Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer

In recent decades, it has been standard practice when treating non-small cell lung carcinoma (NSCLC) to deliver 40 to 50 Gy to the uninvolved regional lymph nodes. Known as elective nodal irradiation (ENI), this therapy is targeted to ipsilateral and contralateral hilar/mediastinal nodes and occasionally to supraclavicular areas, with an additional 20 Gy delivered to the primary gross tumor through reduced fields [1].

In the era of 2-dimensional radiotherapy before the advent of positron emission tomography (PET) scanning for staging and before the use of adjunctive chemotherapy (CHT), Radiation Therapy Oncology Group (RTOG) studies had shown a potential survival benefit from ENI in stage III NSCLC [1]. The staging of regional lymph node involvement has been greatly enhanced with the help of PET. The addition of PET to clinical mediastinal staging with CT has improved sensitivity and specificity compared with CT alone. More accurate clinical staging with PET allows the radiation oncologist to include involved hilar and mediastinal nodes that were not visualized on the CT scan and thereby reduce the probability of elective nodal failure (ENF) [2]. Therefore, the concept of ENI has been challenged with recent data showing very low rates of elective nodal failure (ENF) using only involved-field radiation therapy (IFRT) without ENI in the era of computed tomography (CT)-based 3-dimensional conformal radiotherapy (3D-CRT) [3].

However, these results have been met with caution, and a recent survey reported that only 26% of the members of the American Society of Therapeutic Radiation Oncology treat NSCLC without ENI [4]. The most recent analysis of the pertinent literature conducted by the International Atomic Energy Agency concluded that the indication for ENI in such cases is uncertain [5]. It appears that more studies are needed to address this issue.

In our large single-institution study, we report the clinical outcome and pattern of failure of 3D-CRT without ENI in treating NSCLC after staging with PET scanning.

Using PET for staging and treatment design, we found that definitive 3-D radiotherapy without ENI was associated with less than 2% isolated ENF in our study. IFRT alone appears adequate for inoperable NSCLC. The main rationale for foregoing ENI is that gross disease is not being controlled according to the high local recurrence rates (22%) within the previously irradiated tumor volume and the high rates of DM (36%). If gross disease cannot be controlled, then enlarging the irradiated volumes to include areas that might harbor microscopic disease seems unnecessary. Three major factors have changed since RTOG 73-01 established standard irradiation doses and volumes (including ENI): the advent of CT-based 3D-CRT, the use of chemotherapy, and better staging and target delineation using PET.

Emerging clinical data show that omitting prophylactic lymph node irradiation does not reduce the local control rate for patients receiving definitive radiotherapy, with isolated ENF rates of 0% to 8% [5]. Rosenzweig and colleagues recently published results for a series of 524 patients treated definitively with 3D-CRT targeted to involved-field volumes without ENI [7]. Only 6.1% of patients suffered isolated ENF, while 49% developed IFF. Belderbos et al also reported a 3% isolated ENF rate in patients with PET-staged NSCLC receiving dose-escalated radiotherapy without ENI [8]. Senan and colleagues reported no ENF in patients with stage III disease treated with 70 Gy of radiation without ENI [9]. A recently published randomized trial also supported the benefit of IFRT, with improved overall survival using dose-escalation in the IFRT arm but not in ENI arm [10]. The multicenter study RTOG 9311 also showed that only 6.7% patients developed isolated ENF in NSCLC treated with dose-escalated 3D-CRT without ENI [11].

The explanation for these lower-than-expected ENF rates could be twofold. First, incidental doses to the ipsilateral hilum, paratracheal, and subcarinal nodes approach 40 to 50 Gy when these regions are not intentionally irradiated [12]. Second, lung cancer patients have multiple competing causes of mortality, including cancer and underlying comorbid illnesses. Patients may die of local failure, distant failure, or intercurrent illness without detection of ENF. Therefore, considering the high percentages of IFF/DM and the short duration of overall survival using the current dose (60 to 70 Gy) and technique (3D-CRT) of therapy, the very low rate of isolated ENF justifies the use of IFRT alone in NSCLC.

PET scanning used for staging in our study may explain our very low rate (1.7%) of isolated ENF compared with other studies that did not use PET scans [5]. In addition, our recent published data has shown that tumor size and PET standardized uptake value (SUV) predicted the chance of IFF accurately [13]. In NSCLC, the chance of IFF was 100% when the SUV for lymph node(s) was above 13.8 compared with 15% when the SUV was less than or equal to 13.8 [13]. We found the SUV of the primary tumor to have the same predictive value. Thus, in patients with NSCLC, it is important to deliver adequate doses of radiation to the involved nodal or mediastinal areas, particularly those areas with high SUVs. Adjusting the dose to deliver higher levels of radiation to high-SUV areas seems to be indicated.

Efforts to improve local control in patients treated with radiation therapy for NSCLC have led to the development of dose escalation strategies and concurrent chemoradiotherapy. However, significant toxicities are associated with dose escalation and concurrent CHT and, therefore, ENI needs to be minimized [14]. However, evolution of the increasingly conformal treatment approaches such as IMRT and proton therapy may reduce incidental doses to the elective nodal region [15]. The data from our undergoing clinical trials using IMRT or proton therapy in stage III NSCLC will provide valuable information about the impact of incidental doses on ENF. In addition, as we improve our clinical outcomes (with lower rates of IFF and longer survival) with dose escalated radiotherapy and concurrent CHT, we should re-analyze the ENF data. As patients survive longer and IFF is reduced, the microscopic disease in the elective nodal region may become a greater issue.

In our study, the low rates of isolated ENF were not a consequence of unusually high rates of IFF, which can reduce the observed rate of isolated ENF. The 1- and 2-year local control rates of 83% and 60% were comparable to those previously reported [11]. The pattern of ENF does not suggest any needed modifications to the treatment fields. The ENFs occurred in patients of diverse stages, treatment approaches, and tumor locations. Only 2 of the 5 patients with ENF developed recurrences in next order draining lymphatics. Furthermore, of the 5 ENFs, 3 occurred after IFF and may represent the spread of in-field recurrences rather than true ENF.

In this study, the target volume was generally restricted to involved regions, with some of the first-echelon nodes treated if they were visible and adjacent to gross disease and if coverage of these nodes would not change normal tissue toxicity significantly, as decided on an individual basis by the radiation oncologist. This approach was supported by the observation that the highest rates of micrometastatic disease in mediastinal lymph nodes occurred nearest to the tumor, mainly in peribronchial and hilar locations [16]. Many factors are currently considered in the decision to include first-echelon nodes, such as imaging characteristics of the lymph nodes, proximity to the primary tumor, and the ability to meet dose constraints. Recently, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become widely used to stage mediastinal lymph nodes. Dr. Herth et al [17] reported that EBUS-TBNA detected lymph node involvement in 9/97 patients with clinical stage I NSCLC with a normal CT image and negative PET of lymph node areas. EBUS-TBNA may be considered to verify the lymph node involvement for suspicious lymph nodes in GTV delineation. This procedure may further improve the accuracy of lymph node staging and target delineation. It should be noted, however, that the sensitivity of EBUS-TBNA is about 90% and common lymph node stations sampled are level 2, 4, 7, 10 and 11 but not level 5, 6, 8 and 9.

In the current era of PET-guided radiation treatment planning and 3D-CRT, restricting the target volume to involved nodal regions results in minimal (< 2%) isolated ENF. ENI does not appear to be indicated for unresectable NSCLC. Future strategies should continue to be directed at improving in-field control and preventing distant metastatic disease.