1.
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What is the current
standard treatment for clinical N2 and N3 disease?
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| It has been well-documented that the patients with preoperatively
identified N2 and N3 disease that has been confirmed histologically by nodal biopsy
(mediastinoscopy, thoracoscopy, scalene node biopsy) fare extremely poorly with a primary
surgical approach. Adjuvant chemotherapy and/or radiotherapy has had little impact. Until
very recently, the accepted standard of treatment for patients with this stage of disease
has been primary radiotherapy with only 5 to 10% of patients surviving long-term. More
recently, trials of chemoradiotherapy as primary treatment (usually including induction
chemotherapy followed by chemoradiation) has demonstrated an overall improved median
survival and long-term survival benefit compared to radiotherapy alone. For patients
with N2 disease, over the past 20 years, preoperative chemotherapy or chemoradiotherapy
combined with surgery have also demonstrated improved median survival and long-term
survival. Three randomized trials comparing induction chemotherapy plus surgery to surgery
alone in stage IIIa disease has confirmed this improvement although all three trials are
small and have their innate flaws. It appears that both the surgical and non-surgical
approaches for treatment of this stage of disease yield similar results with 15-20% of
patients surviving long-term. There has never been a comparison of the two forms of
treatment in a randomized trial; however, a trial is presently being carried out by the
North American Intergroup and involves virtually all Cooperative Groups in the United
States. This trial compares induction chemoradiotherapy plus surgery to primary
chemoradiotherapy without any surgical treatment for patients with documented N2 disease.
Physicians treating patients with this stage of disease are encouraged to enter patients
in this trial, which will compare not only survival but quality of life and
cost-effectiveness. |
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2.
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What are the current drug
and radiation regimens used for induction therapy?
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| Virtually all induction chemotherapy and chemoradiotherapy protocols
include cisplatinum as one of two or three drugs that are used in combination. Other drugs
used include vinca alkaloids (vinblastine or vinorelbine), mitomycin, etoposide and
ifosfamide in either two and three-drug combinations. More recently, phase II trials have
reported the use of carboplatinum and taxol as induction therapy agents. All combinations
have toxicity, the commonest ones other than leukopenia include neurologic, renal, and
pulmonary toxicities. The latter toxicity is best identified by pre- and post- treatment
diffusion capacity estimates. Radiotherapy regimens usually limit the preoperative
treatment to 4500 ccGy or less to avoid excessive postoperative complications (especially
bronchus) related to wound healing. |
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3.
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How should patients be
staged prior to induction therapy regimens?
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| Radiologically-identified N2 disease must be confirmed histologically
prior to treatment planning, usually by mediastinoscopy. It is important to distinguish
between N2 and N3 disease (contralateral mediastinal and/or supraclavicular nodal
involvement) that requires contralateral mediastinal biopsies at the time of
mediastinoscopy. In most protocols, full organ scanning to exclude M1 disease is required.
PET scanning, not available everywhere, has the potential to replace both invasive and
non-invasive procedures to identify nodal and distant metastases. |
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4.
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How is clinical response to
the induction therapy assessed?
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| Although serial chest x-rays will demonstrate most responses to
induction treatment by obvious shrinkage of the primary tumor, it is fairly standard to
perform pre-treatment and post-treatment CT scans, the latter usually at least two to
three weeks following completion of the induction program. A partial clinical response
(PR) is defined as a reduction in size of the primary tumor by 50% in two measured
diameters. Anything less than that is often termed " minimal response." A
complete clinical response (CR) demonstrates total ablation of the tumor by all imaging
techniques. In most induction regimens, 40 to 70% of patients will have a PR or CR as
assessed by imaging studies. |
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5.
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Is surgery worthwhile in N3
disease?
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| Although some oncology groups have also employed induction therapy
followed by surgery for N3 disease, only a single phase II trial has ever been reported
(by the SWOG Cooperative Group). As reported by this group, in those patients with N3
disease, especially those with contralateral mediastinal involvement suggesting very bulky
disease, the results were not gratifying and very few patients survived disease-free. In
this trial, surgeons did not necessarily attempt to remove all of the nodal disease at the
time of surgery, but depended on the preoperative chemoradiation as ablative nodal
therapy. On the other hand, surgeons in Japan have advocated extensive mediastinal lymph
node dissection including supraclavicular lymph nodes to totally ablate all tumor. There
have been no long-term reports of this very aggressive surgical treatment. |
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6.
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Is surgical morbidity and
mortality increased by these combined modality techniques?
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| The reported results in most series suggest that, with experience, the
morbidity and mortality of the surgery following induction therapy is not excessive. In
most series, the overall surgical mortality is 5 to 7% and the combined therapy mortality
ranges from 5 to10%. The common major surgical complications that occur include:
postpneumonectomy bronchopleural fistulae and ARDS (especially following right
pneumonectomy). Attempts have been made to lessen t his morbidity with the use of high
dose perioperative steroids (ARDS) and buttressing all bronchial stumps with vascularized
tissue. |
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7.
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What should be the extent
of surgery following induction therapy for N2 disease?
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| In most instances, the plan should include removal of all tumor as
identified by staging procedures prior to the induction therapy. This would include either
a lobectomy or pneumonectomy and a complete mediastinal lymph node dissection. In order to
improve results, surgeons in Japan have included the above-mentioned two-field
lymphadenectomy, also removing bilateral supraclavicular lymph nodes in an attempt to
remove totally all possible tumor. The morbidity of this latter procedure includes a high
incidence of recurrent nerve palsy. |
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8.
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What are the results of
combined modality therapy?
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| In those patients that have been "down-staged" by the
induction therapy to less than N2 disease, the overall 5-year survival appears markedly
improved and approaches 40 to 50%. In the only series reporting 5-year survival results,
surgeons at Memorial Sloan-Kettering Cancer Center have demonstrated an overall survival
in this stage of disease (clinical N2) of 17%. Those patients with T3 N2 disease,
persisting N2 disease after induction therapy, or those with incomplete resections fare
the poorest. |
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9.
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What are the guidelines for
additional postoperative treatment?
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| Most treatment protocols have included postoperative chemotherapy for
two or three cycles with or without radiotherapy although the advantage of this
postoperative treatment (versus no further treatment) have never been proven. In the
above-mentioned Memorial series, postoperative radiotherapy did not improve survival in
those patients with persisting N2 disease although all patients did receive postoperative
chemotherapy. |
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10.
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What is the future of
induction therapy protocols?
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| With these encouraging results in stage IIIa disease, oncology groups
are now investigating the use of this induction therapy in stage II (N1) and T2 N0 (stage
"IB") tumors. Standard surgical therapy yields less than a 50% 5-year survival
in this group of patients. It is hoped that the addition of induction therapy might
improve these results. All postoperative adjuvant treatments have, as yet, produced very
little positive impact in the management of these patients. As well, with the encouraging
results of induction chemoradiotherapy for T4 disease groups are now investigating this
mode of therapy in T3 and T4 tumors (for example, superior sulcus tumors). |
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11.
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Can you suggest further
reading on the subject?
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Non-small cell lung cancer. In Pearson, Deslauriers, Ginsberg et al. (Eds) Thoracic
Surgery pp. 707-782, New York. Churchill Livingstone, 1995.
- Ginsberg RJ, Vokes E and Raben A: Non-Small Cell Lung Cancer. Lung Cancer. In DeVita VT,
Hellman S and Rosenberg SA (eds). Cancer: Principles and Practice of Oncology. Fifth
Edition. 1997, pp 858-911.
- Non-Small Cell Collaborative Group- Chemotherapy in non-small cell lung cancer: A
meta-analysis using updated dataon individual patients from 52 randomized clinical trials
Br Med J 1995,311:899
- Roth JA, Fossella F, Komaki R. A randomized trial comparing perioperative chemotherapy
and surgery with surgery alone in resectable stage IIIa non-small cell lung cancer. J Natl
Cancer Inst l994;86:673-680.
- Rosell R, Gomez-Codina J, Camps C, et al. A Randomized trial comparing preoperative
chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer.
N Engl J Med l994 ;330:l53-58.
- Pass HI, Pogrebniak HW, Steinberg SM, et al. Randomized trial of neoadjuvant therapy for
lung cancer: interim analysis. Ann Thorac Surg 1992;53:992-998
- Dillman R, Seagren S, Proprert K et al: A randomized trial of induction chemotherapy
plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N
Engl J Med 940, 1990
- Martini N, Kris MG, Flehinger BJ et al: Preoperative chemotherapy for stage IIIa (N2)
lung cancer: The Sloan-Kettering experience with l36 patients. Ann Thorac Surg
l993;55:l365-l374.
- Rusch VW, Albain KS, Crowley JJ, et al: Surgical resection of stage IIIA and stage IIIB
non-small cell lung cancer after concurrent induction chemoradiotherapy: A Southwest
Oncology Group Trial. J Thorac Cardiovasc Surg l993;l05:97-l06.
- VanRaemdonck DE, Schneider A and Ginsberg RJ: Surgical Treatment for Higher Stage
Non-small Cell Lung Cancer- "A Collective Review". Ann Thorac Surg 199
2;54:999-l0l3.
- Ginsberg RJand Rubinstein L: The Lung Cancer Study Group: Final Analysis. The Comparison
of Limited Resection to Lobectomy for T1 N0 Non-small Cell Lung Cancer. LCSG 821. Chest
(suppl) 1994; 106:318S-319S.
- Takita H: Perioperative Therapy for locoregional non-small cell lung cancer. J Surg Onc
1996;62:65-74.
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