Abstract
Introduction
Controversy exists as to whether patients with stage IV gastric cancer should undergo surgical resection. We examined the association of gastrectomy with survival in this population.
Methods
Stage IV gastric cancer diagnoses were identified using the SEER database (1988–2005). Analyses examined three subgroups divided on the basis of whether cancer-directed surgery was recommended and performed. Univariate analyses included chi-square and Kaplan–Meier survival analyses. Cox proportional hazards modeling was performed to assess independent determinants of survival.
Results
Of 66,751 identified gastric cancer patients, 23,830 had stage IV disease. Resected patients had a significant survival advantage; survival outcomes of patients who had been recommended for, but had not undergone, surgery were identical to that of patients who had not been recommended (3 months vs. 9 months for resected, p < 0.0001). Furthermore, resection status was the most significant independent predictor of increased risk of death (hazard ratios 2.0 for non-cancer-directed surgery groups).
Conclusions
Patients with stage IV gastric cancer who undergo resection, a highly selected population, have significantly greater survival than unresected patients, including those who were recommended for, but did not receive, resection. Stage IV gastric cancer patients who are reasonable operative candidates should be offered resection.
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Discussant
DR. MARTIN S. KARPEH (New York, NY): I wanted to thank you and your group for bringing up this very important topic and one that we are seeing more and more frequently. With the use of induction chemotherapy, we are seeing more of these patients that are potentially eligible for resection.
I believe this is the largest study of its type to address this question, and your group has very nicely tried to deal with the selection bias by identifying the patients who are recommended for cancer-directed surgery.
There are a couple of key issues that this topic brings up. Clearly, there are issues which are related to quality of life which I don’t believe your data set was able to address and was not addressed in the paper. The other one, of course, is the potential bias in how the patients were selected.
Other investigators have pointed out that Asian ethnicity portends better survival. In your “other group” category, can you go back and tease out what percentage of those patients were of Asian ethnicity? It may be an interesting trend to identify.
Also, the use of induction chemotherapy is more recent, but your analysis goes back to 1988, when many of those patients weren’t getting chemotherapy. Are you able to go back and look at the role of chemotherapy in the survival of these patients that ultimately got resected?
In some of the earlier published analyses, others have pointed out that the extent of resection has a negative impact in the patients that were resected in stage IV gastric cancers. Can you tell us how many patients had extended organ resection or total gastrectomy, and what impact did that have on their ultimate outcome?
There appears to be a greater percentage of M0 stage IVs in the patients that ultimately did get resected. Could that be an explanation for the differences in outcome?
Then lastly, is survival really the right endpoint? Should we really be looking at quality of life in these patients?
Closing Discussant
DR. JILLIAN K. SMITH: Regarding your first question about the survival advantage of gastric cancer patients of Asian race, we did not specifically examine this in our study. However, in our analysis of race, the category of “other” did include patients of Asian race. It would be interesting to take a further look at that analysis to see if a subset analysis of Asian race could be performed within the category of “other.”
Regarding the question of chemotherapy, the use of neoadjuvant treatment for cancers is becoming a very highly discussed topic, and certainly relevant to anyone’s survival. However, this was not studied in our patient cohort as chemotherapy is not recorded in the SEER database. Linkage of SEER data to Medicare does allow for chemotherapy on the basis of examining claims data for Medicare claims, but as we did not use linked Medicare data, I cannot speak specifically to a chemotherapy effect in this population; but I would certainly expect that there would be one with associated adjuvant or neoadjuvant treatment use in any of these populations.
With regard to the type of resection, in our first analysis, we looked at the treatment recommendations and then whether or not the patients underwent resection. We did also examine what type of resections those patients had, but we did not initially perform survival analysis pertaining specifically to each type of resection (these analyses were added to the revised manuscript).
With regard to the M0 versus M1 question, yes, it is possible that the higher percentage of M0 disease is contributing to the survival benefit among the patients who undergo resection. It is likely that among patients recommended for surgery, those that ultimately underwent a cancer-directed surgery were those with M0 disease. Whereas the patients who perhaps had unknown metastatic status and were recommended for surgery, were taken to the operating room, and then upon discovery of M1 disease, had aborted procedures—these patients would fall into the “recommended for, but underwent no surgery or non-cancer-directed surgery” category, who had worse survival.
Finally, your question about whether survival is the right endpoint brings up an important issue—ideally, any analysis of the potential benefit of surgical or any other treatment would examine the outcome of survival in the context of patients’ quality of life. These large databases, unfortunately, are not able to be linked to any quality-of-life studies.
There have been several small series that have looked at quality-of-life questionnaires, even specifically for GI malignancies, examining patients’ quality of life after resection. And those results have been mixed—some studies have shown an improved quality of life and extended survival with resection, and other studies have indicated that patients are not reporting a better quality of that extended life, mostly due to the morbidity associated with such a major operation that they underwent. In any study of our treatment outcomes, quality of life is certainly something that we should always keep in the back of our minds.
Discussant
DR. JONATHAN CRITCHLOW (Boston, MA): I was struck by this interesting paper due to the fact that almost half of the patients with metastatic gastric cancer were recommended to have an operation. Although a number of them did not end up being operated, I find the percentage to be quite high, and I would say almost shocking. The question of selection bias is of interest, whether healthier patients were advised to have surgery. However, you got around this by showing similar survival in non-operated patients, whether they were advised to have resection or not. A major question of interest is if there is a difference in the ratio of M0 to M1 patients being resected.
It’s going to be extremely difficult, but how many of these patients were symptomatic and operated on because they had obstruction or experienced bleeding? Or were they asymptomatic and operated in efforts to “prolong their survival”? I think that’s an important part of this decision making.
Also, the type of operation is key. It’s a whole different kettle of fish to be doing a subtotal gastrectomy for somebody who is obstructed, as opposed to a total gastrectomy for somebody who has no symptoms who may live an extra 6 months, but spend it convalescing and trying to learn how to use a new GI tract.
Those are questions that unfortunately you will have a difficult time answering, but are problems for me in trying to make sense of this. And I would actually say that your patient MH, who has metastatic disease with peritoneal studding, does not appear to be obstructed, and is probably going to need a total gastrectomy, needs to be looked at in a different way and not advised to have a resection.
Closing Discussant
DR. JILLIAN K. SMITH: Our data certainly have limitations with regard to knowing the symptomatology, as well as knowing exactly what the surgeon’s decision process is and ultimately what the patient’s decision process is. The point I would leave with this research is that, it is not meant to replace anyone’s expert clinical judgment, but rather, inform clinicians that there are data to suggest that nearly half of these patients are being recommended for surgery, and nearly half of those are undergoing that surgery. Furthermore, undergoing surgery does appear to have some sort of survival benefit. The idea introduced by this research is that, if a surgeon, or perhaps a step back in the process, a primary care physician, has a patient that he or she believes is healthy enough to tolerate surgery, that patient should not be automatically dismissed from consideration for surgery just because of stage IV disease.
Grant support
Dr. Jennifer F. Tseng is funded by Howard Hughes Medical Institute Early Career Award, the American Surgical Association Foundation, and the American Cancer Society (Grant # MRSG-10-003-01-CPHPS).
This work was presented during Digestive Disease Week in New Orleans, LA as an oral presentation at the SSAT Residents and Fellows Research Conference, May 1, 2010 as well as during a plenary session of the SSAT Annual Meeting, May 5, 2010.
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Smith, J.K., Hill, J.S., Ng, S.C. et al. Potential Benefit of Resection for Stage IV Gastric Cancer: A National Survey. J Gastrointest Surg 14, 1660–1668 (2010). https://doi.org/10.1007/s11605-010-1351-3
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DOI: https://doi.org/10.1007/s11605-010-1351-3