Plain language summary
Comparing chemotherapy with cisplatin or carboplatin in the treatment of people with advanced lung cancer
Lung cancer is the leading cause of cancer death and almost 75% of people are incurable at diagnosis. Non-small cell is the most common type of lung cancer (almost 90% of all lung cancer cases). For many of these people, chemotherapy is a good treatment option and it is associated with longer survival and better quality of life. However, treatment for people with advanced non-small cell lung cancer is palliative, in that it provides relief from pain and other distressing symptoms. Treatments that include cisplatin or carboplatin plus another drug are the most widely used drug combinations, but they can be associated with undesirable toxicity. Thus, it would be desirable to have a treatment that is just as effective but with less toxicity.
We found 10 trials (including 5017 people) that compared cisplatin with carboplatin, both combined with another modern drug, called a third-generation drug. The drugs were equally effective at prolonging survival, but the toxicity profile was different. Cisplatin caused more nausea or vomiting or both and carboplatin caused more numbness and tingling in hands and feet and greater decrease in the number of platelets (which control clotting) in the blood.
Unfortunately, we could not analyse quality of life in our review because only two trials studied this and they used different methods to measure the effects.
Comparaison de la chimiothérapie à base de cisplatine et à base de carboplatine dans le traitement des personnes atteintes du cancer bronchopulmonaire à un stade avancé
Le cancer bronchopulmonaire est la principale cause de décès par cancer et chez presque 75 % des personnes la maladie est incurable au moment du diagnostic. Le type non à petites cellules est le type le plus fréquent de cancer bronchopulmonaire (presque 90 % de tous les cas de cancer bronchopulmonaire). Pour un grand nombre de ces personnes, la chimiothérapie est une option thérapeutique bénéfique et est associée à une survie plus longue et une meilleure qualité de vie. Toutefois, le traitement des personnes atteintes du cancer bronchopulmonaire non à petites cellules à un stade avancé est palliatif, dans la mesure où il apporte un soulagement de la douleur et des autres symptômes éprouvants. Les traitements qui comprennent le cisplatine ou le carboplatine plus un autre médicament sont les associations de médicaments les plus largement utilisées, mais elles peuvent aussi être associées à une toxicité indésirable. Ainsi, il serait souhaitable d'avoir un traitement qui soit exactement aussi efficace mais avec une toxicité moindre.
Nous avons trouvé 10 essais (incluant 5 017 personnes) ayant comparé le cisplatine au carboplatine, tous deux étant associés à un autre médicament moderne, que l'on appelle médicament de troisième génération. Les médicaments ont eu une efficacité comparable pour prolonger la survie, mais leur profil de toxicité était différent. Le cisplatine a provoqué davantage de nausées ou de vomissements, ou les deux et le carboplatine a provoqué davantage d'engourdissements et de picotements dans les mains et les pieds et une plus grande diminution du nombre de plaquettes (qui contrôlent la coagulation) dans le sang.
Malheureusement, nous n'avons pas pu analyser la qualité de vie dans notre revue puisque seuls deux essais ont étudié cet aspect et ont utilisé des méthodes différentes pour mesurer leurs effets.
Notes de traduction
Traduit par: French Cochrane Centre 24th September, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.
Usporedba cisplatina i karboplatina u terapiji osoba s uznapredovalim rakom pluća
Rak pluća vodeći je uzrok smrti od raka i kod gotovo 75% osoba rak je neizlječiv kad se dijagnosticira. Rak pluća nemalih stanica najčešći je tip raka pluća (gotovo 90% svih slučajeva raka pluća). Za mnoge od tih osoba kemoterapija je dobra terapijska mogućnost i povezana je s duljim preživljenjem i boljom kvalitetom života. Unatoč tome, terapija raka pluća nemalih stanica je palijativna na način da pruža olakšanje od boli i drugih neugodnih simptoma. U terapiji se najčešće koriste kombinacije cisplatina ili karboplatina s drugim lijekom, ali one mogu biti povezane s neželjenim štetnim učincima (toksičnost). Stoga je poželjno imati terapiju koja bi bila jednako učinkovita, ali smanjene toksičnosti.
U ovom Cochrane sustavnom pregledu pronađeno je deset studija (s ukupno 5017 osoba) koje su uspoređivale cisplatin i karboplatin, oboje kombinirani s drugim novijim lijekom (antitumorski lijek treće generacije). Lijekovi su bili jednako učinkoviti u produljenju preživljenja, ali je profil toksičnosti bio različit. Cisplatin je uzrokovao više mučnine i povraćanja, a karboplatin je uzrokovao više trnaca i gubitka osjeta u rukama i nogama i veće smanjenje broja trombocita.
Na žalost, nije bilo moguće analizirati kvalitetu života u ovom pregledu jer su samo dvije studije to proučavale i obje su koristile različite metode mjerenja tih učinaka.
Preveo: Adam Galkovski
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針對於晚期肺癌患者所進行的 cisplatin 或 carboplatin 化療進行比較
肺癌乃癌症的主要死因，並且將近 75% 的患者在接受診斷時已無法治癒。非小細胞乃最常見的肺癌類型（約佔 90% 的總肺癌病例）。對於大部份患者來說，化療為較佳的治療選項，並且這項治療提供了較高的生存率與生活品質。 然而，罹患晚期非小細胞肺癌的患者僅能進行安寧治療，以降低病痛以及其它困擾症狀。最常使用的藥物組合乃透過使用 cisplatin 或 carboplatin 搭配另一種藥物來進行治療，不過這些藥物組合可能會造成不良的毒性反應。因此我們希望盡可能透過效果相似，毒性反應則較弱的方式來進行治療。
我們進行了 10 項試驗（包含了 5017 位患者）並針對 cisplatin 與 carboplatin 進行了比較，兩者皆搭配了另一種新藥，稱為第三代化療藥品。這些藥物對於提高生存率的效果程度相似，不過卻含有不同的毒性反應。Cisplatin 會造成患者發生較多作嘔或嘔吐的現象，亦或是兩種情況皆會發生，而 carboplatin 則會造成較多痲痹現象以及手部與腳部的刺痛感，並使血液中的血小板（控制凝血）大幅減少。
Description of the condition
Lung cancer is currently the second most common malignant tumour and is the leading cause of cancer-related mortality in the US (American Cancer Society 2010). About 85% of lung cancers are of the non-small cell type and approximately 75% of people present with locally advanced or metastatic disease (Govindan 2006).
Description of the intervention
Chemotherapy in advanced non-small cell lung cancer (NSCLC) has been under investigation for several decades. In the 1990s, a meta-analysis of 52 randomised clinical trials (RCTs) showed that cisplatin-based chemotherapy had increased median survival by six weeks compared with best supportive care in people with NSCLC (NSCLC Collaborative Group 1995). Since then, cisplatin has been the mainstay component of chemotherapy for any stage of NSCLC. However, cisplatin causes a number of significant side effects, including nausea and vomiting, alopecia, neutropenia, neurotoxicity and renal function impairment (Reed 2005).
Several newer anticancer drugs with different mechanisms of action are available, such as irinotecan, paclitaxel, docetaxel, gemcitabine and vinorelbine; these are known as third-generation drugs. These drugs, combined with cisplatin, are considered the standard chemotherapy regimen for advanced NSCLC (Azzoli 2009).
Since 1990, at least 20 trials have compared cisplatin versus carboplatin in this setting, but a small number of these studies compared regimens containing a third-generation drug. In 2002, Schiller et al published a trial that compared cisplatin plus paclitaxel versus carboplatin plus paclitaxel. They found similar survival and response rates but less toxicity with carboplatin plus paclitaxel, although quality of life (QoL) was not assessed (Schiller 2002).
In 2004, Hotta et al published a meta-analysis that found no differences between cisplatin and carboplatin in survival of people with advanced NSCLC (Hotta 2004). In 2007, another two meta-analyses showed similar findings, but the cisplatin-based regimen had a higher overall response rate (Ardizzoni 2007; Jiang 2007). Moreover, these meta-analyses also showed similar results in terms of toxicity profile. However, these three meta-analyses included studies that used old traditional drugs in combination with a platin and did not assess a combination with third-generation drugs, which seem to be more effective (Baggstrom 2007). QoL assessment has also become extremely important, given the small survival advantage and the toxicity of chemotherapy, but only three of the included trials had used an acceptable QoL analysis (Fossella 2003; Paccagnella 2004; Rosell 2002).
In the modern approach, newly diagnosed advanced NSCLC should be tested for mutation in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocation, which predicts better response to small molecule inhibitors (erlotinib, gefinitib, crizotinib). Chemotherapy is the only option to those patients with EGFR and ALK wild type tumours.
Why it is important to do this review
Given that people with advanced NSCLC are treated primarily in a palliative setting, the requirement to use drugs with low toxicity seems clear. Carboplatin-based chemotherapy a better toxicity profile than cisplatin-based chemotherapy (Reed 2005). In this review, we analysed treatment for advanced NSCLC using carboplatin or cisplatin plus a third-generation drug.
To assess the efficacy and safety of carboplatin-based chemotherapy when compared with cisplatin-based chemotherapy, both in combination with a third-generation drug, in people with advanced NSCLC. To compare QoL in people with advanced NSCLC receiving chemotherapy with cisplatin and carboplatin combined with a third-generation drug.
Since the 1990s, many trials have been published comparing chemotherapy with best supportive care in people with advanced NSCLC and the effectiveness of platin-based chemotherapy on overall survival and control of symptoms is clear (NSCLC Collaborative Group 1995).
The modern approach for these people depends on the presence of a somatic mutation in the EGFR and in the ALK fusion oncogene. For people who have no EGFR or ALK mutations, cytotoxic chemotherapy based on a platin doublet remains the primary treatment. Furthermore, since these people are treated with a palliative intent, the current challenge is to find a treatment with greater effectiveness and a better toxicity profile.
We performed a meta-analysis of trials comparing regimens including cisplatin plus a third-generation drug versus regimens including carboplatin plus a third-generation drug. We found that cisplatin-based regimens were slightly more effective in terms of response rate, as in previous meta-analyses, but there was no significant difference in survival data (Ardizzoni 2007; Hotta 2004; Jiang 2007). This improved response rate could be attributed to one trial, which was the only trial with a significantly higher response rate for cisplatin (Fossella 2003). In this trial, docetaxel was used in both arms, even though paclitaxel and gemcitabine are generally preferred due to their better tolerability and are used in almost all modern trials.
Since only two RCTs evaluated QoL, we could not perform a meta-analysis (Fossella 2003; Rosell 2002). This was also a challenge to the authors of previous meta-analyses (Ardizzoni 2007; Hotta 2004; Jiang 2007), because different scores were used, and some questionnaires could be used only in the countries in which a translated version of the QoL tool with validation was available. Moreover, no one trial compared QoL with cisplatin and carboplatin directly.
Different criteria were applied (RECIST), Southwest Oncology Group (SWOG), WHO and ECOG criteria) to evaluate response rate. Furthermore, different doses of drugs were used in these trials and this could modify the assessment of effect.
Nowadays, the importance of histology as a predictive of response to some therapies is understood (non-epidermoid and pemetrexed; epidermoid and gemcitabine) (Scagliotti 2008). Unfortunately, we were unable to consider histology in our analysis because this criterion was not evaluated in the included trials.
In this review, carboplatin-based chemotherapy was associated with a higher incidence of neurotoxicity. However, only one trial had a significantly higher incidence of neurotoxicity in the carboplatin arm (Schiller 2002). This may be explained by the fact that participants in the carboplatin arm received 225 mg/m2 of paclitaxel whereas participants in the cisplatin arm received only 135 mg/m2 of paclitaxel. Since paclitaxel may cause neurotoxicity, this drug could be a confounding factor in the final analysis.
Although we did not obtain data on second-line chemotherapy, it is possible that some of included participants crossed over to another therapy when the disease progressed. The effect of such a cross-over on the results of this systematic review is unknown and might have affected survival results.
Two trials evaluated the benefit of bevacizumab, a recombinant humanised monoclonal antibody that binds vascular endothelial growth factor (VEGF), in chemotherapy for advanced NSCLC. One trial combined bevacizumab with carboplatin plus paclitaxel (Sandler 2006), while the other trial combined bevacizumab with cisplatin plus gemcitabine (Reck 2010); both showed higher overall survival, response rate and progression-free survival. On that basis, new trials are needed to investigate if there is difference between cisplatin and carboplatin when combined with bevacizumab and a third-generation drug.
Summary of main results
We obtained data on 3973 participants in 10 RCTs. These trials had at least one treatment arm with cisplatin and one treatment arm with carboplatin, both combined with paclitaxel (five trials), gemcitabine (four trials) or docetaxel (one trial).
There was no difference in overall survival (HR 1.00; 95% CI 0.51 to 1.97, I2 = 0%) or one-year survival rate (RR 0.98; 95% CI 0.88 to 1.09, I2 = 24%).
With grade III-IV toxicity measured by the participants, we detected a higher incidence of nausea or vomiting or both in the cisplatin arm (RR 0.46; 95% CI 0.32 to 0.67, I2 = 53%). Carboplatin-based chemotherapy was associated with more neurotoxicity (RR 1.55; 95% CI 1.06 to 2.27, I2 = 0%) and thrombocytopenia (RR 2.00; 95% CI 1.37 to 2.91, I2 = 21%).
Considering the response rate in the 10 RCTs analysed, cisplatin was slightly more effective than carboplatin (RR 0.88; 95% CI 0.79 to 0.99, I2 = 3%).
We also performed a subgroup analysis comparing carboplatin with different doses of cisplatin: 'lower dose' (40 to 80 mg/m2) and 'higher dose' (80 to 100 mg/m2). We found no statistically significant difference in terms of overall survival, 1-year survival rate or response rate between carboplatin and both doses of cisplatin.
We could not perform an analysis of QoL in our review, because data were provided by only two trials (Fossella 2003; Rosell 2002).
Overall completeness and applicability of evidence
With regards to external validation, the doses of drugs were variable among analysed trials and that should be considered while selecting the treatment.
It is also important to note that the trials analysed in our review did not take into account the status of the EGFR and ALK mutations, which are critical in deciding the initial approach in advanced disease.
Quality of the evidence
The categorisation of the quality of the evidence (into high, moderate, low or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest.
Our review included 10 RCTs. Since none of these trials described allocation concealment and blinding process adequately, we considered available data to have moderate quality of evidence for response rate, one-year survival rate and overall survival. However, because different doses of drugs were used and some adverse effects were omitted from analysis in the original trials, we also considered data to have moderate quality of evidence for adverse effects and note that this information has to be considered cautiously.
Potential biases in the review process
We performed an electronic search of the main databases and extended our search to include meetings of the American Society of Clinical Oncology. We found one unpublished trial with our search strategy (Ferry 2011), but it is not known whether there are other reports of unpublished trials in different languages or presented at different meetings.
We found two Chinese trials (Cai 2002; Yan 2001). For Cai 2002, we could not obtain data for overall survival or one-year survival rate and for Yan 2001 there was no information about overall survival. Since both trials recruited a small number of participants, we concluded that they did not cause a significant bias in survival analysis.
We identified no more significant potential biases.
Agreements and disagreements with other studies or reviews
In 2004, Hotta et al published a meta-analysis that included eight trials comparing doublets of cisplatin or carboplatin plus another drug (Hotta 2004). Only five of these trials were included in our analysis because the other three studies used older agents combined with platin. The study author had found results that were comparable to those presented in this review: cisplatin was related to higher response rate but this superiority did not translate into survival benefit. However, a subset analysis of trials consisting of a platin plus a third-generation drug found superior survival in the cisplatin arm.
Jiang 2007 and Ardizzoni 2007 performed two meta-analyses that revealed benefits of cisplatin in response rate and equivalent survival when compared to carboplatin. In a subgroup analyses containing only doublets of platin plus a third-generation drug, Ardizzoni et al yielded a superior HR for mortality in the carboplatin arm.
The authors would like to thank Sera Tort, Joint Co-ordinating Editor of the Cochrane Lung Cancer Review Group; Marta Roqué, Statistical Editor; Desiree West, consumer of the Lung Cancer Group; and the Brazilian Cochrane Center team for the support.
Contributions of authors
Tiago Biachi Castria - background, objectives and outcomes definitions, selection of studies, data extraction, 'Risk of bias' assessment and review organisation in RevMan 5.
Rachel Riera - methodological topics and review organisation in RevMan 5.
Edina Mariko Koga Silva - critical appraisal of the last review.
Aécio Flavio Teixaira de Góis - selection of studies, data extraction, 'Risk of bias' assessment.
Declarations of interest
The review authors declare no conflicts of interest.
Differences between protocol and review
We could not perform a quality of life analysis because only two trials evaluated this endpoint.
We took into account the wide range in doses of cisplatin and performed a separate analysis of 'higher' and 'lower' doses.
We had proposed to use odds ratios (OR) to evaluate dichotomous outcomes in the protocol; however, we reconsidered and used RRs to make the interpretation of the data easier to the reader. We also included one-year survival rate as a primary endpoint because it was used in several trials in this review and expresses a real benefit in clinical practice.
Given the difficulties in evaluating potential biases in unpublished trials, we performed a sensitivity analysis after excluding them.