Over the past 3 or 4 years, we have witnessed a nearly doubled survival rate among patients with metastatic and earlier-stage lung cancer. This substantial increase in survival has prompted substantial changes in the management of lung cancer, ultimately improving patient outcomes. However, it is important to note that these improvements have also increased the risk of cancer-associated thrombosis (CAT).
During the ICTHIC webinar titled “Management of CAT: Lung Cancer Focus,” Professor Nicolas Girard delivered a lecture focused on updating various clinical scenarios within thoracic oncology. Here, we summarize the main points from his speech, discussing how the changing landscape of lung cancer treatment impacts clinical practice. You can also watch Nicolas Girard’s lecture in the video below and the full webinar recording here.
Lung cancer: an overview
Lung cancer is typically classified into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC accounts for the majority (about 85%) of patients at diagnosis, while SCLC makes up the remaining 15% . This article will focus only on NSCLC.
Lung cancer patients generally have a high risk of thrombosis, with approximately 20% developing thrombosis during the course of their disease management. This risk can manifest even before the initial diagnosis, but it is more commonly encountered during managing the disease .
It is important to note that the risk of thrombosis, as in other cancers, is more elevated in patients with metastatic disease . However, a significant majority of lung cancer patients (approximately 70%) are diagnosed with metastatic disease due to the absence of specific symptoms at earlier stages and the limited implementation of lung cancer screening in many countries .
Within the NSCLC category, patients can be further divided into two groups. The first one consists of patients with oncogene-addicted tumors. These tumors are associated with specific molecular alterations that can be targeted with specialized therapies, such as targeted agents or oral medications .
The second group comprises the majority of NSCLC patients who do not have such specific molecular alterations. Targeted agents are not applicable for these patients as a first-line treatment option .
NSCLC: Treatment paradigm shift
As previously discussed, the majority of patients are initially diagnosed with metastatic disease. Recently, there has been a significant shift in the treatment approach, moving away from traditional chemotherapy and towards immunotherapy as the primary treatment modality. These patients typically receive immunotherapy as a first-line treatment, either as a monotherapy or in combination with chemotherapy .
When immunotherapy is combined with chemotherapy, it is important to note that the side effects and the risk of thrombosis are generally consistent with those seen in patients who receive chemotherapy alone .
In clinical trials, such as the one mentioned involving carboplatin, pemetrexed and pembrolizumab, patients who received a combination of chemotherapy and immunotherapy experienced a substantial improvement in overall survival. This combination therapy nearly doubled the median overall survival and achieved a 5-year overall survival rate of approximately 20–25%. This represents a notable enhancement compared to historical data, which reported an 18% survival rate .
Patients who receive both chemotherapy and immunotherapy in the first-line setting typically undergo a more extended treatment period, with a median duration of about 10 months. This extended treatment duration signifies a significant improvement compared to the previous standard of care, where chemotherapy alone provided a median progression-free survival of just 5 months. Consequently, most of these patients continue to receive treatment for an extended period, with around 20–25% of them reaching the 5-year milestone, and many continue to thrive even after treatment cessation .
Focusing on this group of patients, those who achieve remission from metastatic NSCLC, the maximum duration of treatment typically spans 2 years. After this period, the likelihood of disease progression significantly diminishes .
However, among this subset of metastatic NSCLC patients who have responded to chemotherapy and immunotherapy but have discontinued treatment and entered the follow-up phase, there’s a notable incidence of thrombosis, affecting approximately 15–20% of these individuals .
This brings us to a crucial question: What should be the optimal treatment duration, and when should treatment be discontinued in these patients? Moreover, what is the associated risk of thrombosis in this specific patient group? Unfortunately, comprehensive data are scarce regarding thrombosis risk in this specific scenario.
While we do possess data related to chemotherapy alone, suggesting that approximately 20% of patients can develop thrombosis within the first year after a metastatic disease diagnosis, the introduction of immunotherapy and the resulting prolongation of treatment duration have left us with a dearth of comprehensive data on thrombosis risk .
In clinical practice, the Khorana score is often employed to assess the risk of thrombosis. However, it’s important to note that this scoring system was initially developed for patients undergoing chemotherapy with shorter treatment durations, typically less than 6 months [11,12]. Given the current trend toward more extended treatment regimens involving immunotherapy, we may need to adapt our risk assessment strategies accordingly.
Another group of patients, those with high PD-L1 expression in their tumor tissue, have the opportunity to replace platinum-based chemotherapy with immunotherapy as a standalone treatment. This approach has demonstrated comparable outcomes, with roughly one-third of these patients achieving a 5-year survival rate [13, 14].
Questions arise regarding the optimal treatment duration and associated risks within this group, where patients receive immunotherapy alone for approximately 2 years. Although comprehensive data on thrombosis risk in this context are lacking, one study suggests that the risk with immunotherapy alone may be nearly half of the reported with chemotherapy .
Regarding guidelines, one of the central concerns, as seen in other cancers, is the risk of bleeding in lung cancer patients. This risk hinges on factors such as the location of the disease within the thorax or lungs and the presence of metastatic sites, which can elevate the risk of bleeding .
Recent data presented at the World Conference on Lung Cancer in Athens included a study of approximately 300 metastatic lung cancer patients who received thromboprophylaxis, particularly those undergoing chemotherapy and immunotherapy (NCT03292107). Interestingly, about two-thirds of these patients received thromboprophylaxis, which is a notably high proportion – potentially surpassing common practice in many settings. The duration of thromboprophylaxis varied from 5–8 months, primarily utilizing low-molecular-weight heparin (LMWH), and the safety profile of these interventions appeared to align with typical outcomes seen in similar strategies (NCT03292107).
The considerations outlined above predominantly apply to the primary group of patients with non-oncogene-addicted tumors in the metastatic setting.
NSCLC without oncogenic addiction
In patients without oncogenic addiction, approximately 10–15% are diagnosed with early-stage disease. Traditionally, the standard approach for these cases has been surgical lung resection, a well-established practice for quite some time. However, there is a paradigm shift, incorporating immunotherapy and chemotherapy into the perioperative setting – before or after surgery [17-19].
This evolving treatment strategy is reshaping the natural progression of the disease, significantly reducing the risk of disease advancement by nearly half. Consequently, these patients now receive immunotherapy and chemotherapy post-surgery for approximately 1 year as part of studies involving perioperative immunotherapy [17-19].
Notably, there is an increased risk of thrombosis, affecting roughly 25% of patients following thoracic surgeries and resections. While data from thrombosis clinical trials are currently lacking, the management of patients who develop CAT post-surgery remains an important consideration. This includes deliberation on the duration of treatment, as well as the integration of systemic therapies like chemotherapy and adjuvant immunotherapy. The optimal duration of prophylaxis after surgery continues to be a subject of ongoing debate.
The treatment approach is markedly different in the case of oncogene-addicted tumors, which constitute 50% of lung cancer cases with identifiable molecular alterations. In this scenario, chemotherapy and immunotherapy are not utilized. Instead, the primary approach involves targeted agents, often in the form of tyrosine kinase inhibitors (TKIs). These TKIs are typically administered orally and are subject to metabolism via the cytochrome P450 system, necessitating careful consideration of potential drug interactions .
Patients with oncogene-addicted tumors in the metastatic setting experience notably high survival rates, which encompasses the majority of these patients. The anticipated duration of efficacy with these targeted agents is approximately 18 months, representing an extended period of therapeutic benefit. In instances where treatment proves ineffective, second-generation TKIs may be explored, providing additional therapeutic options .
In summary, these patients experience a prolonged period free of chemotherapy, which can be gentler on the heart. This extended treatment-free interval contributes to the anticipated increase in survival. However, the management of CAT remains a critical consideration, particularly in the context of direct oral anticoagulants (DOACs) and TKIs.
A similar scenario emerges for patients with ALK fusions, constituting approximately 5% of cases, who have access to multiple inhibitors. Impressively, the efficacy of these inhibitors is quite high. However, patients with ALK-positive tumors also face an elevated risk of thrombosis, affecting approximately 60% of them. This heightened risk may be attributed to their longer life expectancy, which often extends beyond 8 years .
In light of these complexities, managing CAT poses a significant challenge. Drug–drug interactions are a prominent concern, often necessitating the involvement of a dedicated molecular tumor board comprising oncologists, thrombosis specialists, and pharmacists to make informed decisions about the treatment.
Thrombosis is a common issue in lung cancer patients, and as survival rates increase, the incidence of thrombosis is expected to rise. Several questions surround the duration of treatment following a first thrombotic event, and there is no one-size-fits-all answer.
Decisions depend on various factors, including whether the disease is metastatic or early stage, the presence of oncogene addiction, the expected treatment strategy, and the patient’s anticipated survival duration. Other factors like disease control, tumor burden, location within the thorax, and comorbidities also play a role.
Given these complexities, a multidisciplinary approach is crucial, especially considering the prolonged survival of patients and the need to optimize their quality of life. Many patients are treated with anticoagulants, either LMWH or DOACs, and constant risk assessment is necessary.
In conclusion, regardless of the thrombosis situation, it is imperative to allocate dedicated time for discussion within a multidisciplinary team, as each case is unique and requires a comprehensive evaluation of all relevant factors.
Watch Nicolas Girard’s lecture:
- Basumallik N, Agarwal M. Small Cell Lung Cancer. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482458/
- Vitale C, D’Amato M, Calabrò P, et al. Venous thromboembolism and lung cancer: a review. Multidiscip Respir Med. 2015;10(1):28. doi: 10.1186/s40248-015-0021-4.
- Mandalà M, Falanga A, Roila F; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22 Suppl 6:vi85-vi92. doi:10.1093/annonc/mdr392
- Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. doi: 10.4065/83.5.584.
- Ferrara MG, Di Noia V, D’Argento E, et al. Oncogene-addicted non-small-cell lung cancer: treatment opportunities and future perspectives. Cancers (Basel). 2020 May 8;12(5):1196. doi: 10.3390/cancers12051196.
- Hendriks LE, Kerr KM, Menis J, et al. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(4):358-376. doi:10.1016/j.annonc.2022.12.013
- Nasser NJ, Gorenberg M, Agbarya A. First line immunotherapy for non-small cell lung cancer. Pharmaceuticals (Basel). 2020;13(11):373. doi: 10.3390/ph13110373.
- Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005
- Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41(11):1992-1998. doi:10.1200/JCO.22.01989
- Lyman GH, Eckert L, Wang Y, et al. Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. Oncologist. 2013;18(12):1321-1329. doi:10.1634/theoncologist.2013-0226
- Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. doi:10.1182/blood-2007-10-116327
- Mulder FI, Candeloro M, Kamphuisen PW, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica. 2019;104(6):1277-1287. doi:10.3324/haematol.2018.209114
- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for pd-l1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. doi:10.1056/NEJMoa1606774
- Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol. 2021;39(21):2339-2349. doi:10.1200/JCO.21.00174
- Goel A, Khorana A, Kartika T, et al. Assessing the risk of thromboembolism in cancer patients receiving immunotherapy. Eur J Haematol. 2022;108(4):271-277. doi: 10.1111/ejh.13734.
- Falanga A, Ay C, Di Nisio M, et al. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol. 2023;34(5):452-467. doi:10.1016/j.annonc.2022.12.014
- O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6
- Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
- Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983
- Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
- Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478