Current and Emerging Treatments for Advanced Lung Neuroendocrine Tumors: A Comprehensive Patient Guide

Table of Contents

• Introduction: Understanding Lung Neuroendocrine Tumors
• Tumor Classification and Types
• Current Treatment Options
• Emerging and Experimental Therapies
• Combination Treatment Strategies
• Important Clinical Considerations
• Source Information

Introduction: Understanding Lung Neuroendocrine Tumors

Neuroendocrine tumors (NETs) of the lung are a diverse group of cancers that originate from specialized neuroendocrine cells. These tumors represent a spectrum of diseases ranging from slowly growing pulmonary carcinoid tumors to extremely aggressive forms like small cell lung cancer. The incidence of pulmonary carcinoid tumors has been increasing, likely due to better detection technology and increased lung cancer screening, with current rates of approximately 1.49 cases per 100,000 people according to SEER database studies.

These tumors account for 1-2% of all lung cancers and 20-30% of all neuroendocrine tumors in the body. The increasing incidence has led to improved awareness and the urgent need for more treatment options for this rare cancer type. This article will explore both established treatments and exciting new therapies that are changing how doctors manage advanced lung NETs.

Treatment decisions for advanced disease are complex and depend on multiple factors including symptoms, other health conditions, and how widespread the cancer has become. While many clinical trials have focused on gastrointestinal neuroendocrine tumors, their results are often applied to lung NETs as well, giving doctors more evidence to guide treatment choices.

Tumor Classification and Types

Lung neuroendocrine tumors are classified according to the 2022 World Health Organization (WHO) system, which divides them into well-differentiated and poorly-differentiated categories. This classification helps doctors predict how the tumor might behave and determines the most appropriate treatment approach.

Well-differentiated tumors include:

• Typical carcinoid (Grade 1 NET) - characterized by fewer than 2 mitoses (dividing cells) per 2mm² and no necrosis (dead tissue)
• Atypical carcinoid (Grade 2 NET) - with 2-10 mitoses per 2mm² and/or presence of necrosis
• Carcinoids with elevated mitotic counts and/or Ki-67 proliferative index - atypical carcinoid morphology with more than 10 mitoses per 2mm² and/or Ki-67 greater than 30%

Poorly-differentiated tumors (neuroendocrine carcinomas) include:

• Small cell lung carcinoma - with more than 10 mitoses per 2mm² and distinctive small cell morphology
• Large cell neuroendocrine carcinoma - with more than 10 mitoses per 2mm² and large cell morphology

Another important condition is diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), which is considered a premalignant condition that can occur alongside pulmonary carcinoids or in isolation.

Current Treatment Options

Patients with advanced lung NETs have several treatment options available, with choice of therapy depending on tumor characteristics, symptoms, and individual patient factors.

Somatostatin Analogs (SSA)

Somatostatin analogs have been used since the 1980s for symptom control and remain first-line treatment for advanced NETs. These medications work because pulmonary NETs express somatostatin receptor 2 (SSTR2) 92% of the time, with the highest expression seen in typical carcinoids.

While prospective data specifically in pulmonary carcinoids is limited, evidence from other NET types guides treatment:

• The PROMID trial showed increased progression-free survival with octreotide LAR versus placebo in midgut NETs
• The CLARINET trial demonstrated improved progression-free survival with lanreotide versus placebo in gastroenteropancreatic NETs

Specific data for pulmonary carcinoids comes from retrospective studies and one prospective trial:

• A retrospective study of 30 patients with metastatic pulmonary NETs showed a 5-year overall survival rate of 53% and progression-free survival of 11 months with first-line SSA
• Another review of 61 patients revealed overall survival of 58.4 months and progression-free survival of 17.4 months with first-line SSA
• The randomized phase III SPINET trial compared lanreotide to placebo, showing improved progression-free survival (16.6 vs 13.6 months) and objective response rate of 14% with lanreotide

Notably, patients with typical carcinoids had better median progression-free survival (21.9 months) compared to those with atypical carcinoids (14.1 months). The National Comprehensive Cancer Network (NCCN) guidelines recommend SSA as first-line treatment.

Peptide Receptor Radionuclide Therapy (PRRT)

PRRT represents a significant advancement for patients with SSTR2-positive tumors. The most widely used form is 177Lu-DOTATATE, which was FDA-approved in 2018 for gastroenteropancreatic NETs based on the NETTER-1 trial results.

Key findings from clinical studies:

• The NETTER-1 trial showed dramatically improved progression-free survival (not reached vs 8.4 months) with 177Lu-DOTATATE compared to high-dose octreotide
• Updated analysis showed overall survival of 48 months versus 36.3 months (though not statistically significant due to patient crossover between groups)
• The 20-month progression-free survival rate was 65.2% versus 10.8% favoring the PRRT group

Studies specifically in lung NET patients show promising results:

• A Dutch study of 443 patients (including 23 with bronchial NETs) showed median progression-free survival of 20 months and overall survival of 52 months in the bronchial NET group
• A retrospective analysis of 25 patients with bronchial NETs found median progression-free survival of 17 months and overall survival of 42 months
• Another review of 48 patients showed median progression-free survival of 23 months (95% CI 18-28) at one institution and 59 months (95% CI 50-not reached) at another

While generally well-tolerated, grade 3/4 adverse events include lymphopenia (9%) and vomiting (7%), with 2% of patients developing myelodysplastic syndrome. PRRT is now a standard-of-care option in NCCN guidelines.

Everolimus

Everolimus targets the mTOR pathway that stimulates cell growth and proliferation. FDA approval for pulmonary carcinoids was based on the RADIANT trials:

• RADIANT-2 included 44 patients with pulmonary carcinoids among 429 total participants, showing improved progression-free survival with everolimus (16.4 vs 11.3 months overall; 13.7 vs 5.6 months in pulmonary cohort)
• RADIANT-4 showed significant improvement in progression-free survival with everolimus versus placebo (11 vs 3.9 months), with similar benefit in the pulmonary cohort

The LUNA phase II trial tested everolimus alone and in combination with pasireotide in 124 patients (116 with pulmonary carcinoids). The combination showed the best results with progression-free survival of 16.5 months compared to 12.5 months with everolimus alone and 8.4 months with pasireotide alone. Grade 3/4 adverse events included hyperglycemia (22%), stomatitis (10%), and diarrhea (7%).

Chemotherapy Options

Chemotherapy plays an important role, particularly for more aggressive tumors or those without somatostatin receptor expression:

Platinum-based regimens:

• Typically used for atypical carcinoids which tend to be more aggressive
• A retrospective review of 18 patients showed response rate of 20% with etoposide-based chemotherapy
• Another study of 39 patients showed response in 19% of patients

Temozolomide and Capecitabine (CAPTEM):

• Shows synergistic effects with response rates around 30% in studies
• A retrospective study of 20 lung NET patients revealed objective response rate of 30%, progression-free survival of 13 months, and overall survival of 68 months
• A phase II trial showed progression-free survival of 22 months in the pulmonary carcinoid group
• Temozolomide monotherapy in 31 patients showed progression-free survival of 5.3 months and overall survival of 23.2 months

Treatment duration remains uncertain due to lack of prospective data, and the risk of myelodysplastic syndrome must be considered, especially when sequencing after PRRT.

Emerging and Experimental Therapies

Several promising new approaches are being developed to improve outcomes for patients with advanced lung NETs.

Targeted Alpha Therapy (TAT)

Targeted alpha therapy represents an exciting advancement designed to overcome resistance to current PRRT treatments. Unlike beta-emitting therapies like 177Lu-DOTATATE, alpha emitters deliver higher energy radiation over shorter distances, causing more focused cell damage while minimizing effects on surrounding healthy tissue.

Three radionuclides are being investigated:

1. 213Bi - Has a very short half-life (45 minutes) requiring on-site production but shows promising efficacy
2. 225Ac - Currently being studied in the global ACTION-1 trial (NCT05477576) for patients who have progressed after 177Lu-based therapies
3. 212Pb - Another promising alpha emitter under investigation

Early evidence shows promise:

• In laboratory studies, 213Bi-DOTATOC was more effective than 177Lu-DOTATOC at eliminating cancer cells
• A case report described a 40-year-old patient with pulmonary carcinoid who achieved partial response lasting 34 months after 5 cycles of 213Bi-DOTATOC following progression on other treatments
• Phase 1b of the ACTION-1 trial found patients tolerated 120kBq/kg of 225Ac-DOTATATE well

This approach minimizes systemic effects while delivering powerful targeted radiation to cancer cells.

Immunotherapy Approaches

Immune checkpoint inhibitors have shown limited success in NETs outside of small cell lung cancer, but combination approaches are showing promise:

Initial disappointing results:

• A phase II trial of pembrolizumab in 29 patients with non-pulmonary grade 3 NETs showed response rate of just 3.4%
• The DART SWOG 1609 trial combining nivolumab and ipilimumab showed overall response rate of 25%, but 0% in low/intermediate grade tumors
• The CA209-538 trial showed response rate of 24%, with most benefit in high-grade tumors
• Spartalizumab showed response rate of 7.4% in NETs, with better results in thoracic tumors (16.7%)

Promising combination approach:

• A phase II trial combining nivolumab with temozolomide showed significantly better results
• Overall response rate of 32.1% in all NET patients
• Remarkably, lung NET patients showed response rate of 64%
• Progression-free survival of 11.1 months and overall survival of 32 months
• This suggests temozolomide may make tumors more visible to the immune system

These findings suggest that combination approaches may overcome the typically "cold" immune environment of lung NETs.

Combination Treatment Strategies

Researchers are increasingly exploring combination therapies to improve outcomes beyond what single agents can achieve.

ATLANT trial:

• Combined temozolomide with lanreotide in advanced pulmonary carcinoids and thymic NETs
• Showed disease control rate of 45%, which was statistically significant
• 65.8% of patients had stable disease
• Median progression-free survival of 37.1 weeks
• Treatment was well-tolerated with only 5% experiencing grade 3+ adverse events

LUNA trial:

• Tested everolimus alone, pasireotide alone, and the combination
• ShowED best results with combination therapy (16.5 months progression-free survival)
• 9-month progression-free survival rates were 58.5% (combination) vs 39% (pasireotide) vs 33.3% (everolimus)

These studies suggest that strategically combining treatments with different mechanisms of action may provide better disease control than single agents alone.

Important Clinical Considerations

Several important factors must be considered when making treatment decisions for advanced lung NETs:

Multidisciplinary care: Given the complexity of these tumors, evaluation by a multidisciplinary team is essential for optimal treatment planning. This ensures all available options, including clinical trials, are considered.

Tumor characteristics: Treatment choices should consider:

• Tumor grade and differentiation status
• Somatostatin receptor expression status
• Ki-67 proliferation index
• Rate of disease progression
• Presence and severity of symptoms

Sequencing considerations: The order of treatments matters, particularly regarding risk of myelodysplastic syndrome when using alkylating chemotherapy (like temozolomide) after PRRT.

Clinical trials: Given the rarity of these tumors, participation in clinical trials provides access to cutting-edge treatments and helps advance knowledge for future patients. Several ongoing trials are investigating novel combinations and new agents.

Personalized approach: Treatment must be tailored to individual patient factors including age, overall health, other medical conditions, and personal preferences regarding treatment intensity and side effects.

Source Information

Original Article Title: Current and emerging strategies for the management of advanced/metastatic lung neuroendocrine tumors

Authors: Megan Rutherford, Margaret Wheless, Katharine Thomas, Robert A. Ramirez

Publication: Current Problems in Cancer, Volume 49 (2024) 101061

Note: This patient-friendly article is based on peer-reviewed research and aims to comprehensively translate the original scientific content while making it accessible to educated patients and caregivers. All numerical data, study results, and clinical findings have been preserved from the original publication.