Download Role of Adjuvant Therapy in Resected Stage II/IIIA Non-Small

Role of Adjuvant Therapy in Resected Stage II/IIIA Non-Small-Cell Lung Cancer
Published on Physicians Practice (http://www.physicianspractice.com)
Role of Adjuvant Therapy in Resected Stage II/IIIA
Non-Small-Cell Lung Cancer
Review Article [1] | January 01, 2002
By David W. Johnstone, MD [2]
Advances in the treatment of lung cancer have been precious and few over the past 40 years, as
reflected in the minimal rise in overall survival from this disease since 1960. Significant progress has
occurred in staging accuracy, surgical morbidity, radiation delivery, and new chemotherapeutics.
And yet, patients with stage II disease have a 5-year survival rate of 50% or less, while patients with
stage III disease fare poorly overall.
dvances in the treatment of lung cancer have been precious and few over the past 40 years, as
reflected in the minimal rise in overall survival from this disease since 1960. Significant progress has
occurred in staging accuracy, surgical morbidity, radiation delivery, and new chemotherapeutics.
And yet, patients with stage II disease have a 5-year survival rate of 50% or less, while patients with
stage III disease fare poorly overall.
Technologic advances have greatly reduced risk in the surgical resection of lung cancer. Improved
staging and knowledge of surgical outcomes in locally advanced disease have helped to reduce
unnecessary surgery and have led to the integration of surgical resection into multimodality
frameworks. We can operate on sicker patients, and intraoperative decisions are now based on
better knowledge of the disease process. But the actual mechanics and extent of lung cancer
resection today have not significantly changed since the 1960s.
Negative or Equivalent Trials Predominate
As we look back on the first century of mass nicotine addiction and its lethal offspring, our
knowledge of the role of adjuvant therapy in resected stage II/IIIA non-small-cell lung cancer (NSCLC)
is dominated by trials with negative or equivalent results. Dr. Movsas has elegantly summarized the
important studies in this area, which constitute a tremendous effort on the part of surgical, radiation,
and medical oncologists to improve the outlook for patients with lung cancer.
The only major positive finding at this point is that postoperative radiation therapy reduces local
recurrence in resected stage III NSCLC. Dr. Movsas’ critique of the postoperative radiotherapy (PORT)
meta-analysis is important because, taken at face value, the results of that study can be misleading;
upon closer scrutiny, however, they do not contradict current conventional wisdom. Postoperative
radiation in stage I/II lung cancer is without proven benefit and may be harmful, but prevention of
local recurrence, which is most often seen in resected stage III patients, results in improved quality
of life in many cases.
Survival Benefits of Mediastinal Lymphadenectomy?
The idea that "cleaning out" the mediastinal lymphatics confers a survival advantage is not entirely
without merit. It is worth noting that the control arm of Intergroup trial 0115/Eastern Cooperative
Oncology Group trial 3590 (testing radiation alone) had a median survival of 39 months (61 months
for stage II and 33 months for stage IIIA) and a 5-year survival of about 40%. These data represent
an improvement on historical results in this cohort of patients.[1] This is likely due to selection bias
from accurate surgical staging rather than better surgery or radiation, but without a randomized trial
using surgery alone as the control, the question of a survival benefit remains open.
Even more suggestive is the subgroup analysis from this trial, in which survival among patients with
right-sided resections was improved in those having mediastinal lymphadenectomy, compared with
those undergoing lymph node sampling alone.[2] This benefit was not found with left-sided
resections. One explanation is that the at-risk mediastinal lymphatics are readily resected from the
right, whereas paratracheal lymph nodes are not generally accessible during resection of left-sided
tumors, and are thus left untouched. Another possibility is that unidentified biases account for the
perceived advantage, since the trial was stratified, not randomized, for the extent of mediastinal
lymphadenectomy.
Is it possible that aggressive local eradication of occult mediastinal metastases—whether by resection
A
Page 1 of 2
Role of Adjuvant Therapy in Resected Stage II/IIIA Non-Small-Cell Lung Cancer
Published on Physicians Practice (http://www.physicianspractice.com)
and/or radiation—confers a survival benefit? A small randomized trial has not shown this.[3] We hope
that the American College of Surgeons Oncology Group trial Z0030 will provide a conclusive answer
to this question. If a survival advantage is seen, the benefits of adjuvant radiation therapy may need
to be reexamined.
Newer Chemotherapy Shows Disappointing Results
This issue aside, the equivalent results of Intergroup 0115 were a disappointment, illustrating the
strides still to be made in eradicating systemic metastases. It is unlikely that "old" chemotherapy
was the culprit. Radiation Treatment Oncology Group (RTOG) 9705, a phase II trial of treatment
identical to that in the chemoradiation arm of Intergroup 0115, except that carboplatin
(Paraplatin)/paclitaxel (Taxol) was substituted, yielded a median survival of 38 months—nearly
identical to its predecessor arm in the Intergroup trial.[4] While feasible and perhaps less toxic,
newer chemotherapy has demonstrated no survival advantage in the adjuvant setting.
In the neoadjuvant realm, RTOG 9309 remains a pivotal trial for treatment of stage IIIA disease.
Accrual to this trial is expected to be complete by mid-2002. If this trial does not demonstrate
improved survival with neoadjuvant therapy, "old" chemotherapy will probably not be the culprit.
Local control is often achieved. These patients usually succumb to distant metastatic disease. For
this we have, despite newer chemotherapy, little hope of cure.
The Challenge Before Us
As Dr. Movsas states, the challenge before us is to identify subpopulations at risk of recurrence,
using new genetic, molecular, and immunologic profiles, and then develop targeted group-specific
treatments. The role of angiogenesis modulation, antibody-mediated tumor ablation, and other
developing modalities are currently undefined and must be the focus of future trials. Human genome
research holds great promise in this regard.
We who treat and study patients with lung cancer must never forget its origin. Lung cancer is a
preventable consequence of tobacco abuse. While future therapeutics may achieve a reliable cure,
the cost in suffering, lives, and money can most predictably be curbed by reducing the number of
human beings addicted to nicotine. Prevention and cure are tandem goals, not alternatives.
References:
1. Keller S, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients
with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 343:1217-1222,
2000.
2. Keller SM, Adak S, Wagner H, et al: Eastern Cooperative Oncology Group. Mediastinal lymph node
dissection improves survival in patients with stages II and IIIa non-small-cell lung cancer. Ann Thorac
Surg 70:358-366, 2000.
3. Izbicki JR, Thetter O, Habekost, et al: Radical systematic mediastinal lymphadenectomy in
non-small-cell lung cancer: A randomized control trial. Br J Surg 81:229-235, 1994.
4. Graham M, Paulus R, Wasserman T, et al: Preliminary results of a Radiation Therapy Oncology
Group (RTOG) trial 97-05, a phase II study of postoperative adjuvant therapy in patients with
completely resected stage II and stage IIIA non-small-cell lung cancer. Presented at the International
Association for the Society of Lung Cancer (IASLC). 9th World Conference on Lung Cancer, Tokyo,
2000.
Source URL:
http://www.physicianspractice.com/review-article/role-adjuvant-therapy-resected-stage-iiiiia-non-sma
ll-cell-lung-cancer
Links:
[1] http://www.physicianspractice.com/review-article
[2] http://www.physicianspractice.com/authors/david-w-johnstone-md
Page 2 of 2