TOC |
HEME-ONCO
Lung Cancer
WHO Classification of Lung Tumors
I. Benign
II. Dysplasia and carcinoma in situ
III. Malignant
a. Squamous cell (epidermoid carcinoma) and spindle cell carcinoma
b. Small cell carcinoma
c. Adenocarcinoma: Acinar, Papillary, Bronchoalveolar, Mucus-secreting
d. Large cell carcinoma: Giant cell, Clear cell
e. Adenosquamous carcinoma
f. Carcinoid tumor
g. Bronchial gland carcinoma: Adenoid cystic carcinoma, Mucoepidermoid
carcinoma
h. Others
*Adapted from Kreyberg L, for The World Health Organization: The World Health Organization histological typing of lung tumors. Am J Clin Pathol 77:123, 1982
SYMPTOMS AND SIGNS ASSOCIATED WITH LUNG CANCER AT PRESENTATION
Local-regional
Systemic: Weight loss, Fatigue, Cachexia
Organ-specific : Bone pain, Headache, Neurologic findings, Hepatic and/or abdominal pain.
DIAGNOSIS AND STAGING
Once the diagnosis of lung cancer is made, the disease should be accurately
staged.
In the United States, most patients undergo CT scanning of the chest and
upper abdomen, including the liver and adrenal gland. CT scans of
the head and bone scans should be done if the history and findings on
physical examination and biochemical tests suggest metastatic involvement.
STAGING OF LUNG CANCER
| 1987 TNM STAGING | 1997 TNM STAGING |
| Stage I T1N0M0 T2N0M0
Stage II T1N1M0
Stage IIIB Any TN3M0 Stage IV Any T Any NM1 |
Stage Ia T1 Stage Ib T2N0M0 N0M0
Stage IIa T1N1M0
Stage IIIa T1-3N2M0
Stage IIIb T4 * Any NM0 Stage IV Any T Any NM1 |
*T4, includes ipsilobar satellite nodules.
M1, includes extralobar satellite nodules.
TNM STAGING SYSTEM FOR LUNG CANCER STAGE FEATURES
Tx -Tumor proved by the presence of malignant cells in bronchopulmonary secretions but not visible roentgenographically or bronchoscopically, or any tumor that cannot be assessed, as in a re-treatment staging
T0 -No evidence of primary tumor
T1S - Carcinoma in situ
T1 - A tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy
T2 - A tumor more than 3 cm in greatest dimension, or a tumor of any size that either invades the visceral pleura or has associated atelectasis or obstructive pneumonitis extending to the hilar region; at bronchoscopy, the proximal extent of demonstrable tumor must be within a lobar bronchus or at least 2 cm distal to the carina; any associated atelectasis or obstructive pneumonitis must involve less than an entire lung
T3 -A tumor of any size with direct extension into the chest wall (including sulcus tumors), diaphragm, or the mediastinal pleura of pericardium without involving the heart, great vessels, trachea, esophagus, or vertebral body, or a tumor in the main bronchus within 2 cm of the carina without involving the carina
T4 - A tumor of any size with invasion of the mediastinum or involving the heart, great vessels, trachea, esophagus, vertebral body, or carina or the presence of malignant pleural effusion
N0 - No demonstrable metastasis to regional lymph nodes
N1 - Metastasis to lymph nodes in the peribronchial or ipsilateral hilar region, or both, including direct extension
N2 - Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes
N3 - Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, ipsilateral or contralateral scalene or supraclavicular lymph nodes
M0 - No (known) distant metastasis
M1 - Distant metastasis present specify sites
NON-SMALL CELL LUNG CANCER (as: Squamous Cell Carcinoma, AdenoCarcinoma, etc.)
INCIDENCE
Approximately 80 percent of 170, 000 new cases a year of lung cancer in North
America are non-small cell lung cancer
Most frequent types: adenocarcinoma, squamous cell carcinoma, and large cell
anaplastic
DIFFERENTIAL DIAGNOSIS
Small cell carcinoma of the lung (therapy and prognosis quite different),
metastatic cancer in the lung, or infection
STAGING EVALUATION
History and physical examination, hemogram, standard biochemistry, imaging
of chest, including mediastinum and upper abdomen (liver and adrenals) and
other sites only if indicated; if patient clearly unresectable, then bone
scan and computed tomography (CT) or magnetic resonance imaging (MRI) of
brain
Mediastinoscopy in most potentially resectable patients
Proper sampling of mediastinal nodes at thoracotomy absolutely necessary
Positron emission tomography (PET) scanning may be very useful when it is
more generally available
Treatment of Non-Small Cell Lung Cancer
PRIMARY THERAPY of NSCLC
1. Surgery: For stages I, II and IIIA (some patients); may be
curative
2. Radiation therapy, plus or minus chemotherapy: unresectable
patients with good performance status, or potentially resectable patients
with a medical contraindication or who refuse surgery.
3. Neoadjuvant chemotherapy followed by surgery: under investigation
for stage IIIA disease
Combination chemotherapy of NSCLC
EFFECTIVE SECOND- OR THIRD-LINE THERAPIES of NSCLC
Chemotherapy plus or minus radiation therapy for stages I and II or IIIA patients who relapse after surgery; in patients who have received neoadjuvant chemotherapy or chemotherapy as primary treatment, second-line chemotherapy not indicated except on a clinical trial; radiation therapy possibly useful for palliation of local symptoms
Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of at least
3 distinct histologies of lung cancer including epidermoid or squamous
carcinoma, adenocarcinoma, and large cell carcinoma.
These histologies are often classified together because, when localized,
all have the potential for cure with surgical resection.
Systemic chemotherapy can produce objective partial responses and palliation
of symptoms for short durations in patients with advanced disease.
Local control can be achieved with radiation in a large number of patients
with unresectable disease, but cure is seen only in a small minority
of patients.
At diagnosis, patients with NSCLC can be divided into 3 groups that reflect the extent of disease and treatment approach.
The first group of patients has tumors that are surgically resectable (generally stages I and II). This is the group with the best prognosis, depending on a variety of tumor and host factors. Patients with resectable disease who have medical contraindications to surgery can be considered for curative radiation therapy.
The second group includes patients with either locally (T3-T4) or regionally (N2-N3) advanced lung cancer who have a diverse natural history. This group is treated with radiation therapy or, more commonly, with radiation therapy in combination with chemotherapy or other therapy modalities. Selected patients with T3 or N2 disease can be treated effectively with surgical resection alone.
The final group of patients have distant metastases (M1) found at the time of diagnosis. This group can be treated with radiation therapy or chemotherapy for palliation of symptoms from the primary tumor. Patients with good performance status, women, and patients with distant metastases confined to a single site appear to live longer than others.1 Cisplatin-based chemotherapy has been associated with short-term palliation of symptoms and a small survival advantage. Currently no single chemotherapy regimen can be recommended for routine use.
For operable patients, prognosis is adversely influenced by the presence of pulmonary symptoms, large tumor size (>3 centimeters), and presence of the erbB-2 oncoprotein. Other factors that have been identified as adverse prognostic factors in some series of patients with resectable non-small cell lung cancer include mutation of the K-ras gene, vascular invasion, and increased numbers of blood vessels in the tumor specimen.
Since treatment is not satisfactory for almost all patients with NSCLC, with the possible exception of a subset of pathologic stage I (T1, N0, M0) patients treated surgically, eligible patients should be considered for clinical trials.
Stage I / II Lung Cancer
Early-stage lung cancer is potentially curable by surgery, and every effort should be made to make affected patients eligible for the operation. Patients who have potentially resectable disease but are found to have isolated adrenal or liver metastasis on staging studies should have biopsy of these lesions to confirm metastatic disease. Patients with poor performance status or impaired pulmonary function who initially appear to be poor candidates for surgery may improve with intensive physical and pulmonary therapy. The operation of choice is a lobectomy or pneumonectomy.
The 5-year survival rate for resected stage I patients is 57 to 67% and for stage II patients is 39 to 55%. Numerous studies reported in the literature have shown that chemotherapy or radiation therapy after surgical resection confers no benefit in overall survival. A recent randomized study from Japan utilizing UFT (uracil * and ftorafur * ), an oral form of 5-fluorouracil, showed improvement in overall survival after surgical resection.
Stage III NSCLC
Stage III disease can be divided into stage IIIA, which is potentially resectable, and stage IIIB, which is categorically unresectable. Patients who have stage III disease historically have had a poor prognosis, but, with the advent of combined-modality therapy, the outlook appears to have improved for selected groups of patients.
Stage IIIA patients who have clinically evident N2 mediastinal nodal involvement treated with surgery alone have a 5-year survival rate of less than 10%, and many clinicians would consider these patients ineligible for surgery. Patients with T3N0 disease previously classified as stage IIIA have been reclassified as stage IIA in the revised staging system, owing to a relatively favorable 5-year survival rate of 33% reported with surgery alone .
Pancoast tumors are superior sulcus tumors in the apex of the lung that are associated with pain in the ipsilateral arm or shoulder, atrophy of the intrinsic muscles of the hand, and Horner's syndrome. This entity is most often due to NSCLC, although a few cases of SCLC have also been reported to present in this fashion. In the early stages of Pancoast tumors, symptoms such as cough, hemoptysis, and shortness of breath are not seen, and the tumor may not be evident on the chest film. For this reason the clinician should have a high index of suspicion for Pancoast tumor in a smoker who has pain in the arm or shoulder that is not otherwise explained. Pancoast tumors can be stage IIIA or stage IIIB, depending on the extent of local invasion. For patients with stage IIIA disease, the traditional treatment has been with preoperative radiation therapy followed by surgical resection, with 5-year survival rates of 40 to 50% in those who have complete resection of tumor. Current treatment strategies combine chemotherapy and radiation therapy in the preoperative setting for patients with superior sulcus tumors.
The traditional treatment for stage III patients who are not surgical candidates has been radiotherapy (RT). The impact of RT alone in unresectable locally advanced NSCLC, however, has been minimal, and the use of this modality does not appear to prolong survival. This finding has led investigators to explore new modalities and to combine chemotherapy, aimed at controlling systemic disease, with radiation therapy or surgery for control of local disease. These studies of combined-modality therapy in stage III disease have yielded encouraging results, and these regimens are increasingly being used in community oncology practices.
In stage IIIA disease, systemic failure is common in patients who undergo surgery as the only modality of therapy. For stage IIIA patients with potentially resectable disease, induction or neoadjuvant therapy consisting of chemotherapy, RT, or both chemotherapy and RT has been used in an effort to "down stage" primary tumors and to increase the resectability rate. Early administration of chemotherapy may also eradicate systemic micrometastasis and hence improve overall survival. This concept was tested in phase II trials, with response to induction therapy seen in approximately 50 to 70% of patients, resectability rates of about 60 to 80%, and 2- to 3-year survival rates in the range of 30%. The therapy was well tolerated, and induction therapy did not appear to increase surgical complications.
Two recent randomized studies have evoked enthusiasm among the oncology community for use of a multidisciplinary approach to the management of lung cancer. The first study, published by the M. D. Anderson Cancer Center, randomized 60 patients with stage IIIA disease to surgery alone or to preoperative chemotherapy followed by surgery. The estimated median survival in the patients who underwent preoperative chemotherapy was 64 months compared with 11 months in the surgery-only group. In the second study, reported from Spain, 60 patients were randomized either to chemotherapy followed by surgery or to surgery alone. All patients received postoperative RT to the mediastinum. The median survival was 24 months in the group of patients who underwent preoperative chemotherapy compared with 8 months in the surgery-only group. The results in both studies were highly significant and led to early termination at interim analysis before completing planned accrual. Based on these two studies, it appears that chemotherapy given before surgical resection in patients with stage IIIA N2 disease improves overall survival and should be offered to patients with good performance status outside of a clinical trial. Further research is needed to improve these results. New agents with activity in lung cancer, such as the taxanes, gemcitabine, and vinorelbine, need to be incorporated into induction regimens and tested in randomized studies.
In stage IIIB disease, which is categorically unresectable, combined-modality therapy with chemotherapy and RT appears to be of benefit in selected patients. Most of the large randomized studies with concurrent or sequential chemoradiation therapy in inoperable NSCLC have shown a small survival benefit, although at the cost of increased toxicity. A meta-analysis of 52 randomized trials of RT with or without cisplatin-based chemotherapy revealed that the risk of death was reduced by 13% with the addition of chemotherapy. The absolute survival advantage at 2 years was modest (4%). Paclitaxel, a newer agent derived from the bark of the Pacific yew tree Taxus brevifolia, has radiosensitizing properties. Preliminary studies with paclitaxel and RT in locally advanced NSCLC have shown encouraging activity with tolerable side effects, and these results need to be confirmed in large studies, which have been instituted.
Stage IV NSCLC
Stage IV NSCLC has a particularly poor prognosis and is incurable with currently available therapy. In the past, nihilistic attitudes prevailed among oncologists, with most electing not to offer chemotherapy to patients in view of the poor response rates and associated toxic effects. Early chemotherapy studies reported 1-year survival rates in the range of 12 to 15% for patients with metastatic NSCLC, and these results were similar to those in patients treated with supportive care alone. Progress appears to have been made, and a number of new agents have been developed with promising activity in NSCLC. Use of the new generation of chemotherapeutic agents in combination with other established agents has yielded 1-year survival rates of 40 to 50% in recent trials.
Does chemotherapy improve survival in advanced NSCLC?
Meta-analysis of randomized trials has shown that median survival is prolonged
by about 2 months with the administration of cisplatin-based chemotherapy.
Quality of life also may be improved by chemotherapy, with diminution
of symptoms and fewer days in the hospital necessitated by complications
of cancer.
At present the absolute survival advantage is modest with available
chemotherapeutic regimens, and patients and physicians must weigh the potential
benefits and risks of therapy on an individual basis.
Cisplatin-based regimens have been the most commonly utilized regimens in NSCLC, and, until recently, cisplatin (Platinol), in combination with etoposide (VePesid) or vinblastine (Velban), has been the reference regimen for randomized studies. Carboplatin (Paraplatin), an analogue of cisplatin, has the advantage of easy outpatient administration and has less ototoxicity and nephrotoxicity than cisplatin. The combination of carboplatin and etoposide appears to be as active as the cisplatin-etoposide combination in NSCLC and has gained popularity.
In the last decade a number of new agents have been tested and have shown impressive activity in NSCLC. These agents include the taxanes (paclitaxel [Taxol] * and docetaxel [Taxotere] * , vinorelbine, gemcitabine (Gemzar), * and irinotecan (Camptosar). These agents have shown consistent activity as single agents and are being tested in combination with cisplatin * and carboplatin. * The Eastern Cooperative Oncology Group (ECOG) tested the combination of cisplatin and paclitaxel at two dose levels against the standard regimen of cisplatin and etoposide in 560 patients with advanced NSCLC. The groups receiving the paclitaxel-containing regimens had the highest response rates (27 to 32%) and median survival times (9.6 to 10.0 months). In patients who received cisplatin and etoposide, the response rate was only 12%, and median survival was 7.7 months. Patients who received cisplatin with the higher dose of paclitaxel had an increased incidence of neurotoxicity, and for future ECOG studies the reference regimen is cisplatin in combination with moderate-dose paclitaxel.
The combination of carboplatin and paclitaxel, has shown impressive activity in early studies and is being increasingly used in community practice. In 1999, this has become the most commonly used regimen in advanced and metastatic NSCLC and also is a reference regimen for most ongoing randomized trials. Vinorelbine, or gemcitabine or paclitaxel, in combination with cisplatin are approved regimens for patients with advanced and metastatic disease.
The "definitive" optimum regimen for advanced NSCLC is not known at present. Results of an ongoing ECOG trial that randomizes patients to one of four regimens (cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-vinorelbine, or carboplatin-paclitaxel) will help decipher some of the management issues for this difficult disease. Elderly patients with NSCLC have survival rates similar to those of younger patients when treated with combination chemotherapy provided they have good performance status (ECOG 0 or 1).
Small Cell Lung Carcinoma SCLC (Oat Cell Carcinoma)
INCIDENCE: Approximately 20 percent of new cases a year of lung cancer.
Subtypes: Oat cell, intermediate cell, and combined small cell and squamous cell carcinoma or adenocarcinoma
DIFFERENTIAL DIAGNOSIS
Non-small cell lung cancer, lymphoma, metastases from other small cell tumors
or infection
STAGING EVALUATION
History and physical examination, hemogram, biochemistry including electrolytes,
liver functions, and LDH (prognostic); imaging studies of the chest, abdomen,
brain, and bone scan, plus or minus bone marrow aspiration and biopsy; if
bone scan positive, routine radiographs to verify metastases
Treatment of SCLC
Chemotherapy is currently the mainstay of treatment for all stages of SCLC. At this point, it seems that four to six courses of chemotherapy for patients who show a complete response should be sufficient and that presently available maintenance chemotherapy is not of any added benefit.
PRIMARY THERAPY of SCLC
Limited disease: Six courses of combination chemotherapy including etoposide and cisplatin, plus or minus other agents such as doxorubicin and cyclophosphamide; thoracic irradiation; prophylactic cranial irradiation frequently given in complete responders but considered optional by some investigators
Extensive disease: Usually treated with six courses of combination chemotherapy using the drugs listed above; thoracic irradiation usually not recommended; prophylactic cranial irradiation used in selected patients who obtain a complete response, by some investigators
EFFECTIVE SECOND- OR THIRD-LINE THERAPIES of SCLC
Second-line chemotherapy: Possible short-term response and palliation in patients who have received previous chemotherapy; radiation therapy possibly useful for palliation of local symptoms
New drugs that are active in non-small cell lung cancer seem to be less active in small cell lung cancer; the exception may be topotecan, which is active as second-line therapy
It has also been noted that untreated patients have median survivals of only 6 to 17 weeks, but even with optimum treatment, fewer than 10 percent of patients are alive at 5 years from the start of treatment. In recent years, improved integration of chemotherapy and radiation therapy has produced high survival rates in this once rapidly fatal disease.
Ref:
Conn's Current Therapy 2000
Abeloff: Clinical Oncology, 2nd Ed., 2000
National Cancer Institute Information 2000
01062001