PORTable Indications in Non–Small-Cell Lung Carcinoma

This article is a review of Postoperative Radiation Therapy for Lung Cancer: Where Do We Stand?

Drs. Kelsey, Marks, and Wilson open their excellent review article by asking "Where do we stand?" with respect to postoperative radiation therapy (PORT) for non–small-cell lung cancer (NSCLC).[1] Frankly, PORT has not exactly been standing tall for the past decade-leaning, crouching, or perhaps squatting might be a better verb. Its use has dropped considerably in the past 10 years,[2] since the publication of the well-known meta-analysis in 1998.[3] Has the response to the PORT meta-analysis been exaggerated, and should PORT be reevaluated in 2008?

Treatment Rationale

The rationale for using PORT to treat NSCLC is the same as that for radiotherapy in any other malignancy. It involves three hypotheses: (1) Patients at relatively high risk for local/regional recurrence can be identified; (2) radiotherapy is effective at improving local/regional control; and (3) the benefit in local/regional control outweighs the toxicity of radiotherapy, leading to improved major clinical outcomes. Since quality of life continues to be notoriously difficult to measure, the major clinical outcome of interest is quantity of life (survival).

The first and second hypotheses are supported in the setting of NSCLC. This is nicely shown in Table 6 of the article by Kelsey et al; nine studies are listed and every one showed at least a trend toward improved local/regional control with PORT. (How often does one see such a consistently beneficial distant control benefit with chemotherapy?) Clearly, radiotherapy is effective; NSCLC should not be considered radioresistant. The third hypothesis, however, is very much unproven. This differs from the situation for several other cancers, where radiotherapy-related improvements in local/regional control lead to improved survival.[4-6]

Toxicity and Comorbidity

As Kelsey et al note, the failure of PORT to improve survival may be due to the toxicity and comorbidity challenges faced by lung cancer patients. PORT universally causes fatigue and esophagitis, which can cause cardiopulmonary complications. Furthermore, in some patients thoracic radiotherapy leads to direct and serious radiation injury to the lung(s) and/or heart. Chemical or biologic radioprotectors have not been of demonstrated value. Physical radioprotection, using complex three-dimensional conformal (3D-CRT), intensity-modulated (IMRT), and/or proton-beam radiotherapy improves radiation dosimetric parameters to critical thoracic organs[7] and may decrease certain complications.[8]

The magnitude of the detrimental effects of radiotherapy seen in the Lancet meta-analysis probably reflects suboptimal techniques, as has been discussed elsewhere.[9] However, the belief that modern radiotherapy is much safer than older techniques has not been proven by a randomized trial. Even "perfect" radiotherapy still has some toxicity. For patients at modest risk for local/regional failure (ie, all stage I and most stage II NSCLC patients), this toxicity probably still outweighs the benefits.

Clinical Research Questions

Since properly administered modern PORT is expensive and not risk-free, more insight into identifying patients at high risk for local/regional failure is needed. Perhaps future advances in surgery, pathology, and molecular biology can detect biomarkers for local/regional recurrence, allowing patients to be rationally selected for PORT, just like the ongoing research focus into the individualization of systemic therapies. Detailed patterns-of-failure results from several important studies conducted by the American College of Surgeons Oncology Group (ACOSOG) are anxiously awaited, including the Z0030 (mediastinal nodal dissection vs sampling) and Z0040 (significance of nodal micrometastases in resected NSCLC) trials. These and other new data should help to guide the next generation of clinical trials in local/regional therapy for NSCLC.

The major clinical research question for PORT, though, is the following: Should a new large randomized trial of PORT vs no PORT for resected N2/IIIA disease be developed and activated in North America? A French trial was activated last year.[10] A prior attempt in the United States failed to accrue sufficiently-only 44 patients were enrolled over 2 years.[11] A definitive study would require a large number of patients, perhaps more than 750, to detect a small but clinically meaningful survival improvement. This raises feasibility concerns.

Resected pN2 NSCLC is probably less common than previously, due to improvements in preoperative noninvasive[12] and invasive[13] staging with subsequent triage of patients toward preoperative[14] and/or nonsurgical[15] therapies. Furthermore, reports show a pitifully low rate (< 1%) of all lung cancer patients enrolling onto a clinical trial.[16] Even if this number were to be considerably higher for N2 patients, it would probably require about 10 years of accrual time plus several years of follow-up and analysis to receive a valuable answer to the N2 PORT question. Is society willing to accept this long waiting period, with the risk that the answer might not be completely relevant in 2020? If the answer is yes, then this phase III study is needed-perhaps while allowing patients to concomitantly enroll in separate systemic drug trials.

Patient Selection Criteria

Despite the challenges associated with researching PORT for N2 NSCLC, this is not a rare disease, particularly if patients treated with induction chemotherapy are included. Thus, oncologists will continue to be faced with difficult management decisions for these patients in the absence of quality randomized data. Who should receive PORT after surgery and chemotherapy outside of a clinical trial? There is no consensus; these are the criteria we use at our University practice:

(1) N2 disease (or selected suboptimally resected, potentially understaged N1 disease).

(2) No evidence of distant metastases on restaging positron-emission tomography after adjuvant chemotherapy.

(3) Good performance status (Zubrod PS 0/1).

(4) Good cardiopulmonary reserve and pre-PORT organ function testing as defined in prospective trials.[17]

(5) Treatment with 3D-CRT and careful attention to dose-volume histogram parameters (V10, V20, mean lung dose, etc), and a target dose ≤ 54 Gy.[18]

(6) Patient ability/willingness to comply with careful intratreatment and posttreatment medical care and visits-both with radiation and medical oncologists and with internists (pulmonology, cardiology, etc).

PORT for NSCLC will remain a controversial topic in thoracic oncology for years to come. Despite its decreased use in 2008, it should not be relegated to the Onco-Museum of Historical Interest. Until surgery/chemotherapy can achieve convincingly and reliably high local/regional control rates for NSCLC, PORT should continue to be studied and, yes, even offered to selected patients.

-Mitchell Machtay, MD
 

References:

References
1 . Kelsey CR, Marks LB, Wilson LD: Postoperative radiation therapy for lung cancer: Where do we stand? Oncology (Williston Park) 22:301-310, 2008.
2. Bekelman JE, Rosenzweig KE, Bach PB, et al: Trends in the use of postoperative radiotherapy for resected non-small cell lung cancer. Int J Radiat Oncol Biol Phys 66:492-499, 2006.
3. PORT Meta-analysists Trialists Group: Postoperative radiotherapy in non-small cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 352:257-263, 1998.
4. Clarke M, Collins R, Darby S, et al, for the Early Breast Cancer Trialists’ Collaborative Group: Effects of radiotherapy and differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomized trials. Lancet 266:2087-2106, 2005.
5. Wong RK, Tandan V, DeSilva S, et al: Pre-operative radiotherapy and curative surgery for the management of localized rectal cancer. Chochrane Database Syst Rev (2):CD002102, 2007.
6. Bourhis J, Overgaard J, Audry H, et al: Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet 368:843-854, 2006.
7. Chapet O, Khodri M, Jalade P, et al: Potential benefits of using non coplanar field and intensity-modulated radiation therapy to preserve the heart in irradiation of lung tumors in the middle and lower lobes. Radiother Oncol 80:333-340, 2006.
8. Yom SS, Liao Z, Liu HH, et al: Initial evaluation of treatment-related pneumonitis in advanced stage NSCLC treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 68:94-102, 2007.
9. Machtay M, Kaiser LR, Glatstein E: Reality and meta-analyses. Chest 118:835-836, 2000.
10. Federation Nationale des Centres de Lutte Contre le Cancer: Radiation therapy in treating patients with non-small cell lung cancer that has been completely removed by surgery. Trial summary available at http://clnicaltrials.gov (identifier NCT00410683). Accessed February 26, 2008.
11. Perry MC, Kohman LJ, Bonner JA, et al: A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734. Clin Lung Cancer 2007 Jan; 8(4):268-72.
12. Silvestri GA, Gould MK, Margolis ML, et al: for the American College of Chest Physicians. Noninvasive staging of non-small cell lung carcinoma: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 132(3 suppl):178S-201S, 2007.
13. Detterbeck FC, Jantz MA, Wallace M, et al, for the American College of Chest Physicians: Invasive staging of non-small cell lung carcinoma: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 132(3 suppl):202S-220S, 2007.
14. Burdett S, Stewart LA, Rydzewska L: A systematic review and meta-analysis of the literature: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 1:611-621, 2006.
15. Van Meerbeck JP, Kramer GW, VanSchil PE, et al: for the EORTC. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer. J Natl Cancer Inst 99:442-450, 2007.
16. Murthy VH, Krumholz HM, Gross CP: Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 291:2720-2726, 2004.
17. Bradley JD, Paulus R, Graham MV, et al: Phase II trial of postoperative adjvuant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA NSCLC-promising long-term results of the Radiation Therapy Oncology Group-RTOG 97-05. J Clin Oncol 23:3480-3487, 2005.
18. Machtay M, Lee JH, Shrager JB,
et al: Risk of death from intercurrent disease is not excessively increased by modern
postoperative radiotherapy for high-risk resected NSCLC. J Clin Oncol 19:3912-3917, 2001.