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Ann Thorac Surg 1997;63:611-612
© 1997 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery, University Hospital, Umeå, Sweden
As a junior doctor I reviewed a series of pulmonary metastasectomies (PM-ectomies). In 70 patients the 5-year survival was 31%. I concluded that patients with solitary pulmonary metastases (PM) should undergo operation. However, an older and respected physician asked whether such an apparently favorable result might be due to selection mechanisms. To answer the challenge, I consulted with a pulmonary physician friend. He had studied the medical aspects of PM in general [1] and put his material at my disposal. Reviewing his cases, I found 12 patients who fulfilled operation criteria and would have nowadays been operated upon. These patients had a 5-year survival of 25%. Thus survival after metastasectomy could be due to selection mechanisms [2].
Malignant tumors constitute a heterogeneous disease. Even within each tumor type, there is a marked heterogeneity as regards biological aggressiveness also in tumors with poor prognosis. Nöu [3] showed, for instance, in a 5-year epidemiologic review of lung cancer, that there was a tail of outliers with a comparatively long survival after diagnosis also in unoperated patients.
If any treatment is directed primarily to patients with a favorable spontaneous prognosis, an apparently good effect of the treatment may be construed. Patients considered for PM-ectomy are selected by the criteria for operation. The primary tumor has been removed and no other organ metastases are found (this weeds out patients with spread disease). Locally, the disease is eradicated (this weeds out patients with local recurrence). Some kind of interval between the primary organ operation and the metastasectomy is often advocated (this gives the tumor the chance of showing its real nature). The patient is suitable for operation by ordinary criteria (this weeds out patients with poor prognosis from other diseases). Patients thus are selected out of the benign part of the spectrum in a heterogeneous group. Patients suitable for PM-ectomy and surviving more than 5 years constitute probably less than 0.5% of all malignant cases [2]. However, the spontaneous, unoperated 5-year survival of renal carcinoma, for instance, is in the magnitude of 1.7% [4].
It is a scientific fallacy to assume that PM-ectomy patients have the same untreated prognosis as an unselected group with the same disease (ie, approaching zero) and that the difference to the found 5-year survival of 25% to 30% is large enough to accept PM-ectomy as an efficient treatment. We lack (with the exception of [2]) a control group with the same characteristics as those that are now operated upon.
With this lack of knowledge, it is difficult to scrutinize our current indications for operation. The evidence for the efficacy of PM-ectomy must be sought in other facts than survival. Such evidence is provided already in the classic paper by Turney and Haight [5]. They found the 10- and 15-year survival to be 32% and 28%. Two of 9 patients survived 20 years. They also found patients with metastasectomy who had a long survival, died of other causes, and at autopsy had no recurrent disease. That patients with PM-ectomy occasionally are "cured" is a fact. However, this finding is not often repeated in later literature, possibly due to lack of long-term follow-up.
Some groups have modern treatment modalities including chemotherapy and operation that provide large proportions of patients with the disease with a survival that is remarkably better than historical control groups. Among these may be mentioned osteogenic sarcomas and teratomas. However, little can be said about the relative importance of surgical resection itself.
Our current selection criteria for PM-ectomy give us typically a 25% to 30% 5-year survival. The attrition rate during the first postoperative year(s) is high. We thus select patients for operation who do not benefit from it. The need for refined selection criteria is acknowledged by most scholars in the field. One of the earliest works was that of Morton and associates [6, 7], who studied the tumor doubling time. They found that a tumor doubling time of less than 20 days conferred a dismal prognosis, whereas if the tumor doubling time was more than 40 days there was a 63% five-year survival.
In a study recently presented at the meeting of the European Association for Cardio-Thoracic Surgery, Girard and associates [8] found that the time between first diagnosis of PM and PM-ectomy had a marked influence on survival. The longer the patients had waited (with known PM), the longer was the survival. During the waiting period patients with more aggressive tumor behavior apparently have weeded themselves out. There seems to be no hurry for operation.
In this issue of The Annals, the well-known group from Brompton Hospital, London, report on a 14-year experience of 276 patients [9]. As is usual in reports of PM-ectomy, the design is descriptive with a post hoc analysis of outcome (survival) with no control group. Robert and associates find a good outcome in teratomas (with a concomitant chemotherapeutic treatment) and a dismal outcome in melanomas. The groups with sarcomas and carcinomas have the usual survival found in such studies, around 30%. Survival was not related to disease-free interval (ie, the period between the primary operation and the PM-ectomy), and histology itself (teratomas, sarcomas, carcinomas, and melanomas) was the major predictive factor, with number of metastases as a second significant factor. Robert and associates conclude that short disease-free interval, numerous metastases, or even lung deposits recurring after metastectomy are no reason to despair.
Are these findings interpretable by selection mechanisms? I believe so. Teratomas with an effective chemotherapeutic treatment have a favorable prognosis; malignant melanomas with its low tendency of heterogeneity have a dismal prognosis with few survival outliers. In groups with low disease-free interval, with bilateral PM, or with residual, recurring, or growing (into visibility) PM—factors that in the context of the total material of malignancies indicate an unfavorable prognosis—there may be individuals with a favorable natural prognosis. This is most evident in the case of slow-growing tumors, where survival, the outcome used, is inherent regardless of other properties in the behavior of the tumor.
The sole reason for PM-ectomy given in textbooks and articles is to eradicate the disease and prolong life. Symptom relief has not been claimed as an indication for operation. Are there other reasons? Given the situation of a patient operated on for a malignancy and now informed about a recurrence, it is understandable that the surgeon is put under pressure "to give the patient a chance." One can also look at the situation from the point of view of hope. An operation is a hopeful occurrence; it symbolizes a way out of the claws of death. In offering an operation with a weak indication, we are at least offering hope and thus some kind of quality of life to the patient. Is this reasoning sound? I do not think so. To refer to the placebo effect as a justification for a major operation does not seem right. There is in my mind only one exception to this. Consider the case of a patient with a slow growing malignancy with pulmonary metastases that he or she probably is going to die of in, say, 20 years' time. If an operation is performed, the knowledge of the threatening situation may be taken away from the patient and be replaced by hope. Imagining myself in the same situation I would probably like to have the tumor(s) taken out—with the hope of the disease being eradicated. However, if I had bad prognostic signs, I would not want to spend my few remaining months carrying the burden of a futile operation.
What are the drawbacks of operation? Apart from the obvious pain, discomfort, and costs to the patient, a small but definite mortality and a small rate of permanent complications may be taken as known parts of the game. But what do we know of the body's reaction to surgical trauma in conjunction with malignancies? Even with today's minimally invasive techniques, is there a possibility that we are actually decreasing the total number of life years in the group? These and other uncomfortable questions may only be answered by hitherto neglected, proper prospective studies with rigorous design.
A timely sign of the need for better knowledge is the creation of a metastasectomy registry, the major scientific initiative during the last 20 years [10]. It presently includes more than 5,000 cases. Considerable numbers of cases in various subgroups allow for refined analyses about prognosis and selection criteria. The inclusion in the registry of the probably few patients who abstain from operation after being advised for it would add to the value of the registry. Given enough time much important knowledge will be derived from it, especially from its planned prospective parts.
Operation for PM is a small but interesting clinical problem. Its intellectual and emotional overtones, the difficulties in the decision-making process, and the probability that we presently are overusing the technology make the efforts done by the cited and other authors very worthwhile. In the end we will be better guided by refined selection criteria and tell the unfortunate patient that no operation is the correct treatment and restrict the use of PM-ectomy to those—probably fairly few—fortunate patients who will benefit from it. To study the properties of the individual patient's individual tumor, for instance by its behavior, seems a promising avenue.
Footnotes
Address reprint requests to Dr Åberg, Department of Cardiothoracic Surgery, University Hospital, S-901 85 Umeå, Sweden.
References
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