Mr. P is a retired 71-year-old machinist with severe chronic obstructive pulmonary disease (COPD). He has been smoking cigarettes since he was 15 years old. He says that in the past 2 years he has "cut down" from smoking at least a pack a day to smoking only 3 or 4 cigarettes per day. Mr. P says he feels a little short of breath and chronically tired even when he is just sitting, and he has a persistent cough. Pulmonary evaluation shows forced expiratory volume in 1 second (FEV1) of 0.8 L (33% predicted), forced volume vital capacity (FVC) of 3.11 L (98%), FVC/FEV1 of 24%, and partial pressure of carbon dioxide (pCO2) of 48 mm Hg on arterial blood gas, and homogeneous emphysema. Patient is using tiotropium bromide, fluticasone propionate, and albuterol inhalers.
Chest CT scan performed for possible exacerbation of his condition shows a lesion in his right upper lobe (RUL) but no extrabronchial disease. Bronchoscopy reveals an endobronchial lesion in the RUL orifice. Biopsy findings indicate nonâsmall-cell lung cancer (NSCLC), specifically squamous cell carcinoma. MRI of the brain and PET scan are negative for metastatic disease.
Decision Point 1. Lung Cancer and COPD
Is there a relationship between lung cancer and COPD that goes beyond cigarette smoking as a common etiology?
- Yesâthey share common pathophysiologic pathways as well as a common etiology
- Noâsmoking alone accounts for their frequent co-occurrence
Answer (a) It is well established that smoking is an etiologic factor for both COPD and lung cancer, but recent evidence strongly suggests that the relationship between these two diseases goes beyond that. COPD itself is associated with an increased risk of lung cancer. Data from the First National Health and Nutrition Examination Survey (NHANES I) indicate that moderate to severe obstructive lung disease is a significant predictor of lung cancer even after controlling for age, smoking status, gender, education level, pack-years of cigarette smoking, and years since quitting smoking (odds ratio [OR] 2.4; 95% confidence interval [CI] 1.5â3.8).1 Even mild emphysema without airway obstruction is associated with a substantial increase in risk of lung cancer (risk ratio 4.33).2 Furthermore, a case-control study determined that COPD increases the risk of squamous cell carcinoma in particular by more than fourfold.3
The connection between COPD and lung cancer has been demonstrated even for nonsmokers. The Cancer Prevention Study II, which included 448,600 lifelong nonsmokers, found an increased risk of lung cancer mortality among patients with emphysema (hazard ratio [HR] 1.66; 95% CI 1.06â2.59) and those with both emphysema and chronic bronchitis (HR 2.44; 95% CI 1.22â4.90).4
It is likely that COPD and lung cancer share a common pathophysiology. Smoking induces inflammation in the lungs, which leads to increased production of proteinases that destroy the matrix and lead to emphysema. One theory holds that these same proteinases release growth factors that stimulate growth and proliferation of tumor cells.5 In addition, inflammatory cytokines may inhibit apoptosis and cellular repair and promote angiogenesis, contributing to the development of lung cancer.6 Another theory holds that progenitor cellsâpossibly including bronchoalveolar stem cellsâunder constant pressure to proliferate in order to replace chronically destroyed matrix cells, overproliferate giving rise to tumors.5 Nuclear factor kappa B (NF-ÎºB) may also be a common link given that NF-ÎºB is a possible contributor to lung cancer and is also known to be activated in alveolar macrophages and epithelial cells in COPD.6 Despite these hypotheses regarding a common pathophysiology, it remains unclear as to why some smokers develop COPD, some develop lung cancer, some develop both conditions, and many develop neither.7
Audio Commentary by Dr. Unger
Decision Point 2. Treatment of Lung Cancer in Patients with COPD
Is this patient a candidate for lobectomy?
Answer: (b) Based on his poor pulmonary function, he is not a surgical candidate.
Resection offers the best opportunity for cure to eligible candidates and is recommended by the American College of Chest Physicians (ACCP) as the first choice for primary therapy for stage I and II NSCLC, in the absence of contraindications. When possible, lobectomy is the procedure of choice for resectable NSCLC. Sleeve lobectomy, if feasible, is recommended over pneumonectomy. Five-year survival rates following surgery are approximately 60% to 80% for stage I NSCLC and 40% to 50% for stage II NSCLC.8 However, postoperative respiratory failure is a well-recognized complication of surgery that limits resection in many patients with COPD.9 Decreased pulmonary function following resection is attributable to surgical trauma to the lung and chest wall, increased bronchial secretions, and postoperative pain.10
A retrospective review of patients at Indiana University Hospital revealed that more than half (52.6%) of COPD patients experience pulmonary complications following resection compared with less than one fifth (19.3%) of patients who do not have COPD (P <.001). The COPD patients were more likely to have air leak prolonged â¥10 days, pneumothorax, atelectasis, pneumonia, oxygen supplementation required for â¥2 weeks, and mechanical ventilation required for â¥1 week. COPD patients also had a higher mortality rate than non-COPD patients during the month after surgery (14.1% versus 3%; P = .003), and although there was no significant difference in overall and cancer-related survival, respiratory failure was a more frequent cause of death in the COPD group (P = .0008).11
Similarly, Italian and French researchers reported that more than half of COPD patients have postoperative exacerbations following resection for lung cancer. These exacerbations typically presented in the first 72 hours after surgery as worsening dyspnea, purulent secretions, and wheezing, and were associated with increased rates of overall mortality (5.4% versus 2.3%), respiratory complications (55% versus 11.5%), and longer hospital stay compared with patients without exacerbations.12
Some practices use a cutoff of FEV1 â¥40% of predicted as the threshold for determining candidacy for surgery. Italian researchers have reported that patients with COPD and presurgical FEV1 â¥40% of predicted can undergo lobectomy with operative mortality rates and actuarial survival rates comparable to patients without COPD.13 However, authors from Yale University School of Medicine have published an algorithm they developed from the ACCP guidelines14 that provides a more individualized method of determining surgical eligibility based on cardiopulmonary assessment (Figure. 1).15 Patients with FEV1 >1.5 L or >80% predicted value are candidates for lobectomy. Those with lower FEV1 require further evaluation, including prediction of postoperative FEV1, to determine surgical candidacy. Postoperative FEV1 can be predicted as preoperative FEV1 x (1Â âÂ fractional contribution of lung to be resected, as estimated by lung perfusion scanning). Patients with a predicted postoperative FEV1 <40% are generally not surgical candidates, particularly if percent of predicted postoperative diffusing capacity of the lung for carbon monoxide (DLCO) is also <40%; however, exceptions are sometimes made based on cardiopulmonary exercise testing.15
Figure 1. Algorithm for the Physiologic Evaluation of Patients Being Considered for Surgical Resection of Lung Cancer15
With permission from Decker RH, et al. Oncology. 2006;20:727-736.
It should be noted that in some cases of COPD, lobectomy may actually improve pulmonary function by providing a volume reduction benefit.9,10,16,17 Predictors of postoperative improvement include preoperative FEV1 <65% of predicted, ratio of FEV1 to FVC â¤55% to 60%, COPD index <1.5, and upper (as opposed to lower) lobectomy.9,16,17 According to one author, combined resection for lung resection and lung volume reduction surgery may be performed if the cancer is located in the target areas of destroyed lung tissue. In such cases, she argued, patients with poor pulmonary function tests should not automatically be considered unsuitable for resection.18
Audio Commentary by Dr. Unger
Decision Point 3. Radiation Therapy in the Medically Inoperable Patient
How would you treat this patient?
- Standard 3-dimensional conformal radiation therapy (3DCRT) or standard external beam radiation therapy (EBRT)
- Stereotactic body radiotherapy (SBRT)
Answer: (a, b, or c) 3DCRT/EBRT, SBRT, or brachytherapy would be appropriate for this patient. Local control rates with SBRT are high.19 However, because this is a centrally located lesion, the risk of complications from SBRT is higher than it would be with more peripherally located tumors, and the dose is not standardized. Brachytherapy for carefully selected endobronchial disease spares extrabronchial tissue with good local control and limited pulmonary toxicity. 3DCRT is still considered standard management for medically inoperable lung cancer, but requires larger fields and lower doses, which are associated with increased risk of pulmonary toxicity and reduced likelihood of tumor control.
When potentially curative surgery is not an option, the ACCP guidelines recommend fractionated radiotherapy with curative intent.8 Definitive radiotherapy at a minimum dose of 60 Gy may offer a chance of disease control and/or palliation and is preferable to observation alone.15 Data extracted from the Surveillance, Epidemiology, and End Results (SEER) registry indicated that survival was better for patients who underwent radiation therapy than for untreated patients, with respective median survivals of 21 months versus 14 months for stage I NSCLC (P = .0001) and 14 months versus 9 months for stage II NSCLC (P = .001).20
Conventional radiation therapy for a medically inoperable patient is EBRT or 3DCRT. Reviewing data from two randomized and 35 nonrandomized trials, Rowell et al21 found that radiation was associated with an overall survival of 22% to 72% at 2 years, 17% to 55% at 3 years, and 0% to 42% at 5 years in patients with medically inoperable NSCLC. Notably, 11% to 43% of deaths were attributable to causes other than cancer. They further noted that about half of patients with tumors <4 cm and about 20% of those with larger tumors had a complete response.
Pneumonitis is a common complication of radiation therapy, correlating with the volume of lung irradiated, and may lead to further respiratory deterioration for patients with pre-existing pulmonary dysfunction.22 COPD has been identified as a risk factor for late grade â¥3 pneumonitis (OR 10.5; P = .007) following radiation therapy.23 Researchers from The Netherlands Cancer Institute measured pulmonary function before and after high-dose radiotherapy for NSCLC in medically inoperable patients. They observed a significant decrease in diffusion capacity and alveolar volume at months 3, 18, and 36, and a significant decrease in FEV1 at months 18 and 36. Patients with COPD had the greatest declines in pulmonary function.24
Pulmonary toxicity associated with radiation therapy is reduced with newer techniques that minimize treatment volumes and exposure of uninvolved nodal regions.15 Use of CT and FDG-PET scans allows more accurate targeting of radiation to affected or at-risk areas.15 Researchers from Washington University School of Medicine, St Louis, Missouri, compared 33 patients who received radiation with fields limited to the primary lung cancer plus a margin with 22 patients who received 3DCRT therapy that included elective regional lymph nodes. Although two patients treated with limited fields had regional nodal failure, there was no significant difference in cause-specific or overall survival between the two groups.25 Similarly, Hayakawa reported that 5-year survival is 40% without elective regional irradiation and 39% with elective regional irradiation.26 Other series of limited-field radiation that lacked a comparison group reported overall survival rates of 56% to 59% at 2 years,27,28 42% at 3 years29 and 12% at 5 years.30
Audio Commentary by Dr. Gore
SBRT is a reasonable consideration in node-negative inoperable NSCLC.31 SBRT precisely targets a high dose of radiation in a short courseâusually 20 to 60 Gy in three to six fractions31âdirectly to the tumor, largely sparing healthy tissue. Radiation total dose and dose per fraction are decreased for centrally located tumors to minimize the risk of severe pulmonary complications. The Radiation Therapy Oncology Group is currently conducting a phase I/II dose-escalation SBRT study for centrally located tumors.32 Linear accelerators, patient immobilization frames, treatment markers, and control of breathing-related diaphragmatic movement are generally used with SBRT to minimize setup variability and tumor motion during administration.31 There are few data other than a small number of single-institution phase II studies, in which local tumor control has ranged from 63% to 100% at 6 to 12 months and 44% to 100% at 2 to 3 years.33-43 Reported overall survival following SBRT has ranged from 52% to 81% at 1 year, 32% to 64% at 2 years, and 42% to 72% at 3 years.35-42
Toxicity is greater in patients with central tumors compared with peripheral tumors.37,44 Seventy patients with early-stage (T1â2, N0) inoperable NSCLC were treated in a phase 2 single-institution study with 60 Gy in three fractions for T1 and 66 Gy in three fractions for T2. After median follow-up of 17.5 months, three patients demonstrated a local recurrence. Adverse events were primarily respiratory events (decline in pulmonary function, pneumonia, pleural effusion, apnea) and/or skin reactions, and they occurred a median of 7.6 months after completion of SBRT. Six patients may potentially have had grade 5 (fatal) toxicity. In five patients, these grade 5 adverse events were respiratory: one fatal hemoptysis (associated with a local recurrence) and four infectious pneumonias; the sixth patient died of complications from a pericardial effusion. Tumor location was a strong predictor of toxicity, with hilar or pericentral tumors showing an 11-fold increased risk in grades 3 to 5 adverse events compared with more peripheral tumors (P = .004). Two-year freedom from severe adverse events was 54% for these central tumors, as compared with 83% for peripheral tumors. Peripheral tumors were defined as outside the "zone of the proximal bronchial tree," which is a 2-cm radius around the main tracheo-bronchial tree encompassing the trachea; left and right main stem bronchi; right upper, middle, and lower lobe bronchus; and left upper, lingular, and lower lobe bronchus.44
The potential for pulmonary toxicity is, of course, of particular concern in patients with impaired pulmonary function pretreatment.31 However, researchers from Indiana University School of Medicine found that poor baseline pulmonary function did not predict for worse survival or pulmonary function following SBRT and that FEV1 and DLCO should not be used as exclusion criteria.45 Furthermore, researchers from Aarhus University Hospital in Denmark found that while 40% of patients treated with SBRT experience worsening of dyspnea in the 6 months thereafter, there was considerable interindividual variability in the onset and duration of these symptoms, suggesting that they may reflect habitual exacerbations of COPD rather than toxicity from SBRT.46 Worsening of pulmonary function following SBRT does remain a concern, though. A multicenter phase II study from a Nordic study group found that while SBRT did not significantly reduce FEV1 it was associated with low-grade pneumonitis in 18%, fibrosis in 33%, and pleural effusion in 13% of the COPD patients. On the other hand, it also resulted in local tumor control in 96% at a median follow-up of 23 months with no grade 4 or 5 toxicity, so careful risk: benefit analysis should be undertaken.47
Audio Commentary by Dr. Gore
Brachytherapy may be considered for endobronchial tumors without measurable disease on CT scan if standard 3DCRT is not felt to be a reasonable option given the patient's pulmonary function and if SBRT is not available or not appropriate for a centrally located tumor. Endoluminal brachytherapy has limited penetration and therefore is not effective for relatively thick lesions. Hennequin and colleagues48 reported a retrospective review of high-doseârate endobronchial brachytherapy in 106 patients. Forty-three patients relapsed after surgery, 27 relapsed after radiation therapy, and 36 patients were newly diagnosed. Complete histologic response after 3 months was 59.4%. The 3-year local control rate was 60.3%. Local failure was associated with prior endoscopic treatment and high tumor volume defined as length >2 cm, bronchial obstruction >25%, and tumor visibility on CT scan.
Spanish researchers have reported on seven medically inoperable patients treated with CT-guided permanent interstitial brachytherapy for early-stage NSCLC. At a median of 13 months of follow-up, there were no local or regional failures; one patient has developed a contralateral second primary tumor. There were two cases of pneumothorax, one of which was accompanied by hemothorax, and one case of focal pneumonitis/respiratory infection. Two patients died of causes unrelated to lung cancer or treatment.49
Audio Commentary by Dr. Gore
Mr. P was not felt to be a surgical candidate and there were concerns about EBRT due to his compromised lung function. He was treated with three fractions of brachytherapy, totaling 30 Gy. About 13 months later, he was found to have a local recurrence in the same area but extending into the right main stem bronchus, with no evidence of dissemination.
Decision Point 4: Therapy for Local Recurrence
What are the options for treating this patient?
- Systemic therapy
- Photodynamic therapy
Answer: (d) Given the case patient's prior exposure to radiation and his pre-existing pulmonary dysfunction, it is appropriate to consider options other than radiation for this patient. Photodynamic therapy (PDT) is most likely the best treatment option, if available, although arguments could be made for any of the options. Literature is lacking to support one choice over another. Treatment choice is usually dictated by local expertise, physician comfort level with the different options, individual patient risk, and other nuances that require interdisciplinary discussion.
Audio Commentary by Dr. Gore
PDT is an attractive treatment option for this case patient with COPD primarily because it is a conservative endobronchial treatment that avoids further reduction of respiratory function. However, PDT is currently available only at specialized centers and is by no means a standard approach. The photosensitizers used in PDT are retained primarily in tumor tissue as opposed to normal tissue.50 The visible light that is used to activate the photosensitizer only penetrates several millimeters into tissue, which spares normal tissue.50 In the 2008 National Comprehensive Cancer Network (NCCN) guidelines, PDT is recommended as a "simple and effective alternative to conventional techniques" to achieve debridement of endobronchial obstructions.51
A prospective study was conducted in 32 patients with inoperable (n = 15) or recurrent (n = 17) NSCLC, who received PDT (porfimer sodium, 2 mg/kg) followed 6 weeks later by five fractions of brachytherapy at a dose of 4 Gy every week.52 Complete response was seen in 24 patients (75%) after PDT, and in seven patients following brachytherapy, for a response rate of 97% after combined treatment. The one patient without complete response underwent further brachytherapy and was alive at 37 months after initial treatment. At a mean follow-up of 24 months, six patients had recurrent disease and underwent various treatments, including PDT, brachytherapy, Nd:YAG laser coagulation, or EBRT, which eradicated tumors in three patients. Two patients had distant metastases that were successfully treated with EBRT. All 32 patients were alive at mean follow-up of 24 months (range, 3â46 months). No serious side effects were described. Interestingly, the investigators surmised that reversing the treatment order, with brachytherapy first followed by PDT, would be acceptable, but noted that tissue vascularization affected by radiation could hinder uptake of the photosensitizer and possibly compromise the effectiveness of PDT.
High response and survival rates with PDT also were reported in a retrospective study of 40 patients, 12 with inoperable stage I disease and 28 with local recurrence after surgery, radiation therapy, or Nd:YAG laser therapy.53 PDT was administered via intravenous injection, with 20 patients receiving hematoporphyrin derivative (5 mg/kg) and 20 patients receiving porfimer sodium (2 mg/kg). In patients with local recurrence, the complete response rate was 75%, with 1-, 2-, and 5-year survival rates of 92.7%, 81.5%, and 67.9%, respectively. Median survival was 120.4 months. PDT was well tolerated, and no severe toxicities were noted. Although more study is needed to determine optimal indications for PDT, the investigators recommended incorporating PDT in clinical practice for patients with local recurrence.
Audio Commentary by Dr. Unger
EBRT is a potential second-line therapy for patients with reasonable pulmonary function. However, in patients with compromised pulmonary function, such as the case patient, the risk of pneumonitis is the limiting factor.22 Small retrospective studies of reirradiation conducted to date report satisfactory results regarding symptom relief and tolerance, as well as prolonged survival.54-58 Two studies have demonstrated that the interval between initial treatment and reirradiation serves as a prognostic indicator for overall survival, such that longer intervals predict longer survival (10â12 months, <12â18 months, <18+ months).57,58
One retrospective study of reirradiation using EBRT in 34 patients with local recurrence after initial EBRT looked at symptomatic treatment to improve symptoms as well as radical treatment to achieve cure or prolonged survival.56 Dosing for radical treatment ranged from 30 to 70 Gy (median 50 Gy) in daily fractions of 1.5 to 2.0 Gy, whereas dosing for symptomatic treatment ranged from 10 to 60 Gy (median 46 Gy) in daily fractions of 2.0 to 3.0 Gy. Response rates were similar between the symptomatic and radical treatment groups, but the overall survival rate was much higher with radical treatment compared with symptomatic treatment at 77% versus 6% at 1 year and 51% versus 0% at 2 years, respectively. The median survival time was 15 months (range 3â58 months) with radical treatment and 3 months (range 1â14 months) with symptomatic treatment. Symptomatic radiation pneumonitis occurred in 19 patients and symptomatic radiation esophagitis occurred in six patients but were not fatal. The investigators stated that radical reirradiation should be considered a treatment option for local recurrence in patients who had a good response to initial radiation treatment and when no other effective treatment is available.
A prospective study by Kramer et al57 focused on achieving palliation of symptoms with EBRT in 28 patients with local recurrence after initial radiation therapy. EBRT was effective in relieving hemoptysis and superior vena cava syndrome in all patients and coughing and dyspnea in 67% and 35% of patients, respectively. The median duration of symptom relief was 4 months, compared with the median survival of 5.6 months.
Data are limited on the utility of SBRT as second-line treatment in patients with local recurrence. Two recent studies of SBRT have shown favorable response rates and adequate tolerance to therapy.59,60 It should be noted that study patients' initial therapy varied (ie, surgery or definitive radiation therapy with or without chemotherapy) and that study outcomes are not categorized according to patients' initial treatment or pulmonary function.
Chang et al59 evaluated SBRT in 27 patients, 13 with primary stage I NSCLC and 14 with local recurrence after initial radiation therapy with or without chemotherapy or surgical resection. The first seven patients received 40 Gy delivered in 4 consecutive days, and three of these patients had local recurrences; thereafter, the dose was escalated to 50 Gy delivered in 4 consecutive days for all remaining patients. With the 50-Gy dose, a 100% local control rate was achieved at the treated site at a median follow-up of 17 months. In the subgroup of patients receiving SBRT for treatment of local recurrence, mediastinal lymph node metastases or distant metastases developed in three (21.4%) and five (35.7%) patients, respectively, and grade 2 pneumonitis occurred in four (28.6%) patients. There were no cases of esophagitis in either patient group. The investigators concluded that SBRT delivered at 50 Gy in four fractions is a "feasible" treatment option.
A retrospective study by Coon et al60 evaluated outcomes of SBRT in patients with primary, recurrent, or metastatic lung lesions. All patients received a dose of 60 Gy delivered in three fractions. Local, regional, or distant disease progression was seen in 9 of 12 (75%) patients undergoing SBRT for local recurrence, with a median time to disease progression of 3 months (range 2â7 months). At median follow-up of 11 months (range 2â25 months), local control at the treatment site was noted in 92% of patients. The overall 1-year survival rate was 67%. Tolerability was not described. The investigators suggested that SBRT may have a role as salvage therapy in patients with local recurrence.
There are few data to support use of systemic therapy. Studies of systemic therapy in recurrent NSCLC have focused on patients with brain metastases whose initial treatment was either surgery or chemotherapy. These trials hold little relevance for second-line treatment in patients who are surgically inoperable with compromised pulmonary function and no prior treatment with chemotherapy, such as the case patient. The 2008 NCCN guidelines for NSCLC recommend systemic chemotherapy (or observation) after treatment for local recurrence, if no disseminated disease is evident.51
Audio Commentary by Dr. Gore
Given continued concerns about the potential for pulmonary toxicity with radiation therapy in this patient with already compromised pulmonary function, Mr. P was given photodynamic therapy. Forty-eight hours after receiving an intravenous injection of porfimer sodium, he underwent bronchoscopy during which a calculated dose of red light (630 nm wavelength) was delivered by a dye laser. He underwent a cleaning bronchoscopy 2 days later to remove an eschar of destroyed neoplastic tissue. He was advised to take precautions to avoid exposure to sunlight and other intense light for about 4 weeks. Mr. P developed aspergillosis 3 years later. His cancer and aspergillosis recurred after 5 years and he was treated again with brachytherapy and antifungal therapy. Mr. P died from massive pulmonary hemoptysis.
For patients with medically inoperable NSCLC, treatment options are available that provide effective relief of symptoms and improve survival. Even patients with severe COPD can benefit from treatment of lung cancer and should be considered for therapy. The case patient survived 5 years, outliving even his prognosis with regard to his COPD. The data presented in this case study emphasize the need for practicing physicians to increase their awareness and understanding of first-line and second-line treatment options available for medically inoperable NSCLC to ensure its optimal management.
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