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a Heart, Lung, and Esophageal Surgery Institute at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
b The University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pennsylvania
Accepted for publication December 17, 2008.
* Address correspondence to Dr Luketich, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh PA 15213 (Email: luketichjd{at}upmc.edu).
Presented at the Fifty-fourth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 7–10, 2007.
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Abstract |
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Methods: Thoracic surgeons evaluated and performed RFA under computed tomography (CT) guidance or combined with surgical resection. Patients were monitored in the thoracic surgery clinic for recurrence and survival.
Results: Twenty-two patients (10 men, 12 women; median age, 63 years [range, 37 to 88]) underwent RFA. The primary cancer was colorectal in 9 (41%), renal in 2 (9%), sarcoma in 4 (18%), and other in 7 (32%). CT-guided RFA was the sole treatment in 17 patients (77%) and combined with surgical resection in 5 (23%). No procedurally related deaths occurred. At a mean follow-up of 27 months (range, 13.3 to 53.6 months), 9 patients are alive. The median survival was 29 months (95% confidence interval, 9.1 to 33.8). Lesion size was an important prognostic variable associated with overall and disease-free survival (p < 0.05).
Conclusions: RFA is safe in this group of pulmonary metastases patients, with reasonable results. Surgical resection remains the standard for resectable patients, but RFA offers an alternative in selected patients or may be used as a parenchymal-sparing approach in combination with surgical resection in selected patients.
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Introduction |
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One of the factors associated with a survival benefit is complete resection of all pulmonary metastases. Further, even patients who have undergone a complete resection have a high incidence of repeat recurrence and may need a redo thoracotomy with resection [6, 7]. Radiofrequency ablation (RFA) is a relatively new modality of treatment that may be potentially applicable in this group of patients, who are high-risk or who require repeated thoracotomies, or as a parenchymal-sparing adjunct to surgery to completely treat all lesions.
Several studies have shown that RFA is feasible, but few longer-term outcomes have been reported [8, 9]. Data are also lacking on the intermediate-term results of RFA as an adjunct to surgical resection for pulmonary metastases. The primary objectives of this study were to (1) evaluate the outcomes after RFA either alone or as an adjunct to surgical resection as a lung parenchymal-sparing approach in selected patients with pulmonary metastases and (2) to evaluate the prognostic variables associated with both overall survival (OS) and disease-free survival (DFS).
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Material and Methods |
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Patients
Patients with metastatic lung cancer who underwent RFA were identified. We excluded patients who had recurrent or metastatic primary non-small cell lung cancer. All patients underwent chest computed tomography (CT) scan, and 17 (77%) also underwent a positron emission tomography (PET) scan. The selection criteria for RFA treatment for pulmonary metastases included complete control of the primary tumor, extrathoracic disease that was controlled or being treated, and completely treatable pulmonary metastases. The inclusion criteria for image-guided RFA were (1) patients who were considered medically inoperable due to poor pulmonary function (predicted postoperative forced expiratory volume in 1 second or diffusion capacity of the lung for carbon monoxide of less than 40%), high cardiac risk, or other comorbidities; (2) patients in whom prior treatments had failed; or (3) patients who refused surgery. Exclusion criteria included central tumors. In some patients who were operable, RFA was used as an adjunct parenchymal-sparing procedure in addition to surgical resection. All patients were evaluated by a thoracic surgeon to determine suitability for RFA either as sole treatment or as an adjunct to surgical resection.
Treatment Protocol
The technique of RFA has been discussed in detail previously [10, 12]. In brief, a percutaneous CT-guided approach was used in 17 patients (with 1 open conversion), and as described previously, thoracic surgeons performed all procedures. RFA was performed as an adjunct to surgical resection in 5 patients.
RFA was administered using two different radiofrequency generators and needle electrodes. One system comprised a RF generator, the RITA Starburst XL Electrosurgical Device (RITA Medical Systems Inc, Moutainview, CA). The multi-tined expandable array (Starburst XL Electrosurgical Device, RITA Medical Systems Inc) was deployed according to the size of the target tumor. A temperature-based algorithm was followed. The second system comprised the RF generator (RF3000; Boston Scientific, Natick, MA) and needle electrodes (LeVeen Needle Electrode; RadioTherapeutics Corporation, Sunnyvale, CA). A two phase, impedance-based algorithm was used according to the protocol suggested by the manufacturer.
Follow-Up of Patients and Response Assessment
Patients were followed up in the thoracic surgery clinic. Our current protocol is follow-up at 3-month intervals with a clinical examination, CT scan, and selectively, with PET scan. A modified Response Evaluation Criteria in Solid Tumors (RECIST) criterion was used to assess the initial response to treatment, as described previously [10, 12] (Table 1). Patients were evaluated for initial response rate, time to progression, and overall survival.
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The OS was calculated as the time interval between date of the operation and date of death. OS was censored by the last follow-up date if a patient was still alive. The PFS was calculated as the time interval between date of the operation and date of any progression or death. For alive and progression-free patients, PFS was censored by the last follow-up date when patient was known as progression-free. OS and PFS were estimated by the Kaplan-Meier method. The Greenwood formula was used to estimate the 95% confidence interval (CI) for OS and PFS [13]. A log-rank test was used to assess the association between OS, PFS, and categoric covariates, such as primary cancer cell type, approach, nodal disease, and site of first metastasis. The univariate Cox regression model was used to assess the association between OS, PFS, and continuous covariates such as age, disease-free interval between the treatment of the primary and date of first recurrence, the disease-free interval between the treatment of the primary and treatment of lung metastases, the size of the largest lesion, site of first metastases, and gender.
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Results |
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The median disease-free interval from the treatment of the primary lesion to first metastasis (any site) was 17. 5 months, and to lung metastases, was 35 months. Seven patients had prior treatment for intrathoracic metastatic disease.
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Extrathoracic disease was present in 3 patients and was controlled. One patient underwent resection and RFA of liver metastases before RFA of the lung lesion. Surgical resection was done in 2 patients (1 adrenalectomy, 1 hysterectomy) after RFA of the lung lesion.
Approach to RFA
RFA was performed as a sole treatment in 17 patients (77%). RFA was planned to be performed under CT guidance. Of these 17 patients, one patient required an open conversion (mini-thoracotomy) because the hard consistency of the lesion caused difficulty in placement of the probe. RFA was combined with surgical resection (by thoracotomy) in 5 patients (23%). The most common complication in patients who underwent a CT-guided RFA was pneumothorax, which required a pigtail catheter in 12 (70%).
Response
Initial response was determined by the modified RECIST criteria (Table 1). An initial complete response was observed in 2 patients (9%), partial response in 8 (36.4%), stable disease in 8 (36.4%), and was not evaluable in 1 (4.5%). Early progression occurred in 3 patients (13.6%). The patient who was not evaluable did not want to follow-up after 1 month, and the response could not be evaluated. She lived for 5 years after the procedure.
Analysis of Survival and Progression
Nine patients were alive at a mean follow-up of 27 months (median, 26.9; range, 13.3 to 53.6 months). The median overall survival for the entire group was 29.4 months, and the estimated 2-year overall survival rate was 68% (95% CI, 44% to 83%; Fig 1). During follow-up, 13 patients died, of which 10 were cancer-related deaths, 1 was not cancer-related, and the cause of death was not determined in 2 patients.
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Analysis of Prognostic Factors Associated With Survival and Progression
We analyzed the following covariates associated with overall and disease-free survival: size, number of metastases, disease-free interval to first recurrence (any site), and to lung recurrence, approach (RFA alone or RFA as adjunct to surgical resection); primary cell type; single vs multiple lesions; site of first metastases; age; and gender.
Size (< 3 cm vs > 3 cm) was a significant factor in both overall and disease-free survival (p < 0.05). The median survival for patients with lesion diameter of 3 cm or less was 39.1 months (95% confidence limit, 18.3, NR) vs 7.9 months (95% confidence limit, 6.3 months, NR) for patients with lesion size exceeding 3 cm (p = 0.002). Similarly, the PFS was better in patients with a lesion smaller than 3 cm. The median overall PFS (all sites) for patients with size of largest lesion of 3 cm or smaller was 7.15 months vs 3.2 months for patients with size of largest lesion exceeding 3 cm (p = 0.01; Figs 2 and 3).
Similarly, the progression interval in the treated nodule site was significantly longer in patients with a lesion size of 3 cm or smaller (p < 0.05).
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Comment |
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The International Registry for Lung Metastases (IRLM) reported the results in 5206 patients, of which 4572 had complete resection [1]. The estimated 5-year survival after complete resection was 36%, and the median survival was 35 months. In multivariate analysis, disease-free interval of more than 36 months, single metastases, and germ cell primary tumor were independent predictors of better outcome. Recurrences occurred in 53% of patients at a median of 10 months. Complete resection of all lesions was an important prognostic factor. When the metastases were resectable and when all factors were favorable, the median survival was 61 months; when they were unresectable, the median survival was 14 months, with an estimated 5-year OS of 5%.
Potential Role of RFA in Pulmonary Metastases
With complete resection being an important predictor of outcome, RFA may be used in combination with surgical resection as a parenchymal-sparing approach or in lesions that are not resectable. In the current series, 5 patients had RFA as an adjunct to surgical resection as a parenchymal-sparing procedure. This may be applicable in patients who have peripheral lesions that can be resected; lesions that are more central can be treated with RFA during a thoracotomy, with care taken to be away from the bronchus and pulmonary vessels. This use of RFA as an adjunct may be helpful in avoiding a lobectomy in some instances and may serve as a parenchymal-sparing procedure.
Further, the IRLM study showed that recurrences occurred in 53% of patients at a median of 10 months. Many of these recurrences present in the ipsilateral chest even after open thoracotomy. The morbidity of a redo thoracotomy is higher, and about 60% of patients may present again with recurrent disease even after a redo thoracotomy [14]. CT-guided RFA may offer an alternative in some of these patients, particularly as a parenchymal-sparing procedure.
Rolle and colleagues [2] also demonstrated the importance of complete resection in using the 1318-nm neodymium-doped yttrium aluminium garnet laser. The 5-year OS was 40% after complete resection and 7% after incomplete resection. The overall survival after complete resection of single, 10 or more, and more than 20 resected metastases was 55%, 28%, and 26%, respectively. These authors stressed the importance of complete resection, even when multiple lesions were present, as a very important determinant of survival. The recurrence rate was 60%, and the median time to recurrence was 9 months. Among local pulmonary recurrences, only 32% underwent redo resection.
RFA may be useful in the treatment of repeat recurrent metastases when the risks of redo surgery are high. Further redo resection is associated with a high repeat recurrence rate and may point to a more aggressive behavior of the primary tumor [14]. In these circumstances, RFA may be a reasonable choice, particularly in patients who have had one or more previous resections, to avoid the morbidity of redo thoracotomy. About one-third of the patients in this series underwent a previous resection, and RFA was used to treat repeat recurrences.
Prognostic Factors Associated With Survival After RFA Treatment
In addition to complete resection, other prognostic factors have been examined after surgical resection of pulmonary metastases [3, 4]. Pfannschmidt and colleagues [3] reported the results in 167 patients who underwent resection for colorectal metastases. Single vs multiple lesions and lymph node involvement were among the significant factors, whereas disease-free interval, resection of hepatic metastases, age, and sex were not significant factors.
In the current study, we examined the prognostic factors associated with survival and progression. Size was a significant predictor of both OS and disease-free survival. The median OS was 39.1 months when the lesion size was smaller than 3 cm vs 7.9 months when the lesion was 3 cm or larger. We did not find a significant association for covariates such as cell type of primary, disease-free interval, site of first metastases, and single vs multiple lesions, and survival; however this may be a limitation of a small group of patients.
In summary, with a mean follow-up of 27 months, the median OS was 29.4 months, with an estimated 2-year OS of 68%, and the median time to progression was 5.8 months. Although these results are not equivalent to the reported results of complete surgical resection, they are better than reported results when the metastases are not completely resectable. Further, other therapies before RFA were not successful in several patients, including previous surgical resection; thus, these patients may represent a group with biologically more aggressive tumors.
Other investigators have reported the results of RFA in the treatment of primary and metastatic lung tumors [5, 11, 15–17]. Recently Yan and colleagues [5, 15] reported the results of RFA for the treatment of pulmonary metastases in 55 patients with colorectal neoplasm. The median follow-up in their series was 24 months, the median survival was 33 months, and the estimated 2-year survival was 64%. Multivariate analysis showed the only factor that was associated with survival and overall progression was size (>3 cm). Interestingly, we also found that the size of the largest lesion was a significant factor in both OS and PFS in patients treated with RFA.
Strengths and Limitations
One interesting aspect of this study that is applicable to thoracic surgeons is the combination of surgical resection and RFA as a parenchymal-sparing procedure. Minimal data have been reported on the intermediate-term results of a combination of RFA with surgical resection. In addition, this study represents one of the longest follow-up periods (mean, 27 months) reported on RFA for the treatment of pulmonary metastases. We also evaluated prognostic variables that are associated with progression and survival, with size of the lesion being significantly associated. This information may lead to better patient selection and prospective studies with development of protocols for larger lesions such as combining RFA with stereotactic radiosurgery or adjuvant therapy, or both, in these patients.
The current study, however, has the limitations that are inherent to retrospective studies, such as selection bias. The patients treated in this study comprise a very heterogeneous group, encompassing patients with different primary tumors who had metastatic disease. Longer follow-up is required for greater maturity of time-to-event data. Several factors merit further investigation, including optimal patient selection and the role of combination therapy or adjuvant therapy.
Conclusion
Our experience indicates RFA is safe and has reasonable results in this group of patients with pulmonary metastases. Surgical resection remains the standard for resectable patients, but in selected patients with pulmonary metastases, RFA offers an alternative or may be used as a parenchymal-sparing approach in combination with surgical resection. Thoracic surgeons should continue to evaluate new technology and add these techniques to their armamentarium in the treatment of lung neoplasm. Prospective studies are necessary, and are ongoing at our institution and others, to define the role of RFA in the treatment of metastatic lung neoplasm.
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Discussion |
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As you mentioned both in your presentation and in the manuscript, these outcomes are clearly below that of surgical resection. So my first question is, how did you determine that a patient was not a candidate for surgical resection, because if I understand correctly, most of these procedures are done with the patient under general anesthetic, and most of them receive a chest tube, and a significant number have a pneumothorax. So, one, how did you determine that a patient was not resectable? Did you use FEV1 [forced expiratory volume in 1 second] percent, was it comorbid factors, was it DLCO [diffusion capacity of the lung for carbon monoxide] percent, but what did you use as your cutoff; particularly in the 7 patients who had a single lesion, that I am not going to do, say, just a thoracoscopy and a wedge, or a thoracoscopic lobe if that was required?
The second question is, since 63% of your patients had air leaks, speaking from my own experience and from my interventional radiologist of having to take a patient to the OR [operating room] and resect an area with a persistent air leak 7 days later and finding a residual tumor and finding that patient tolerated the surgical procedure, the question would be, did you have to do additional procedures, or how many patients had persistent prolonged air leaks after the procedure? Thank you.
DR PENNATHUR: Thanks, Dr Howington, for your comments and questions. The criteria of who are candidates for a metastasectomy or not, I think, varies a lot between institutions, and people use multiple criteria, including single lesion and a disease-free interval that is greater than 36 months, to name the two most common criteria which have been utilized, and also sometimes the cell type. So I think the criteria for surgical resection is a little bit varied in the literature among the surgeons' practices. At the other end of the spectrum, some surgeons do not consider even 30 metastases on both lungs as a contraindication to surgical resection as long as they can be completely resected. One such series was presented at the AATS [American Association for Thoracic Surgery] by Dr Rolle [2].
Our criterion for RFA includes a predicted postoperative FEV1 of less than 40%, in addition to associated severe comorbidities. We have included more details in the manuscript and about one-third of these patients had had a previous—sometimes three—thoracotomy for resection of metastatic lesions. So the RFA was not the first procedure which was performed for intrathoracic disease. It was, in some instances, performed to avoid a fourth time redo thoracotomy that the RFA was performed. In some instances a thoracotomy was performed several times for different reasons, and so the patient was not enthusiastic about having repeat surgery done. And so those are some of the considerations, which we utilized in patient selection.
Now, in terms of the operable patients, I think, for example, that if you have 4 lesions, which we think we can resect, in order to spare some lung parenchyma, we have utilized RFA as an adjunct, so that you resect about maybe 3 lesions and perform RFA on 1 lesion to prevent perhaps a lobectomy, because the natural history of this disease is we are going to find recurrences. We resect them, and it keeps coming back depending on the aggessiveness of the tumor. Therefore, it is important to save parenchyma while we treat these patients.
The second question was air leaks. I think one of the problems with this particular procedure with air leak is mainly because of patient selection. These patients have bad pulmonary function, perhaps severe emphysematous changes, and so we do have an air leak. And our threshold for placing a chest tube in is very low, because we want a chest tube in place, and on suction, so that the lung comes against the chest wall and this facilitates proper placement of the probe. And so, for any pneumothorax, we generally place a chest tube. We don't generally observe them. In this series, we have not had a problem in which we had to operate on a patient because of a prolonged air leak, although this sometimes occurs. Thank you for your kind comments and excellent questions.
DR WILLIAM H. WARREN (Chicago, IL): Congratulations to the coauthors on a very nicely presented paper. One of your slides showed distal progression. Was that distant progression in other sites, or is that further down the tracheobronchial tree?
DR PENNATHUR: This was distant progression to other sites. Thank you for your question.
DR SHANDA HALEY BLACKMON (Houston, TX): Nice presentation. I had a question relating to Dr Reed's presidential address. I have had 2 patients referred to me this year with bronchopleural fistulas who were considered medically inoperable patients. Do you have a conversation with these people about how far they want to go, knowing the complication of bronchopleural fistula is possible with radiofrequency ablation. Since we know it can happen, do you ask them if they want to have such a complication treated or go straight to hospice if it looks as though they may require a complicated repair? I am thinking of patients who were poor surgical candidates that have been sent to me requiring a surgical muscle flap to close bronchopleural fistulas created by non-surgical alternative therapy.
DR PENNATHUR: Informed consent was obtained on all these patients, and we have a long discussion with the patients about doing RFA, along with the risks, benefits, and alternatives of the procedure, and the fact that we don't have long-term results for this procedure. In this series, we have 2 years' median follow-up. As you point out, it is important to have a detailed discussion with patients, and how aggressive they want to be, and the risks and benefits of the procedure. Thank you for your comments.
DR ROBERT J. CERFOLIO (Birmingham, AL): What you, Dr Luketich and Dr Landreneau have done is really outstanding—we all stand on your shoulders. You guys have led the world in this. And so one of the questions I have centers around education. Now, in my institution, we have done eight or nine of these; we are just starting. But I am up there in the CT [computed tomography] scanner in the radiology department. I bronch the patient, put a chest tube in, and then the radiologist does it. You guys are actually doing it, correct? There is no radiologist present?
DR PENNATHUR: No radiologist.
DR CERFOLIO: But you are using a CT scanner. You have got to get a CT scanner to use. It is their domain. Are you doing it in the OR?
DR PENNATHUR: Yes, we have a CT scanner in the operating room, and we use this for the procedure.
DR CERFOLIO: Okay, so you have your own—that is important, because many do not have that option at their center. And so are you educating all the residents, everybody is coming through and the fellows and learning how to do this?
DR PENNATHUR: Yes.
DR CERFOLIO: And if they are, how are you going to wrestle with the fact that most ORs don't have CT scanners in them, and how are we going to capture the volume when the radiologist says "not in my house?"
DR PENNATHUR: I think that those are very, very relevant points, Dr Cerfolio. First with regard to education, we want to involve the fellows and the residents in every case, which we do, whether it is a CT-guided RFA or when we do our own biopsies before the RFA, and sometimes placing fiducials for stereotactic radiosurgery. So we get them involved and allow them to participate in every single case. Second, with regard to education, is to attend CME approved courses on RFA. We conduct such courses throughout the year, and STS has also been conducting annual courses.
I think it is an issue that the leadership of the Society has to take up in the future, because what I hear from some of the thoracic surgeons going out and practicing is that they are having difficulties in terms of getting CT scanner time. And perhaps one thing to do is to develop a good working relationship with the radiologists. And I know that the way some thoracic surgeons have done it is to perform the procedure in close collaboration with the radiologist. For example, the radiologist does the biopsy. So they are an integral part of it, and when the time comes for RFA, for example, then the thoracic surgeon performs the RFA.
DR CERFOLIO: He can bill for letting you use the scanner.
DR PENNATHUR: The radiologist may also charge for the reading of the CT scan, et cetera. And so it can be done so that the radiologist does the first part, or 75% of it, and the thoracic surgeon does the rest, and this can establish a good working relationship. So some thoracic surgeons have successfully worked it out with radiology. Thank you again for your very kind comments and excellent questions.
DR BRYAN FITCH MEYERS (St. Louis, MO): Just to interject, there is another solution I have heard about. Just about every radiation oncology department now has CT scanners that they control, because they do the CT planning for their radiation therapy. It may be that because the radiation oncologist is more of an allied partner with you in treating cancer, you can partner with rad onc to do an end-run around any obstacles presented by the unwillingness of interventional radiology to share equipment.
DR PENNATHUR: Yes, that is an excellent point, Dr Meyers. In fact, in Pittsburgh before we had the CT scan in the OR, we start out doing it with radiological oncology. They were very collaborative, and so one could effectively use their CT scanners.
DR STEPHEN C. YANG (Baltimore, MD): Arjun, again, I echo my colleagues on congratulations and your patience in working with the radiologists. I just had a comment and a quick question. When we did our open resect RFA trial a few years ago, one of the problems we had with the sarcomas, especially with the osteosarcs, was that the probe was very difficult to place; the tines would bend as they got extracted out of the main needle. And the sarcomas actually gave us the lowest RFA percentage of tumor kill in the pathologic specimen; I think they averaged around 60%. I know you only had 4 in your series. How many of those were osteosarcs vs soft tissues?
DR PENNATHUR: Thank you, Dr Yang. As you pointed out, with the osteosarcomas, there may be a difficulty in terms of placing the probe, the probe bends, et cetera, and it can be a potential problem.
DR YANG: Have you tried it with the osteosarcs?
DR PENNATHUR: Yes, we have tried it, and there is sometimes difficulty with the osteosarcomas. In this series, there was one patient, where there was difficulty in placing the probe percutaneously.
DR J. MICHAEL DIMAIO (Dallas, TX): I again applaud you, as Dr Cerfolio did. You are leading the way in Pittsburgh with this technique. What we have done in Dallas is coordinate with our interventional radiologist so that we go downstairs to the CT scanner with them, and, as you said, let them get the code for the biopsy of the lesion. Then we do the RFA with them. At least at our institution, and I am sure at others as well, they have a lot of experience with the renal cell cancers with our urologists. So I talked to my urologist and asked, "how are you working this out?" He said, "I keep control of these patients; we go together downstairs." So he led the way for me, again, with kidney lesions. So that is another thing to consider with what Dr Meyers is talking about with radiation oncology, to talk to your urology colleagues and see how he or she has worked that deal out. Again, at our institution they led the way. They control the patients. You book it with the interventional radiologist to share the CT scanner and do it that way.
DR CERFOLIO: Do you wait for the frozen section on pathology, and if it comes back negative, do you not treat the patient? Because we do a biopsy before we get there.
DR DIMAIO: We have held off, yes. But usually we have often had a biopsy before, as you have done. So we haven't gone to the operating room cold very often. It is a second lesion if you are getting 2 at the same time. If you have got one tissue-proven and you have got a second lesion you are going to hit as well, is that second lesion the same as the first, for example? But there are other ways. If you don't give the biopsy coding to them, then you can give them the CT interpretation and some type of a procedure fee that they get. I have not done as many as you have done, but we have not had a problem. And I picked one interventional radiologist who is the most cooperative working with me and not against me. And again, I will just repeat myself, the urologists have led the way to control this situation.
DR KEITH S. NAUNHEIM (St. Louis, MO): Dr Pennathur, that was a great presentation. The strategy we have employed at St. Louis University is for our surgical services to have control of the CyberKnife [Accuray, Sunnyvale, CA], and thus we don't send patients to interventional radiology for ablation. But I know that you have both the CyberKnife and RFA ablation in Pittsburgh. We believe the CyberKnife is better than RFA in some ways, worse in others. I was hoping that since you have experience in both modalities, you could give us the benefit of your wisdom regarding the pros and the cons of those two different options. Ideally, thoracic practitioners would be involved in both CyberKnife and RFA, but if they had to pick one, is one better than the other?
The nice thing about the CyberKnife methodology is that the needles are smaller and thus the air leaks generally are smaller. Also the more central the lesion and the closer it is to vascular structures, the better CyberKnife would seem as an option. Adjacent large vascular structures can act as a heat sink and thus decrease the effectiveness of RFA by preventing adequate thermal necrosis. So I wonder if you would just give us the benefit of your experience for picking one vs the other.
DR PENNATHUR: Thanks, Dr Naunheim, for those questions and comments. In our institution we frequently use RFA and stereotactic radiosurgery, and use the CyberKnife in a complementary fashion. For the peripheral lesions, it is a toss-up; one can use either RFA or stereotactic radiosurgery. But I think on the central lesions we absolutely avoid RFA because it is close to the hilum. And so those patients are almost exclusively treated with the CyberKnife.
And I think that one of the issues is there is a fair degree of local progression that happens with RFA. And so when we do the RFA, the other thing that we do many times is to place fiducials, which don't have to exactly be on the tumor but around it, and so if it is a recurrence, these patients can be treated with stereotactic radiosurgery.
Now, in terms of the pros and cons, I think the cost of the CyberKnife is quite expensive; it requires a huge investment by the institution. However, it can be used for lesions in both central and peripheral location. Cost-wise the RFA is less expensive, in terms of investment for the institution. But ideally, I think it would be best to have both options available so one could use whichever is more advantageous and can also use them in a complimentary fashion.
DR DANIEL L. MILLER (Atlanta, GA): Arjun, I enjoyed your presentation. We have had some problems with the RITA system (RITA Medical Systems Inc, Mountainview, CA) because of patients who came with bad lung function, elevated pulmonary artery hypertension, which wasn't picked up by the interventional radiologist. The RITA system was used and the patient bled to death. So we have gone to the single Core system, and I just wonder if you could comment, do you all use both?
DR PENNATHUR: For this study it was basically the Boston Scientific and the RITA system, and now we are using all three probes, which is the Cool Tip system (Valley Lab, Tyco Healthcare, Boulder, CO), which is a single probe.
I think pulmonary hypertension itself is probably an underrecognized risk factor for this procedure or for pulmonary resection. I don't have data on pulmonary hypertension in these patients. One patient early on in the experience had a central lesion who also had a brachytherapy done in addition to the RFA. The patient had a massive hemoptysis somewhere like 3 weeks down the road. I don't know whether it was related to the probe or whether it was the brachytherapy catheter. But that is what prompted us to completely stop doing any more central lesions. For the peripheral lesions, I am not sure whether the pulmonary hypertension makes a difference, but I don't have the data to tell you whether the complications were more or less. Thank you for your questions and comments.
DR MILLER: We got burned on that, because the patients come into our service after the procedure. We don't do it, but they come in to us because interventional radiology does not have a service.
DR PENNATHUR: That is difficult.
DR MILLER: So this patient ended up dying, and that was my mortality because I am the admitting physician. That is why we worked that situation out now with our interventional radiologists, with better inclusion criteria. But also they get a lot of referrals that they send to us, and their lung function isn't that bad. So we have gotten a lot of wedge excisions for a brachytherapy trial or for VATS [video-assisted thoracic surgery] lobes. So it has been a nice working relationship. I wish we had a CT scanner that we could use, but you have got to work through all that.
DR MEYERS: I realize that the medically inoperable patients are the ideal patients to treat initially, and I imagine that if some of the bugs could be worked out, there would be a goal to roll this out to other healthier patients to avoid operation. With these really sick patients that have comorbidities such as pulmonary hypertension or emphysema, is there any plan to create a control group that receives some other treatment? Patients who have multiple metastases often have distant recurrence of additional metastases as the most common cause of failure, so it therefore raises the question about what actual benefit you are adding to their survival.
DR PENNATHUR: Those are all excellent points. We can't change the biology of the primary tumor, and the benefit and long-term outcomes of treating 2 or 3 metastatic lesions locally with therapies such as RFA should be carefully investigated. We do have a prospective protocol in which we enroll and we have strict criteria, and this might define who might benefit or not.
But unfortunately we need to have better systemic therapy, and the current systemic therapies for several of these metastatic cancers are not good enough for us to impact on the distant progression at the current time. But the local therapy can potentially help in terms of problems such as hemoptysis or other local problems that the tumor may cause.
DR MEYERS: Yes, but in order to show that you still would need an untreated group to compare to.
DR PENNATHUR: That's right.
DR MEYERS: I know from the ACOSOG [American College of Surgeons Oncology Group] 4033 trial discussions and preparations, there are at least three anecdotal reports of exsanguinating hemoptysis and death after this procedure. Nobody knows what the denominator of RFA treated patients is, and the goal of the ACOSOG 4033 trial is to lend some multi-institutional estimate of the morbidity and mortality of this procedure. But right now, nobody knows; and there is no comparison group to say that these patients are better off than they would be if you just left them alone or gave them some potentially effective chemo.
DR PENNATHUR: Yes. I think those are excellent points. The International Registry of Lung Metastases registry was a single arm; investigators entered the patients on the registry. We don't know how the control arm did. The trial we have currently ongoing in Pittsburgh, also a phase II design; it doesn't have a control arm and the group is really heterogeneous. But I think, to answer this question, we do need a randomized trial, and the ACOSOG trial again is a phase II trial with the goal of enrolling about 55 patients. And so I think the only way to answer that question would be to have a randomized study, and I think that is going to be difficult to design because of the tremendous heterogeneity of the patients. These patients may want something done, and to randomize them to not doing anything versus RFA or any of the modalities is going to be a little bit difficult.
DR MEYERS: But just because they want something doesn't mean that it needs to be done.
DR PENNATHUR: That's right, and we have to discuss this in detail with our patients and request their participation. I think it is going to be a challenge to do it, but the right way to answer this question, Dr Meyers, I think is to conduct a randomized trial. And I think one of the points which was raised earlier, in terms of education, is one way to get started with RFA would be when you do a thoracotomy and resect 3 or 4 metastases. One can get comfortable and place the RFA probe for an ablation as an adjunct, and I think Dr Yang had presented the original ablate and resect study 4 or 5 years ago at the AATS. That might also be a good way to get started in terms of getting comfortable with the equipment, et cetera, before we do it under CT guidance. Thank you for your comments and questions.
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3 cm (solid line) and >3 cm (dashed line). The time shown in the x-axis is months from radiofrequency ablation. The number of patients at risk is shown above the x-axis. (Log-rank p = 0.002.)