Platinum vs non‐platinum chemotherapy regimes for small cell lung cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effectiveness of platinum chemotherapeutic agents compared with non‐platinum chemotherapeutic agents in the treatment of small cell lung cancer with respect to survival, tumour response, toxicity and quality of life, by undertaking the following comparisons:
a)Platinum agents versus other chemotherapeutic agents [P v A]
b)Platinum agents combined with other chemotherapy agents versus the same chemotherapy regime without the platinum agents [(P+A) v A]
c)Platinum agents combined with other chemotherapy agents versus any other chemotherapy regimes without platinum agents [(P+A) v B]
Where P = platinum chemotherapy agents, A = non‐platinum chemotherapy regimes, B = non‐platinum chemotherapy regimes (different from A)
Background
Lung cancer is one of the most common cancers in the world both in terms of incidence and mortality (Ferlay 2001). Smoking is the largest cause of lung cancer, associated with 90% of cases (Doll 1978) Other risk factors include occupational and environmental exposures e.g. asbestos (van Loon 1997). Lung cancer is divided into small cell lung cancer (SCLC) and non‐small cell cancer (NSCLC) based on histological apperance. SCLC makes up about 20‐25% of lung cancers (Le Pechoux 2004).
SCLC is divided into two stages ‐ limited disease stage and extensive disease stage. International Association for the Study of Lung Cancer (IASLC). This system defined limited disease 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" (Stahel 1989)
Extensive disease was given the definition:
"All patients with sites of disease beyond the definition of limited disease" (Stahel 1989)
In SCLC, long‐term survival is quite poor. Untreated, the median survival is 4 to 12 weeks (Kato 1969). Because SCLC is a very aggressive type of cancer and early metastasis (both local and distant is common), chemotherapy is the first line treatment (Cohen 1978). Even with treatment, the long‐term survival is poor. One study reported a 2‐year survival rate of 8.5% for limited disease and 2.2% survival rate for extensive disease (Souhami 1990). In another study, the overall survival was 3.5% at five years and 1.8% at ten years. (Lassen 1995).
Chemotherapy is the most common treatment for SCLC because of early metastasis. Platinum therapy has been widely used and is regarded as first line treatment, often with the non‐platinum agent etoposide (Berghmans 1999). Platinum agents are cytotoxic alkylating agents that are active throughout the cell cycle (Rosenberg 1965). The most widely used platinum agents in SCLC are cisplatin (cis‐diamine‐dichloroplatinum II) and carboplatin (cis‐diamine‐(1,1‐cyclobutane dicarboxylato)platinum).
Non‐platinum agents for SCLC include vincristine, adriamycin (doxorubicin), cyclophosphamide, ifosfamide. All of these agents have been shown to have anti‐tumour activity and have also been used in combination in SCLC (Pujol 2000). One of the most common non‐platinum combinations that has been shown to be effective in SCLC is the vincristine, adriamycin (doxorubcin) and cyclophosphamide regime (Fukuoka 1991).
With varying success rates of the available treatments and various advantages and disadvantages of different agents, a systematic review will be useful in determining optimal treatment regimes for SCLC.
Objectives
To determine the effectiveness of platinum chemotherapeutic agents compared with non‐platinum chemotherapeutic agents in the treatment of small cell lung cancer with respect to survival, tumour response, toxicity and quality of life, by undertaking the following comparisons:
a)Platinum agents versus other chemotherapeutic agents [P v A]
b)Platinum agents combined with other chemotherapy agents versus the same chemotherapy regime without the platinum agents [(P+A) v A]
c)Platinum agents combined with other chemotherapy agents versus any other chemotherapy regimes without platinum agents [(P+A) v B]
Where P = platinum chemotherapy agents, A = non‐platinum chemotherapy regimes, B = non‐platinum chemotherapy regimes (different from A)
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) that compared platinum based chemotherapy regimes with other non‐platinum based chemotherapy regimes.
Types of participants
Adult patients of either sex with histologically confirmed small cell lung cancer (SCLC).
Types of interventions
a)Platinum agents at any dose or for any number of cycles compared with any other chemotherapy regime [P v A]
b)Platinum agents at any dose or for any number of cycles in combination with other chemotherapy regimes versus the same chemotherapy regime without the platinum agent. (i.e. non‐platinum chemotherapy is identical in both interventions) [(P+A) v A]
c)Platinum agents at any dose or for any number of cycles in combination with any other chemotherapy regime versus any other chemotherapy regime not containing platinum agents [(P+A) v B]
Where P = platinum chemotherapy agents, A = non‐platinum chemotherapy regimes, B = non‐platinum chemotherapy regimes (different from A)
Studies where platinum agents were administered to the control group will be excluded from this review.
Radiotherapy
RCTs that involve the use of radiotherapy (RT) will be included, provided that RT was planned to be given in an identical way (dose, fractionation, timing and technique) in both treatment arms. If RT is given unequally to a treatment arm, or if the chemotherapy regime to which patients are randomised routinely affects the way in which the RT is given, then the RCT will be excluded.
Types of outcome measures
The primary outcome measure will be survival at 6 months, 12 months and 24 months of follow‐up. Other outcomes measures such as tumour response, quality of life and treatment‐related toxicity will also be considered. Toxic events will be classified (if they have not already been) according to the WHO scale and only grades 3 and 4 of toxicity will be analysed. The following toxic events will be considered: toxic death, alopecia, infection, nausea and vomiting, anaemia, leukopaenia, thrombocytopaenia and granulocytopenia.
Search methods for identification of studies
We will design a search strategy to search MEDLINE (access through PubMed), EMBASE (access through Ovid), CINAHL (access through Ovid) and The Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library). We will not restrict that strategy by date or language. We provide below the search string that we will use to retrieve studies in MEDLINE (access through PubMed):
#1 (carcinoma, small cell AND lung neoplasms[MeSH]) OR SCLC[ti] OR ((lung[ti] OR lungs[ti] OR pulmonary[ti] OR bronchus[ti] OR brochogenic[ti] OR bronchial[ti] OR bronchoalveolar[ti] OR alveolar[ti]) AND (small‐cell[ti] OR oat‐cell[ti]) AND (cancer*[ti] OR carcinoma*[ti] OR malignan*[ti] OR tumor*[ti] OR tumour*[ti] OR neoplasm*[ti]))
#2 "Platinum Compounds"[MeSH] OR "Cisplatin"[MeSH] OR platinum[tiab] OR cisplatin[tiab] OR Platinol[ti] OR carboplatin[tiab] OR Paraplatin[ti] OR oxaliplatin[tiab] OR Eloxatin*[ti]
#3 #1 AND #2
We will combine the strategy with a validated filter to retrieve clinical trials (Robinson 2002). This search strategy will be adapted as appropriate for the other databases
In addition to the search strategy, references from relevant studies will be searched to identify any further studies. In addition, principal authors will be contacted to identify any further studies or data that may be relevant to this review.
Data collection and analysis
Eligibility of articles retrieved via the search strategy will be assessed from the title and abstracts. Where there is insufficient information for assessment, the full articles will be reviewed by authors.
All RCTs found in the search will be evaluated by two independent authors in order to rule out those that do not meet the inclusion criteria. Those studies for probable inclusion will be evaluated by critical reading of the whole article. There will be no blinding of the author as to the origin, or conclusions of the article for eligibility assessment, data extraction or quality assessment.
Where necessary information will be sought from the principal investigator of the trial concerned. The data will be extracted by 2 authors independently to ensure validity, and if necessary discrepancies will be solved by an open discussion between all investigators.
To evaluate the methodological quality of selected studies, the authors will independently assess the methods section of the RCTs, considering the randomisation process, the presence or not of adequate randomisation concealment, adherence to intention‐to‐treat, the description or not of follow‐up and losses of included patients. Each study will be classified into categories A, B or C following the criteria set out in the Cochrane Collaboration Handbook with the aim of estimating the selection bias, performance bias, attrition bias and detection bias.
The extraction and registration of data from each study will be undertaken independently by each author using data and study forms specifically designed for this review. The data extracted will include 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.
Any disagreement will be resolved by consensus, or with the input of a third member of the review team.
All patients initially randomised with intention to treat will be included in the analysis. For dichotomous variables, relative risk will be calculated with a 95% confidence interval. For continuous variables standardized mean difference will be calculated. The pooled analysis will be undertaken using the random effects model. The meta‐analysis will be undertaken in Review Manager 4.2.
Heterogeneity assessment
Heterogeneity is expected to occur as the result of many potential factors (postulated a priori), and if this is indeed observed, the effect of potential sources of heterogeneity will be explored in an attempt to identify subgroups where the results are homogenous. Statistical heterogeneity will be considered to exist when the I‐squared value (as calculated by Review Manager 4.2) is greater than 50%. Meta‐analysis will be undertaken if the results for the various endpoints of interest are sufficiently homogenous.
Potential sources of heterogeneity:
a)Quality of studies
b)Full article publication versus full and abstract publications
c)Co‐interventions (including radiotherapy)
Sensitivity analysis
Sensitivity analysis will be performed systematically excluding studies from the overall analysis based on the potential sources of heterogeneity hypothesized above and if homogenous subgroups have not already been identified and analysed separately.
In addition, a sensitivty analysis involving only studies that used RT treatment will be conducted in order to explore the potential influence of platinum based chemotherapy regimes on RT toxicity.
Sub‐group analysis
Sub‐group analyses will be done for the outcomes of survival (at 6 months, 12 months and 24 months) and tumour response. Data from included studies will be categorised into the sub‐group:
*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 is to be done in order to determine if there are differences between the treatment groups depending on the stage of the SCLC.
