ABSTRACT
Aim:
Around 40% of non-small cell lung cancers have stage 3b or 4 disease at the time of diagnosis. In the treatment, platinum-based therapy can still be used in patients who do not carry a driver mutation or who are not suitable for immunotherapy with advanced non-small cell lung cancers (NSCLC). The objective of this study was to compare the effectiveness of weekly carboplatin-paclitaxel regimen with triweekly carboplatin-paclitaxel regimen.
Materials and Methods:
This is a retrospectively structured study. Patients who were followed-up and treated for lung cancer in Adana City Training and Research Hospital’s Oncology Department between January 1, 2017 and July 1, 2021 were included.
Results:
Out of the 104 patients, 52 (50%) patients received weekly carboplatin-paclitaxel (C-P), and 52 (50%) received C-P every 3 weeks. The mean overall survival was 19.64±2.53 months in the weekly C-P group and 17.47±1.64 months in the triweekly C-P group (p=0.675). The mean progression-free survival (PFS) was 8.5±1.01 months in the weekly C-P group and 5.76±0.61 months in the triweekly C-P group (p=0.017).
Conclusion:
We demonstrated that weekly C-P treatment, which is known to have fewer toxicity in NSCLC, provided better PFS compared to triweekly treatment.
INTRODUCTION
Among all cancers, lung cancer is the one that most frequently leads to death, according to World Health Organization data1. Approximately 80% of lung cancers are non-small cell lung cancers (NSCLC)2. Around 40% of the patients in this group have stage 3b or 4 disease at the time of diagnosis3. Platinum-based systemic chemotherapy is currently the established conventional treatment for patients with advanced NSCLC4,5. Immunotherapies are included in current treatment guidelines as important therapeutic agents for lung cancer. Because immunotherapies are expensive and therefore, difficult to access, they have not yet become a standard for care outside developed countries. However, these agents are not routinely used in the first line due to reimbursement issues in our country, pemetrexed is also not reimbursed in the first line treatment of NSCLC in Turkey. As a result, platinum-based treatments are predominantly used in our country. One of these regimens is carboplatin-paclitaxel (C-P) treatment. Studies have compared C-P protocol with other treatment protocols and found no superiority of any of these against others4. In studies investigating the side effect profile, the most frequently seen toxicities in patients receiving treatment with C-P may include myelosuppression, neuropathy, nausea, weakness, and arthralgia. While no difference is seen in terms of effectiveness compared to triweekly C-P treatment, toxicity rates have been shown to decline when paclitaxel is given weekly and carboplatin is administered every 3 weeks6. The objective of this study was to compare the effectiveness of weekly C-P regimen with triweekly C-P regimen in NSCLC.
GİRİŞ
Dünya Sağlık Örgütü verilerine göre tüm kanserler arasında en sık ölüme yol açan kanser türü akciğer kanseridir1. Akciğer kanserlerinin yaklaşık %80’i küçük hücreli dışı akciğer kanserleridir (KHDAK)2. Bu gruptaki hastaların yaklaşık %40’ı tanı anında evre 3b veya 4 hastalığa sahiptir3. Platin bazlı sistemik kemoterapi, ileri evre KHDAK’li hastalar için şu anda uygulanan geleneksel tedavidir4,5. İmmünoterapiler, akciğer kanseri için önemli terapötik ajanlar olarak güncel tedavi kılavuzlarında yer almaktadır. İmmünoterapiler pahalı olduğundan ve dolayısıyla erişimleri zor olduğundan, gelişmiş ülkeler dışında henüz bir bakım standardı haline gelmiş değillerdir. Ancak ülkemizde geri ödeme sorunları nedeniyle bu ajanlar ilk basamakta rutin olarak kullanılmamaktadır, ayrıca Türkiye’de KHDAK’nin birinci basamak tedavisinde pemetrekset de geri ödenmemektedir. Sonuç olarak ülkemizde ağırlıklı olarak platin bazlı tedaviler kullanılmaktadır. Bu rejimlerden biri karboplatin-paklitaksel (K-P) tedavisidir. Çalışmalar K-P protokolünü diğer tedavi protokolleriyle karşılaştırmış ve bunların hiçbirinin diğerlerine üstünlüğü bulunmamıştır4. Yan etki profilini araştıran çalışmalara göre, K-P tedavisi alan hastalarda en sık görülen toksisiteler arasında miyelosüpresyon, nöropati, bulantı, halsizlik ve artralji sayılabilir. Üç haftada bir yapılan K-P tedavisiyle karşılaştırıldığında etkinlik açısından bir fark görülmezken, paklitakselin haftalık, karboplatinin ise 3 haftada bir verildiğinde toksisite oranlarının azaldığı gösterilmiştir6. Bu çalışmanın amacı, KHDAK’de haftalık K-P rejiminin etkinliğini üç haftalık K-P rejimi ile karşılaştırmaktır.
MATERIALS AND METHODS
This study assessed patients followed-up and treated for lung cancer in Adana City Training and Research Hospital’s Oncology Clinic between January 1, 2017 and July 1, 2021. Ethical approval was obtained from Adana City Training and Research Hospital (decision no: 1913, date: 21.04.2022). Patients evaluated were those diagnosed with lung cancer in the hospital automation system. The files of 104 patients with pathologically diagnosed lung cancer were screened for suitability for the study. A total of 181 patients with neuroendocrine carcinoma or small cell lung cancer were excluded from the study. In the second step treatments given to 623 patients with NSCLC were evaluated. Four hundred forty patients who received first line therapy other than C-P were excluded. Among the remaining 176 patients, 49 who first received chemo-radiotherapy for primary lung cancer were also excluded from the study. Out of remaining 127 patients, 23 patients who received weekly C-P treatment 3 times or less, or 1 cycle of triweekly C-P treatment were also excluded. Patients with driver mutations (EGFR, ALK, ROS etc.) were not included in the study.
Patients receiving paclitaxel at a dose of 80 mg/m2 weekly and carboplatin 2 AUC (area under the curve) for the weekly treatment protocol, or paclitaxel at a dose of 175 mg/m2 every 3 weeks and 5 AUC doses of carboplatin every 3 weeks for the triweekly treatment protocol were included.
Data from 104 eligible patients were evaluated statistically. Response to treatment and progression were adjudicated based on the assessment of conventional imaging reports registered in the hospital automation system according to RECIST 1.1. For patients who were followed up with positron emission tomography/computed tomography, adjudication was made by the assessment of final reports.
Statistical Analysis
Statistical Package for the Social Sciences 23.0 package software was used for the statistical analysis of the data. Categorical measurements were summarized in terms of number and percentage, continuous measurements were summarized as mean, deviation and minimum-maximum. Suitability for normal distribution was examined using the Shapiro-Wilk test. The chi-square test and Fisher’s exact test were used for comparison of categorical variables. The Independent Student’s t-test was used in groups conforming normal distribution and the Mann-Whitney U test in those not conforming normal distribution. The Spearman correlation test was used to investigate the relationship between overall survival (OS) and progression-free survival (PFS) values and continuous measurement values. The Kaplan-Meier and log-rank tests were used in survival analyses. Statistical significance level was set to 0.05 for all tests.
RESULTS
Out of the 104 patients included in the study, 90 (86.5%) were male and 14 (13.5%) were female. Fifty-two (50%) patients received weekly C-P and 52 (50%) received C-P every 3 weeks. Fifty-seven (54.8%) patients were followed-up for the diagnosis of adenocarcinoma, 21 (20.2%) for squamous cell carcinoma, and 26 (25%) for not otherwise specified (NOS). During the course of the treatment, 48 (46.2%) patients experienced radiological progression and 66 (63.5%) patients died. Clinical and demographic findings of the patients are presented in Table 1. Patients in the weekly C-P group received treatment for a median of 7 weeks and those in triweekly C-P group received a median of 3 cycles. Size of the primary mass was the same in both groups while SUV value of the primary mass was higher in the weekly C-P group (p=0.029). No difference was noted between the groups in terms of laboratory parameters (Table 1).
The mean OS was 19.64±2.53 months in the weekly C-P group and 17.47±1.64 months in the triweekly C-P group (p=0.675) (Figure 1).
The mean PFS was 8.57±1.01 months in the weekly C-P group and 5.76±0.61 months in the triweekly C-P group with a significantly higher value (p=0.017) (Figure 2). There was no difference regarding lactate dehydrogenase (LDH) level between the groups (p=0.413). Considering all the patients included in the study, a correlation was found between LDH value and OS (r=-0.227; p=0.021) (Figure 3).
DISCUSSION
Many studies are available about the first-line therapy of patients with advanced NSCLC. In our study, we found that the PFS value was statistically longer with weekly C-P treatment, which is preferred because it is less toxic in advanced NSCLC patients6. Although it did not reach statistical significance, we found a 2.2-months prolongation in the OS value. Our study is the first to compare the effectiveness of weekly and triweekly C-P treatments. Comparative studies demonstrated that treatment with cisplatin-gemcitabine, cisplatin-vinorelbine, C-P and cisplatin-irinotecan had no superiority to each other4,5,7,8.
OS value for triweekly C-P treatment varies between 7.3 and 11.4 months in different studies9-12. In the phase 2 study performed by Kallab et al.13 in stage 3B and 4 NSCLC, paclitaxel was given at a weekly dose of 100 mg/m2 and carboplatin was given weekly as 2 AUC. These two treatments were given during the first 3 weeks of 4-week cycle. The last week was left empty and effectiveness of the treatments was compared. In our study, paclitaxel was given at a dose of 80 mg/m2, which is lower than they administered, and carboplatin was continuously administered weekly at 2 AUC with no breaks. Kallab et al.13 found a PFS value of 5.4 months and OS of 10.8 months, which were longer with 8.57 and 19.64 months, respectively, in our study. Although the patients were of similar age, we attribute the difference between the spans to the fact that 97% of the patients in their study had stage 4 disease.
In the study by Sakakibara et al.14, in which they investigated the effectiveness and toxicity in patients over the age of 70 years with stage 3B, stage 4 NSCLC and postoperative recurrence, paclitaxel was given at a weekly dose of 70 mg/m2 and carboplatin as 3-week cycles at 6 AUC. PFS was found to be 6 months and OS 14.7 months. Despite advanced patient age, statistically fewer neutropenia and febrile neutropenia were found in weekly C-P compared to C-P every 3 weeks (p<0.0001 and p=0.018, respectively). The lower frequency of side effects makes weekly treatment favorable. Although ECOG score was not evaluated in our study, weekly treatment is preferred for patients with poorer health in our clinic owing to lower toxicity. While PFS was still longer compared to weekly treatment, our opinion is that weekly C-P treatment may be preferred to triweekly C-P in patients with advanced stage NSCLC without driver mutation.
Although the reason for not preferring weekly treatment is more frequent hospital visits and the additional financial burden on healthcare system15, we think that lower toxicity compared to triweekly treatment may reduce hospitalizations due to side effects.
Despite the fact that the age, sex and histological subtypes of the two groups were the same, PFS was found to be statistically different between the groups. Because the groups were homogeneous, this difference was thought to be treatment-related. It may be related to the stable course of active drug blood concentration in weekly treatment.
We found a correlation between LDH value and OS (r=-0.227; p=0.021), which demonstrated that patients with higher tumor burden lived shorter as expected. Similarly, previous studies have also shown that high LDH levels are associated both with the presence of metastasis and with lower OS16-18.
Study Limitations
The retrospective nature of the study and the inclusion of single center patients were our limitations. ECOG performance status could not be evaluated since patient data were accessed through hospital automation system. However, we consider the presence of a bias between the two groups while weekly treatment was preferred for patients with clinically poorer health and triweekly treatments were preferred in those with better health condition. Besides, drug toxicities could not be assessed in detail.
TARTIŞMA
İlerlemiş KHDAK hastalarının birinci basamak tedavisine ilişkin birçok çalışma mevcuttur. Çalışmamızda ileri evre KHDAK hastalarında daha az toksik olması nedeniyle tercih edilen haftalık K-P tedavisiyle PFS değerinin istatistiksel olarak daha uzun olduğunu saptadık6. İstatistiksel anlamlılığa ulaşmasa da OS değerinde 2,2 aylık bir uzama bulduk. Çalışmamız haftalık ve üç haftalık K-P tedavilerinin etkinliğini karşılaştıran ilk çalışmadır. Karşılaştırmalı çalışmalar sisplatin-gemsitabin, sisplatin-vinorelbin, K-P ve sisplatin-irinotekan ile tedavinin birbirine üstünlüğü olmadığını göstermiştir4,5,7,8.
Üç haftalık K-P tedavisi için OS değeri farklı çalışmalarda 7,3 ile 11,4 ay arasında değişmektedir9-12. Kallab ve ark.13 tarafından yapılan faz 2 çalışmasında, evre 3B ve 4 KHDAK’de paklitaksel haftalık 100 mg/m2, karboplatin ise haftalık 2 AUC (eğri altında kalan alan) dozunda verilmiştir. Bu iki tedavi 4 haftalık kürün ilk 3 haftasında verilmiş, son hafta boş bırakılarak tedavilerin etkinliği karşılaştırılmıştır. Bizim çalışmamızda paklitaksel, diğer çalışmada uygulanan dozdan daha düşük olarak, 80 mg/m2 dozunda ve karboplatin ise haftada bir 2 AUC’de ara vermeden sürekli olarak uygulandı. Kallab ve ark.13, bizim çalışmamızda sırasıyla 8,57 ve 19,64 ay ile daha uzun olan PFS değerini 5,4 ay ve OS’yi 10,8 ay olarak bulmuşlardır. Hastalar benzer yaşlarda olmasına rağmen aralıklar arasındaki farkı çalışmamızdaki hastaların %97’sinde hastalığın evre 4 olmasına bağlıyoruz.
Sakakibara ve ark.14, 70 yaş üstü evre 3B, evre 4 KHDAK ve postoperatif nüks olan hastalarda etkinliğini ve toksisitesini araştırdıkları çalışmada, paklitakseli haftalık 70 mg/m2 dozunda ve karboplatini 3 haftalık kürler halinde 6 AUC’de vermişlerdir. PFS 6 ay, OS 14,7 ay olarak belirlenmiştir. Hastanın ileri yaşına rağmen haftalık K-P’de, 3 haftada bir yapılan K-P’ye göre istatistiksel olarak daha az nötropeni ve febril nötropeni saptandı (sırasıyla p<0,0001 ve p=0,018). Yan etki sıklığının düşük olması haftalık tedaviyi daha avantajlı yapmaktadır. Çalışmamızda ECOG skoru değerlendirilmemesine rağmen kliniğimizde sağlık durumu kötü olan hastalarda daha düşük toksisite nedeniyle haftalık tedavi tercih edilmektedir. PFS, haftalık tedaviye göre hala daha uzun olsa da, bizim görüşümüz, driver mutasyonu olmayan ileri evre KHDAK hastalarında, haftalık K-P tedavisinin, üç haftalık K-P tedavisine tercih edilebileceği yönündedir.
Haftalık tedavinin tercih edilmemesinin nedeni hastane ziyaretlerinin daha sık olması ve sağlık sistemine ek mali yük getirmesi olsa da15, üç haftalık tedaviye göre daha düşük toksisitenin yan etkilere bağlı hastaneye yatışları azaltabileceğini düşünüyoruz.
Her iki grubun yaş, cinsiyet ve histolojik alt tipleri aynı olmasına rağmen gruplar arasında PFS’nin istatistiksel olarak farklı olduğu görüldü. Gruplar homojen olduğundan bu farklılığın tedaviye bağlı olduğu düşünüldü. Haftalık tedavide aktif ilaç kan konsantrasyonunun stabil seyri ile ilişkili olabilir.
LDH değeri ile OS arasında bir korelasyon bulduk (r=-0,227; p=0,021), bu da daha yüksek tümör yükü olan hastaların beklendiği gibi daha kısa yaşadığını gösterdi. Benzer şekilde önceki çalışmalar da yüksek LDH düzeylerinin hem metastaz varlığı hem de düşük OS ile ilişkili olduğunu göstermiştir16-18.
Çalışmanın Kısıtlılıkları
Çalışmanın retrospektif olması ve tek merkez hastalarının dahil edilmesi bizim sınırlılıklarımızdı. Hasta verilerine hastane otomasyon sistemi üzerinden ulaşıldığı için ECOG performans durumu değerlendirilemedi. Bununla birlikte, klinik olarak sağlık durumu daha kötü olan hastalarda haftalık tedavi, sağlık durumu daha iyi olanlarda ise üç haftalık tedaviler tercih edilirken, iki grup arasında bir önyargı olduğunu düşünüyoruz. Ayrıca ilaç toksisiteleri detaylı olarak değerlendirilemedi.
CONCLUSION
In conclusion, a considerable portion of patients with lung cancer have shorter survival because of not being suitable for local therapies at the time of diagnosis. Some of the patients who received systemic treatment die from tumor progression, and some due to drug toxicity. We demonstrated that weekly C-P treatment, which is known to have fewer toxicity, provided better PFS in the similar patient group compared to triweekly treatment. Therefore, we assert that weekly C-P treatment may be used as the first option in patients with advanced stage NSCLC. Studies with prospective study design are needed to compare these two treatment protocols in terms of toxicity and effectiveness.
