Abstract
Purpose/objective:
Treatment of presumed early-stage lung cancer with definitive radiation therapy in the absence of a pathologically confirmed specimen frequently occurs. However, it is not well described in the literature, and there are few North American series reporting on this patient population. We report outcomes in patients treated with stereotactic body radiotherapy (SBRT) for presumed lung cancer and compare them to outcomes in patients treated with SBRT with pathologically confirmed non-small cell lung cancer (NSCLC).
Materials/methods:
This study is based on a retrospective review of 55 patients with presumed or confirmed lung cancer: 23 patients had nondiagnostic or absent pathologic specimens while 32 patients had pathologically confirmed NSCLC. All patients had hypermetabolic primary lesions on a positron emission tomography (PET) or PET/computed tomography (CT) scan. SBRT was delivered as 48–56 Gy in four to five fractions via a four-dimensional CT treatment plan.
Results:
Of the patients without pathological confirmation, the mean age was 78 (range 63–89 years) and 17 (74%) were men. The mean tumor size was 2.5 cm (range 1.0–5.1). Reasons for not having confirmed pathologic diagnosis included indeterminate biopsy specimen or an inability to tolerate a biopsy procedure due to poor respiratory status. SBRT was chosen due to noncandidacy for surgery in 17 patients (74%) or patient refusal of surgery in six (26%). Median follow up was 24.2 months (range 1.9–64.6): 2 of the 23 patients (8.7%) had local failure at the site of SBRT and 3 (13%) had regional failure. The actuarial 12-month overall survival was 83%. The median overall survival was 30.2 months. At last follow up, 12 patients (52%) were alive up to 64.6 months after treatment. SBRT was tolerated well in this series. Acute toxicity was noted in two patients (8.7%) and chronic toxicity in three (13%). These patient characteristics and results were shown to be similar to the 32 patients with pathologically confirmed NSCLC. On Kaplan–Meier analysis, there was no significant difference (p = 0.27) in overall survival between patients with pathologically confirmed NSCLC and those with presumed lung cancer (which was deemed most likely NSCLC).
Conclusion:
While biopsy confirmation remains a goal in the workup of suspected NSCLC, SBRT without pathologic confirmation may represent a safe and effective option for the treatment of presumed NSCLC among patients who cannot tolerate or refuse surgery.
Keywords
Introduction
Lung cancer is the leading cause of cancer mortality in both men and women in the USA and worldwide, with estimated incidence rates of over 2 million cases annually, and death rates nearing 1.5 million annually [Hansen, 2009b; Jemal et al. 2011]. Despite declines in the rate of smoking in the USA [Pierce et al. 2011], lung cancer is expected to continue to be the leading cause of mortality in the USA, with a current base of over 90 million current or former smokers posing a major future challenge [Jemal et al. 2010]. Worldwide, lung cancer rates are expected to rise in the coming years due to the increased prevalence of smoking in developing countries [Jemal et al. 2010]. Approximately 75% of lung cancers are non-small cell lung cancers (NSCLCs) [Hansen, 2009a], and if diagnosed early (i.e. International Association for the Study of Lung Cancer, 7th edition stage I or II), without the development of mediastinal or distant metastasis, the disease may be cured with surgical resection or curative radiotherapy in patients not undergoing surgery [Detterbeck et al. 2009].
While most cases of NSCLC present at an advanced stage with heralding signs and symptoms, the incidentally detected solitary pulmonary nodule (SPN), discovered on common thoracic imaging studies [i.e. chest X-ray often followed by computed tomography (CT) scan for further workup], frequently results in referral for the diagnosis and treatment of possible early-stage NSCLC [Albert and Russell, 2009]. If remote imaging studies are not available to document lesion stability, a SPN (defined as a lesion less than 3 cm in diameter and completely surrounded by lung parenchyma) [Edey and Hansell, 2009] of sufficient size (>0.8 cm) is often pursued with pathologic biopsy confirmation in order to make a clinical diagnosis of lung cancer. This is most often carried out through a percutaneous fine needle aspirate (FNA) for peripheral lesions; and while the rate of false negatives may be substantial (>20%, even for lesions in the outer third of the lung) the approach is especially important in attempting to obtain a diagnosis for lesions of low or intermediate risk [Siegelman et al. 1986; MacMahon et al. 2005]. Assessment for the latter is often facilitated through a preprocedure positron emission tomography (PET)/CT scan. However, the pretest probability of malignancy for some lesions may be so high (e.g. PET-positive spiculated lesion in a smoker) that the risk/benefit ratio of proceeding to curative surgical excision (with intra- and postoperative surgical pathologic diagnosis) weighs in favor of foregoing the needle biopsy altogether [Ost and Gould, 2012]. In a large, retrospective study of 1755 patients, Sato and colleagues determined that 27% of patients who underwent surgical resection had no preoperative diagnosis [Sato et al. 2010]; and in another series, Sawada and colleagues found that 46% of patients lacked a preoperative histological diagnosis [Sawada et al. 2007].
In patients with advanced obstructive or restrictive lung disease, the decision to embark on a curative irradiation course for what appears to be early-stage NSCLC by combined clinical exam and PET/CT imaging, without the need for FNA, may be considered using the same reasoning as outlined above. Moreover, when the lesion is lower or moderate risk, and would otherwise be approached with a needle biopsy for attempting to rule in the diagnosis of lung cancer, the degree of lung disease may be so advanced that the risk of severe life-threatening pneumothorax justifiably precludes a needle attempt. Provided that there are no noninvasive data (e.g. serology, cultures etc.) that would otherwise rule in an alternative infectious/inflammatory diagnosis in such patients with medically inoperable disease, the decision to curatively irradiate without an attempt at tissue/needle diagnosis may be reasonable. In addition to severe lung disease, pathologic diagnosis may be difficult to obtain secondary to patient refusal or coexisting comorbidities. While SBRT has been well validated as an efficacious and safe approach for similar patients with a tissue diagnosis of NSCLC [Scott et al. 2007], there is a need for further study of postirradiation outcomes and survival of such patients with presumed (but not pathologically confirmed) lung cancer. Bradley and colleagues reported a series of 91 patients treated with SBRT, of which 24% were treated without biopsy-proven NSCLC [Bradley et al. 2010]. They observed no difference in local control between patients with versus without biopsy proven NSCLC. Also, Verstegen and colleagues compared patients with and those without biopsy-proven NSCLC treated with SBRT and observed no difference in local control or overall survival [Verstegen et al. 2011].
Addressing the clinical issue of treatment of NSCLC without biopsy confirmation is important in this era of medicine. It is not only commonly encountered during the approach toward an incidental SPN in patients with medically inoperable disease, but it will become a future challenge in the setting of lung cancer screening using low-dose CT scanning [Aberle et al. 2011]. With screening CT scanning the appreciable rate of SPNs detected will require either repeat imaging [MacMahon et al. 2005] or the decision of possible biopsy versus SBRT without biopsy confirmation in high-risk patients with medically inoperable disease. We report a series of 55 patients from our institution treated with SBRT: 23 patients with clinically diagnosed but nonpathologically confirmed NSCLC, and 32 patients with similar baseline with pathologically confirmed NSCLC. We analyze patient outcomes with a standardized uptake value (SUV) ≥2.5 and discuss these in light of the experiences in the literature wherein high-risk SPN is managed with curative irradiation and without histologic confirmation.
Materials and methods
This research was conducted with approval by the Institutional Review Board of the University of California, San Diego from November 2002 to June 2012. We reviewed the records of all patients treated with SBRT for early stage lung cancer. Of those patients, we identified 23 who were treated for primary lung cancers without pathological confirmation of their diagnosis and 32 with pathologically confirmed NSCLC. Pathologic diagnosis was not possible in these 23 patients because the biopsy was either nondiagnostic or not performed because the patients could not tolerate a biopsy due to poor cardiopulmonary reserve or additional comorbidities. All lesions treated were found to be hypermetabolic with a standardized uptake value (SUV) ≥2.5 on PET/CT scan.
Tumors without pathologic confirmation were clinically diagnosed as primary lung cancer (most likely NSCLC) based on radiographic and clinical evidence when the risks of additional biopsy were felt to be greater than the clinical benefit of obtaining a biopsy specimen (or additional biopsy specimens). Criteria for definition of a tumor as lung cancer without biopsy confirmation included the following: progressive growth on CT imaging or presence of a hypermetabolic lesion on PET scan, which was described in a radiology report as being suggestive of lung cancer; no prior cancer diagnosis that was judged to be a source of lung metastasis; absence of clinical signs or symptoms of infection; and multidisciplinary tumor board consensus on the clinical diagnosis of lung cancer.
A description of the methods for SBRT at our institution has been published previously [Nath et al. 2011]. Briefly, four-dimensional CT was acquired on every patient using GE four-slice LightSpeed scanner, with real-time position management for tracing the breathing (Varian Medical Systems, Palo Alto, CA, USA). The Eclipse treatment planning system (Varian Medical Systems) was used for contouring as well as planning. The internal target volume (ITV) was contoured on the image set and lesions in the upper one-third of the lungs were expanded 5 mm uniformly to generate a planning target volume (PTV). Lesions in the lower two-thirds of the lungs were expanded 5 mm axially and 8-10 mm in the superior-inferior direction to generate a PTV. Plans were created with IMRT in four to seven coplanar beams, and also using RapidArc (Varian Medical Systems) treatment delivery. The range of doses prescribed was 48–56 Gy (median 50 Gy) in four to five fractions. In general, plans were normalized such that 100% of the ITV received at least 100% of the prescription dose. Maximum point doses were generally less than 110% and within the ITV. Setup was performed by skin marking alignment with lasers, orthogonal kilovoltage films, and daily cone-beam computed tomography (CBCT) scans. Patients received respiratory gating unless the tumor motion was insignificant on the four-dimensional simulation CT scan.
Data were gathered upon a review of each patient’s medical record to assess for local control, disease progression, treatment toxicity, and overall survival. Local failure was defined as any evidence of disease progression at the site of primary disease in any provider’s clinical notes or any mention of disease progression in any radiologic report or radiologic evaluation on CT or PET scan without other clinical explanation. Regional failure was likewise defined for disease progression in regional lymph nodes. Treatment toxicity was assessed by reviewing all clinical notes for discussion of toxicity or new symptoms during or after treatment based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE V 3.0). A Kaplan–Meier analysis of overall survival and disease-free survival was performed to compare outcomes for patients with NSCLC with pathological confirmation versus patients with presumed NSCLC without pathological confirmation. A Cox proportional hazard regression was created to determine which variables independently predicted survival.
Results
Patient characteristics are shown in Table 1 for all 55 patients treated with SBRT. Patient characteristics in the group with nonpathologically confirmed lung cancer were similar to those for the group with pathologically confirmed NSCLC. For the 23 patients with nonpathologically confirmed lung cancer, the mean age was 78 years (63–89) and 17 (74%) were men. For the 32 patients with pathologically confirmed lung cancer, the mean age was also 78 years (60–88) and 18 (56%) were men. There was one patient in both groups that had two separate contralateral tumors treated, which were felt to be independent primary lesions, and they were treated together, with one combined course of SBRT. Reasons for not having confirmed pathologic diagnosis included indeterminate biopsy results or the absence of a biopsy based on the judgment that the patient’s respiratory status was so poor that needle biopsy posed excessive procedural risk. For the 23 patients with nonpathologically confirmed lung cancer, all but one of the 23 (96%) had a history of smoking; and among the 32 patients with pathologically confirmed lung cancer, all but one of the 32 (97%) had a history of smoking. In the nonpathologically confirmed group, SBRT was chosen due to noncandidacy for surgery in 17 patients (74%) or patient refusing surgery in six (26%). In the pathologically confirmed group, SBRT was chosen due to noncandidacy for surgery in 26 patients (81%) or patient refusing surgery in six (19%).
Patient characteristics.
Lesion characteristics were also similar in both groups. For the 24 lesions that were not pathologically confirmed, the lesions ranged from 1.0 to 5.1 cm (mean 2.5 cm, standard deviation 1.1 cm) in size. The lesions were central in seven cases (29%) and peripheral in 17 cases (71%). For the 33 lesions that were pathologically confirmed, the lesions ranged from 1.0 to 5.7 cm (mean 2.7 cm, standard deviation 1.25 cm) in size. The lesions were central in nine cases (27%) and peripheral in 24 cases (73%). For the 24 lesions of nonpathologically confirmed lung cancer, 11 (46%) were stage T1aN0, seven (29%) were T1bN0, five (21%) were T2aN0, and one (4%) was T3aN0. In comparison, for the 33 lesions of pathologically confirmed NSCLC, 11 (33%) were stage T1aN0, eight (24%) were T1bN0, 13 (39%) were T2aN0, and one (3%) was T2bN0.
In both groups, all patients completed SBRT as prescribed. All patients were followed until study closure or death, and no patients were lost during follow up. The median follow-up time from initial SBRT was 24.2 months (range 1.9–64.6) in the nonpathologically confirmed group while the median follow-up time was 25.8 months (range 4.3–53.4) in the pathologically confirmed group (Table 2).
Average patient outcomes.
Of the 23 patients with nonpathologically confirmed lung cancer treated with SBRT, 21 (91%) showed local control at last follow up. In both of the lesions with local failure, the location was central. The cases of local failure occurred 10.6 and 53.0 months after diagnosis. Of the 32 patients with pathologically confirmed NSCLC treated with SBRT, 30 (94%) showed local control at last follow up. The location was peripheral in one of the cases but central in the other. The cases of local failure occurred 2.8 and 6.5 months after diagnosis. Of the 23 patients with nonpathologically confirmed lung cancer treated with SBRT, 20 (87%) showed regional control at last follow up. The cases of regional failure occurred 6.1, 10.6, and 11.3 months after diagnosis at last follow up. Of the 32 patients with pathologically confirmed NSCLC treated with SBRT, 30 (94%) showed regional control at last follow up. The cases of regional failure occurred 2.7 and 9.2 months after diagnosis at last follow up.
For the nonpathologically confirmed group, the actuarial 1-year overall survival was 83% and the median overall survival was 30.2 months. At last follow up, 12 patients (52%) were alive up to 64.6 months after treatment. For the pathologically confirmed group, the actuarial 1-year overall survival was 78% and the median overall survival was 16.8 months. At last follow up, 17 patients (53%) were alive up to 53.4 months after treatment. On Kaplan–Meier analysis there was no significant difference between patients with NSCLC with pathological confirmation versus patients with presumed NSCLC without pathological confirmation in terms of overall survival (p = 0.274) (Figure 1).
Kaplan–Meier survival analysis.
In the nonpathologically confirmed group the Cox proportional hazard regression analysis observed that elevated tumor stage (p = 0.048) and decreased diffusion capacity of carbon monoxide (DLCO) (p = 0.040) were predictors of survival, but patient age (p = 0.39) was not. Of the 23 nonpathologically confirmed patients there were three that subsequently had biopsy confirmation of NSCLC at a metastatic site. None were clinically diagnosed after SBRT with a condition other than NSCLC to explain the presence of a lung tumor.
SBRT was well tolerated in both groups of patients in this series. For the 23 patients in the nonpathologically confirmed group, acute toxicity was noted in two patients (8.7%) and included grade 1 hemoptysis and grade 2 pleural effusion. Chronic toxicity was noted in three (13%) patients and included grade 2 dyspnea, grade 2 cough, and grade 1 pulmonary fibrosis. All of the patients in this group had complete resolution of symptoms. For the 32 patients in the pathologically confirmed group, four patients (13%) experienced acute toxicity to treatment, which included grade 3 esophagitis, grade 2 pneumonitis, grade 1 cough, and grade 1 pruritis. Chronic toxicity was noted in six of the 32 patients (19%), and included grade 2 pneumonitis, grade 1 cough, grade 1 pneumonitis, grade 2 pneumonitis, grade 2 dyspnea, and grade 2 atelectasis. All but one of the patients in this group had complete resolution of symptoms. One patient developed a chronic cough.
Discussion
Surgical resection is the primary modality of treatment for early stage NSCLC [Halperin et al. 2007; Smolle-Juettner et al. 2010]. However, a portion of the NSCLC population has impaired cardiopulmonary reserve, often due to severe COPD, which places them at increased risk of postoperative complications. In accord with well validated physiologic limitations [Colice et al. 2007] this group is reasonably deemed medically inoperable; but an observation-only approach for this group is unacceptable due to the rapidly fatal course of untreated lung cancer [McGarry et al. 2002; Raz et al. 2007]. SBRT has repeatedly been shown to be a safe and effective alternative treatment for medically inoperable early stage NSCLC [Onishi et al. 2007; Baumann et al. 2009; Inoue et al. 2009; Stephans et al. 2009; Takeda et al. 2009; Chi et al. 2010; Palma et al. 2010; Videtic and Stephans, 2010; Haasbeek et al. 2012; Murai et al. 2012], and it is increasingly considered to be a standard of care for the treatment of this population [Videtic and Stephans, 2010; Haasbeek et al. 2012; Murai et al. 2012]. Previously, we reported our own institutional experience using modern techniques [Sandhu et al. 2009; Ahmad et al. 2011], including stereotactic body radiotherapy [Nath et al. 2011], in early stage lung cancer demonstrating good local control and favorable toxicity profile. The Radiation Therapy Oncology Group 0236 trial was the first North American multicenter, cooperative group study to test SBRT in treating patients with medically inoperable early stage NSCLC. This prospective study showed a high rate of primary tumor control (97.6% at 3 years) and a good 3-year overall survival of 55.8% with the use of SBRT [Timmerman et al. 2010].
The diagnostic approach to a SPN in patients with poor cardiopulmonary reserve is limited to one of a few options that ultimately may result in therapy with curative irradiation (or occasionally sublobar resection) when lung cancer is implicated. It is important to approach the subject of diagnostic options from a general standpoint: On one hand, lesions with low to intermediate risk (most often incorporating PET/CT in the risk assessment of a lesion that exceeds 0.8 cm in diameter) may ultimately be proven malignant through a needle biopsy, and thus deemed not safe for continued observation through serial imaging. Ideally, in Bayesian terms, the decision to embark on a FNA attempt in the first place should be taken only when a nondiagnostic result (commonly encountered) reduces the post-test probability of cancer so much that subsequent serial imaging (as opposed to definitive treatment in the setting of a cancer-positive biopsy) becomes justified. This approach is constrained further by the risk (and consequences) of pneumothorax in any given patient. Rarely, and typically in the setting of a low pretest probability, a needle biopsy rules in a diagnosis that is not cancer (e.g. infection). On the other hand, a very common scenario is the intermediate- to high-risk lesion (e.g. PET positive >1 cm or even PET negative with concerning CT characteristics), which needs no such needle-approach since the decision to treat for cancer immediately would not be changed by the results of needle biopsy.
With these general considerations in mind, we specifically focus on patients with ‘low cardiopulmonary reserve’ defined as the state of severe lung disease. In that setting, the significance of the study findings presented herein most heavily impact the first scenario outlined in the previous paragraph; that is, when a needle biopsy would perform reasonably in the probability-driven decision process but the risk of morbidity and even mortality from the procedure (e.g. significant in patients with emphysema or lung fibrosis) must be weighed against the ‘downside’ of foregoing the biopsy with a chance that one might be exposing the patient to any risks associated with definitive empiric treatment with SBRT for presumptive early-stage lung cancer in the setting of a benign lesion. While appropriate decisionmaking incorporating PET/CT among a variety of demographic and clinical variables typically makes such ‘false-positive’ judgments relatively unlikely, we must consider such situations to discuss the most challenging scenarios in which one may employ ‘curative’ SBRT for presumed lung cancer treatment without pathologic confirmation.
PET/CT is an important tool in staging NSCLC, which can decrease the need for invasive surgical procedures [Herder et al. 2006]. Gupta and colleagues found PET/CT to have a sensitivity of 93% and a specificity of 88% for the detection of malignancy [Gupta et al. 1996]. The majority of malignancy was subsequently determined to be NSCLC; however many of the tumors were metastases from previous malignancies or occult malignancies. In terms of using PET/CT for clinical diagnosis of NSCLC, clinical factors such as history of smoking and lack of prior malignancy make hypermetabolic lesions more likely to be primary lung cancer. Nevertheless, we must acknowledge that use of SBRT for a presumed diagnosis of NSCLC will result in treating a small proportion of benign masses, small cell lung cancer, and metastases from other tumors. However, we feel that exposing this small proportion of patients without NSCLC to the limited toxicity of a carefully planned course of SBRT is outweighed by the clinical benefit of giving a highly effective treatment to the majority of patients who are correctly diagnosed presumptively with NSCLC. In these cases of presumed NSCLC, reaching a multidisciplinary consensus and having full disclosure with patients is extremely important. Unfortunately data from the present series are limited in that we do not know how many of the patients had clinically diagnosed NSCLC, except for 3 of 23 patients who eventually had biopsy confirmation of NSCLC at a metastatic site.
In the present study, all of the patients were found to have suspicious lesions on CT, hypermetabolic lesions on PET scan, and relatively high pretest probability of having early-stage lung carcinoma. Thus, given the reasonable combined predictive accuracy of these modalities when used together [Swensen et al. 1997; Davies et al. 2005; Herder et al. 2005; MacMahon et al. 2005; Meyers et al. 2006; Wahidi et al. 2007; Sato et al. 2010], the probability of treating a benign lesion with empiric radiotherapy may have been relatively low in this series. Consistent with our findings, a few studies have reported comparable outcomes for SBRT in early-stage lung cancer with versus without pathologic confirmation [Lagerwaard et al. 2008; Stephans et al. 2009; Bradley et al. 2010; Verstegen et al. 2011; Takeda et al. 2012]. Nevertheless, performing SBRT in pathologically unconfirmed cases of lung cancer may raise the question of some degree of bias toward benign lesions in that group [Cerfolio and Bryant, 2009]. While the baseline characteristics as well as outcomes of both groups were comparable in this study (Tables 1 and 2, and Figure 1), it should be noted that, overall, the median survival of 30 months and 1-year overall survival of 83% were quite good given the high rate of comorbid illnesses and poor cardiopulmonary function in this medically inoperable patient population. In fact, there was a trend toward a slightly better outcome in the nonpathologically confirmed group, wherein an additional explanation might also lie in the fact that there was a slightly higher proportion of T1b, T2a versus T1a lesions in the pathologically confirmed group compared with that in the nonconfirmed group. Among patients with pathologically unconfirmed disease a Cox regression analysis found elevated tumor stage and decreased DLCO to be significant predictors of survival, which is generally in keeping with survival as it correlates with lung cancer staging and advanced lung disease respectively. Interestingly age itself was not independently correlated with survival, perhaps because physiologic age is more relevant in this population with inherent substantial comorbidities.
Finally, in the group of patients with nonpathologically confirmed cancer, acute toxicity was noted in two patients (8.7%) and chronic toxicity was noted in three (13%). In comparison, in the group of patients with pathologically confirmed lung cancer, four (13%) had acute toxicity and six (19%) had evidence of chronic toxicity. All but one of the patients with SBRT toxicity had complete resolution of symptoms. SBRT thus seems to be an efficacious treatment for clinically diagnosed early-stage lung cancer, with acceptable toxicity and overall survival in our experience at a rate that is at least comparable to that of pathologically confirmed lesions.
Conclusion
While biopsy confirmation of lung cancer should always be obtained if possible, significant safety concerns in patients with advanced lung disease often lead to empiric SBRT without a biopsy. SBRT appears to be a safe and effective choice in such cases.
Footnotes
Funding
This material is the result of work supported with resources of the VA San Diego Healthcare System.
Conflict of interest statement
The authors have no conflicts of interest to report.