Further Thoughts on a Rare Entity

November 1, 2006

Primary neuroendocrine neoplasms of the lung represent a clinical spectrum of tumors ranging from the relatively benign and slow-growing typical carcinoid to the highly aggressive small-cell lung carcinoma. The rarity of carcinoids has made the role of radiation therapy in their management controversial. This review considers the results of published studies to generate treatment recommendations and identify areas for future research. Surgery remains the standard of care for medically operable disease. Histology plays the most important role in determining the role of adjuvant radiation. Resected typical carcinoids likely do not require adjuvant therapy irrespective of nodal status. Resected atypical carcinoids and large-cell neuroendocrine carcinomas have a significant risk of local failure, for which adjuvant radiation likely improves local control. Definitive radiation is warranted in unresectable disease. Palliative radiation for symptomatic lesions has demonstrated efficacy for all histologies. Collaborative group trials are warranted.

Although relatively uncommon, carcinoid tumors of the lung seem to be discussed at thoracic tumor board conferences more frequently than their incidence would suggest, likely reflecting the uncertainty many feel when faced with managing patients with this rare entity.
In this issue of ONCOLOGY, Drs. Mackley and Videtic have written a concise and thoughtful review categorizing these lesions, presenting aspects of natural history, and describing treatment approaches, with a focus on the role of radiotherapy (RT).

Distinct Pathologic Entities

The importance of correctly classifying these lesions into one of the four distinct pathologic entities can not be overemphasized, given the profound differences in behavior, and thus, management and prognosis.

It is estimated that 170,000 cases of lung cancer will be diagnosed in the United States in 2006,[1] and of these, approximately 15% will be the small-cell type. Primary carcinoids of the lung make up about 2%, 10% of which are classified as atypical. The incidence of large-cell neuroendocrine carcinoma (LCNECs) is estimated at 3%, or 5,000 cases.[2]

Bronchoscopic Therapy

We agree that surgery remains the standard of care for primary pulmonary carcinoid. Emerging evidence suggests, however, that initial bronchoscopic therapy (BT) and close surveillance is a potential alternative to surgical resection for selected patients.[3]

Dr. T.G. Sutedja (personal communication) has a series of 67 patients-52 typical carcinoids (TCs) and 15 atypical carcinoids (ACs)-treated in this fashion, now with long-term follow-up. Fifty percent were spared resection, including 5 of the patients with AC. Further, in those who ultimately required resection following BT, a delay of even up to 10 years did not lead to either more extensive resection or worse outcome. Only one patient (1.5%), who initially presented with metastatic AC, died of metastatic disease. Luckratz et al came to a similar conclusion in his series of 28 patients published earlier this year.[4] Such studies suggest that BT with close surveillance is an underrecognized, tissue-sparing alternative management option.

Role of Radiotherapy

Given that radiotherapy is a local modality, understanding the patterns of failure is critical in determining whether there is in fact a potential benefit for radiotherapy in this spectrum of disease. Considering the rarity of carcinoid tumors, we are unlikely to ever have prospective randomized data. Estimates of local failure in TC in a number of series following resections have consistently been reported in the single digits,[5] and we agree with Drs. Mackley and Videtic that there is no support in the literature for adjuvant RT in TC, even in those rare instances when N1 or N2 disease is documented. Indeed, this is the same conclusion reached in a previously published review coauthored by one of us.[5]

The documented higher risk of locoregional recurrence, as well as the perception that higher-grade tumors are more sensitive to fractionated radiotherapy, suggests that there may be a benefit for adjuvant RT in AC with pathologic N2 disease. It is reasonable to treat LCNEC patients as one would other non-small-cell histologies, ie, stage I and II disease with resection and stage III with combined chemotherapy and radiation therapy, perhaps followed by resection. Completely resected patients with pathologically confirmed N2 disease should be considered for chemotherapy followed by mediastinal RT. Finally, patients with positive surgical margins and no evidence of distant disease are candidates for radiation therapy.

There is quite limited published experience regarding the use of definitive RT for medically inoperable or surgically unresectable bronchial carcinoids. Stereotactic radiotherapy is theoretically attractive, because lower-grade lesions such as TCs and ACs may be more sensitive to higher-dose-per-fraction treatment than standard fractionation. However, the frequent central location raises concern regarding the late risk to the bronchus and nearby large blood vessels in these histologies, which tend to have a long natural history. Perhaps the use of stereotactic radiotherapy should be explored in a peripherally located, medically inoperable carcinoid, given the much lower risk of complications than in a central lesion.

Whereas there are limited data to support the use of radiation therapy in a definitive setting, we agree with Drs. Mackley and Videtic that there is ample experience to indicate a beneficial role in the palliative setting. High rates of symptomatic relief have been reported, both in the chest and at distant sites,[5,6] as noted in this article.

The authors briefly mention the potential role of "targeted" radiotherapy in the systemic management of neuroendocrine lung tumors. As noted, carcinoid tumors frequently express somatostatin receptors. Published experience with the administration of high doses of

90

Y-,

111

In-, and

177

Lu-labeled octeotide has suggested a benefit from this approach.[7,8] This strategy should be further explored.

Conclusions

In summary, Drs. Mackley and Videtic have provided a valuable, well-researched review of the clinical spectrum of primary carcinoid tumors of the lung, and have provided guidelines for management. They have helped delineate the role of radiation therapy based on the limited data for this rare entity. In addition to those indications described in their review, one could envision a future role for RT following bronchoscopic resection to potentially improve on what appear to be promising results, as well as to further expand the role of targeted radiotherapy with radiolabeled somatostatin analogs.

—Kenneth J. Levin, MD
—Paul A. Kvale, MD, FCCP
—Benjamin Movsas, MD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Jemal A, Siegal R, Ward E: Cancer statistics, 2006. CA Cancer J Clin 56:106-130, 2006.

2. Chen LC, Travis W, Krug L: Pulmonary neuroendocrine tumors: what (little) do we know? J Natl Compr Canc Netw 4:623-629, 2006.

3. Sutedja TG, Schreurs AJ, Vanderschueren RG, et al: Bronchoscopic therapy in patients with intraluminal typical bronchial carcinoid tumor. Chest 107:556-558, 1995.

4. Luckratz H, Amer K, Thomas, L: Long-term outcome of bronchoscopically resected endobronchial typical carcinoid tumors. J Thorac Cardiovacs Surg 132(1): 113-115, 2006.

5. Kaminski J, Langer C, Movsas B: The role of radiation therapy and chemotherapy in the management of airway tumors other than small-cell carcinoma and non-small cell carcinoma. Chest Surg Clin N Am 13:146-167, 2003.

6. Chakravarthy A, Abrams RA: Radiation therapy in the management of patients with malignant carcinoid tumors. Cancer 75:1386-1390, 1995.

7. Forrer F, Waldherr C, Maecke HR, et al: Targeted radionuclide therapy with 90Y-DOTATOC in patients with neuroendocrine tumors. Anticancer Res 26(1B):703-707, 2006.

8. Dejong M, Valkema R, Jamar F, et al: Somatostatin receptor targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med 32:133-140, 2002.