Platinum versus non‐platinum chemotherapy regimens for small cell lung cancer

Isuru U Amarasena; Saion Chatterjee; Julia AE Walters; Richard Wood‐Baker; Kwun M Fong

doi:10.1002/14651858.CD006849.pub3

. 2015 Aug 2;2015(8):CD006849. doi: 10.1002/14651858.CD006849.pub3

Platinum versus non‐platinum chemotherapy regimens for small cell lung cancer

Isuru U Amarasena ^1,^✉, Saion Chatterjee ², Julia AE Walters ³, Richard Wood‐Baker ¹, Kwun M Fong ⁴

Editor: Cochrane Lung Cancer Group

PMCID: PMC7263420 PMID: 26233609

Abstract

Background

Small cell lung cancer (SCLC) is a very fast growing form of cancer and is characterised by early metastasis. As a result, chemotherapy is the mainstay of treatment. A number of different platinum‐based chemotherapy regimens and non‐platinum‐based chemotherapy regimens have been used for the treatment of SCLC, with varying results. This review was conducted to analyse the data from these studies in order to compare their effectiveness.

Objectives

To determine the effectiveness of platinum chemotherapy regimens compared with non‐platinum chemotherapy regimens in the treatment of SCLC with respect to survival, tumour response, toxicity and quality of life.

Search methods

We searched the biomedical literature databases CENTRAL (TheCochrane Library 2014, Issue 7), MEDLINE, EMBASE and CINAHL from 1966 to August 2014. In addition, we handsearched reference lists from relevant resources.

Selection criteria

All randomised controlled trials involving patients with pathologically confirmed SCLC (including both limited‐stage disease and extensive‐stage disease) and the use of a platinum‐based chemotherapy regimen in at least one treatment arm and a non‐platinum‐based chemotherapy regimen in a separate arm.

Data collection and analysis

We used standard methodological procedures expected by the Cochrane Collaboration. Two authors independently assessed search results. We assessed included studies for methodological quality and recorded the following outcome data: survival, tumour response, toxicity and quality of life. We combined the results of the survival, tumour response and toxicity data in a meta‐analysis. Quality‐of‐life data were analysed individually.

Main results

A total of 32 studies involving 6075 patients with SCLC were included in this systematic review. The majority of studies were multi‐centre randomised controlled trials conducted throughout Europe, North America and Asia with the earliest study publishing data in 1981 and the latest in 2014. The duration of studies ranged from 12 to 72 months with a median of 32 months. The median age of patients in the vast majority of studies was between 60 and 65 years of age. Eighteen studies presented data on extensive‐stage disease. Nine studies presented data on limited‐stage disease. Eleven studies did not present data based on the disease stage. These data were analysed separately in subgroup analyses. Sixteen (50%) studies were of good quality with a low risk of bias and the data from these studies were analysed separately in a heterogeneity analysis.

There was no statistically significant difference between treatment groups in terms of survival at 6 months, 12 months and 24 months. There was also no statistically significant difference in terms of overall tumour response. However, platinum‐based treatment regimens did have a significantly higher rate of complete response. Platinum‐based chemotherapy regimens had significantly higher rates of nausea and vomiting and thrombocytopenia toxicity. Four trials presented quality‐of‐life data, but, due to the different systems used to measure quality of life this data could not be combined in a meta‐analysis.

Authors' conclusions

Platinum‐based chemotherapy regimens did not offer a statistically significant benefit in survival or overall tumour response compared with non‐platinum‐based regimens. However, platinum‐based chemotherapy regimens did increase complete response rates, at the cost of higher adverse events including nausea and vomiting, anaemia and thrombocytopenia toxicity. These data suggest non‐platinum chemotherapy regimens have a more advantageous risk‐benefit profile. This systematic review highlights the lack of quality‐of‐life data in trials involving chemotherapy treatment for SCLC. With poor long‐term survival associated with both treatment groups, the issue of the quality of the survival period takes on even more significance. It would be beneficial for future trials in this area to include a quality‐of‐life assessment.

Plain language summary

A comparison of platinum‐based and non‐platinum‐based chemotherapy regimens for the treatment of small cell lung cancer

Review question

Do patients with small cell lung cancer (SCLC) who receive platinum‐based chemotherapy treatment live longer than those who receive non‐platinum‐based chemotherapy treatment?

Other questions include: do these patients also respond better to treatment, experience fewer side‐effects and have a better quality of life?

Background

SCLC is a type of cancer that originates in the lungs. It is a very aggressive form of cancer that tends to grow and spread throughout the body quickly. As a result, chemotherapy is often the first type of treatment used for this type of cancer. Another type of treatment used for SCLC is radiotherapy, which is often given to the lung or to the brain.

A combination of a number of chemotherapy drugs used together is called a ‘chemotherapy regimen’. Currently, there are two main chemotherapy regimens used for treating SCLC:

• platinum‐based chemotherapy regimens – containing a chemotherapy drug known as a “platinum agent” in combination with other chemotherapy drugs and;

• non‐platinum‐based chemotherapy regimens – containing other chemotherapy drugs without a “platinum agent”.

Over the past years, many studies have been done comparing the use of platinum‐based chemotherapy regimens and non‐platinum‐based chemotherapy regimens in SCLC.

We carried out a study, called a meta‐analysis, which included patients with SCLC who took part in randomised controlled trials comparing platinum‐based chemotherapy regimens and non‐platinum‐based chemotherapy regimens.

Study characteristics

We searched for studies up to 1st August 2014. A total of 32 studies were part of this review and included 6,075 patients in total. The studies were carried out in many different countries throughout Europe, Asia and North America. The studies were conducted between 1981 and 2014.

Key results

The review showed that patients who received platinum‐based chemotherapy were not any more likely to be alive at 6 months, 12 months and 24 months after treatment compared with patients who received non‐platinum‐based chemotherapy.

Platinum‐based chemotherapy, however, showed higher rates of complete tumour response (the complete disappearance of tumours, at least for a period of time after treatment) compared to non‐platinum‐based chemotherapy. Platinum‐based chemotherapy also caused some more side effects, including nausea and vomiting, and low platelets.

Only four studies looked at quality of life but because they each used different methods to measure the effects, their results could not be combined. However, in each study there was no difference in the quality of life between the platinum‐based chemotherapy group and the non‐platinum‐based chemotherapy group.

Background

Lung cancer is one of the most common cancers in the world, both in terms of incidence and mortality (Dela Cruz 2011). Smoking is the biggest risk factor for lung cancer and is associated with 90% of cases (Alberg 2003). Other risk factors include occupational and environmental exposure, for example asbestos (Heintz 2010). Lung cancer is divided into small cell lung cancer (SCLC) and non‐small cell lung cancer (NSCLC) based on histological appearance. SCLC makes up about 20% of lung cancers (Le Pechoux 2004).

SCLC is divided into two stages ‐ limited disease stage and extensive disease stage. Based on the Veterans' Administration Lung Study Group (VALG) classification, The International Association for the Study of Lung Cancer (IASLC) defined limited disease (LD‐SCLC) as: "Disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and ipsilateral and contralateral supraclavicular nodes and should also include patients with ipsilateral pleural effusion independent of whether cytology is positive or negative" (Micke 2002).

Extensive disease (ED‐SCLC) was given the definition: "All patients with sites of disease beyond the definition of limited disease" (Micke 2002).

In SCLC, long‐term survival is quite poor. Untreated, the median survival is 4 to 12 weeks (Chan 2013). Because SCLC is a very aggressive type of cancer and early metastasis (both local and distant) is common, chemotherapy is the first line treatment (Stinchcombe 2010). Even with treatment, long‐term survival is poor. Median survival is in the order of 15 to 20 months for LD‐SCLC and 8 to 13 months for ED‐SCLC. Two‐ and five‐year survival rates for LD‐SCLC range from 20% to 40% and 10% to 13% respectively. For ED‐SCLC, survival rates are even poorer ‐ less than 5% at two years and 1% to 2% at five years (Glisson 2014).

Chemotherapy is the most common treatment for SCLC because of early metastatic spread. Platinum therapy has been widely used and is regarded as first line treatment, as it has been considered one of the most efficacious agents. It is often combined with the non‐platinum agent etoposide (Stinchcombe 2010). Platinum agents are cytotoxic alkylating agents that are active throughout the cell cycle (Chabner 2010). The most widely used platinum agents in SCLC are cisplatin (cis‐diamine‐dichloroplatinum II) and carboplatin (cis‐diamine‐(1,1‐cyclobutanedicarboxylate) platinum) (Stinchcombe 2010).

Non‐platinum agents for SCLC include vincristine, doxorubicin (Adriamycin), cyclophosphamide and ifosfamide. All of these agents have been shown to have anti‐tumour activity and have also been used in combination regimens in SCLC (Pujol 2000). One of the most common non‐platinum combinations that has been shown to be effective in SCLC is the vincristine, doxorubicin and cyclophosphamide regimen (Stinchcombe 2010).

As the available treatments have varying success rates and the different treatments have various advantages and disadvantages, a systematic review will be useful in determining optimal treatment regimens for SCLC.

Objectives

To determine the effectiveness of platinum chemotherapy regimens compared with non‐platinum chemotherapy regimens in the treatment of small cell lung cancer (SCLC) with respect to survival, tumour response, toxicity and quality of life.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) that compared platinum‐based chemotherapy regimens with other non‐platinum‐based chemotherapy regimens.

Inclusion criteria:

Studies involving only patients with pathologically confirmed (cytological or histological) small cell lung cancer.
Studies with at least one platinum‐based treatment group.
Studies with at least one non‐platinum‐based treatment group.

Exclusion criteria:

Studies with platinum agents used in all treatment groups.
Studies with no platinum agent used in any treatment groups.

Types of participants

Adult patients of either sex with pathologically confirmed (cytological or histological) small cell lung cancer.

Types of interventions

Platinum agents at any dose or for any number of cycles compared with any other chemotherapy regimen [P versus A].
Platinum agents at any dose or for any number of cycles in combination with other chemotherapy regimens versus the same chemotherapy regimen without the platinum agent (i.e. non‐platinum chemotherapy is identical in both interventions) [(P+A) versus A].
Platinum agents at any dose or for any number of cycles in combination with any other chemotherapy regimen versus any other chemotherapy regimen not containing platinum agents [(P+A) versus B].

(Where P = platinum chemotherapy agents, A = non‐platinum chemotherapy regimens and B = non‐platinum chemotherapy regimens (different from A)).

Studies where platinum agents were administered to the control group were excluded from this review.

Radiotherapy

RCTs that involve the use of radiotherapy (RT) were included, provided that RT was planned to be given in an identical way (dose, fractionation, timing and technique) in both treatment arms. If RT was given unequally to a treatment arm, or if the chemotherapy regimen to which patients were randomised routinely affected the way in which the RT was given, then the RCT was excluded.

Types of outcome measures

The primary outcome measure was survival at 6 months, 12 months and 24 months of follow up. Other outcome measures, such as tumour response, treatment‐related toxicity and quality of life were also considered. Tumour response for objective overall response and complete response were defined as per World Health Organization (WHO) guidelines for tumour response evaluation (Park 2003). Toxic events were classified (if they had not already been) according to the WHO scale (WHO 1979) and only grades 3 and 4 of toxicity were analysed. The following toxic events were considered: toxic death, nausea and vomiting, alopecia, infection, anaemia, leukopenia, thrombocytopenia and granulocytopenia. Quality‐of‐life data were recorded qualitatively.

Search methods for identification of studies

Please see Appendix 1 and Appendix 2 for the search strategies used in the original review and current update, respectively

In 2007, we designed a search strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 2), MEDLINE (accessed through PubMed), EMBASE and CINAHL (accessed through EBSCO). The date of the search was from 1966 to April 2007. The search strategy was not restricted by date or language.

The search strings used to retrieve studies are reported in Appendix 1

For this update, a search strategy generated by the Cochrane Lung Cancer Group was used to search the following databases:

Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2014, issue 7)
MEDLINE (accessed through PubMed) (1966 to 1 August 2014)
EMBASE (accessed through Ovid) (1966 to 1 August 2014)

The search strings used are reported in Appendix 2.

The strategy was combined with a validated filter to retrieve clinical trials (see section 6.4.11 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011)).

In addition to the search strategy, we handsearched references from relevant studies to identify any further studies. We contacted principal authors to identify any further studies or data that may be relevant to this review.

Data collection and analysis

Two authors (IA and SC) assessed eligibility of articles retrieved via the search strategy from the title and abstract, with differences resolved through the input of a third author (JW). When there was insufficient information for assessment, the authors reviewed the full articles.

Two authors (IA and SC) independently evaluated all RCTs found in the search in order to rule out those that did not meet the inclusion criteria. We evaluated those studies for probable inclusion by critical reading of the whole article. There was no blinding of the author as to the origin or conclusions of the article for eligibility assessment, data extraction or quality assessment.

If necessary, we sought information from the principal investigator of the trial concerned. Two authors (IA and SC) independently extracted the data to ensure validity, and we resolved any discrepancies by an open discussion between all investigators (IA, SC, JW, KF).

To evaluate the methodological quality of selected studies, the authors independently assessed the studies with respect to the criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0.(Higgins 2011a)

Each author independently undertook the extraction and registration of data from each study using data and study forms specifically designed for this review. The data extracted included details of the methodology used, the characteristics of the study participants, the type of interventions undertaken, the comparison groups, and the results obtained including the follow‐up period.

We resolved any disagreement by consensus, or with the input of a third member (JW) of the review team.

We analysed all patients initially randomised on an intention‐to‐treat (ITT) basis. The ITT population was defined as randomised patients, irrespective of whether they received any form of treatment. For dichotomous variables, we calculated risk ratio (RR) with a 95% confidence interval (CI). We used a random‐effects model for the pooled analysis. We undertook the meta‐analysis in Review Manager 5.3 (RevMan 2014).

We also calculated the proportion of people alive at 6, 12 and 24 months from both treatment groups. This data was used to generate survival curves for each of the subgroups.

Subgroup analysis

We performed subgroup analyses for the outcomes of survival (at 6 months, 12 months and 24 months) and tumour response. We categorised data from included studies into the subgroups:

'undifferentiated' ‐ if the study did not differentiate between patients with limited disease and extensive disease small cell lung cancer;
LD‐SCLC ‐ if the study presented data specifically from patients with limited disease small cell lung cancer;
ED‐SCLC ‐ if the study presented data specifically from patients with extensive disease small cell lung cancer.

This was undertaken in order to determine if there are differences between the treatment groups depending on the stage of the SCLC.

Heterogeneity assessment

Where substantial heterogeneity occurred, we explored the effect of potential sources of heterogeneity in an attempt to identify the cause of the heterogeneity. Substantial heterogeneity was considered to exist when the I² value was greater than 50% (Higgins 2003).

We identified the following potential sources of heterogeneity (postulated a priori).

Quality of studies. We deemed studies to be of higher quality if they satisfied the following criteria in the risk of bias assessment:

- incomplete outcome data addressed for all assessed outcomes;
- free of selective reporting;
- free of other bias.

(Please refer to the 'Risk of bias' table for quality assessment).

In the current update, the studies were also assessed for quality using the GRADE approach as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0(Schünemann 2011). Using this method, studies were given a quality rating of High, Moderate, Low or Very Low.

Full article publication versus abstract publication.

Use of radiotherapy as a co‐intervention.

Sensitivity analysis

We performed a sensitivity analysis, systematically excluding studies from the overall analysis based on the potential sources of heterogeneity hypothesised above. This included conducting a sensitivity analysis involving only studies that used radiotherapy treatment in order to explore the potential influence of platinum‐based chemotherapy regimens and the use of radiotherapy on toxicity.

Results

Description of studies

Search results

The search strategies used for this review are outlined in Appendix 1 (strategy for the original review) and Appendix 2 (strategy for the update). The search yielded 3669 search results. We excluded 112 results as they were duplicates. A further 3525 records were excluded by abstract as they did not meet the inclusion criteria. This left 32 studies to be included in the review, including 29 from the original review (Figure 1).

Study characteristics

The 32 studies included 6075 participants who were randomised. Of these, 3036 were assigned to platinum‐based chemotherapy and 3039 to non‐platinum‐based chemotherapy regimens. All studies reported ITT analyses, thus recomputation of outcomes was not required.

Of the included studies, nineteen were conducted in centres throughout Europe, nine in North America, three in Asia and one (Quoix 2005) conducted in both Canada and Europe. All studies were one or more years in duration. The shortest study, Wolf 1987, lasted 12 months and the longest study, Urban 1999a, lasted six years.

A summary of the included studies is presented in Table 1. A detailed description of each study is presented in the section 'Characteristics of included studies'.

1. Summary of included studies.

Study ID		Number of Patients			Radiotherapy
First Author	Year	Platinum group	Non‐platinum group	Total
Baka	2008	141	139	280	PCI, TRT
Chahinian	1989	105	103	208	PCI
Creech	1982	21	19	40	‐
de Jong	2007	101	102	203	‐
Eagan	1981	31	31	62	TRT
Evans	1987	145	144	289	PCI, TRT
Farris	1993	56	57	113	PCI, TRT
Fukuoka	1986	35	34	69	TRT
Fukuoka	1991	97	97	194	TRT
Gatzemeier	1994	171	173	344	‐
Goodman	1990	194	194	388	PCI, TRT
Greco	2005	60	60	120	PCI
Havemann	1987	150	152	302	PCI, TRT
Jones	1993	54	50	104	PCI, TRT
Kanitz	1992	59	52	111	‐
Lyss	2002	12	13	25	PCI
Postmus	1992	60	63	123	PCI
Postmus	1996	70	73	143	‐
Quoix	2005	41	41	82	‐
Roth	1992	148	146	294	PCI
Sculier	1990	95	106	201	PCI
Sculier	1993	107	108	215	PCI, TRT
Sekine	2014	30	32	62	‐
Smith	1991	47	48	95	PCI
Souhami	1997	80	75	155	‐
Sundstrom	2002	218	218	436	PCI, TRT
Urban	1999a	191	203	394	PCI, TRT
Urban	1999b	229	228	457	PCI, TRT
Veronesi	1994	70	66	136	PCI, TRT
Wampler	1991	85	85	170	‐
White	2001	60	59	119	PCI, TRT
Wolf	1987	73	68	141	PCI, TRT
Total: 32	‐	3036	3039	6075	‐

Undifferentiated		LD‐SCLC		ED‐SCLC
Creech	1982	Eagan	1981	Chahinian	1989
Farris^	1993	Fukuoka	1986	Fukuoka	1986
Fukuoka^	1991	Goodman	1990	Gatzemeier	1994
Postmus	1992	Havemann	1987	Greco	2005
Sculier	1990	Jones	1993	Havemann	1987
Sculier	1993	Sundstrom	2002	Jones	1993
Smith	1991	Urban*	1999a	Kanitz	1992
Souhami	1997	Wolf	1987	Lyss	2002
Urban	1999b	Baka*	2008	Postmus	1996
Veronesi	1994	‐	‐	Quoix	2005
White	2001	‐	‐	Roth	1992
‐	‐	‐	‐	Sundstrom	2002
‐	‐	‐	‐	Urban*	1999a
‐	‐	‐	‐	Wampler	1991
‐	‐	‐	‐	Wolf	1987
‐	‐	‐	‐	de Jong	2007
‐	‐	‐	‐	Sekine	2014
				Baka*	2008

Subgroup	% Survival
Subgroup	6 months	12 months	24 months
Undifferentiated	68.09%	30.92%	8.08%
LD‐SCLC	88.70%	57.98%	21.09%
ED‐SCLC	65.36%	29.37%	6.93%

Outcome	All studies	Higher quality studies
6‐month survival	NSSD	NSSD
12‐month survival	NSSD	NSSD
24‐month survival	NSSD	NSSD
Overall response	NSSD	P
Complete response	P	P
Toxic death	NSSD	NSSD
Nausea and Vomiting	NP	NP
Alopecia	NSSD	NP
Infection	NSSD	P
Anaemia	NSSD	NSSD
Leukopenia	NSSD	P
Thrombocytopenia	NP	NSSD
Granulocytopenia	NSSD	NSSD

Outcome	All studies	Only studies using radiotherapy
6‐month survival	NSSD	NSSD
12‐month survival	NSSD	NSSD
24‐month survival	NSSD	NSSD
Overall response	NSSD	NSSD
Complete response	P	P
Toxic death	NSSD	NSSD
Nausea and Vomiting	NP	NP
Alopecia	NSSD	NSSD
Infection	NSSD	NSSD
Anaemia	NSSD	NSSD
Leukopenia	NSSD	NSSD
Thrombocytopenia	NP	NP
Granulocytopenia	NSSD	NSSD

Date	Event	Description
13 June 2015	New search has been performed	New author for update ‐ Saion Chatterjee
18 May 2015	New search has been performed	A new search was run in August 2014
18 May 2015	New citation required but conclusions have not changed	3 new studies were identified (Baka 2008; de Jong 2007; Sekine 2014). A meta‐analysis was carried out. Conclusions not changed

Date	Event	Description
12 November 2008	Amended	Contact details updated
8 May 2008	Amended	Converted to new review format.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 6‐month survival	30	5755	Risk Ratio (M‐H, Random, 95% CI)	1.04 [1.00, 1.09]
1.1 Undifferentiated	10	1808	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.94, 1.10]
1.2 Limited Disease	8	1044	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.94, 1.07]
1.3 Extensive Disease	18	2903	Risk Ratio (M‐H, Random, 95% CI)	1.09 [1.02, 1.17]
2 12‐month survival	31	6034	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.97, 1.16]
2.1 Undifferentiated	10	1808	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.82, 1.22]
2.2 Limited Disease	9	1209	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.95, 1.39]
2.3 Extensive Disease	19	3017	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.94, 1.18]
3 24‐month survival	27	5398	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.85, 1.31]
3.1 Undifferentiated	10	1808	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.71, 1.33]
3.2 Limited Disease	9	1209	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.70, 1.65]
3.3 Extensive Disease	15	2381	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.71, 1.75]
4 Overall response	31	5651	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.98, 1.13]
4.1 Undifferentiated	11	2225	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.89, 1.21]
4.2 Limited Disease	8	809	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.94, 1.12]
4.3 Extensive Disease	18	2617	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.96, 1.19]
5 Complete response	30	5599	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.14, 1.54]
5.1 Undifferentiated	10	2175	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.90, 1.77]
5.2 Limited Disease	8	809	Risk Ratio (M‐H, Random, 95% CI)	1.19 [1.02, 1.40]
5.3 Extensive Disease	18	2615	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.17, 1.80]
6 Toxic Death	20	3696	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.72, 1.62]
7 Nausea and Vomiting	22	3961	Risk Ratio (M‐H, Random, 95% CI)	1.52 [1.22, 1.88]
8 Alopecia	8	1526	Risk Ratio (M‐H, Random, 95% CI)	1.14 [1.00, 1.30]
9 Infection	12	2184	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.43, 1.09]
10 Anaemia	12	2219	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.86, 1.67]
11 Leukopenia	17	2556	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.67, 1.05]
12 Thrombocytopenia	19	3276	Risk Ratio (M‐H, Random, 95% CI)	1.89 [1.37, 2.61]
12.1 New Subgroup	19	3276	Risk Ratio (M‐H, Random, 95% CI)	1.89 [1.37, 2.61]
13 Granulocytopenia	5	1229	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.79, 1.00]

Methods	STUDY DESIGN: Parallel group LOCATION, NUMBER OF CENTRES: United Kingdom, 2 DURATION OF STUDY: April 1999 – February 2005 CONCEALMENT OF ALLOCATION: B DESCRIBED AS RANDOMISED: Yes DESCRIBED AS DOUBLE BLIND: No METHOD OF RANDOMISATION WELL DESCRIBED/APPROPRIATE: Appropriate METHOD OF BLINDING WELL DESCRIBED/APPROPRIATE: N/A  DESCRIPTION OF WITHDRAWALS/DROPOUTS: Adequate GRADE ASSESSMENT QUALITY RATING: High TYPE OF ANALYSIS (AVAILABLE CASE/TREATMENT RECEIVED/ ITT): ITT COMPLIANCE: CONFOUNDERS:
Participants	INCLUSION CRITERIA: Previously untreated patients with histologically or cytologically proven SCLC and a maximum of two adverse prognostic factors (extensive stage disease, PS >2, raised LDH, serum sodium <130mmol/l:, Alk Phos >1.25 ULN) were eligible. Other eligibility criteria included age >18 years, normal blood count, serum bilirubin <35 mmol/l and creatinine clearance >50 ml/min. In patients with impaired renal function, that is, creatinine clearance >30 ml/min but <50 ml/min and/or patients with significant cardiovascular disease, carboplatin could be substituted for cisplatin in the first or subsequent cycles. EXCLUSION CRITERIA: A CT brain scan was not routinely performed, but patients with known brain metastases were not eligible. N SCREENED: Unknown N RANDOMISED: 280 (ACE – 139; PE – 141) N COMPLETED: 143 (ACE – 52; PE – 91) ASSESS STAGE: Yes (N LIMITED): 165 (ACE – 84; PE 81) (N EXTENSIVE): 114 (ACE – 54; PE – 60) M: 142 (ACE – 67; PE – 75) F: 138 (ACE – 72; PE – 66) MEAN AGE: Median – ACE – 66 (38‐81); PE – 65 (39‐89) BASELINE DETAILS: Physical examination, Histological diagnosis, CT scan of thorax and abdomen, blood tests Tumour stage was assessed with CT scan of thorax and abdomen. Disease measurement was performed within 4 weeks before the start of treatment.
Interventions	TYPE: Chemotherapy REGIMENS, DOSE, DELIVERY: ACE ‐ (doxorubicin 50 mg/m2 i.v., cyclophosphamide 1 g/m2 i.v. and etoposide 120 mg/m2 i.v. on day 1, followed by etoposide 240 mg/m2 orally for 2 days) PE ‐ (cisplatin 80 mg/m2 and etoposide 120 mg/m2 i.v. on day 1, followed by etoposide 240 mg/m2 orally for 2 days every 3 weeks). For patients where cisplatin was not suitable, carboplatin was substituted at an AUC of 6, calculated according to the Calvert formula (ie, carboplatin dose 1⁄4 target AUC of 6 (glomerular filtration rate þ 25 mg), where glomerular filtration rate was based on EDTA or measured creatinine clearance). CYCLES: 6 cycles every 3 weeks CO‐INTERVENTIONS PERMITTED: Thoracic radiotherapy CO‐INTERVENTIONS: Thoracic radiotherapy was given to patients with limited stage disease achieving a complete or partial response to chemotherapy, beginning 3 weeks after the last cycle of chemotherapy (30 Gy in 10 daily fractions). Patients with ED SCLC received thoracic irradiation only if they had thoracic symptoms amenable to palliation with radiotherapy after completion of chemotherapy. Prophylactic cranial irradiation was considered for all LD patients achieving a complete response; suitable patients received 25 Gy in 10 daily fractions after completion of chemotherapy.
Outcomes	OUTCOMES MEASURED: Primary – 1 year survival Secondary – 2 year survival, median survival, response rate, toxicity FOLLOW‐UP ASSESSMENT POINTS: During chemotherapy, patients were assessed on days 1 and 15 with physical examination, and weekly, with blood count, biochemistry and WHO Performance Status. A chest X‐ray (CXR) was carried out after every second cycle of treatment, but assessment of response was made according to the WHO criteria by CT scanning at the end of chemotherapy unless progressive disease was detected in the interim by CXR. Toxicities were graded according to the National Cancer Institute Common Toxicity Grading Criteria version December 1994 (revised). OUTCOMES INCLUDED IN ANALYSES: Survival Response Rate Toxicity TYPE: Chemotherapy REGIMENS: ACE ‐ (doxorubicin 50 mg/m2 i.v., cyclophosphamide 1 g/m2 i.v. and etoposide 120 mg/m2 i.v. on day 1, followed by etoposide 240 mg/m2 orally for 2 days) PE ‐ (cisplatin 80 mg/m2 and etoposide 120 mg/m2 i.v. on day 1, followed by etoposide 240 mg/m2 orally for 2 days every 3 weeks). For patients where cisplatin was not suitable, carboplatin was substituted at an AUC of 6, calculated according to the Calvert formula (ie, carboplatin dose 1⁄4 target AUC of 6 (glomerular filtration rate þ 25 mg), where glomerular filtration rate was based on EDTA or measured creatinine clearance). CYCLES: 6 cycles every 3 weeks DOSE: DELIVERY: IV CO‐INTERVENTIONS PERMITTED: Thoracic radiotherapy CO‐INTERVENTIONS: Thoracic radiotherapy was given to patients with limited stage disease achieving a complete or partial response to chemotherapy, beginning 3 weeks after the last cycle of chemotherapy (30 Gy in 10 daily fractions). Patients with ED SCLC received thoracic irradiation only if they had thoracic symptoms amenable to palliation with radiotherapy after completion of chemotherapy. Prophylactic cranial irradiation was considered for all LD patients achieving a complete response; suitable patients received 25 Gy in 10 daily fractions after completion of chemotherapy.
Notes	SUB‐GROUPS INDENTIFIED: Limited disease stage Extensive disease stage
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Described and appropriate
Allocation concealment (selection bias)	Low risk	Not described
Blinding (performance bias and detection bias)   Participants	Unclear risk	Not described
Blinding (performance bias and detection bias)   Investigators	Unclear risk	Not described
Blinding (performance bias and detection bias)   Survival	Unclear risk	Not described
Blinding (performance bias and detection bias)   Tumour Response	Unclear risk	Not described
Blinding (performance bias and detection bias)   Toxicity	Unclear risk	Not described
Blinding (performance bias and detection bias)   Quality of Life	Unclear risk	Not described
Incomplete outcome data (attrition bias)   Survival	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Incomplete outcome data (attrition bias)   Tumour Response	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Incomplete outcome data (attrition bias)   Toxicity	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Incomplete outcome data (attrition bias)   Quality of Life	Unclear risk	Not assessed

Methods	STUDY DESIGN: Parallel study  LOCATION, NUMBER OF CENTRES: 20 Cancer and Leukaemia Group B (CALGB) main member institutions  DURATION OF STUDY: February 1981 to May 1984  CONCEALMENT OF ALLOCATION: D  DESCRIBED AS RANDOMISED: Yes  DESCRIBED AS DOUBLE BLIND:  METHOD OF RANDOMISATION WELL‐DESCRIBED/APPROPRIATE: Not described  METHOD OF BLINDING WELL‐DESCRIBED/APPROPRIATE: Not described  DESCRIPTION OF WITHDRAWALS/DROP‐OUTS: Not described GRADE ASSESSMENT QUALITY RATING: Low  TYPE OF ANALYSIS (AVAILABLE CASE/TREATMENT RECEIVED/ ITT): ITT
Participants	ELIGIBILITY  INCLUSION CRITERIA:  CALGB performance status of 0 to 3  Informed consent  One measurable tumour EXCLUSION CRITERIA:  Prior chemotherapy  Myocardial infarction within 6 months  Cardiac failure  Serious arrhythmia not directly attributable to metastatic small cell lung cancer  Patients with any contraindications to the use of warfarin  Patients already on warfarin N RANDOMISED: 294  ASSESS STAGE: Yes  (N LIMITED): 0  (N EXTENSIVE): 294  M: 199 (MACC ‐ 62; MACC + W ‐ 70; MEPH/MACC ‐ 67)  F: 95 (MACC ‐ 24; MACC + W ‐ 33; MEPH/MACC ‐ 38  AGE:
Interventions	TYPE: Chemotherapy  REGIMENS:  MACC ‐ methotrexate (30 mg/m² intravenously [IV]), doxorubicin (40mg/m2 IV), cyclophosphamide (400 mg/m² IV) and lomustine (30 mg/m² orally) given once every 3 weeks. Doxorubicin was discontinued after a total cumulative dose of 450 mg/m² MACC + W ‐ methotrexate (30 mg/m² intravenously [IV]), doxorubicin (40 mg/m² IV), cyclophosphamide (400 mg/m² IV), lomustine (30 mg/m² orally) and warfarin sodium (single oral daily dose of 10 mg starting on day 1) given once every 3 weeks. Doxorubicin was discontinued after a total cumulative dose of 450 mg/m². MEPH/MACC ‐ Mitomycin (7 mg/m² IV on day 1), etoposide (40 mg/m² IV on days 1 to 3), cisplatin (50 mg/m² IV on day 1) and hexamethylmelamine (100 mg/m² orally from day 3 to 17). This was the MEPH regimen. On day 35 (week 6) of each cycle, patients received MACC chemotherapy as described above. On day 56 (week 9), MEPH component was given again 3 weeks after MACC. The two regimens were alternated in this fashion (MEPH/MACC) CO‐INTERVENTIONS: Radiotherapy CLASSIFICATION OF INTERVENTION (ADJUVANT/NEO‐ADJUVANT/PALLIATIVE):  Palliative
Outcomes	OUTCOMES MEASURED:  Tumour response  Overall survival  Toxicity FOLLOW UP ASSESSMENT POINTS:  OUTCOMES INCLUDED IN ANALYSES:  Tumour response  Overall survival
Notes	Only data from arms MACC + W and MEPH/MACC were considered for this systematic review
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Participants	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Investigators	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Survival	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Tumour Response	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Toxicity	Unclear risk	N/A
Blinding (performance bias and detection bias)   Quality of Life	Unclear risk	N/A
Incomplete outcome data (attrition bias)   Survival	Unclear risk	Reasons for withdrawals, drop‐outs and exclusions not reported
Incomplete outcome data (attrition bias)   Tumour Response	Unclear risk	Reasons for withdrawals, drop‐outs and exclusions not reported
Incomplete outcome data (attrition bias)   Toxicity	Unclear risk	N/A
Incomplete outcome data (attrition bias)   Quality of Life	Unclear risk	N/A
Selective reporting (reporting bias)	Low risk	Adequate
Other bias	Low risk	Adequate

Methods	STUDY DESIGN: Parallel group  LOCATION, NUMBER OF CENTRES:  DURATION OF STUDY: July 1976 to July 1978  CONCEALMENT OF ALLOCATION: D  DESCRIBED AS RANDOMISED: Yes  DESCRIBED AS DOUBLE BLIND: No  METHOD OF RANDOMISATION WELL‐DESCRIBED/APPROPRIATE: Not described  METHOD OF BLINDING WELL‐DESCRIBED/APPROPRIATE: Not described  DESCRIPTION OF WITHDRAWALS/DROP‐OUTS: Not described GRADE ASSESSMENT QUALITY RATING: Low  TYPE OF ANALYSIS (AVAILABLE CASE/TREATMENT RECEIVED/ ITT): ITT
Participants	ELIGIBILITY  INCLUSION CRITERIA: Previously untreated limited stage small cell lung cancer EXCLUSION CRITERIA: Patients with significant cardiac disease or serum creatinines > 1.5 mg/dl N RANDOMISED: 62  N COMPLETED:  ASSESS STAGE: Yes  (N LIMITED): 62 (VOCA ‐ 31; VOCAP ‐ 31)  (N EXTENSIVE): 0  M: 45 (VOCA ‐ 22; VOCAP ‐ 23)  F: 17 (VOCA ‐ 9; VOCAP ‐ 8)  AGE: Median VOCA ‐ 58 (39 to 74); VOCAP ‐ 59 (38 to 77)
Interventions	TYPE: Chemotherapy  REGIMENS:  VOCA ‐ VP‐16 50 mg/m² IV on days 1, 2 and 3; vincristine (Oncovin) 1.4 mg/m² IV on day 1; cyclophosphamide 150 mg/m² IV on days 1, 2 and 3; and Adriamycin 15 mg/m² IV on days 1, 2 and 3. VOCAP ‐ VP‐16 50 mg/m² IV on days 1, 2 and 3; vincristine (Oncovin) 1.4 mg/m² IV on day 1; cyclophosphamide 150 mg/m² IV on days 1, 2 and 3; Adriamycin 15 mg/m² IV on days 1, 2 and 3; and cisplatin 40 mg/m² IV on day 1. Both treatment arms were administered for 8 cycles CO‐INTERVENTIONS: Thoracic radiation therapy was administered concomitantly with the third and fourth courses of chemotherapy  CLASSIFICATION OF INTERVENTION: (ADJUVANT/NEO‐ADJUVANT/PALLIATIVE): Palliative
Outcomes	OUTCOMES MEASURED:  Regression rates  Time to progression  Survival  Tumour response  Toxicity FOLLOW UP ASSESSMENT POINTS:  OUTCOMES INCLUDED IN ANALYSES:  Survival  Tumour response  Toxicity
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Participants	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Investigators	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Survival	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Tumour Response	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Toxicity	Unclear risk	Not reported
Blinding (performance bias and detection bias)   Quality of Life	Unclear risk	N/A
Incomplete outcome data (attrition bias)   Survival	High risk	Reasons for withdrawals, drop‐outs and exclusions not reported
Incomplete outcome data (attrition bias)   Tumour Response	High risk	Reasons for withdrawals, drop‐outs and exclusions not reported
Incomplete outcome data (attrition bias)   Toxicity	High risk	Reasons for withdrawals, drop‐outs and exclusions not reported
Incomplete outcome data (attrition bias)   Quality of Life	Unclear risk	N/A
Selective reporting (reporting bias)	Unclear risk	Insufficient information
Other bias	Low risk	Adequate

Study	Reason for exclusion
Artel‐Cortes 2004	Platinum agents used in all treatment groups
Blackstock 2005	Does not compare chemotherapy regimens
De Marinis 2005	Platinum agents used in all treatment groups
Eckardt 2006	Platinum agents used in all treatment groups
Hanna 2006	Platinum agents used in all treatment groups
Lara 2006	Platinum agents used in all treatment groups
McClay 2005	Platinum agents used in all treatment groups
Niell 2005	Platinum agents used in all treatment groups
Paccagnella 2004	Platinum agents used in all treatment groups
Pathak 2005	Study disease is non‐small cell lung cancer
Schild 2004	Does not compare chemotherapy regimens
Seifart 2005	Platinum agents used in all treatment groups

PERMALINK

Platinum versus non‐platinum chemotherapy regimens for small cell lung cancer

Isuru U Amarasena

Saion Chatterjee

Julia AE Walters

Richard Wood‐Baker

Kwun M Fong

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Radiotherapy

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Subgroup analysis

Heterogeneity assessment

Sensitivity analysis

Results

Description of studies

Search results

1.

Study characteristics

1. Summary of included studies.

Study chemotherapy interventions

Radiotherapy as a co‐intervention

Subgroups

2. Studies by subgroup.

Risk of bias in included studies

2.

Effects of interventions

Survival

Survival at six months

Subgroup: 'undifferentiated'

Subgroup: LD‐SCLC

Subgroup: ED‐SCLC

Survival at 12 months

Subgroup: 'undifferentiated'

Subgroup: LD‐SCLC

Subgroup: ED‐SCLC

Survival at 24 months

Subgroup: 'undifferentiated'

Subgroup: LD‐SCLC

Subgroup: ED‐SCLC

Survival by subgroup

3. Survival by subgroup.

3.

Tumour response

Overall response

Subgroup: 'undifferentiated'

Subgroup: LD‐SCLC

Subgroup: ED‐SCLC

Complete response

Subgroup: 'Undifferentiated'

Subgroup: LD‐SCLC

Subgroup: ED‐SCLC

Toxicity

Toxic death

Nausea and vomiting

Alopecia

Infection

Anaemia

Leukopenia

Thrombocytopenia

Granulocytopenia

Quality of life

Sensitivity analysis

Quality of studies