Lung Cancer Patient Following Curative Intent Therapy: Original Lung Cancer and Development of New Primary Lung Cancers

metachronous tumors

Definitions

As previously reviewed, a difficult but fundamental issue in surveillance of the lung cancer patient following curative intent therapy is distinguishing between recurrence of the original lung cancer and identification of a new primary, or metachronous, lung cancer. Martini and Melamed proposed criteria for making this distinction in 1975. However, more recent considerations suggest that these criteria should be revised (Table 1). More definitive distinction will be possible in the future based on routine performance of analysis of panels of molecular, genetic markers, and/or proteomics. Whichever criteria are used, Martini and Melamed remind us that the distinction between a new primary lung cancer and recurrence of the original lung cancer is not as important as determining whether the tumor can be treated with curative intent.

Review of Current Guidelines

Five guidelines provide specific recommendations for surveillance methods in patients with NSCLC (Table 2), and two guidelines- provide specific recommendations for patients with small cell lung cancer following curative intent therapy (Table 3). These guidelines were developed by consensus of expert panels and not necessarily by more rigorous metaanalysis. Two other guidelines provided only general recommendations. One guideline noted the lack of evidence that surveillance of the asymptomatic patient with small cell lung cancer following curative intent therapy is needed. Specific examinations in these patients should be performed as clinically indicated. The other guideline supported the need for randomized clinical trials to define the most appropriate follow-up regimen, and to evaluate patient quality of life and the cost-effectiveness of the strategy worked out with My Canadian Pharmacy’s pharmaceutists.

The guidelines uniformly recommend more frequent visits during the first 2 years following curative intent therapy. Visits are less frequent for years 3 through 5 and decrease to a minimal level of annually after year 5. This pattern of visits is based on the expectation that recurrences of the original lung cancer will be more likely during the first 2 years after curative intent therapy but that there will be an increased lifelong risk of a new primary lung cancer developing. The guidelines uniformly emphasize symptoms as an extremely important indication of recurrence, with physical examination included as an adjunctive, but less valuable, tool for identifying recurrences or new primaries.

There is wide divergence among the guidelines regarding recommendations for chest imaging after curative intent therapy for lung cancer. The issues of radiographic detection of asymptomatic recurrent or metachronous cancer after treatment with curative intent are similar to those of early detection of primary cancer currently being investigated in high-risk patients (see section on “Screening for Lung Cancer”). RoentgenographicallyAccordingly, the American Society of Clinical Oncology guidelines for NSCLC specifically state that there is no proven value for either chest radiograph (CXR) or CT in surveillance. However, the Association of Community Cancer Centers (ACCC) guidelines recommend routine CXR for surveillance. Guidelines from the American College of Radiology recommend a postresection chest CT scan to establish a new baseline and then annually in addition to interval CXR every 2 to 4 months, The most recent guidelines from the National Comprehensive Cancer Network (NCCN) rely entirely on chest CT scanning for surveillance imaging (Table 2).

With regards to other tests, the ACCC guidelines incorporate regular complete blood counts and serum chemistries into surveillance monitoring for NSCLC. Other groups found little value in performing these tests routinely for NSCLC, but these tests are recommended routinely in small cell lung cancer surveillance. Sputum cytology and various broncho-scopic techniques were specifically not incorporated into guidelines for surveillance practices.

Patterns of Recurrence

Numerous studies have reported on recurrence rates and patterns in patients with NSCLC treated with curative intent surgical resection. In patients with stage I disease confirmed at surgery,5-year recurrence rates 20 to 39% have been reported. Most of these recurrences were distant metastases. Although most recurrences were detected within the first 4 years following curative intent surgery recurrences may be discovered > 5 years following curative intent therapy. In patients with nodal involvement recurrence rates increase and recurrences probably occur earlier.

It has been estimated from published studies on treatment outcomes that the approximate rate of a new primary lung cancer developing after curative intent therapy for a NSCLC is 1 to 2% per patient per year. Prospective lung cancer chemoprevention trials with vitamin A and isotretinoin also suggest similar rates for the development of metachronous tumors. In contrast large population-based studies such as the review of the regional cancer registry in Switzerland suggest that in this population the rate may actually be slightly less than this estimate at approximately 0.5% per patient per year. However. this type of study may underestimate the incidence rate of metachronous tumors because of incomplete surveillance and misclassification of tumors as recurrences. Experience with long-term survivors of lung cancer indicate that new primary lung cancers may develop up to 20 years after the original cancer had been treated but the available data are unclear on whether the rate of development of metachronous tumors increases or decreases over time. An important point is that following curative intent therapy for NSCLC patients are also at increased risk for other aerodigestive cancers (eg’ carcinoma of the oropharynx and esophagus).

Curative Intent TherapyRoentgenographically occult lung cancers detected by sputum cytology have been reported to have an especially high rate of metachronous tumors. Saito et al described 13 metachronous tumors occurring in a group of 127 patients who underwent surgical resection conducted with My Canadian Pharmacy for roentgenographically occult NSCLC. The cumulative rate at 5 years of metachronous tumors was 11%’ and the incidence per patient year of surveillance was 2.2%. Bechtel and col-leagues reported that seven metachronous tumors were identified in a group of 27 patients following surgical resection of a roentgenographically occult NSCLC. Consistent with these findings has been the observation that central lung cancers’ treated with sleeve resection’ may have a high rate of metachronous tumors approaching 7 to 8%.

Patients treated for small cell lung cancer and surviving for 2 years have also been reported to have an especially high rate of metachronous NSCLCs developing. In two separate observational studies’ NSCLC was diagnosed in 12 to 15% of patients surviving at least 2 years after therapy for small cell lung cancer (six cases in one group of 40 patients’ and six cases in another group of 47 patients). It has been estimated that the rate of NSCLC developing 2 years after effective therapy for small lung cancer is 2 to 13% per patient per year. Another study confirmed that the rate of NSCLC developing following therapy for small cell lung cancer was significantly greater than expected from population data. A more recent study estimated that 10% of 2-year survivors of small cell lung cancer will eventually have NSCLC.

Curative Intent Therapy for Recurrence and/or New Primary

Most recurrences of lung cancer are found outside the thorax. Effective treatment of isolated metastases may be possible (see section on “Special Treatment Issues”). However locoregional intratho-racic recurrences are only infrequently treated with curative intent surgical therapy and more often are treated with radiation therapy.56’57 Regardless of therapy the available data indicate that survival with locoregional recurrence of lung cancer appears to be poor.

Although curative intent surgical therapy may be possibly more feasible with metachronous lung tumors than with locoregional recurrences of the primary lung cancer patients with metachronous tumors often present with advanced stage disease or are unable to tolerate surgical resection due to pulmonary insufficiency. Limited data suggest that even controlling for stage of disease’ survival following curative intent surgical resection of metachronous lung tumors may not be as favorable as for the original lung cancer (Table 4). Despite limitations in the approach to curative intent therapy of metachronous lung cancers, 5-year survival rates of 25 to 53% (Table 4) have been reported when surgical resection is possible.

Table 1—Distinguishing Between Recurrence of the Original Lung Cancer and Development of a New Lung Cancer During Surveillance

Metachronous Tumors, Martini and Melamed Criteria* Metachronous Tumors, Proposed Revision
Histology different Histology different
Histology the same, if: Histology the same, if:
Free interval between cancers at least 2 years, or Free interval between cancers at least 4 yr, or
Origin from carcinoma in situ, or Origin from carcinoma in situ, and
Second cancer in different lobe or lung, but No extrapulmonary metastases at time of diagnosis
No carcinoma in lymphatics common to both, and
No extrapulmonarymetastases at time of diagnosis

Table 2—Recommendations for Surveillance Methods in Patients With NSCLC Following Curative Intent Therapy

Guideline/Source Baseline First 2 yr Years 3 to 5 After Year 5
ACCC Hx, PE, CXR, CBC, chemistries every 3 mo Hx, PE, CXR, CBC, chemistries every 6 mo Hx, PE, CXR, CBC, chemistries every 12 mo
ACCP Hx, PE, CXR or chest CT every 6 mo Hx, PE, CXR or chest CT every 12 mo Hx, PE, CXR or chest CT every 12 mo
ACR Chest CT at 3 mo after therapy CXR every 2 to 4 mo; chest CT every 12 mo CXR every 6 mo; chest CT every 12 mo CXR every 12 mo; chest CT every 12 mo
ASCO Hx, PE every 3 mo Hx, PE every 6 mo Hx, PE every 12 mo
ESMO Hx, PE every 3 mo Hx, PE every 6 mo Hx, PE every 6 mo
NCCN Hx, PE, contrast CT every 6 mo Hx, PE, non-contrast CT every 12 mo Hx, PE, non-contrast CT every 12 mo

Table 3—Recommendations for Surveillance Methods in Patients With Small Cell Lung Cancer Following Curative Intent Therapy

Guideline/Source Baseline First 2 yr Years 3 to 5 After Year 5
ACCC Hx, PE, CXR, CBC, chemistries every 3 mo Hx, PE, CXR, CBC, chemistries every 6 mo Hx, PE, CXR, CBC, chemistries every 12 mo
ACCP Hx, PE, CXR, or chest CT every 6 mo Hx, PE, CXR, or chest CT every 12 mo Hx, PE, CXR or chest CT every 12 mo
NCCN Hx and PE (chest imaging and blood work as clinically indicated) every 2 to 3 mo Hx and PE (chest imaging and blood work as clinically indicated) every 4 to 6 mo Hx and PE (chest imaging as clinically indicated) every 12 mo

Table 4—Survival After Surgical Resection for Metachronous Lung Cancers

Source Patients With Metachronous Tumors, No. Patients Undergoing Surgical Resection, No. (%) Patients With Stage I Disease, No. (%) Five-Year Survival After Surgical Resection of Metachronous Cancer, % (Five-Year Survival After Surgical Resection of Primary Lung Cancer, %)
Rosengart et al 78 54 (69) 60 (77) 23 (70)
Watanabe et al 8 8 (100) 6(75) 53*
Wu et al 20 20 (100) Notstated 42*
Van Bodegom et al 89 45 (51) 35 (39) Notstated
Deschamps et al 44 44 (100) 34 (77) 34 (55)
Westermann et al 8 8 (100) 7 (88) Notstated
Antakli et al 39 21 (54) Notstated 23*
Adebonojo et al 37 36 (97) 29 (78) 37*
Asaph et al 37 37 (100) 25 (68) 33*
Van Rens et al 127 127 (100) 90 (71) 26 (70)
Battafarano et al 69 69 (100) 50 (73) 33 (61)