Unclear riskNo information provided. Probably unblinded

Blinding of outcome assessment (detection bias)
Survival
Low riskNo information provided. Probably unblinded. Outcome measure is not likely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided. Probably unblinded

Incomplete outcome data (attrition bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided in tumour response and lost to follow-up

Incomplete outcome data (attrition bias)
Survival
High riskNo Information provided

Selective reporting (reporting bias)High riskAuthors did not present all the information considered relevant

Other biasHigh riskNo information of baseline patient characteristics per group. Pharmaceutical sponsorship

Kokron 1977b

MethodsRandomised controlled trial


ParticipantsRandomised 34 patients with extensive disease

Evaluable 33, (only male), 70 years or less (median age 64.5, 66, and 63 years), no prior therapy, no brain metastases, no relevant secondary diseases, good general condition (able to work)


InterventionsArm A (n=17): supportive care.
Arm B (n=17): Ifosfamide: 1500 iv day 1, followed by 1000 iv days 2 to 3, repeated on week 2 and 3, with initial dose of 1000 iv day 1. Repetition after 6 weeks. Two cycles


OutcomesMean survival time
Tumour response (complete and partial response)
Toxicity

Follow-up: until death (no data)


NotesPatients with extensive disease form a separate group

Bias with high probability


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe randomisation was conducted from the Institute of Cancer Research

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
Survival
Low riskNo information provided. Probably unblinded, but to determine survival it is probably not biased

Blinding of participants and personnel (performance bias)
Toxicity, tumour response, quality of life
Unclear riskNo information provided. Probably unblinded

Blinding of outcome assessment (detection bias)
Survival
Low riskNo information provided. Probably unblinded. Outcome measure is not likely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided. Probably unblinded

Incomplete outcome data (attrition bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided of patients lost to follow-up or toxic deaths

Incomplete outcome data (attrition bias)
Survival
Unclear riskNo Information provided

Selective reporting (reporting bias)Unclear riskAuthors did not present results on all important outcomes

Other biasUnclear riskNo information of baseline patient characteristics per group. Statistical analysis inadequate

Kokron 1982

MethodsRandomised controlled trial


ParticipantsRandomised 54 patients, 53 evaluable (32 extensive)
Extensive: Randomised 41, evaluable 32, (only male), 70 years or less (median age 62, 60.5, and 64 years), no prior therapy, no brain metastases, no relevant secondary diseases, good general condition (able to work)


InterventionsArm A (n=8): no active anticancer treatment, Ringer solution 1000 ml + 1 g vitamin C iv 3 times wk, 6 weeks
Arm B (n=12): Ifosfamide: 1500 iv day 1, followed by 1000 iv days 2 to 3, repeated on week 2 and 3, with initial dose of 1000 iv day 1
Repetition after 6 weeks
Arm C (n=12): Ifosfamide + CCNU (cyclohexylnitrosourea), Ifosfamide as in Arm B + CCNU 60 mg/m2 day 1
Repetition after 6 weeks


OutcomesMean survival time
Tumour response (complete and partial response)
Toxicity

Follow-up: until death (no data)


NotesPatients with extensive disease form a subgroup

Bias with high probability


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe randomisation was conducted from the Institute of Cancer Research

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
Survival
Low riskNo information provided. Probably unblinded, but to determine survival it is probably not biased

Blinding of participants and personnel (performance bias)
Toxicity, tumour response, quality of life
Unclear riskNo information provided. Probably partially blinded because a placebo infusion of Ringer's solution and Vitamin C was given

Blinding of outcome assessment (detection bias)
Survival
Low riskNo information provided. Probably unblinded. Outcome measure is not likely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided. Probably unblinded

Incomplete outcome data (attrition bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided of patients lost to follow-up, toxic deaths. Tumour response is reported for extensive and limited disease combined

Incomplete outcome data (attrition bias)
Survival
Unclear riskNo Information provided

Selective reporting (reporting bias)Unclear riskAuthors did not present results in all important outcomes

Other biasUnclear riskNo information of baseline patient characteristics per group. Statistical analysis inadequate

O'Brien 2006

MethodsRandomised controlled trial


ParticipantsRandomised 141 patients at relapse (38 female)

Evaluable 141, > 18 years (median age = 58.6, 59.6 years), previous chemotherapy, no previous topotecan, no symptomatic brain metastases, no severe co-morbidities, performance status 0-2


InterventionsArm A (n = 70): BSC

Arm B (n = 71): topotecan in capsules containing the equivalent to 0.25 mg, dosed 2.3 mg/m2 on days 1-5 every 21 days, at least 4 cycles + BSC                 


OutcomesMedian survival time
Tumour response (complete and partial response)
Toxicity

Quality of life

Follow-up: until death  (within 30 days of random assignment: 9 patients (13%) in arm A, 10 (7%)  in arm B

Attrition data: 33 in arm A, 21 in arm B


NotesCompliance with topotecan was documented by returned capsule count (99% of patients took ≥ 90% of capsules)

Sponsor: GlaxoSmithKline Pharmaceuticals

Low risk of bias


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients were randomly assigned 1:1

Allocation concealment (selection bias)Low riskCentralised automated registration

Blinding of participants and personnel (performance bias)
Survival
Low riskNo information provided. Probably unblinded, but to determine survival it is probably not biased

Blinding of participants and personnel (performance bias)
Toxicity, tumour response, quality of life
Unclear riskNo information provided. Probably unblinded

Blinding of outcome assessment (detection bias)
Survival
Low riskNo information provided. Probably unblinded. Outcome measure is not likely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided. Probably unblinded

Incomplete outcome data (attrition bias)
Tumour response, toxicity, quality of life
Low riskPatients did not complete the study due to toxicity 9BSC, 13 topotecan, other 13 BSC

Incomplete outcome data (attrition bias)
Survival
Low riskinformation provided

Selective reporting (reporting bias)Low riskAuthors presented results on all outcomes measures that were pre-specified as relevant

Other biasLow riskThe study appears to be free of other bias. Pharmaceutical sponsorship

O'Brien 2007a

MethodsReport the results of quality of life of the O'Brien 2006 study


ParticipantsSame as O'Brien 2006


InterventionsSame as O'Brien 2006


OutcomesQuality of life


NotesIt is the same study as O'Brien 2006


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSame as O'Brien 2006

Allocation concealment (selection bias)Unclear riskSame as O'Brien 2006

Blinding of participants and personnel (performance bias)
Survival
Low riskSame as O'Brien 2006

Blinding of participants and personnel (performance bias)
Toxicity, tumour response, quality of life
Unclear riskSame as O'Brien 2006

Blinding of outcome assessment (detection bias)
Survival
Low riskSame as O'Brien 2006

Blinding of outcome assessment (detection bias)
Tumour response, toxicity, quality of life
Unclear riskSame as O'Brien 2006

Incomplete outcome data (attrition bias)
Tumour response, toxicity, quality of life
Low riskSame as O'Brien 2006

Incomplete outcome data (attrition bias)
Survival
Low riskSame as O'Brien 2006

Selective reporting (reporting bias)Low riskSame as O'Brien 2006

Other biasLow riskSame as O'Brien 2006

Spiro 1989

MethodsRandomised controlled trial


ParticipantsIncluded 616 participants, 414 extensive. Randomised 390 patients on disease progression, (122 female). Evaluable 170 active treatment; no data in symptomatic; 75 years or less; (median age 62.5, 61.5 years); previous first-line chemotherapy, no severe co-morbidities, any performance status 


InterventionsArm A (n= 198): symptomatic therapy  

Arm B (n= 192): methotrexate 50 mg/m2 iv plus doxorubicin 50 mg/m2 iv, repeated every 3 weeks up to a maximum of 9 courses                              


OutcomesMedian survival time
Tumour response (complete and partial response)
Toxicity

Follow-up: until death (no data)

Attrition data: 124 in arm B, no data in arm A 


NotesHigh risk of bias


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
Survival
Low riskNo information provided. Probably unblinded, but to determine survival it is probably not biased

Blinding of participants and personnel (performance bias)
Toxicity, tumour response, quality of life
Unclear riskNo information provided. Probably unblinded

Blinding of outcome assessment (detection bias)
Survival
Low riskNo information provided. Probably unblinded. Outcome measure is not likely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
Tumour response, toxicity, quality of life
Unclear riskNo information provided. Probably unblinded

Incomplete outcome data (attrition bias)
Tumour response, toxicity, quality of life
High riskPatients lost to follow-up not provided. Relapse chemotherapy was not administered to 124 patients, 54 (37.5%) assigned to four cycles of first-line chemotherapy and 70 (47%) assigned to eight of first-line chemotherapy. No toxicity was reported

Incomplete outcome data (attrition bias)
Survival
Unclear riskNo information provided

Selective reporting (reporting bias)Unclear riskAuthors did not present results on all outcomes measures considered relevant

Other biasLow riskNo information of baseline patient characteristics per group at treatment with second-line chemotherapy

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

AlIan 1984Phase II study of vinorelbine, no control group

Anderson 1993Ifosfamide-adryamicin in bolus plus oral etoposide versus continuous pump infusion of ifosfamide-adriamycin plus oral etoposide

Ardizzoni 2002Standard cyclophosphamide adriamycin etoposide versus intensified cyclophosphamide adriamycin etoposide

Beith 1996Induction chemoradiotherapy after randomisation to vincristine, doxorubicin,cyclophosphamide versus observation, in responding patients

Bleehen 1989Induction etoposide, cyclophosphamide, methotrexate, vincristine, after randomisation to further chemotherapy versus observation in partial or complete response

Bleehen 1993Etoposide, cyclophosphamide, methotrexate, vincristine versus etoposide, ifosfamide

Bleehen 1996Etoposide, cyclophosphamide, methotrexate, vincristine versus etoposide, vincristine

Candido 2002Phase II study of ifosfamide, epirubicin, carboplatin, no control group

Chen 2007Report the same quality of life results as O'Brien 2006, study included in the review

Ciuleanu 2002Phase II study of teniposide, etoposide, no control group

CuIlen 1986Induction therapy with vincristine, adriamycin, cyclophosphamide after randomisation to further courses or no more chemotherapy. Patients received as second-line treatment the same chemotherapy regimen of first-line treatment

EarI 1991Planned chemotherapy with cyclophosphamide, vincristine, etoposide versus chemotherapy given for tumour-related symptoms

Eridani 1978Adryamicin, cyclophosphamide versus bleomycin, adriamycin, cyclophosphamide, oncovicin combination versus cyclophosphamide, vincristine, cisplatin

Ettinger 1990Randomisation to cyclophosphamide, doxorubicin, vincristine vs the same regimen alternating with hexamethylmelamine, etoposide, methotrexate. Incomplete response randomisation to maintenance chemotherapy versus observation

Garassino 2011Retrospective report of outcomes in SCLC patients following various regimens of second-line chemotherapy

Giaccone 1993Induction cyclophosphamide, doxorubicin, etoposide. Incomplete or partial response randomisation to maintenance chemotherapy versus observation

Green 1969Cyclophosphamide vs placebo or nitrogen mustard versus placebo in previously treated patients with radiotherapy, surgical resection or previous chemotherapy not clarified

GrideIIi 2002Phase II study of carboplatin, vinorelbine, no control group

Hainsworth 2002Phase II study of paclitaxel, carboplatin, teniposide, etoposide, no control group

Hanna 2002Induction etoposide, ifosfamide cisplatin, and randomisation to oral etoposide or no further therapy in partial, complete or stable response

James 1996Cisplatin, etoposide, adriamycin, vincristine versus the same drugs at half the dose but twice the frequency

Joss 1995Carboplatin, teniposide versus cisplatin, adriamycin, etoposide alternating with cyclophosphamide, methotrexate, vincristine, carmustine

Kokron 1974aPreliminary results of the study of Kokron 1977b. Same as Kokron 1974b

Kokron 1974bPreliminary results of the study of Kokron 1977b

Kokron 1977aSame as Kokron 1977b

Korfel 2002Phase II study of teniposide as second-line chemotherapy in relapsed SCLC

Lebeau 1992Lomustine, cyclophosphamide, doxorubicin, etoposide plus aspirin versus same chemotherapy regimen. Incomplete response randomisation to same chemotherapy versus observation. Patients received more cycles of first-line treatment versus fewer cycles

Lyss 2002Phase II study of cisplatin, teniposide versus cisplatin, paclitaxel vs paclitaxel, teniposide versus paclitaxel teniposide at different doses

Mattson 1992Cyclophosphamide, vincristine, etoposide. Incomplete or partial response randomisation to interferon alfa versus cyclophosphamide, doxorubicin, cisplatin versus observation

Mattson 1997Cyclophosphamide, vincristine, etoposide. Incomplete or partial response randomisation to interferon alfa vs cyclophosphamide, doxorubicin, cisplatin versus observation

Maurer 1980Cyclophosphamide, methotrexate, vincristine pus cerebral irradiation vs cyclophosphamide. Incomplete response randomisation to further chemotherapy or observation. Patients received as second therapy more cycles of first-line chemotherapy versus fewer cycles

Mok 2002Phase I-II study of sequential administration of teniposide and oral etoposide

Naka 2002Phase II study of irinotecan and carboplatin for relapsed SCLC

Noda 2002Irinotecan, cisplatin versus etoposide cisplatin

Reck 1998Phase II study of bleomycin, no control group

Rosenthal 1991Phase II study of epirubicin in recurrent SCLC, no control group

Schiller 2001Cisplatin, etoposide. No progression randomisation to topotecan versus observation

Sculier 1996Ifosfamide, etoposide, anthracycline. Incomplete or partial responses randomisation to maintenance chemotherapy with etoposide, vindesine versus no further chemotherapy

Smit 1989Phase II study of etoposide in SCLC patients older than 70 years, no control group

Souhami 1997Oral etoposide versus cisplatin, etoposide intravenous

Sundstrom 2002Cisplatin, etoposide versus cyclophosphamide, etoposide, vincristine

Tada 2002Phase II study of carboplatin etoposide in SCLC patients older than 76 years, no control group

Thatcher 1996Oral etoposide versus etoposide, vincristine versus cyclophosphamide, adriamycin, vincristine

Thomas 2002Phase II study of CI-980, no control group

Tjan-Heíjnen 2001Cyclophosphamide, adriamycin, vincristine versus intensified same chemotherapy

Vanseenkiste 2001Phase II study of gemcitabine, etoposide, no control group

von Pawel 1990Phase II study of etoposide, vincristine, no control group

Zhang 2002Phase II study of teniposide, cisplatin, no control group

 
Comparison 1. Second-line chemotherapy at relapse versus best supportive care (BSC)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival2Hazard Ratio (Random, 95% CI)0.73 [0.55, 0.96]

 
Summary of findings for the main comparison. First-line chemotherapy compared with BSC for extensive SCLC

First-line chemotherapy compared with BSC for extensive SCLC

Patient or population: patients with extensive SCLC without previous treatment

Settings: one hospital in Vienna

Intervention: first-line chemotherapy

Comparison: Supportive treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Supportive careFirst-line chemotherapy

Overall survivalThe mean survival ranged across control groups from
56-93 days 1
The mean survival in the intervention groups was
134-172 days 1
Not estimable65 (2 studies)⊕⊝⊝⊝
very low,2,3

Adverse effectsHaematological: 0%

Leucopenia:0%

Vomiting and hair loss: 0%

Other: 0%
Haematological:   94.1%

Leucopenia:15% ifosfamide; 15.8% ifosfamide + CCNU

Vomiting and hair loss: 70% ifosfamide; 68.4% ifosfamide + CCNU

Other: 55% ifosfamide; 52.6% ifosfamide + CCNU
Not estimable65 (2 studies)⊕⊝⊝⊝
very low2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. The corresponding median survival time in extensive SCLC in the control and intervention groups has been obtained from Kokron 1977 and Kokron 1982
2. Significant risk of bias across the studies
3. Small sample sizes across the studies
 
Summary of findings 2. Second-line chemotherapy at relapse or progression in extensive SCLC

Second-line chemotherapy compared with BSC for extensive SCLC

Patient or population: patients with extensive SCLC who relapsed or progressed after first-line chemotherapy

Settings: multi-institutional-multicentre

Intervention: second-line chemotherapy

Comparison: BSC

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

BSCSecond-line chemotherapy

Overall survivalThe median survival ranged across control groups from 97.3-138 days1The median survival in the intervention groups was 144-181.3 days2HR: 0.73

(0.55, 0.96)
542

(2 studies)
⊕⊕⊝⊝
low 4,5

Toxic death0%6% topotecan

0% picoplatin
Not estimable542

(2 studies)
⊕⊕⊕⊝
moderate 4

Adverse effectsDyspnoea 3%

Fatigue 4%

Non sepsis infection 12%

sepsis 1%
Haematological: 18%-61% neutropenia, 38%-41% Thrombocytopenia, 25%-29% anaemia,

Non sepsis infection 14%

Sepsis 4%

Asthenia 11%
Not estimable542

(2 studies)
⊕⊕⊕⊝
moderate 4

Quality of lifeSee footnotes 3See footnotes 3Difference in rate of deterioration per 3-month intervals in the EQ-5D score: 0.15 (95% CI 0.05, 0.25)

In the PSA questionnaire:

shortness of breath RR: 2.18 (1.09 to 4.38)

interference with sleep RR: 2.16 (1.15 to 4.06)

fatigue RR: 2.29 (1.25 to 4.19)3
141

(1 study)
⊕⊕⊝⊝

low 4,5

*The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
BSC: best supportive care; CI: Confidence interval; RR: Risk ratio; HR: hazard ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. The corresponding median survival time in extensive SCLC in the control group has been obtained from O'Brien 2006 and Ciuleanu 2010
2. The corresponding median survival time in extensive SCLC in the intervention group has been obtained from O'Brien 2006 and Ciuleanu 2010
3. The difference in rate of deterioration was obtained through the EQ-5D (EuroQol-5-Dimensions Health) questionnaire, consisting of five health status dimensions: mobility, self-care, usual activities, pain and discomfort, anxiety and depression, with rating of 1 (no problem) to 3 (extreme problem). Patients were evaluated before each course of second-line chemotherapy, or at each visit in the BSC arm.
The PSA (Patient Self Assessment) questionnaire rating scale for severity is from 1 (not at all), to 4 (very much)
4. Some significant risk of bias across the studies
5. Some significant risk of other bias in one study
 
Table 1. First-line chemotherapy versus best supportive care (BSC)

StudyGroup AGroup BGroup C

Kokron 1977bSupportive care: mainly antibiotics and analgesicsIfosfamide monotherapy: 1500 mg/m2 ifosfamide

as short infusion iv. on day 1, followed by ifosfamide

1000 mg/m2 iv.on days 2 and 3. Repetition of ifosfamide

1000 mg/m2 iv on days 8, 9, 10 and 15,16,17.

Continuation of the therapy after six weeks with three day therapy (1000 mg/m2 daily each).
-------------------------------------------------

Kokron 1982No active anticancer treatment: infusion of Ringers solution 1000 ml + 1 gr vitamin C iv three times a week during an in-patient stay.Ifosfamide monotherapy: same schedule as the first studyIfosfamide + CCNU (chloroethyl-cyclohexyl-nitrosourea):

ifosfamide therapy as described under Group B,

in addition to CCNU 60 mg/m2 on day 1 with repetition after six weeks.

 
Table 2. Second-line chemotherapy at relapse versus best supportive care (BSC)

StudyGroup AGroup B

Spiro 1989*Symptomatic treatment including palliative irradiationMethotrexate 50 mg/m2 iv plus doxorubicin 50 mg/m2 iv, repeated every

three weeks with a maximum of nine courses

O'Brien 2006**BSCaTopotecan in capsules containing the equivalent to 0.25 mg, doses

2.3 mg/m2 on days 1 to 5 every 21 days, at least four cycles + BSC.

Ciuleanu 2010***BSCaPicoplatin 150 mg/m2, every 3 weeks median cycles 3

 *Patients with disease progression. First-line chemotherapy treatment consisted of either four or eight cycles of cyclophosphamide 1 g/m2 iv; vincristine 1.4 mg/m2 iv; on day 1, and etoposide capsules 100 mg orally eight hourly on days 1 to 3, every 21 days
**Patients with relapse and who were unsuitable for further intravenous chemotherapy
***Patients with refractory disease or progression within six months after first-line platinum-based chemotherapy
a = Best Supportive Care
 
Table 3. Results of the studies included in the review (first-line chemotherapy versus best supportive care (BSC)

Study

ID
ObjectiveSurvivalTumour responseToxicity

Kokron 1977bTo compare supportive care vs IfosfamideMST1: supportive care group = 93 days vs 172 Ifosfamide group (range:11 to 544 vs 1 to 1096)PR2 = 0%  supportive care group vs 47% Ifosfamide group

CR3= 0%
Haematological: 0%  supportive care group vs  94.1% Ifosfamide group

Kokron 1982To compare no active anticancer treatment vs ifosfamide vs Ifosfamide + CCNUMST: in extensive disease: no active anticancer treatment = 56 days vs 134 Ifosfamide vs 122 Ifosfamide + CCNU. Grouped data: no active anticancer treatment, median = 161.5 (MST = 208.4), Ifosfamide, median = 341 (MST = 348.5), Ifosfamide + CCNU, median = 252 (MST = 322.3)Grouped data (extensive and limited disease): CR = 1.9% Ifosfamide; PR = 16.9 Ifosfamide, and 13.2% Ifosfamide + CCNUGrouped data: leucopenia:0% no active anticancer treatment; 15% Ifosfamide; 15.8% Ifosfamide + CCNU. Vomiting and hair loss: 0% no active anticancer treatment, 70% Ifosfamide; 68.4% Ifosfamide + CCNU. Other: 0% no active anticancer treatment; 55% Ifosfamide; 52.6% Ifosfamide + CCNU

 MST = mean survival time; PR = partial response; CR = complete response; CCNU = cyclohexylnitrosourea
 
Table 4. Results of the studies included in the review (second-line chemotherapy versus best supportive care (BSC)

Study

ID
ObjectiveSurvivalTumour responseToxicityQuality of life

Spiro 1989To assess the effects of duration of chemotherapy on survival, and at relapse, the effects of further chemotherapy compared with symptomatic treatmentMST1: symptomatic = 77 to 84 days vs 140 to 105 days methotrexate-doxorubicin group (in previous chemotherapy: 4 cycles-8 cycles, vs 4 cycles-8 cycles) Only significant 77 vs 140 days (P < 0.001)PR2 or CR3 in methotrexate-doxorubicin group = 22.3%Not provided for second-line chemotherapy-------------------

O'Brien 2006To define risk and benefit of second-line chemotherapy at relapse vs BSC in patients unsuitable for standard intravenous chemotherapyMST: in BSC 97.3 days (95% CI, 77.7 to 130.2) vs  181.3 days (95% CI, 128.1 to 221.2) in Topotecan group (log-rank P = 0.01)

Subgroup analysis

a) treatment-free interval <=60 days of first-line chemotherapy: topotecan 163.1 (95% CI 74.9 to 216.3) vs BSC 92.4 (95% CI 49 to 147)

b) performance status 2: topotecan 146.3 (93.8 to 188.3) vs BSC 53.9 (37.1 to 91.7)

c) female: HR 0.38 (95% CI 0.18 to 0.76)

d) liver metastasis: HR 0.58 (95% CI 0.38 to 0.88)
PR  in the topotecan group = 7% (95% CI, 2.33 to 15.67)

CR 0%

In treatment-free interval <=60 days: PR 18% (5.2 to 40.3) vs 2% 80.05 to 10.9) in treatment-free interval >60 days
Topotecan group: Haematological: neutropenia ¾, 61%; thrombocytopenia ¾, 38%, anaemia ¾, 25%. Nonsepsis infection>= grade 2, 14%, vs 12% in BSC. Sepsis 4% in topotecan vs 1% in BSC.

Non-haematological 3/4 in topotecan vs BSC: dyspnoea 3% vs 9%; fatigue 4% vs 4%.

Toxic deaths in topotecan: 6%

all-cause mortality within 30 days: 7% topotecan vs 13% BSC
Difference in rate of deterioration per 3-month intervals in EQ-5D was 0.15 (95% CI 0.05 to 0.25)

In PSA questionnaire:

shortness of breath RR 2.18 (1.09 to 4.38)

interference with sleep 2.16 (1.15 to 4.06)

fatigue 2.29 (1.25 to 4.19)

All in favour of topotecan

Ciuleanu 2010To assess survival of patients treated with second-line chemotherapy who were refractory or who progressed within six months of first-line platinum-based chemotherapyMST: in BSC 138 days (95% CI 112 to 168)

in picoplatin 144 days (95% CI 133 to 175)

HR: 0.817 95% CI 0.65 to 1.03 (P=0.00895)

Time to progression:79 days picoplatin, 47 days BSC

HR: 0.610 (P=0.0002)

Median progression-free survival: 63 days picoplatin, 46 days BSC

HR: 0.783 (P=0.0281)

Subgroup analysis

a) patients who did not receive chemotherapy post-study (273: 194 picoplatin vs 79 BSC): picoplatin 128 days (95% CI 112 to 140), BSC 101 (77 to 140), HR 0.730 (P=0.0345)

b) patients refractory or relapsed within 45 days of first-line chemotherapy (294: 202 picoplatin vs 92 BSC):

picoplatin 149, BSC 129,

HR 0.717 (P=0.0173)
No data providedPicoplatin group: Haematological: 3/4 in >10%:

44% thrombocytopenia

29% anaemia

18% neutropenia

<1% febrile neutropenia

No deaths to haematological toxicity, no bleeding

Nonhaematological:

0.8% grade 3 neuropathy

11% asthenia
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 MST = median survival time; PR = partial response CR = complete response; BSC = best support care; CI = confidence interval; EQ-5D = EuroQol-5-Dimensions (mobility, self-care, usual activities, pain and discomfort, anxiety and depression) with rating 1 (no problem) to 3 (extreme problem); PSA = Patient Self Assessment questionnaire, with rating 1 (not at all) to 4 (very much)