STAGE III BRONCHOGENIC CARCINOMA

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TO BE GIVEN AT SURGICAL GRAND ROUNDS CITY OF HOPE NATIONAL MEDICAL CENTER

F.W.GRANNIS Jr. MD

Bronchogenic carcinoma is now the number one killer neoplasm, and although most general and oncologic surgeons will not have a major involvement with it, the sheer number of cases renders it an important topic to all physicians. At present non-surgical therapies have little impact in achieving cure. The most important decision in patient care is therefore whether the patient is a candidate for surgical resection. For the purpose of this talk we will leave out consideration of physiology and confine the discussion to staging. It should be noted , however, that data from staging must be viewed in combination with physiologic information in arriving at a final recommendation for treatment. This is often a complex and difficult process and tragic mistakes can occur when inexperienced physicians make judgements based on improper assumptions. In the private sector, the initial diagnosis and workup of the lung cancer patient is being carried out by pulmonologists, radiologists and oncologists. Frequently non-surgeons are making the critical determination as to whether the patient is operable -- sometimes incorrectly, based on a misunderstanding of the proper indications and limitations of operative treatment. One who doubts these statements has only to review cases coming for second opinions after having been turned down for surgery elsewhere.

Decision making in patients with Stage I and II lung cancer is relatively straightforward and most difficulties arise in assessing the physiologic capability of the patient. Patients in Stage III often represent a difficult decision and these are the patients who will be reviewed at this time.

The problem of Stage III and IV lung cancer is staggering ; more than half of the 150,000+ cases diagnosed yearly fall into these groups. It is important to note at this point that only a small proportion of these patients are operated upon and that all of the data that will be presented, therefore, concerns a HIGHLY SELECTED group of patients. There are NO controlled series, and none of the data is statistically compelling.

The new International Staging System of Lung Cancer was adopted two years ago to reflect changes in the general perception as to what factors rendered bronchogenic carcinoma inoperable. Stages I and II stay as is and Stage III is subdivided into IIIA and IIIB.

The most important change is in the N classification. N2 nodes are now restricted to ipsilateral mediastinal and subcarinal nodes reflecting current surgical thought that such nodal involvement does not render the patient inoperable in all cases. N3 nodes include supraclavicular and contralateral intrathoracic nodes . N2 nodes place the patient in Stage IIIA ; N3 nodes relegate him into IIIB.

T4 status reflects local factors that almost always render the patient inoperable :

• malignant pleural effusion
• mediastinal invasion
• great vessel involvement
• trachea invasion
• carinal proximity
• esophagus invasion
• heart invasion
• SVC occlusion syndrome
• vertebral invasion

T4 status places the patient in Stage IIIB.

T3 tumors reflect factors that although advanced, can sometimes allow for curative resection. These include:

• tumor within 2 cm. of the carina
• chest wall invasion
• superior sulcus invasion (including minor vertebral invasion)
• diaphragm invasion
• pericardial invasion

Any distant metastasis places the patient in M1-Stage IV .

With rare exceptions patients in Stages IIIB and IV are not considered candidates for resection.

The first raw data on 5 year survival in the various new Stages comes from the National Cancer Center Hospital, Tokyo, Japan. (Naruke, JTCVS 1988;96:440-7) restaged 1737 resected cases and found 5 yr survival of 20.2% and 5.1% for clinical Stages IIIA and IIIB, and 22.2% and 5.6% for postoperative Stages IIIA and IIIB.. Individual items included 5 yr survivals of T3 25.8% ,T4 8.4%, N2 13.8% N3 0%. This data provides a more favorable outlook for Stage IIIA patients than one would expect and substantiates the generally pesimistic attitude toward IIIB disease. This data , however is still crude and is not generally helpful in approaching the individual patient with advanced disease. More information is needed on the prognosis for specific areas of tumor involvement.

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STAGE IV:

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The only survivals in Naruke's series were in patients with intralobar pulmonary metastases. The only accepted indication for surgical treatment of Stage IV bronchogenic CA is staged resection of the primary and an isolated brain metastasis. Numerous series have demonstrated that some patients in this category can be salvaged. Magilligan, Henry Ford Hosp. Detroit (SClinNA Oct 1987 1073-80) reports 21% 5 yr. surv. in a highly selected group of 41 pts. Other surgeons have reported lower survival in similar trials. My personal experience includes three cases with resected brain metastases, two cases of solitary rib metastases, one case of solitary contralateral lung metastasis and one solitary small bowel metastasis resected. Two of these patients (brain and small bowel) are five year survivors.

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STAGE IIIB

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PLEURAL EFFUSION: Rare long term survival has been reported after resection in patients with ipsilateral pleural effusion (Ochsner).Such pleural effusion should be repeatedly negative on cytologic exam. Recent series report the utility of pleuroscopy in proving pleural metastasis even in the presence of cytologic negativity (Canto, Chest 87:649-652,1985). Naruke (1988) noted survivals of 39.2 and 10.7% for negative and positive cytology of effusions found at the time of thoracotomy. If the pleural effusion is cytologically negative, the Stage in not affected. My personal experience with these patients has been less favorable, and I have no long term survivors in such patients.

CARINAL PROXIMITY: Tumor within 2 cm. of the carina presents many problems for the surgeon. First it is almost impossible to attain a negative margin of resection. Next, there is the problem of accomplishing a secure bronchial closure. Preoperative radiation therapy has been used in an attempt to "down-stage" the tumor. In general preoperative radiation therapy has not been found to enhance survival and has been associated with a higher than usual operative morbidity and mortality. Faber supports the use of pre-op Ro Rx in patients with bulky central tumors or where poor pulmonary function argues for attempt at seeve resection. Where actual carinal or tracheal involvement is found tracheal sleeve pneumonectomy can be considered but in general the operative mortality can be expected to exceed the 5 yr. survival. (Faber S.Clin. NA 67:1001-1014,Oct 1987). Darteville et al report 32 consecutive cases without a death with long term survival of 23% (Ann Thor Surg 46:68-72, july 1988). In summary it should be safe to say that surgical attempts at cure in tumors with carinal proximity (including stump recurrences) should be attempted only in highly selected cases. The recent discovery of the utility of omemtoplasty in preventing bronchial dehiscences following lung transplantation (Cooper JTCVS 84:204-210,1982)argues for utilizing the omentum to protect tracheo-bronchial anastomoses in this setting.

CHEST WALL INVASION: Chest wall invasion cannot be assumed when a radiographic tumor abuts the parietes but should be expected when the patient reports severe unrelenting local pain. A number of series from surgical centers have clearly demonstated that patients without nodal metastases can achieve survivals in the range 23-45% with pulmonary and en bloc chest wall resection.(Piehler et al, Ann Thor Surg 34:685-91,1982) . The value of pre-operative radiation therapy is controversial. If there is questionable invasion into the parietal pleura it is probably wiser to resect the chest wall in continuity (Trastek, JTCVS 87:352,1984). The indication for surgery in Stage III patients is clearest in these patients. The main problem in decision making is whether the older patient with marginal pulmonary performance can tolerate the operation, since operative mortality can be as high as 20% in older patients . Decisions regarding reconstruction are based on the size and location of the resulting defect and the pulmonary function of the patient.

SUPERIOR SULCUS TUMOR:

This entity carries double jeopardy for the patient in view of the terrible pain problem he faces if curative treatment cannot be attained. When Paulson (JTCVS 70:1095,1975) reported a cure rate of 30-40% in this setting with a protocol of preoperative radiation (3000 rad in 10 days) followed by radical resection of the upper three ribs, portions of the spine and brachial plexus in conjunction with lobectomy, most surgeons were sceptical . Time has proved him correct and numerous other reputable groups have achieved similar 5 year survival :Lahey Clinic 56% (Ann. Thor Surg 43:32-38,1987), UCLA 34% (J Clin Oncol 4:1598,1986), MGH 27% (JTCVS 94:69,1987), Emory, (Ann. Thor Surg 28:44,1979). Paulson selects his patients carefully , rejecting for surgery those with gross spinal invasion and those with N2 nodes on mediastinoscopy. There is a high incidence of invasion intradurally along the nerve roots . This fact combined with the limited experience of most thoracic surgeons in operations on the thoracic spine have led Martini to suggest a combined approach with a neurosurgeon.

Radiation therapy can achieve control of pain in many patients, but few 5 year survivals have been attained. Local and epidural blocks and neurosurgical proceedures are often necessary for pain control in those unfortunates with recurrent tumor.

MEDIASTINAL INVASION:

Meaningful data on management of bronchogenic carcinoma invading into the mediastinal structures other than lymph nodes is very limited.Figures cited below will refer to Martini (SClinNA Oct 1987 987-1000) Overall 5 yr survival of 225 operative patients with direct invasion of mediastinal structures at Memorial Hospital was 7%. Complete surgical resection without brachyradiotherapy in 49 patients yielded a 5 yr survival of 2%! Operative mortality for pneumonectomy was >10%.

SUPERIOR VENA CAVA: (0%) There are a few reports of local resections with long term survivals but I can find no long term report in a patient with resection and graft replacement of the SVC. SVC occlusion syndrome is an absolute contraindication to resection.

PERICARDIUM: (11%)Invasion does not contraindicate resection . There is no good data on survival. As with other large hilar lesions the main problem in these cases is the high incidence of nodal metastases. There is a definite hazard in these cases, in that multiple cases of post-operative cardiac herniation and death have been reported after pericardial resection. For this reason, a large pericardial defect should probably be closed with a PTFE patch.

ATRIUM: (0%) is not an unusual site of invasion, the tumor growing inside the pulmonary veins(7%)Occasionally such tumors can be resected with long term survival.

ESOPHAGUS:(14%)Partial resections of esophageal muscularis and even full thickness have been performed. I could find no report of long time survival in a case of more extensive resection of the esophagus for involvement by bronchogenic carcinoma.

PHRENIC NERVE: (7%) Involvement carries the same implications as pericardium, and preoperative phrenic nerve palsy, per se, should not be interpreted as a sign of inoperability.

RECURRENT NERVE:(0%) Palsy is almost always associated with extensive nodal metastases. Resectability and long term survival is very unusual.

AORTA and SUBCLAVIAN ARTERY: (0%)Iinvasion is rarely amenable to resection. I could find no report of 5 yr survival after aortic resection and grafting for bronchogenic carcinoma.

DIAPHRAGM: Invasion is not uncommon. I could find no meaningful data. Resection and repair in such cases should involve no increased risk and should probably be attempted.

PULMONARY ARTERY (4%)

MEDIASTINAL LYMPH NODES: Last and most important is the problem of metastatically involved mediastianal lymph nodes. This represents by far the largest group of patients with potentially resectable Stage III lung cancer. It is interesting to examine this problem from a historical perspective. Brock in 1948 first described a technique of "radical pneumonectomy" involving en bloc dissection of mediastinal lymph nodes after the fashion of radical node dissections in the neck and axilla (Brit J Surg 43:8-24,1955). The concept was widely accepted in the USA and advocated by Watson and Cahan at Memorial Hospital in NYC (J Thor Surg 22:449-470,1951,Cancer 9:1167-72,1956) . In 1960, Johnson (J Thor Surg 36:309-315) showed that mortality was much increased with this type of surgery, without any improvement in survival. He concluded that " It would appear obvious that if there is not blood vessel invasion and if the tumor has spread through the lymphatics, a radical pneumonectomy might offer a better chance of getting around "that last lymph node" which may be involved. Our fear has been that the occasional gain made on this basis might be more that offset by an increase in the mortality."

In 1962, the National Cancer Institute refereed a sort of heavyweight championship bout wherein the surgical results of pulmonary resection at the Overholt (lobectomy) and Ochsner (pneumonectomy) Clinics were compared. It was convincingly demonstrated that pneumonectomy was not necessary for cure of lung cancer in most cases; and again there was no data to show that mediastinal node dissection was of survival benefit. After this time, the radical approach to pulmonary resection all but disappears from the surgical literature and no technical description of the operation is to be found either in journals or texts for the ensuing 25 years.

Mediastinoscopy was introduced in the early 1960s and was extensively applied . This had the benefit of reducing the M+M resulting from thoracotomy in inoperable cases but also meant that almost all patients with mediastinal nodal disease were rejected as candidates for surgical attempts at cure.

In the late 1970s there was a resurgence of interest in surgical treatment of patients with N2 disease and optimistic reports of survivals of 30% and higher in these patients were reported. There is now a reasonably large set of data from Japan (Naruke), Memorial (Martini) ,Toronto (Pearson), Chicago (Shields) and Houston (Mountain). This data is mostly retrospective and is highly selective. Much of it is presented in a highly selective manner that can be misleading , and that makes interpretation difficult. None of the surgeons involved give a clear idea of what surgical proceedure was being done and techniques seem to vary between " plucking" of clinically involved nodes, a more systematic "sampleing" all the way to true radical node dissection. The role of adjuvant radiation therapy is hard to segregate out. The philosopy and practicality of the selective process involved is unclear--but a careful analysis of the data shows that only a small percentage of total patients with apparent nodal metastasis are being explored. Some statistics don't include percentages of inoperable cases ; some give results only on patients with complete resections.

Out of this whelter of information certain facts stand out

• -patients can have five year cures after N2 nodal resection
• -better results with T1 and T2 primaries
• -better results with squamous CA
• -but results with adeno and large.cell not strikingly worse
• -poor results <10% if N2 on pre-op staging
• -poor results if multiple node areas are positive
• -poor results if there is extranodal disease
• -favorable sites include azygos and aortic window nodes
• -unfavorable sites ant. mediastinum and upper paratracheal
• -mixed results with subcarinal nodes positive

The data would seem to be strong enough to support a surgical approach in patients who are good surgical risks , whose tumor can be encompased by less than a pneumonectomy and whose nodal disease is minor, confined to "favorable" sites . Post-operative radiation therapy would seem prudent. Prospective , double-blind studies with carefully determined selective factors, a standard reproducible surgical proceedure and protocol adjuvant therapies are mandatory to hammer down the appropriate place for surgery and radiation therapy in this huge group of patients.

Finally, it must be emphasized that even after such careful studies have been done , it is virtually certain that the total impact of surgery and radiation therapy on the entire group of Stage III patients will be minor. True impact can only be achieved by private and governmental efforts to decrease the numbers of new and already addicted cigarette smokers e.g.

YES ON 99 !

, by an organized program of surveillance in long term smokers and by continuing trials of new chemotherapeutic protocols in the hopes of finding an effective regimen.

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