Pancoast tumors: current management and outcomes—a narrative review

Introduction

Lung malignancy remains the leading cause of cancer-related deaths in the United States, with non-small cell lung cancer (NSCLC) characterized in up to 80% of all lung cancer cases (1). The vast majority of Pancoast tumors account for less than 3–5% of lung tumors with adenocarcinoma the more frequent histologic type (up to 60%) (2-4). Of the different varieties of NSCLC, superior sulcus tumors (also known as Pancoast tumors) are among the most challenging thoracic tumors to treat particularly due to their usual involvement of key neurovascular structures of the superior sulcus, leading to oftentimes significantly life altering symptoms. Pancoast tumors have historically been known to have significantly poor prognosis and early surgical and medical therapy had discouragingly poor outcomes. Previous reviews have abundantly described the currently followed trimodal treatment options including induction chemoradiation followed by surgery through the well-known posterior and anterior approaches. However, there is a lack of acknowledgment and elaboration on current advancements in treatment. The following review reflects the characteristics of Pancoast tumors and the current treatment options while highlighting new surgical advances as well as advances in therapy involving immunotherapy. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-29/rc).

Methods

A literature search was performed during the month of May 2024 using the PubMed databases. Broad search terms included “Pancoast tumor management”, “Pancoast tumor surgical approaches”, “Immunotherapy treatment of Pancoast tumors”, “Multimodal treatment of Pancoast tumors”. Only papers published in peer-reviewed journals between January 1930 and May 2024 and any article published in languages other than English were excluded. Of 126 results flagged, 38 were used in this review (Table 1).

Characteristics and diagnosis of Pancoast tumors

Superior sulcus tumors were originally described by the radiologist Henry Pancoast in 1932 and are frequently described as Pancoast tumors as a result (5). Preoperative radiation and en-bloc resection in the 1950s were found to potentially improve morbidity and mortality outcomes of these tumors, considered universally fatal until then (5-7). Pancoast tumors are tumors that invade anatomical structures at the apex of the thorax, including the first thoracic ribs or periosteum, the brachial plexus, particularly the lower nerve roots, the sympathetic chain, especially the stellate ganglion, or the subclavian artery and vein (8,9). The wide range of superior sulcus lesions invading the apical chest wall and, thus, various vital structures can produce a characteristic syndrome named the Pancoast syndrome. Since the thoracic inlet is a narrow compartment, even little growth or direct extension into the inlet can produce symptoms. Symptoms include severe, relentless shoulder and arm pain along the distribution of the ulnar nerve (eighth cervical nerve trunk and first and second thoracic nerve trunks), Horner’s syndrome (characterized by ptosis, miosis, and anhidrosis), and intrinsic hand muscle degeneration and atrophy (4).

Chest radiography can show a lesion or thickening of pleura in the lung apex with or without involvement and/or destruction of ribs or neighboring vertebrae (8). However, the lesion may be easily missed on simple chest radiographic imaging. Therefore, chest computed tomography (CT) without contrast will confirm the presence of an apical mass and its relation to other structures of the thoracic inlet. Magnetic resonance imaging (MRI) is recommended to more accurately characterize suspected invasion of the brachial plexus, subclavian vessels, spine, and neural foramina (2,4,8).

The vast majority of Pancoast lesions account for less than 3–5% of lung masses and are usually bronchogenic carcinomas, with adenocarcinoma the more frequent histologic type (up to 60%) followed by squamous cell carcinomas (35–40%) while small cell carcinomas are rare (2-4). Historically, Pancoast tumors were thought to have different biology from that of other NSCLCs in that there is a higher tendency for local invasion and decreased incidence of lymphatic or hematogenous spread (7). However, as pointed out by Detterbeck, the rates of resected Pancoast tumors with involved pathologic N2 positive nodes were not significantly different from other clinically stage-matched NSCLCs, and survival rates were higher when lobectomy was chosen as resection strategy compared to a non-anatomical resection (10).

According to the American Joint Committee on Cancer (AJCC) 8^th edition of tumor-node-metastasis (TNM) staging of NSCLC, Pancoast tumors are classified as T3 tumors if they involve the chest wall and/or the sympathetic chain alone (11). Tumors that invade the brachial plexus, vertebral bodies, and vascular structures are hence categorized as T4. Based on their positive nodal involvement (N status), the final stage is IIB if the tumor is T3N0, IIIA with T3N1 or T4N0-1, IIIB with T3N2 or T4N2, IIIC with T3N3 or T4N3 (11). Accurate mediastinal staging is necessary as pN2 or pN3 involvement in Pancoast tumors represents poor prognostic outcomes for patients (12). Combined positron emission tomography-computed tomography (PET-CT) and CT chest scans are mandatory before and after operative therapy while there are varying opinions on the necessity of mediastinoscopy or endobronchial ultrasound for definitive diagnosis of nodal involvement (4).

Diagnosis of Pancoast tumors is often delayed due to the frequent lack of typical lung malignancy symptoms such as cough and shortness of breath (13). Patients initially address their neuromotor symptoms with neurology and orthopedics, further delaying diagnosis of the underlying tumor.

Management of Pancoast tumors

Between the 1930s–1950s, Pancoast tumors were recognized as a separate clinical entity that was treated as inoperable and incurable. The first reported successful treatment and cure of a superior sulcus tumor was undertaken in the 1950s by Chardack and MacCallum, who conducted a surgical resection with adjunctive radiation therapy (6). The patient survived disease-free 5 years later. In 1956, Shaw discussed a new management model by describing a patient with a Pancoast lesion that initially underwent radiotherapy as a palliative option only to resolve symptoms and shrink tumor size allowing for radical resection (7). Since then, bimodal therapy of radiotherapy and surgery has become the standard of care. A significant group of series with this bimodal approach have reported comparable survival rates between 26% and 35% at 5 years and complete resection rates of approximately 60% (4,12,14). These results remained discouraging and unchanged for more than four decades. In addition, surgical resection was limited to only tumors involving ribs, and any case with tumor invading vascular or neural structures was considered a contraindication to surgery (4). With the introduction of innovative surgical methods and the involvement of multi-specialty surgical teams, radical surgery with adequate local tumor control became a promising option (4).

During the 1990s, increasing experience with multimodal therapies suggested that induction chemoradiotherapy with subsequent surgical resection showed potential as an effective treatment option for stage III NSCLC (15). Over the following years, various studies have examined how trimodal therapy used in stage III NSCLC can affect outcomes specifically for Pancoast tumors. Robinson et al. describe their retrospective study of 102 patients comparing outcomes after standard induction chemoradiotherapy followed by resection vs. induction chemotherapy alone followed by resection (16). Patients received 2 cycles of induction platinum-based doublet chemotherapy with concurrent 45 Gy radiotherapy or a chemotherapy-only regimen of 3 cycles of platinum-based doublet chemotherapy. There were significantly more complete pathological responses in the combined chemoradiotherapy group (38%) vs. the chemotherapy-only group (3%), aligning with previous studies that pathological complete response, downstaging, and/or negative margins are positive predictive factors for better prognosis in Pancoast tumors (16). Interestingly, there was a non-significant 5-year survival rate between the chemoradiation therapy group (44.5%) vs. the chemotherapy-only group (54.6%; P=0.44) (16). The finding has been correlated to the use of post-operative adjunctive radiation therapy in the induction chemotherapy group, especially in stage IIIA patients where resected N2 disease more likely had residual microscopic nodal disease (16).

Similarly, Barnes et al. describe their pilot experience of eight patients with Pancoast tumors treated with the combined use of chemotherapy and radiation (17). Patients had received 5 weekly cycles of chemotherapy with cisplatin (dosing ranged from 50 to 60 mg/m²) and concomitant external beam radiotherapy with doses between 4,000 to 6,300 cGy. After completion of induction therapy, five patients underwent surgical resection. One patient presented with complete response, while one patient died before planned surgical resection, and one patient refused surgery. At the minimum 3-year follow-up, four patients showed no signs of recurrence based on serial radiographic and clinical examinations (17). These and other similar studies support the application of concurrent platinum-based chemoradiotherapy as an essential component of treatment for Pancoast tumors. These promising findings then led to the development of trimodal therapy as the modern standard of care.

Trimodal treatment

The current standard treatment for Pancoast tumors has come to include the combination of induction chemoradiotherapy followed by radical surgical resection. The Southwest Oncology Group (SWOG) 9416 prospective multi-institutional phase II trial remains fundamental in the development of this modern standard of treatment. From April 1995 to November 1999, 110 patients were treated with chemotherapy consisting of alternating cisplatin 50 mg/m² and etoposide 50 mg/m² and a total radiation dose of 45 Gy administered in 1.8 Gy daily fractions over the course of 5 weeks (9). Thoracotomies were then performed 3 to 5 weeks after induction chemoradiation. Five-year survival was 44% overall and 54% after complete resection with no significant difference between T3 and T4 lesions (9). This trial shows that survival at 5 years using a trimodal approach was significantly better than in previous series using induction radiotherapy and resection alone. In addition, the SWOG 9416 trial also demonstrated that 5-year survival for patients with residual disease considerably exceeded the approximately 30% survival rate that was previously reported for patients treated with just bimodal therapy (9).

Results from multiple other studies have confirmed results from the SWOG 9416 trial. Kunitoh et al. reported 3- and 5-year overall survival rates of 61% and 56%, respectively, in 76 patients enrolled in the Japan Clinical Oncology Group (JCOG) Trial 9806 (18). In this trial, patients received two treatments of cisplatin-based induction therapy with subsequent 45-Gy induction radiotherapy before surgical resection. R0 resection was achieved in 89% of the 57 patients who then had surgical resection after chemoradiation therapy (18). Lin et al. performed a similar study but presented data examining longer survival outcomes in patients who underwent trimodal therapy (19). In the 32 patient cohort, 5- and 10-year overall survival rates were 50.1% and 31.8%, respectively while 5- and 10-year disease-free survival rates were 47.1% and 28.2%, respectively (19). In another study, Marulli et al. performed a retrospective analysis on of 56 patients treated with concurrent chemoradiotherapy and subsequent surgical resection in a single institution (20). Surgery was performed between 2 weeks and one month after completion of induction therapy. Radical resection was achieved in 85.7% of patients but found in only 17.9% of patients with complete pathological response, underlining an important prognostic factor of T4 disease and microscopic residual disease (20). Overall, the 5-year survival of 38% was relatively low compared to other studies underlying the negative prognostic characteristic of nodal involvement and T4 tumors. When results of patients with T3 disease were analyzed, 5-year survival reached 60% comparable to the SWOG 9416 trial (20).

A retrospective study of 36 patients by Jeannin et al. presented 5-year disease free survival of 37.5% and 57% for patients with resected disease and complete pathologic response (21). What is interesting, however, is that 53% of patients with N2-N3 disease were included, though such a characteristic was excluded in both the SWOG 9416 and JCOG 9806 trials (9,18,21). There was no statistical difference in overall survival or disease-free survival according to nodal status because N3 ipsilateral supraclavicular node involvement seemed to behave like N1 nodes (21). N3 ipsilateral supraclavicular nodes located in the vicinity of the lesion were considered to be local nodes with behavior similar to N1 nodes (21). On the other hand, N2 tumor diseases demonstrated worse outcomes than those with N0 or N1 diseases with 9 patients with N2 disease relapsing within 2 years in the study (21). Similar tumor staging inclusion is presented in a retrospective study by Kwong et al. where 36 patients underwent high-dose radiation and chemotherapy followed by surgical resection (22). Complete pathologic response was seen in 40.5% and median survival time for such patients was 7.8 years (22). Another retrospective study performed by Unal et al. examined 18 patients, all of whom had T4 stage tumors, who underwent induction chemoradiation therapy followed by surgical resection (23). Five-year disease-free survival was 40% with overall 5-year survival of 55%, with survival outcomes possibly contributed to higher doses of radiation (at least 60 Gy) compared to the 45 Gy in the SWOG 9416 trial, similar to other studies mentioned (23). The previously mentioned studies provide potential to the safety and efficacy of using higher dose induction radiotherapy in present trimodal therapy. The survival analysis of Kwong et al. compares favorably with those from the SWOG 9416 trial especially with relatively few occurrences of significant radiation toxicity (22). While it is standard to provide induction radiotherapy at about 45 Gy, these promising findings can help guide multidisciplinary teams to exercise higher radiation doses.

Five-year survival rates reported in the previously mentioned trials, amongst others, are significantly high, though a considerable percentage of patients who did not respond to trimodal therapy developed systemic metastases (9,18). In response to this observation, the SWOG designed the Intergroup Trial S0220, a phase II trial examining outcomes in treating Pancoast tumors with induction chemoradiotherapy and surgical resection followed by adjuvant consolidation chemotherapy with docetaxel (24). The neoadjuvant treatment regimen was identical to the regimen used in SWOG 9416 trial with an addition of docetaxel 75 mg/m² given every 21 days for three doses beginning 3 to 8 weeks after completion of surgery (24). Three-year disease-free survival and overall survival were 56% and 61%, respectively, showing promise to additional treatment that can be used in patients with systemic recurrences after completion of trimodal therapy (Table 2).

Surgical approaches in trimodal therapy

The multifaceted anatomy of the thoracic inlet has led to the development of various surgical approaches for proper exposure of the tumor and the involved structures, allowing for the most thorough resection that any tumor presentation can allow. Current practice at most centers is based on a specific treatment that is frequently developed by a multidisciplinary team with attention to adverse prognostic factors (25,26). The primary objectives of surgical resection, similar to those for non-apical lung tumor resection, include achieving R0 resection margins, completing lobectomy, and conducting a comprehensive mediastinal lymph node dissection. Depending on the degree of local involvement of structures, surgical treatment may include removing the paravertebral sympathetic chain, stellate ganglion, brachial plexus lower trunks, subclavian artery, or sections of the thoracic vertebrae (26). The first surgical approach described and still most commonly used, is the high posterolateral thoracotomy which extends beyond the inferior border of the scapula to halfway between the posteromedial edge of the scapula and the spinous processes, up to the level of C7 (4). This provides wide exposure of the posterior chest wall, transverse processes, vertebrae, roots of the thoracic nerves, and the brachial plexus. However, it limits access to the anterior thoracic inlet, including the subclavian artery and vein.

Multiple anterior approaches have also been described, but Dartevelle is widely credited for developing the most popular anterior approach. The incision runs along the anterior border of the sternocleidomastoid muscle, continuing laterally superior to the clavicle, with the most medial segment of the clavicle is excised (27). This anterior approach allows for exposure of the entire thoracic inlet, especially the subclavian vessels and brachial plexus. However, resection of the clavicle can cause shoulder anatomy alterations, decreasing mobility and affecting cervical posture. In response to this postoperative complication, the transmanubrial L-shaped approach was developed. The incision begins along the anterior border of the sternocleidomastoid muscle and continues across the sternal notch, extending laterally along a transverse line two fingerbreadths inferior to the clavicle. The upper portion of the manubrium is divided, and the first rib is then mobilized. This approach helps preserve the clavicle and its muscular insertions with an osteomuscular flap (4,28). An alternative anterior approach involves a hemi-clamshell thoracotomy with an optional suprasternal, or trapdoor, extension. The incision begins longitudinally in the sternal midline extending laterally in the third or fourth intercostal space towards the axilla in an L-shaped fashion (28). Anterior approaches to Pancoast tumors that invade the vertebrae may necessitate a second posterior incision, usually as a staged procedure (29,30).

While open surgical approaches have been widely used, the use of minimally invasive approaches through video-assisted thoracoscopic surgery (VATS) has been used. A comparative retrospective study by Caronia et al. revealed that VATS can be used to manage Pancoast tumors. Compared to the standard thoracotomy group, patients were observed to have less pain, better recovery of forced vital capacity, and a reduction in opioid and analgesic consumption (31). Hybrid approaches have also been described where VATS lobectomy is performed along with either posterior thoracotomies or anterior surgical incisions (32). In addition, VATS allows for a lobectomy to be performed through well-known access points compared to the lesser known transmanubrial approach (26). The VATS approach is also used as an initial observation step that allows the exclusion of previously undetected pleural dissemination and to precisely define tumor location before proceeding with a more invasive approach (33). It is reasonable to expect that the frequency and rate of minimally invasive superior sulcus tumor resections will increase as more institutions attempt to expand the use of VATS (Table 3).

Role of immunotherapy in Pancoast tumor management

Immunotherapy has recently been revolutionizing the treatment landscape of advanced NSCLC, particularly those that inhibit programmed death 1 (PD-1) or its ligand, programmed death ligand 1 (PD-L1) (34,35). The most common inhibitor used for NSCLC has been PD-1 inhibitors such as nivolumab that has shown superior disease free outcomes compared to chemoradiotherapy alone in patients with NSCLC as seen in the landmark CheckMate 816 trial (36). Favorable evidence for other PD-1 inhibitors such as pembrolizumab and durvalumab after definitive chemotherapy in unresectable stage III NSCLC is allowing for more robust treatment outcomes (34,35). With several studies showing the growing use and improved outcomes of both pembrolizumab and durvalumab, groups have turned towards implementing these treatments into the management of Pancoast tumors. Tang et al. describe a case of combining tislelizumab and chemotherapy as a neoadjuvant treatment for a patient with a superior sulcus tumor (37). The tumor was clinical stage IIIA and the patient received one 200 mg dose of tislelizumab in addition to three cycles of cisplatin-based chemotherapy. A partial response was seen, with the tumor decreasing in size by 71%, and the TNM stage was downgraded to IA2 (37). The patient subsequently underwent successful surgical resection with complete pathological response. Tislelizumab has a greater affinity to PD-1 than pembrolizumab and has shown good tolerance as a first-line treatment for advanced lung cancer in multiple studies (37-39). Though further comparative studies still need to be done to determine the strength of efficacy on improved outcomes of immunotherapy, the use of anti-PD-1/PD-L1 agents provides promising additions and alternatives in the future treatment of Pancoast tumors. What is more, various clinical trials have studied neoadjuvant concurrent immunotherapy with chemoradiation for resectable stage IIIA–B NSCLC, allowing for promising additional therapies for such advanced tumors. There are several ongoing trials such as the SQUAT trial (WJOG 12119L) is currently studying the effect of durvalumab on major pathologic response as well as progression-free survival, overall survival and safety on advanced stage NSCLC (40). In addition, the current DUMAS trial will look to study the effect of nivolumab-based neoadjuvant regimens on 2-year overall and disease-free survival as well as objective treatment response rate. Trials like these will help to bring forward the treatment of Pancoast tumors to the future allowing for more effective and efficient treatments.

Strengths and limitations

This review has adequately described in detail the characteristics of Pancoast tumors as well as provided a summary of the evolution of treatment options for the disease. The review in addition, has provided an accurate summary on current multimodal treatment strategies that are backed by peer-reviewed studies that will act as guides to help multidisciplinary teams in formulating appropriate treatment options for patients. Limitations of this review include the mention of every study and/or case report/series on various Pancoast tumor treatments as a representation of the variety of clinical presentation of Pancoast tumors. In addition, at the time of writing this review, the National Comprehensive Cancer Network (NCCN) 8^th edition of NSCLC staging was used, but it is acknowledged that a proposed 9^th edition will be published, and guidelines will be updated, allowing for critical analysis of the studies referenced in this review article. Immunotherapy treatments are still in the beginning stages of clinical trials and thus further research is warranted in assessing the safety, efficacy and overall outcome on Pancoast tumor treatment.

Conclusions

Pancoast tumors remain more difficult to treat compared to other NSCLC given their anatomical position and intimate relation to vital neural and vascular structures in the thoracic inlet. The past 10 decades, however, have shown great advancement in the management of Pancoast tumors, allowing patients to improve their qualities of life and improve their prognosis. The standard of care is typically trimodal therapy, which includes induction chemoradiotherapy followed by surgery, with the ultimate goal of achieving a complete pathologic response and R0 resection. Regardless of what type of therapy is utilized, a multidisciplinary approach is of paramount importance in the management of Pancoast tumors. The cooperation of surgeons, clinicians, and radiologists represents the gold standard today to the trimodal therapy approach in order to improve survival rate. With more advanced staged tumors, the collaboration between thoracic, spine, and vascular surgeons is becoming essential in achieving complete resection in cases with vertebral and vascular involvement, making such advanced tumors no longer contraindications to resection. More research is warranted to evaluate the role of targeted therapy or immunotherapy as well as minimally invasive surgical approaches to allow the advancement of knowledge and treatment of Pancoast tumors.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-29/rc

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