Navigating the Patient Journey for Unresectable Stage III Non-Small Cell Lung Cancer

Lung cancer accounts for a sizeable portion of cancer diagnoses and death in the United States. In 2020, 13% (228,820) of all new cancer cases in the United States were lung cancer and 22% (135,720) of all US cancer deaths were attributable to lung cancer.¹ There are two main types of lung cancer: small cell lung cancer and non-small cell lung cancer (NSCLC). Small cell lung cancer accounts for 10% to 15% of lung cancers and tends to be aggressive and fast-growing.^2,3 NSCLC accounts for 80% to 85% of lung cancers.³ Once diagnosed, NSCLC is staged based on the extent and severity of the disease: stage I (21%), stage II (4%), stage III (26%), and stage IV (40%).⁴

While every case of lung cancer is different, the patient journey following a diagnosis of stage III lung cancer typically follows the same pattern (Figure 1).⁵ Generally, a patient is first diagnosed by their primary care provider (PCP) or pulmonologist.⁶ Upon appropriate referral, the patient will transition to a medical oncologist who will confirm diagnosis and complete staging using imaging and diagnostic tests. Surgery will provide a consult to determine the patient’s resectability status. Following all assessment, if an unresectable diagnosis is made, the patient will likely be treated with chemoradiotherapy (CRT). Following CRT, medical oncology may treat the patient with a certain consolidation immunotherapy agent, if eligible.⁷ The patient should be evaluated for progression following CRT. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) recommend up to 12 months of immunotherapy, barring disease progression or unacceptable toxicity.⁷ 

With the goal of optimizing care delivery and the patient journey in the real world, this article compiles the latest data and best practices from experts in the treatment of unresectable stage III NSCLC, including: (1) the importance of early referral, proper staging, and timely consolidation treatment; (2) how treatment with curative intent impacts patient management and communication; and (3) the significance of multidisciplinary team (MDT) care.^9,10

Striving for Early Diagnosis
Currently, only 21% of lung cancers are diagnosed while the tumor is localized (stage I), whereas 40% of lung cancers are diagnosed once metastases are present (stage IV).⁴ The 5-year survival rate for stage I cancer is 59.8% but drops dramatically to 6.3% in patients who have metastatic lung cancer.¹¹

Newly developed screening technologies allow for earlier detection of cancer. A major challenge is that individuals with lung cancer may only be symptomatic when they are in later stages of the disease. A low-dose computed tomography (LDCT) scan (or low-dose spiral CT scan or helical CT scan) has proven to be effective among high-risk individuals. Compared to chest x-rays, LDCT is much more sensitive and able to detect smaller abnormalities that may prove to be lung cancer.¹² While many factors contribute to a patient’s prognosis, diagnosis as early as possible through annual screening using LDCT can prevent lung-cancer-related deaths.¹³ 

In the unresectable stage III NSCLC setting, treatment with curative intent concurrent chemoradiotherapy (cCRT) followed by initiation of consolidation immunotherapy (trimodality treatment) is the standard of care for eligible patients.¹⁴ Provider education of available technologies and treatments must begin in the primary care setting, where patients typically present first, and PCP knowledge can facilitate speedy referral of patients to lung cancer specialists.⁶

Emphasizing Curative Intent in Primary Care and in Patient Discussions
After patients receive an NSCLC diagnosis from a PCP or a pulmonologist, the goal is for the patient to then be referred to an oncology specialist.⁵ Patients with advanced NSCLC (stages III and IV) who were referred to a medical oncologist and a radiation oncologist were much more likely to receive treatment with guideline-based therapies, in comparison to those who saw medical oncology only.¹⁶ Treatment wait time can be shortened at no cost if patients are able to be diagnosed, staged, and treated under the supervision of the same lung cancer specialist (ie, medical oncologist or pulmonary specialist).^17,18

Some experts say there is a perception in the general population and among PCPs that tolerable treatment options in lung cancer are lacking, which may contribute to patients not being referred appropriately to medical oncologists.¹⁹ Of the patients who present to a PCP or pulmonologist with stage III NSCLC, data shows 20% never receive care from other MDT members, including oncologists.²⁰ Earlier referral of NSCLC patients to medical oncology may be improved through better PCP/pulmonologist understanding of the drastically enhanced prognosis in these patients today.

Because of the volume of treatment advances over the past decade,⁸ widespread understanding and uptake of treatment with curative intent may take time to be adopted widely. A change in the view of diagnosis may be achieved via physician-physician education calls, community visits, and seminars. Even for large tumors or bulky lymph nodes, experts note that techniques and therapies are improving every day; what may have been untreatable yesterday may be treatable today with radiation, so each patient should receive appropriate medical and radiation oncology consultation (Box 1).¹⁵

According to oncologists from AdventHealth Cancer Institute and Moffitt Cancer Center, patients are also self- referring to cancer centers.⁹ With patient self-education increasing, there is opportunity for industry and advocacy groups to educate patients directly on treatment with curative intent.

Multidisciplinary Team Care
The NCCN Guidelines^® recommend multidisciplinary evaluations prior to treatment.⁷ However, data from a study of patients with stage III and IV NSCLC show that patients with stage IIIA and IIIB NSCLC who do receive treatment by a medical oncologist still lack exposure to an MDT, with only 41% and 32%, respectively, receiving care from all cancer specialists (radiation oncologists, surgeons, etc).¹⁶

Experts often face difficult patient cases where multiple perspectives are essential; for example, whether to approach a patient with stage IIIA disease with surgical resection vs a non-surgical chemoradiation approach. In a select group of stage IIIA NSCLC, surgical resection may offer a better curative potential. For cases such as this, patients benefit from multidisciplinary tumor board assessment—live or virtual, if necessary—with input from multiple specialists (eg, radiology, pathology, surgery, radiation, and medical oncology).⁹ The opportunity to assess a patient case from the perspectives of surgeons, radiation oncologists, and pulmonologists who have different training perspectives deepens the understanding of the disease for all providers involved while ensuring the optimal treatment plan is chosen.⁹

Even in institutions with comprehensive MDT care, significant opportunity remains for continuous quality improvement in communication and collaboration, especially when new treatments are approved and leaders must determine how best to integrate new standards into the care flow. Florida Cancer Specialists, a large medical oncology/hematology practice in the United States, is one such example of a network that took stock of its teams and practices to ensure the standard of care was being implemented efficaciously as part of its ongoing mission of continuous care improvement (Case Vignette 1). 
 

Roadmap of Treatment Journey

Accurate Staging
Following diagnosis, accurate staging is paramount in determining next steps in the patient journey. Suboptimal staging can affect both prognosis and treatment selection. In 34% of patients with early-stage NSCLC, their diagnoses were understaged.²³ One way to improve staging is to conduct pathologic mediastinal staging. However, 45% of patients with stage II-IIIB NSCLC do not receive invasive mediastinal sampling.²⁴ Experts agree that staging is critical in ensuring patients get the most appropriate and relevant care, as treatments can change significantly based on stage. Inaccurate staging, whether upstaging or downstaging, has tremendous implications for treatment options.^10,19

As imaging technology has improved, so too has the survival rate. There has been substantial improvement in the 2-year survival rate due to more accurate staging provided by increased imaging technology.⁸ Endobronchial ultrasound (EBUS) is a minimally invasive assessment that can gather samples from hilar lymph nodes and mediastinal stations. A specific form of EBUS, the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), has demonstrated a lesser median time to treatment 
compared to conventional diagnosis and staging.²⁵ In one study, patients who were diagnosed with conventional diagnoses and staging had a median time-to-treatment decision of 29 days compared to 14 days for patients who received EBUS-TBNA.²⁵

Experts believe that all patients referred with suspected lung cancer due to a lung mass should receive diagnostic bronchoscopy, invasive mediastinal staging, and EBUS (diagnostic and staging procedures can be done simultaneously).¹⁹ Evaluation should involve all treatment modalities upfront to determine resectability and treatment path. For example, multidisciplinary tumor board review of equivocal positron emission tomography (PET) and computed tomography (CT) scan findings is helpful (Box 2).

Unresectable Stage III NSCLC Sub-Staging
Approximately 82% of patients with stage III NSCLC have unresected disease (ie, patients who were diagnosed with unresectable disease as well as patients who chose to not undergo surgery).²⁶ In patients with stage IIIA disease and positive mediastinal nodes (T1-2, N2), treatment should be based on pathologic mediastinal lymph node evaluation findings.⁷

Patients who are stage IIIB fall into two groups: T1-2,N3 tumors and T3-4,N2 tumors. Stage IIIC includes T3-4 tumors and contralateral mediastinal nodes, which are almost always unresectable (Table 1).^7,27

Radiotherapy Advances and Concurrent Chemoradiotherapy 
Advances in radiotherapy (RT) have improved the patient radiation experience. Researchers have developed a 3D CT-based simulation that allows for better anatomic definition of target lesions when planning treatment.²⁸ Use of this technology has been shown to improve survival outcomes compared to conventional simulations.²⁸ In addition, the development of intensity-modulated radiation therapy (IMRT), an advanced form of RT, has improved patient radiation experience. IMRT allows radiology oncologists to sculpt radiation intensity, providing high-dose volumes at the site of disease and sparing the surrounding organs.²⁹ This technique allows for consistent and, in some patients, improved radiation efficacy with decreases in lung and nearby organs toxicity.^29,30 Of note, a long-term follow-up study found that 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care vs high dose 74 Gy for stage III NSCLC.³¹ A prospective phase 1 study evaluating IMRT in 24 patients with advanced lung cancer was conducted between 2009 and 2014. The study demonstrated that use of IMRT decreased the unnecessary dose to critical organs, including the lung.³² 

cCRT has demonstrated a survival advantage in stage III NSCLC and is recommended by National Comprehensive Cancer Network (NCCN^®) for unresectable stage III NSCLC.⁷ Consistent with guidelines, the majority of patients (71.2%) with unresected stage III NSCLC receive cCRT as first-line therapy, according to a real-world study.³³ While concurrent delivery of CRT is associated with higher rates of toxicities vs sequential delivery, the benefits outweigh the risks.^34,35 In a study of 577 patients across the United States and Canada, where the primary endpoint was overall survival (OS) and secondary endpoints included tumor response and time to tumor progression, 5-year survival was statistically significantly higher with cCRT compared with the sequential treatment.³⁵ The rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent therapy vs sequential therapy (median follow-up time of 11 years), but late toxic effects were similar.³⁵

Consolidation Immunotherapy
The NCCN recommends a certain consolidation immunotherapy agent (category 1) for patients with unresectable stage III NSCLC whose disease has not progressed following treatment with 2 or more cycles of definitive cCRT.⁷ 

Key time points along the treatment journey have been identified as areas where better care coordination and education is needed. Unnecessary treatment delays, suboptimal duration of treatment or poor adherence to regimens, inadequate supportive care for side effects, and communication breakdowns are common areas where providers face challenges. The data behind specific timelines in therapy and the clinical implications of delays in treatment should be communicated across the whole care team and explained (and reinforced consistently) to patients.⁹ On a broader scale, data has also shown that facility-wide tools like high-quality clinical pathways can aid in care coordination and delivery of guideline-concordant care.³⁶

Failure to Receive cCRT
cCRT can lower mortality risk and improve survival in comparison to single modality treatments. A study of 3799 patients with stage III NSCLC found that patients who received cCRT (n=1976) had a lower mortality risk compared to patients who received systemic therapy (ST) (n=823) or RT alone (n=1000).³⁷ Patients who received CRT had a median OS of 14.7 months compared to 11.0 months and 8.0 months in patients who received ST and RT, respectively.³⁷ ST or RT patients were at a higher risk of mortality compared to cCRT patients (HR (95% CI): ST:1.38 [1.26-1.51]; RT 1.75 [1.61, 1.91]); P <.001).³⁷ As mentioned above, cCRT is superior to sequential CRT. In a study of 577 patients divided into 3 arms, in which 2 arms received cCRT and 1 received subsequent therapy, there was a demonstrated decrease in the hazard ratio for death in patients who received cCRT.³⁵ The HR for death was 0.812, 95% CI (0.663-0.996, P=.046).³⁵

Suboptimal Support Throughout CRT
Suboptimal supportive therapy during the course of CRT leading to delays and interruptions can ultimately have an impact on OS and progression-free survival (PFS). CRT-related adverse events may prevent patients from completing CRT and could negatively impact patient outcomes. CRT can cause severe toxicity and may cause a patient to miss chemotherapy administrations or stop treatment all together. When administered concurrently, some patients may struggle with the intense treatment. In a randomized phase 3 trial of sequential vs cCRT in 205 locally advanced NSCLC patients, 19 patients who received sequential therapy and 23 patients who received cCRT had to stop treatment due to acute severe toxicity.³⁸

While cCRT is considered the standard of care for unresectable stage III NSCLC, the associated toxicities can affect all organs of the body.³⁹ Because of this, supportive care is very important both to allow for completion of treatment and to prevent long-term, permanent side effects. One of the most common side effects associated with cCRT is acute esophagitits.³⁹ The current standard of supportive care includes local anesthetics, a proton pump inhibitor, and systemic analgesics as needed.³⁹ A trial of antifungal medications may be required if symptoms persist, as candidiasis is not uncommon in patients receiving cCRT who are relatively immunocompromised.³² Providers may consider treatment breaks if symptoms are severe, but treatment delays should be avoided if at all possible so as not to prolong overall RT treatment time, risking tumor repopulation and impacting clinical outcomes.³² Reducing chemotherapy may also be considered, although this may relatively have less impact if the esophagus is receiving high RT doses.³² Maintaining good hydration can help with esophagitis (intravenously, if necessary) in addition to overall proper nutritional health.⁴⁰

One of the most important practical strategies for the management of CRT symptoms are ongoing symptom monitoring and proactive management (Box 3). This can include periodic coaching sessions, reminding the patient of the end goal, reinforcing what to expect from treatment, and encouraging open communication.^9,10 There should be multiple touch points from the full care team, as discussed earlier.⁹

Suboptimal CRT duration
The duration of CRT will impact patient response to treatment as well. Insufficient duration of or prolonged exposure to RT caused by treatment delays can have a detrimental effect on outcomes. A study investigating the effects of prolonged overall RT duration on survival outcomes of stage IIIB/IIIC NSCLC (n=956) treated with cCRT found a negative association between overall radiation treatment duration (ORTD) and OS and PFS.⁴¹ Patients with an ORTD of <50 days had a significantly superior median OS compared to patients whose ORTD was ≥50 days (28.6 months vs 16.8 months, P<.001).⁴¹ The study found that the main factors contributing to an increased ORTD included failure to start treatment on Mondays, treatment machine breakdowns, national/religions holidays, and acute toxicity.⁴¹ Analysis of the National Cancer Database found that, for patients (n=14,154) with stage III NSCLC who received cCRT, radiation treatment time (RTT) was prolonged in 44.2% of all treatment cases.⁴² The median OS was worse in patients who had prolonged RTT, 18.6 months compared to 22.7 months in patients who received standard RTT.⁴² As the RTT lengthened, the OS of patients worsened.⁴²

Failure to Receive Timely Post-CRT Imaging
Following cCRT, eligible patients should start immunotherapy within 42 days.⁴³ Experts believe it is essential patients receive CT scans after CRT and before consolidation immunotherapy within an appropriate window to confirm that they do not have progressive disease and can promptly continue to immunotherapy treatment.¹⁰ They also underscore the importance of avoiding delays of scans and evaluation of disease progression after CRT, with some clinicians aiming to get scans 2 to 3 weeks following CRT and even submitting the authorization request for immunotherapy following initial consultation to avoid backend delays.⁴⁴ Oncologists should be keeping patients aware of the importance of timing for these evaluations and starting immunotherapy.⁴⁴ Having an oncology nurse navigator (ONN) or care coordinators to facilitate scheduling and prompt follow-up can assist in avoiding delays as well.⁴⁴

Failure to Receive Immunotherapy Post-CRT
Of the patients with stage III NSCLC who complete cCRT and are left in a state of surveillance, up to 89% may eventually progress to metastatic disease.⁴⁵ 

Supporting Transition to Immunotherapy Treatment for Eligible Patients
A team approach is critical to ensure eligible patients are beginning immunotherapy in a timely manner.¹⁰ Experts from Levine Cancer Institute focus on supportive care to ensure that patients are able to recover quickly after CRT and can go on to receive immunotherapy.¹⁰ Part of this process means side effects need to be managed aggressively and appropriately. Educating patients and caregivers regarding the potential side effects and toxicities is important so that they better understand to reach out to their care team as soon as they see any changes. Similarly, educating all providers on this information is also essential so that they can recognize changes in patients and address them quickly.¹⁰

Introducing the concept of immunotherapy as part of the treatment pathway at the outset is helpful in adequately preparing patients mentally for the transition following cCRT.¹⁰ Differences between CRT and immunotherapy should be reviewed. and potential immune-mediated adverse effects should be explained to the patient ahead of immunotherapy initiation. Oncologists should stress the importance of adhering to the treatment schedule for the full duration, where appropriate, up to 12 months, or until disease progression or unacceptable toxicity. The care team at Levine Cancer Institute stressed the importance of following up consistently with patients to manage CRT effects, such as issues with swallowing, mucositis, and poor appetite, to support them in transition to immunotherapy. Similarly, ahead of immunotherapy, patients should know what to expect regarding immune-mediated adverse effects. The care team should make them feel supported, so they may be more likely to report reactions early and receive adequate assistance.¹⁰

Revisiting the typical treatment journey for patients with stage III unresectable NSCLC, best practices from lung cancer experts from a range of distinguished cancer centers are collected and described in Figure 2. Employing these strategies and increasing focus on particularly challenging phases of the treatment journey may help to optimize care coordination and the patient experience. 

Care Planning and Setting Expectations
Prior to beginning treatment in unresectable stage III NSCLC, experts recommend setting expectations and practical strategies with the patient for the coming journey (Box 3). Patients should understand that the goal of treatment is curative intent.⁹ 

At every touchpoint, the MDT and care coordinators should remind patients of the overall goal of treatment. Experts from Moffitt Cancer Center and Florida Cancer Specialists have encouraged use of a nurse navigator/educator to maximize patient engagement and adherence to and compliance with the treatment plan.^9,22 The Oncology Nursing Society defines an ONN as “a professional RN [registered nurse] with oncology-specific clinical knowledge who offers individualized assistance to patients, families, and caregivers to help overcome healthcare system barriers. Using the nursing process, an ONN provides education and resources to facilitate informed decision making and timely access to quality health and psychosocial care throughout all phases of the cancer continuum.”⁴⁸

Effective communication among patients, ONNs, and the care team could result in earlier identification of adverse events, fewer treatment interruptions, and better patient outcomes. If ONNs identify patients’ real-world barriers to care early, proactive steps can be taken to resolve them, such as finding an adequate support system, financial assistance, or better transportation to treatments. ONNs can meet with physicians to identify what each patient will need, then contact each department to determine ideal scheduling and what patients may need ahead of time. They can also keep the patient on track along the way with reminders and encouragement.⁴⁶

Survivorship
Appreciating cancer survivorship before, during, and after a patient’s treatment journey can facilitate better communication, collaboration, and shared decision-making. Comprehensive survivorship care planning should be completed to ensure whole-person care is delivered.⁴⁹ 

According to the American Society of Clinical Oncology (ASCO), there are two common definitions of cancer survivorship: (1) the period following treatment when signs of cancer are no longer present, and (2) “living with, through, and beyond cancer” starting with diagnosis.⁴⁷ The second meaning is how the National Cancer Institute defines survivorship, ie, focusing on “the health and well-being of a person with cancer from the time of diagnosis until the end of life. This includes the physical, mental, emotional, social, and financial effects of cancer that begin at diagnosis and continue through treatment and beyond.”⁵⁰

ASCO further delineates three phases of survivorship: acute, extended, and permanent survivorship (Box 4). ASCO has developed a survivorship care plan that summarizes the treatment the patient received, when they will need to receive check-ups and follow-up testing, the potential long-term effects of treatment, and ways to improve the survivor’s health.⁵¹ In patients with NSCLC, the recommended survivorship care model is 

a shared care model.⁵² In a shared care model, patients continue to see their PCP but keep continued communication with their oncology team and pulmonologist.⁵² Following treatment for NSCLC, survivors can experience a change in their quality of life (QoL).⁵² Due to the long-term effects of toxicity from treatment, patients can experience adverse psychological and physical symptoms including cancer-related pain, fatigue, dyspnea, cough, distress, and anxiety.⁵² 

Providing resources to cancer survivors may help improve QoL and improve the survivor experience. Patients should be provided with resources to aid in smoking cessation, physical activity, and nutrition. Evidence-based resources from authoritative societies and government organizations are listed in Table 2.

Potential of Clinical Pathways for Care Delivery Optimization
High-quality, comprehensive clinical pathways can contribute to enhanced MDT coordination, promote guideline-adherent care, and assist in implementation of consensus-based best practices. Institutions, such as Moffitt Cancer Center, Levine Cancer Institute, AdventHealth, among others, have integrated pathways—whether vendor-purchased or created in-house—into their daily care delivery.^9,53 In 2017, ASCO released criteria for high-quality clinical pathways in oncology, noting that “well-designed and effectively implemented clinical pathways can be an important tool for improving adherence to evidence-based medicine and reducing unwarranted variation in care.”³⁶ In addition, pathways can “enhance communication and patient education, serving as a way for oncology providers to share evidence-based information with patients about the complex details of treatment options.”³⁶

As recommended by ASCO, pathways should be comprehensive, meaning they should cover the full spectrum of care spanning diagnostics, medical, surgical, and radiation oncology treatment, enabling MDT input to be built into pathways foundation.³⁶ Pathways also facilitate ongoing multidisciplinary discussion via yearly or more frequent updates or upon release of practice-changing data, as the pathways team reconvenes to determine how clinical pathways and the patient journey should reflect new information.⁹ ASCO also recommends that pathways programs have efficient reporting processes and technology, which aids in internal reviews of real-world physician practice patterns and real-world data collection for subsequent studies.³⁶ 

Electronic health record (EHR) integration is ideal for data collection, as this decreases administrative burden on physicians who would otherwise have to navigate outside of the EHR program to view a pathway. At institutions such as Moffitt Cancer Center, EHR data filters into the pathways to help populate information, removing duplicative work and enabling prompts for follow-up care or tests, among other helpful alerts.⁹ Pathways become especially useful across regional networks or for general and community oncologists, as they allow for decision support and guidance on the latest standard of care to be implemented at the point of care.⁵³

Streamlining and optimizing the patient journey is critical in supporting patients in achieving their best possible outcome. Implementing standards of care and fully involving the MDT are critical in the formation of a patient’s treatment plan. Continuous quality improvement initiatives, physician education, peer-to-peer collaboration, and clinical pathways programs can be effective strategies to support guideline-concordant care and optimal care delivery in practice.

US-56061 Last Updated 8/21