Great Debates in Oncology: The Use of Adjuvant And Neoadjuvant Chemotherapy in Soft-Tissue Sarcoma - Round 2

Dr Van Tine: Here is the next question I would like to pose to both of you: Do you feel that the benefits of adjuvant/neoadjuvant chemotherapy outweigh the associated toxicities? And I’m going to throw in a little bit of a ringer into this also—and how do you think that is applicable as patients get older?

And so, with that, let’s start with Dr Trent this time.

Dr Trent: Great, thank you again for this opportunity. And so, this section we’re really talking about benefit–risk ratio and this really comes down to selection, selection, selection. We spend a lot of the time studying patients, patient history, comorbidities, a number of factors. We spend a lot of time studying the diseases, talking to our sarcoma pathologists. What is the risk of developing metastases in this patient? And the pathologists have a very good ability to understand the grade of the tumor, which is an important factor.

So, I really break it down in my mind into 3 categories in determining whether the proven benefits of adjuvant chemotherapy really outweigh the potential and theoretical risks. And so, the first thing I consider is the patient, and there’s data that identifies a number of factors that put patients at higher than expected risk for recurrence.

Now, remember, if you look at all grades, if you look at grade III soft-tissue sarcomas >5 cm, patients have a primary tumor in the thigh, it’s resected, that the patient is followed over time, there’s a 50% chance that that tumor is going to come back overall. Well, we use certain characteristics to figure out, is that risk higher than that or is it lower than that? And some of the features we look at are the patient’s age, patient’s performance status (performance status 0, 1, 2 can usually tolerate chemotherapy), organ function. The ifosfamide is a fairly harsh chemotherapy. It has to be given with great prudence, and it’s not for patients that have borderline renal function. And so, there is a number of factors that we identify from the patient.

Also, we look at factors from the tumor. There are certain tumors that are at higher risk for recurrence, such as primitive neuroectodermal tumors, rhabdomyosarcomas, desmoplastic small round cell tumors, angiosarcomas, high proliferative ray myxoid liposarcoma, unclassified pleomorphic sarcoma, the list is pretty long. These patients have a high risk of recurrence after resection of a large high-grade tumor. But we also have an understanding of chemosensitivity, so we know that the primitive neuroectodermal tumors, the rhabdomyosarcomas, the desmoplastic small round cell tumors, myxoid round cell liposarcoma, these are very chemosensitive tumors. Even angiosarcoma is fairly chemosensitive, as is fibrosarcoma, leiomyosarcoma. It’s just a matter of understanding the tumors and understanding the chemosensitivity. Because if I have a patient who has one of these highly aggressive sarcomas, and that sarcoma is a very chemosensitive sarcoma, then there’s a higher probability that that patient is going to benefit from adjuvant chemotherapy based on the tumor. Of course, we have to also take into consideration the patient’s ability to tolerate the effective chemotherapy that is needed to really see the benefit from the chemotherapy.

And then the last factor I use in considering adjuvant chemotherapy is the chemotherapy itself. We know that doxorubicin has been studied in the adjuvant setting. We know that the combination doxorubicin plus ifosfamide has been studied in the adjuvant setting. The most effective doses of doxorubicin and ifosfamide are the higher doses, 75 g/m2 to 90 g/m2 of doxorubicin and 10 g/m2 of ifosfamide. This is pretty high-dose chemotherapy and it’s not for everybody. And, you know, the randomized studies that show no benefit from chemotherapy tend to use lower doses of chemotherapy. For instance, the EORTC study, again, randomized patients to either chemotherapy or no chemotherapy after resection, and some patients received radiation. And, but that study used a dose of 5 g/m2 of ifosfamide. There are a number of other critiques as to why that study was negative, but since we’re talking about chemotherapy I think it’s reasonable to understand, you know, what dose your patient can tolerate before you recommend it.

So those are really the 3important factors that I use when I am considering chemotherapy for a patient with a resected primary tumor.

Dr Van Tine: So, Dr Jones?

Dr Jones: I agree, and I think all of these things come into play regarding the benefits of chemotherapy, both in the localized and in the metastatic setting. I think in the localized setting performance status, comorbidity, age, histological subtype, grade, tumor location are all very important factors to bear in mind, and I think it comes back to our previous discussion regarding, in a way regarding a selection of patients for clinical trials. The EORTC trial that Jon mentioned is very limited in terms of the suboptimal dose of ifosfamide, 5 g/m2.

In addition, tumor size in that trial was a big problem, to use a pun, so in the control arm the smallest tumor measured 3 mm and even the biggest proponents of adjuvant chemotherapy would not propose administering chemotherapy for such a small tumor. In addition, they included intermediate grade tumors and both arms of the trial included central tumors, 22% in the chemotherapy arm and 19% in the control arm. So, again, we have to be very thoughtful and clear regarding the selection of patients for chemotherapy both in terms of the patient factors, but also in terms of the tumor factors in terms of anatomic site, grade, and histological subtype.

I think, as I mentioned earlier on, because of the limitations of the evidence base, it’s very important to be clear with patients and their families that there is an ongoing controversy regarding the use of neoadjuvant and adjuvant chemotherapy, and that drugs we use have potential long-term complications. And I think in a way, the benefit of adjuvant and neoadjuvant chemotherapy is theoretical, because as I say, there is no conclusive result from a randomized trial showing a durable benefit in terms of overall survival (OS) for neoadjuvant or adjuvant chemotherapy, and we have to be very, very honest and very, very clear with patients and their families that this is a, as Jon mentioned, this is in many ways a judgment decision based on experience, based on retrospective analysis of clinical trial data, and I think it’s really, really important to weigh all of that out with patients and their families. And as I say, to take into consideration both the patient factors in terms of performance status, comorbidity, age, as well as the tumor-related factors, such as location, grade, size, depth, and anatomic location.

Dr Trent: All very good points, Robin, and I appreciate your criticism of the EORTC randomized adjuvant chemotherapy study (62931). I really appreciate your pointing out all of the reasons why it was a negative study.

Dr Jones: I think one of the things, people say, “Well, it was a randomized trial and it was conclusive in terms of proving that adjuvant chemotherapy is not effective,” but I don’t think that you can extrapolate that from the trial because of its inherent limitations. As I say, the suboptimal chemotherapy dosing, the huge range in terms of tumor size, the inclusion of intermediate-grade tumors, as well as the inclusion of sarcomas from a variety of anatomic locations. And as I say, at 22% and 19% of tumors were from some central locations in the chemotherapy and control arms, respectively.

So, I think as I say, even though my remit is no chemotherapy, I do not think you can use the EORTC trial (62931) as conclusive evidence that chemotherapy does not work because the trial has inherent limitations that everybody should be aware of.

Dr Trent: I agree, and that’s why it’s, it’s one of the larger randomized trials, but it was conducted in such a way that the results are really uninterpretable. That’s why we really focus on the best data available.

When I go see a new sarcoma patient in clinic, like I have this week, who had the primary extremity sarcoma, larger than 5 cm, high grade, resected, and has already had radiation therapy (or it’s planned in the future), I have a discussion with that individual patient really based on the patient, the tumor, and the chemosensitivity of that tumor. And so, we, as we do in every clinic visit, have shared decision-making, and share the best data that we have, which is the, in my opinion, the Italian cooperative group study and the sarcoma meta-analysis and the combined analysis, present and discuss the findings of benefit and recurrence-free survival and OS. And also, clearly outline all of the potential toxicities from chemotherapy, including the very small risk of developing leukemia, which is <1% ever in their lifetime, as well as cardiomyopathy among others. You know, I and you and Brian, we all owe due diligence to the patients to discuss the potential harm from anything we do from chemotherapy to a biopsy to not giving chemotherapy. So, it’s all, all part of what we do.

And the reason I talked about the combined analysis is although it also has limitations like any study, the purpose really was to include patients who had received ifosfamide at more contemporary doses in combination with doxorubicin. You know, and again, it’s all randomized studies, but the addition of ifosfamide and more contemporary data into the sarcoma meta-analysis really gave us data showing with more reliability an 11% absolute survival advantage when the patient had ifosfamide included with their adjuvant doxorubicin. And so, when I have this discussion with patients, you know, some patients say, “Chemotherapy is not for me.” Some patients say, “Yeah, I think that risk is definitely worth it,” that “Even though the data is limited I think that with that risk I want to take the chance.” And so, some patients do and some patients don’t.

And then, you know, we also run into patients that Brian alluded to, those patients that might not tolerate ifosfamide. So, if I have a patient who I don’t think would benefit from adjuvant chemotherapy, or would tolerate doxorubicin ifosfamide, then I might consider substituting cyclophosphamide for ifosfamide. And there’s even less data to support that, but that would be, since cyclophosphamide is very similar to ifosfamide but albeit less active, as per Vivian’s study. You know, something that we talk about, but it could be single-agent doxorubicin, realizing that there’s only about a 5% benefit in survival.

Dr Jones: I suppose one of the things that is of interest now is the role of neoadjuvant chemotherapy following the publication of initial results from a trial led by Alessandro Gronchi of anthracycline plus ifosfamide neoadjuvant chemotherapy for 3 cycles versus histology tailored chemotherapy in 5 different histological subtypes, including myxoid liposarcomas, synovial sarcoma, leiomyosarcoma, malignant peripheral nerve sheet tumor, and undifferentiated pleomorphic sarcoma. And the trial basically has been presented after the third interim analysis for futility, suggesting that the anthracycline/ifosfamide combination was superior to the histology-tailored chemotherapy schedules.

There have been question marks regarding the statistical design (ie, the design of the trial was originally one-sided), basically, it was designed to show that the histology-tailored therapy was effective compared to the anthracycline/ifosfamide combination. But it wasn’t statistically designed to show that the standard anthracycline/ifosfamide combination was better than histology-tailored chemotherapy. They changed the design to 2-sided testing now and have further analyzed the data, but there is a good message from that trail in many ways that the French, Italian, and Spanish sarcoma groups were able to perform a randomized trial in the neoadjuvant setting. It was an academic trial, and in the context of the discussion that we just had regarding the poor quality of previous data these investigators had fairly rigorous inclusion criteria so the high-grade tumors, all high-grade tumors, deeply-seated extremity or trunk tumors, and all were 5 cm or greater, and they were able to recruit patients into this trial very, very quickly.

So, I think, you know, it is possible to do trials in the neoadjuvant setting, and following on from Jon’s point regarding the challenges of I think subtype-specific trials, I think this, this trial by Alessandro Gronchi and colleagues is really, really promising in that respect. And maybe we should be exploring more the use of imaging the molecular markers in the neoadjuvant setting to try and identify patients more likely to benefit from chemotherapy. And I’d sort of throw that back to you, Jon, and to Brian for your comments and thoughts regarding this.

Dr Trent: Robin, those are all great points, and I personally do utilize neoadjuvant chemotherapy fairly frequently and neoadjuvant or preoperative chemotherapy shares some of the same goals as adjuvant chemotherapy, and that is to decrease the local recurrence rate and to improve the patient’s OS.

Additional benefits of neoadjuvant chemotherapy are that you can rapidly alleviate tumor-related pain and even patient suffering. If there’s a tumor pressing on a nerve, shrinkage will often alleviate that pain. You may also be able to downstage an unresectable tumor to enable organ-sparing surgery. For instance, if the tumor is abutting the femoral nerve/femoral artery, the patient may have to have an amputation whereas neoadjuvant therapy may induce regression of the sarcoma, such that the patient can now have limb-sparing surgery. And I’ve seen, it’s not just extremities, I have had a patient with a tumor overlying and invading the eyelid that was able to respond to preoperative chemotherapy and have orbit-sparing surgery. I had another patient with an endometrial stromal sarcoma that had invaded into her vagina and she was offered a vaginectomy and we were able to induce regression. In fact, this patient had 100% necrosis at the time of surgery and still remains disease-free 4 years later, today. So those are some of the additional benefits to neoadjuvant chemotherapy.

And one other somewhat controversial approach and advantage to neoadjuvant chemotherapy is in order to understand an individual tumor’s chemosensitivity. For instance, if a patient has a pelvic sarcoma and has this big resection, a hemipelvectomy, and then you see that patient 2 to 3 weeks after surgery, do another scan, now there’s 50 lung metastases. Well, that patient is probably not going to benefit from that big, morbid surgical resection, whereas if the same patient had been able to start chemotherapy immediately and very early, then one might be able to not only eradicate the microscopic disease, but also sparing that individual patient from a highly morbid procedure that was not going to help them in any way, whereas the chemotherapy would be the more beneficial approach.

So, those are my basic rationale for utilizing neoadjuvant therapy, and I agree completely with Robin’s assessment of the histology-tailored neoadjuvant therapy. This is nearly 300 patients and 3 large groups coming together, so they deserve a lot of kudos. They were able to pull off a histology specific study. They were able to administer meaningful doses of chemotherapy with epirubicin 120 mg/m2 and ifosfamide 9 g/m2, and, in fact, the synovial sarcoma patients received high-dose ifosfamide 14 g/m2.

Though it was a very compelling study, the disease-free survival for the epirubicin/ifosfamide arm was almost double the disease-free survival in the patients that received histology specific therapy. So, I think we still have a little ways to go in learning how to utilize these approaches, and I believe that it’s compelling and pushing us towards perhaps combination therapy. Perhaps patients with myxoid liposarcoma should receive preoperative anthracycline plus ifosfamide, postoperative trabectedin, or vice versa. Perhaps patients with a leiomyosarcoma, that are high risk for recurrence, should be receiving doxorubicin/ifosfamide or doxorubicin/dacarbazine, and then should be receiving also gemcitabine/docetaxel. And perhaps these combination, now that we have all these active therapies, perhaps these multi-drug combinations may one day be analogous to the benefits that have been manifest in osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma.

Dr Jones: And I suppose, Jon, you know, that’s the thing we need to do more trials to assess the sequential treatment in this setting. And I think one of the things, particularly given my remit as the “no chemotherapy” advocate, given the challenges of the evidence base of neoadjuvant/adjuvant chemotherapy in localized soft-tissue sarcoma, the neoadjuvant setting appears to be more attractive in that respect because as you say, it gives an in vivo measure of the chemosensitivity of the tumor itself because even with the sort of heterogeneity between histological subtypes, it’s clear that there is heterogeneity in terms of chemosensitivity even within some of the more common subtypes like leiomyosarcoma and undifferentiated pleomorphic sarcoma. So, I think the neoadjuvant setting is a very attractive arena for conducting further clinical trials and exploring the use of putative markers as well as the use of sequential combination schedules.