A number of factors complicate the selection of best therapy for a patient with radiographically occult sputum-positive lung cancer. Patients with isolated stage I lung cancer who have good performance status and isolated disease are treated best by surgical resection. To review minimally invasive and traditional methods to control early-stage lung cancer, see Part 8.
However, as the disease becomes more multicentric, or when there is a severe degree of lung impairment such that lung capacity preservation is compelling, other therapies may be safer. Figure 86-7 presents an algorithm for the management of early-stage sputum-positive lung cancer. The sections that follow describe methods that ablate localized lung cancer or premalignant lesions.
Treatment flow diagram for management of superficial central lung cancers. Given institutional experience, other forms of ablative therapy could be used for small mucosal lesions. EBBT, endobronchial brachytherapy; PDT. photodynamic therapy; XRT, radiation therapy.
Some have argued that squamous cell carcinoma in situ represents a “pseudodisease” associated with overdiagnosis bias. This argument is supported by the indolent tumor biology of some malignancies. It is clear that not all cases of carcinoma in situ progress to invasive squamous cell carcinoma, but many do. Moreover, even preneoplastic lesions (e.g., squamous metaplasia and dysplasia) have been shown to progress when followed by AF bronchoscopy over a period of years, and this issue is currently under investigation in the setting of a national registry. Carcinoma in situ of the lung has a much higher frequency of stromal invasion than carcinoma in situ of the cervix. When 44 sputum-positive patients from a large-scale screening study who refused intervention were followed prospectively, two-thirds died within 10 years of lung cancer, whereas there was a greater than 90% survival in treated patients. Therefore, sputum-positive patients with normal anticipated longevity should be treated definitively, but the management of frail patients with intermediate-risk lesions is uncertain.
Lesion characteristics aid in selection of the proper approach. A symptomatic lesion warrants treatment to improve quality of life, but over half of patients have no new complaints.24 Concerns about lymph node metastasis suggest a resectional approach that would permit concomitant nodal resection. Lesions less than 3 mm thick and less than 20 mm in length typically remain node negative.25 If there is mucosal invasion (approximately 5 mm thickness), there is an 8% incidence of N1 disease, and if the bronchial wall is invaded, the chance is 78%. Another criterion is whether the lesion is visible by WLB. For lesions that are not seen on chest x-ray or bronchoscopy, the risk of nodal metastasis is low. Radiographically occult lesions that are visible by bronchoscopy have a 23% chance of nodal metastasis.
PDT is a treatment modality for surface cancers that combines a photosensitizer with a specific light wavelength to achieve a nonthermal photochemical reaction that destroys tumor cells. This technique is facilitated by the relative concentration gradient of the photosensitizer within the tumor compared with normal bronchial epithelium following a systemic bolus. Success of this technology has required parallel advancements in laser technology that allow targeted delivery of specific wavelengths of light and in the refinement of the photosensitizer compounds. Currently, porfimer sodium (Photofrin) is the only photosensitizer approved by the Food and Drug Administration for PDT, and it is designated for use in the palliation of central airway obstruction from endobronchial tumor, as well as for ablation of small endobronchial microinvasive carcinomas with curative intent. Although this compound has peak absorbency at 405 nm, it also has a lower peak at a wavelength of 630 nm, which is associated with deeper tissue penetration and for this reason has become standard for PDT.25
Originally, this wavelength was produced by tunable dye modules added to popular lasers such as the neodymium:yttrium-argon-garnet (Nd:YAG) laser, and dedicated lasers for this purpose also have been developed. In Japan, excimer lasers have been used since 1985.26 A dose density of 200 J/cm2 is customarily used for the argon dye laser, and half this dose is used for the excimer laser. Diode laser systems have become available commercially (Diomed) and are designed specifically for PDT. These systems are smaller, menu-driven, and economical. The light is administered with diffuser probes that measure from 1 to 2.5 cm in length, and they deliver light circumferentially to the target lesion, penetrating the bronchial epithelium (or tumor) to a depth of 5 to 8 mm. Two to three days after the procedure, a “clean-out” bronchoscopy is necessary to remove necrotic tissue. The debris sometimes can be removed en masse by first loosening it circumferentially with biopsy forceps and then withdrawing the scope while dragging the plug behind. Rigid bronchoscopy permits the use of large forceps, or alternatively, a small cryoprobe can be placed within the debris, activated, and withdrawn with the frozen coagulum attached. At that time, an additional dose of PDT also can be given if there is residual tumor. The primary side effect of porfimer administration is profound skin photosensitivity, which persists for 4 to 6 weeks. Patients can completely avoid the skin rash or sunburn if they observe careful sunlight precautions during this period; however, normal room light exposure hastens the departure of the compound. This side effect may be obviated with new investigational compounds such as 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH or Photochlor).27
The early reports of the use of PDT for endobronchial therapy were limited by variations in light delivery as well as heterogeneous patient groups. Such an experience cited a complete response rate of only 30%. Selective use on thin neoplasms with visible distal margins by bronchoscopy yielded complete response rates exceeding 90%.25,26 Table 86-1 shows the relation of tumor size and distal margin to complete response rate. Edell and Cortese reported a group of 13 patients with 14 early-stage lung cancers.28 These patients received 200 to 400 J/cm2 of 630-nm irradiation 2 to 4 days following injection of 2.5 mg hematoporphyrin derivative. Eleven tumors showed a complete response after a single treatment and the remaining three after a second treatment; 77% of the tumors showed no recurrence after 7 to 49 months. No substantial complications were observed in these patients. Three patients had a mild sunburn reaction. The authors conclude that PDT may be an alternative to surgery for patients with early squamous cell carcinoma. Kato et al. described a study involving use of Photofrin PDT on 95 lesions in 75 patients with early lung cancer.26 The complete response rate was related to the tumor size, with a complete response rate of 96.8% for lesions less than 0.5 cm but only 37.5% for those greater than 2 cm. The overall 5-year survival rate for all 75 patients predicted according to Kaplan–Meier analysis was 68.4%.
Table 86-1Pdt Success and Lesion Characteristics |Favorite Table|Download (.pdf) Table 86-1Pdt Success and Lesion Characteristics
|TUMOR CHARACTERISTICS ||NUMBER OF LESIONS ||CR (RATE) ||PR ||REC |
|Size (cm) |
|<0.5 ||31 ||30 (96.8%) || 1 ||2 |
|0.5–0.9 ||38 ||35 (92.1%) || 3 ||3 |
|0.9–1.9 ||10 || 8 (80.0%) || 2 ||1 |
|≥2.0 ||16 || 6 (37.5%) ||10 |
|Total ||95 ||79 (83.2%) ||16 ||6 |
|Distal margin |
|Visible ||67 ||59 (86.8%) || 8 ||5 |
|Invisible ||28 ||20 (71.4%) || 8 ||1 |
|Total ||95 ||79 (83.2%) ||16 ||6 |
If patients are referred for the treatment of radiologically occult lung cancer, then high-resolution CT scanning and AF bronchoscopy should be used before an endobronchial-based therapy such as PDT. AF bronchoscopy permits pretreatment “mapping” of the flat, sometimes poorly visible early endobronchial cancers. At one center, 70% of patients had the endobronchial procedure aborted because of these findings and the treatment switched to resection for cure or palliative intent.4
For other patients, however, PDT may be a second-line consideration for cure by avoiding resection or to make a lesser resection surgically feasible.25 In situations where tumor control is suboptimal, it is generally occult extrabronchial disease and inadequate light delivery that account for the failure.4 In an updated series from Edell and Cortese, the patients who received PDT had a high complete response rate (93%), and 77% were spared an operation28; however, 15% of patients developed recurrence and required surgery. At another center, 44 of 45 patients with a tumor size of less than 1 cm had a complete response. Figure 86-8 illustrates the use of PDT in a patient with superficial central squamous cell carcinoma that was localized to the superficial mucosa of the right upper lobe (RB2).
It illustrates the use of PDT in a patient with superficial central squamous cell carcinoma that was localized to the superficial mucosa of the right upper lobe (RB2). In (A), a 1-cm cylindrical fiber is positioned adjacent to the superficial tumor that is visible with WLB, in (B) the fiber is shown at full-power when red light at 630 nm is administered to a total dose of 200 J/linear cm, in (C) post-PDT necrotic white debris is seen in the airway, and in (D) the post-cleanout mucosa is seen which is erythematous and abraded but histologically free from malignant cells.
Skin toxicity from porfimer sodium includes a sunburn-like reaction that may resemble second-degree burns in severe cases. Skin toxicity generally can be eliminated if patients carefully observe sunlight precautions and avoid full-spectrum light. Patients of darker skin, including African Americans, may experience further darkening of the skin with porfimer. Local toxicity from PDT effect is seen in all patients; this includes endobronchial erythema with tenacious mucus formation in the area of treatment. The patient's ability to tolerate this local reaction must be weighed against the severity of the underlying lung disease (e.g., chronic obstructive pulmonary disease) before PDT is considered. Other toxicities of porfimer are uncommon and generally are grade 2 or less and include rises in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels, pleural effusion, and allergies. Posttreatment chest soreness or mild-to-moderate pain is seen occasionally and resolves quickly with oral analgesics. Most of these studies were dominated by men with squamous cell carcinoma cell types.26 Bronchial stenosis from PDT is rare and is not a feature of any of the major series that have been reported in lung cancer.
Current research in PDT includes new methods of light delivery and new photosensitizers, as described earlier. For example, investigators are examining the delivery of light more distally throughout the branched airway structures using substances of various refractive indices.29 In summary, PDT has been used more extensively than any other endobronchial modality for the treatment of microinvasive endobronchial carcinoma and carcinoma in situ and has the advantage of being a diffuse and somewhat selective therapy in the airway. The advent of less costly diode-based laser systems and the eventual use of second-generation photosensitizing agents that are largely free from skin photosensitivity will contribute to the growing acceptance of PDT.
There is less experience with radiation therapy, but early reports using new treatment techniques have been promising. Two centers reported the use of a combination of brachytherapy and external beam radiation therapy for the treatment of sputum-positive lung cancer.30All 27 patients showed a complete response. Iridium wire was used to provide the brachytherapy, although one center used a high-dose rate, whereas the other used a low-dose rate (192Ir). Unfortunately, many of these patients sustained a severe bronchial stenosis or other serious complications generally not observed with PDT. Care needs to be taken with brachytherapy for early-stage lung cancer because of the difficulty of positioning a radiation dose wire at the optimal distance from the targeted tissue.
Another center decided to use external beam radiation therapy for patients who failed PDT and raised their overall complete response rate from 64% to 90%. These treatments often were delivered with an external dose of a roughly 40 Gy delivered in 20 fractions and escalating intraluminal therapies of 5 Gy up to a total dose of 25 Gy.25 Although the complete response and long-term results of brachytherapy approach those of PDT, there is a 50% asymptomatic bronchial stenosis rate and an occasionally unexpected fatal complication such as hemoptysis.25 PDT has been combined in a sequential manner with high-dose–rate brachytherapy for palliation of bulky tumor central airway obstruction, but this strategy has not been reported for microinvasive disease or carcinoma in situ.
Brachytherapy has allowed treatments to areas invisible to conventional imaging, such as needed by the radiation oncologist for external beam planning. This problem has been addressed by use of endoscopically guided three-dimensional conformal radiation planning where the bronchoscope was used to mark the radiographically occult tumors in four patients.31 There were no adverse events in this small series, as compared with the 16% major complication rate found in brachytherapy trials probably caused by suboptimal catheter positioning.32
Since PDT historically has required special expertise, expensive light sources, and a systemic dose of an expensive drug to achieve ablation at a localized level, less expensive technology that delivers similar local tissue destruction is appealing. In a pilot investigation, van Boxem et al. studied 13 patients using 30 W of high-frequency electrocautery to cause nonselective tissue destruction. Cautery was applied until all visible tumor showed necrosis. An 80% complete response rate was observed. In the three patients who did not achieve a complete response, PDT was attempted and also failed.33 Recently, argon plasma coagulation guided by AF bronchoscopy has been used to ablate radiographically occult lung cancer. Since these therapies are less expensive and do not cause photosensitivity, they will be watched with interest as more experience accumulates. Unlike PDT, this method relies on delivering therapy to areas visible by bronchoscopy and is a focal treatment rather than diffuse. In contrast, PDT may affect small tumor patches not visible to the bronchoscope and can treat a much wider disease area. Cautery generally is limited to lesions less than or equal to 1 cm,25 and even with argon plasma cautery, tissue penetration is only 1 to 2 mm. Cautery can be performed by using probes designed for other therapeutic endoscopes provided that the bronchoscope working channel is sufficiently large. For instance, a snare cautery wire used for colonic polypectomy can be used if only a few millimeters of the electrode is deployed from the insulated oversheath.
Laser ablation is another technique by which superficial mucosa is destroyed. Some centers use a laser with rigid bronchoscopy because the larger available forceps expedite debridement. In general, the technique employs an Nd:YAG laser in which the initial beam of radiation (<30 W) is applied to the tumor for coagulation. Then a power setting near 50 W can vaporize residual superficial tumor. For a subset of early neoplasms from a large palliative laser report, a complete response rate was achieved in all 23 patients with no evidence of recurrence.34 In contrast to other ablative techniques, this type of ablative therapy may be more risky because of a deeper penetration potential of certain laser wavelengths. This is generally not a problem during the ablation of bulky tumors that occlude the airway—a commonly accepted indication for laser bronchoscopy. However, it may be a problem when full-thickness bronchial penetration occurs without the “protection” afforded by tumor encasement. Because of this concern and the other options available, the Nd:YAG laser for superficial malignancy is not recommended and may be best saved for investigational use.
Cryotherapy provides another potentially economical and simple way in which to treat radiologically occult lung cancer. Cryotherapy was once used to treat large pulmonary malignancies but was limited by the variations in heat transmission caused by trapped air insulation and warming of great vessel blood flow. Vascular rupture is less with cryotherapy because transmural destruction is prevented by the heat-sinking capability of nearby vessels. Accordingly, this treatment may have a safer theoretical therapeutic index than others. A recent experience demonstrated 91% complete response with no adverse events,35 but long-term effects, including bronchial stenosis, have not been explored. Cryotherapy usually is performed by flexible bronchoscopy, but it also may be performed by rigid bronchoscopy because it allows introduction of a nitrous oxide cooled cryoprobe. Three cycles of freezing and thawing are performed on each lesion, and each cold application lasts approximately 20 seconds. The tumor surface is treated with a marginal area of 5 mm of normal mucosa around the tumor.35 If the lesion occurs on a carina, the cryoprobe is applied to each side of the carina and then to the tip itself. About 2 weeks following the initial cryotherapy, an additional bronchoscopic evaluation is necessary, and multiple treatments also may be required.
Unless the site of occult lung cancer is missed, surgical resection should achieve 100% complete response compared to the nonresectional methods described earlier. Accordingly, survival curves have more defined starting points, and these will be compared later. Also, surgeons will establish the presence of lobar lymph node metastases with certainty as opposed to nonresectional methods. Furthermore, the quality of surgical results can be assessed by the detection of metachronous lung cancers or synchronous malignancies.
Saito et al. found that 17% of radiographically occult malignancies had extrabronchial invasion. In a series of 94 patients, 10% had multiple primary malignancies, and the location of these malignancies was found to be in the segmental bronchus in 36% of patients, subsegmental in 20%, and divisional in 18%. The remainder appeared in more distal sites or tracheal sites. Most of these patients were detected by sputum cytology found in large-scale screening. Of 127 patients in their subsequent report, 97 were either T1N0M0 or earlier stage; only 8 of the entire group had N1 or N2 nodes.36 The techniques and results of lung resection for various stages of lung cancer are described in Part 8.
Medical Treatment for Sputum-Positive Lung Cancer
For the various chemotherapy options for patients with invasive lung cancer, the reader is referred to Chapter 76. Secondary chemoprevention actually refers to the medical treatment of premalignant bronchial epithelial lesions, including metaplasia and dysplasia but not including carcinoma in situ. There have been multiple secondary chemoprevention trials for patients with premalignant lesions (Table 86-2). Lee conducted a secondary chemoprevention trial in 152 smokers with biopsy-confirmed metaplasia or dysplasia of the lung epithelium and found that isotretinoin (13-cRA; 1 mg/kg) did not cause regression of the lesion when compared with placebo.37 In a more recent study from the same institution, 9-cis-retinoic acid was compared with 13-cRA plus α-tocopherol or placebo. This group of 226 former smokers was randomly assigned to treatment groups and re-evaluated in 3 months. Six biopsies from predetermined sites were evaluated. The results showed that while neither treatment affected the histology of the sites, 9-cis-retinoic acid did restore the retinoic acid β receptor (RARβ) in a significant number of lesions. Other compounds that have been tried in this effort include fenretinide, etretinate, β-carotene with retinol, anethole dithiolethione, vitamin B12, budesonide, and folic acid. The only trials that have shown a beneficial effect in the histology of the bronchial epithelium were those that used AF bronchoscopy for detection of the endpoint (see Table 86-2). Oral prostacyclin has shown potential benefit in the treatment of endobronchial dysplasia. In a multicenter double-blind, randomized, phase II placebo-controlled trial of 125 patients with dysplasia, oral iloprost improved the dysplasia index in former (but not current) smokers over a 6-month treatment period.38 Other chemoprevention agents under investigation include targeted agents (e.g., gefitinib and erlotinib), COX-2 inhibitors (e.g., exisulind and celecoxib), and antiproliferative agents (e.g., vitamin D). The success of retinoids in the prevention of head and neck malignancies is proof in principle that such a strategy may be useful in the secondary chemoprevention of lung cancer. Ultimately, if any of these agents proves to be effective for premalignant lesions, it also potentially may find application in the treatment of carcinoma in situ.
Table 86-2Selected Secondary Chemoprevention Trials in Lung Cancer |Favorite Table|Download (.pdf) Table 86-2Selected Secondary Chemoprevention Trials in Lung Cancer
|AUTHOR ||ENDPOINT ||METHOD ||COMPOUND ||RESULT ||N |
|Lee et al.37 ||Dysplasia/metaplasia index ||WLB ||Isotretinoin ||Neg ||152 |
|Kurie et al.39 ||Metaplasia and dysplasia ||WLB ||4HP retinamide ||Nega ||139 |
|Lam et al.40 ||Dysplasia grade ||AFB ||ADT ||Posb ||112 |
|Kurie et al.41 ||Metaplasia and RARβ expression ||WLB ||9-cis-retinoic acid ||Posc ||226 |
|Lam et al.42 ||Dysplasia and MI ||AFB ||Retinol ||Neg || 81 |
|Kohlhaufl et al.43 ||Metaplasia and dysplasia ||AFB ||Inhaled retinol ||Pos || 11 |
|Ayoub et al.44 ||RARβ ||WLB ||13-cis-retinoic acid ||Posd || 44 |
|Lam et al.45 ||Dysplasia ||AFB ||Budesonide ||Neg ||112 |
|Keith et al.38 ||Dysplasia ||AFB ||Iloprost ||Pos ||152 |
Summary of Treatment Options
Surgery is considered the optimal therapy for patients with late- to early-stage sputum-positive lung cancer. However, patients who have sputum-positive lung cancer seem to have notable differences. Generally, survival for these patients is better than that in the stage I lung carcinoma population, with survival rates between 81% and 90%.36 In one screening population, the overall survival rate was 74% in those resected for cure and 55% when combining those receiving radiation and/or surgical therapy.46 This is much greater than an overall expected survival of unscreened patients, which is expected to be about 17%.
Because of a selection effect, these patients have 4% per year or higher rates of developing secondary lung carcinomas, many of which are also occult. This is double the rate of a general population. In addition, the survival rate falls from 90% to 59% if the patients have multiple sites of malignancy rather than a solitary site detected by sputum.36 In one center, the operative mortality was double that of other patients receiving lobectomy, possibly because of the increased incidence of airflow obstruction and other comorbidities associated with higher rates of sputum positivity. We have found that there is a direct relationship between the degree of airway obstruction and the presence of premalignant lesions in the airway.47
For the other therapies listed earlier, such as PDT, radiation (with brachytherapy), electrocautery, and cryotherapy, approximately 30% to 35% of patients suffer recurrences 1 to 5 years following the initial therapy.26,28,48 This, combined with the repetitive application of such therapies, makes it difficult to construct clean survival curves like those after a definitive event such as surgical resection. For patients in whom surgery is not an option because of multicentricity or the need to conserve pulmonary function, PDT is a good option that has the most experience to support it, and because it can be repeated in the event of local recurrence. The other therapies listed earlier are considered alternative options with less supporting evidence. A recent review suggested that Nd:YAG laser therapy has the weakest evidence to support it and carries a relative high risk of perforation.48