Cytotoxic Chemotherapy for Adult Soft-Tissue Sarcomas: A Lesson in Humility

“I was told chemotherapy doesn’t work for sarcoma” is a statement frequently heard during consults with new patients who have metastatic adult soft-tissue sarcomas. Patients often ask why I am offering them chemotherapy now, when they have heard from both surgeons and medical oncologists that it is not helpful. Of course, the notion that chemotherapy has no place in the treatment of sarcoma sometimes stems from a misunderstanding of the difference between adjuvant and palliative therapy; however, even in the adjuvant setting the discussion is far more complicated than what many patients have heard. I commend Drs. Ravi, Patel, and Benjamin on their attempt to dispel the myth of chemotherapy’s irrelevance in the setting of soft-tissue sarcoma, and their emphasis on the importance of consultation at high-volume sarcoma centers.[1]

Pazopanib, which was approved by the US Food and Drug Administration (FDA) for adult soft tissue sarcomas in 2012, is just the second drug approved for this indication in the United States; therefore, much of the treatment patients receive is off-label. A reading of this concise review of the dizzying array of primarily single-arm, often single-institution studies that guide our treatment choices leads to an almost inevitable conclusion: it is no wonder that physician attitudes regarding the options for patients with sarcoma are nihilistic.

Risk vs benefit

All oncologists make treatment recommendations for their patients based on perceived benefits weighed against potential risks. However, for physicians who treat patients with sarcoma, this assessment can be particularly challenging for two important reasons. First, as described in the accompanying review, studies suggest that there is a clear dose-response relationship, and many of the negative phase III studies are criticized because of the use of perceived insufficient dose intensity. The commonly used first-line options, doxorubicin and ifosfamide, at the commonly accepted standard doses, are associated with a relatively high risk of both short-term and long-term toxicities. In a patient who is undergoing potentially curative chemotherapy, balancing the risk of secondary malignancies, congestive heart failure, renal impairment, and impaired fertility against a statistically unproven survival benefit on the order of 0% to 13% can prove challenging.[2,3] Second, most clinical trials in this population treat all intermediate- to high-grade adult soft-tissue sarcomas the same, despite differences in risk based on histology, primary site, grade, and size-and differences in chemotherapy sensitivity based on histology; thus, for the individual patient the honest answer regarding risk vs benefit is “I don’t know.”

Similarly, for patients with metastatic disease, the decision regarding single-agent doxorubicin vs doxorubicin-based doublet therapies can prove difficult. Several phase III trials, as detailed in the review by Ravi et al, have clearly shown no statistically significant overall survival benefit for multi-agent chemotherapy compared with single-agent doxorubicin; yet there are instances where the benefit may outweigh the risk. The added toxicity of doxorubicin with ifosfamide may be warranted in patients with clearly symptomatic or rapidly progressing disease; however, we still must consider whether subjecting a patient with an average survival of 12 months to potentially toxic and logistically difficult regimens is the right thing to do. To complicate things further, sarcoma oncologists must also try to predict whether patients may potentially be eligible for curative metastatectomy. In patients who undergo metastatectomy, about 23% will be alive at 3 years, and in a retrospective analysis, patients who received preoperative systemic therapy seemed to do better than those who did not (25.5 months vs 18 months; P = NS).[4] Certainly there are tools we can use to help predict benefit-histology, the exclusion of patients who quickly develop new metastases, and time from initial diagnosis. However, if 25% of patients with pulmonary metastases are ultimately deemed eligible to undergo metastatectomy, and 25% of those patients go on to have long-term survival, we must treat 10 patients to potentially, but not definitely, help cure one patient.

Where are the randomized studies?

The sarcoma community has proved it can rapidly accrue and complete studies. Patients are savvy. They know they have a rare disease and seek out better options. Unfortunately, with the exceptions of the pazopanib trial and trials in gastrointestinal stromal tumors (GIST), no sarcoma trials have met their planned primary endpoint. We can argue whether progression-free survival or overall survival is the ultimate goal, but the fact remains that sarcomas are a diverse group of tumors that do not behave the same or respond the same to various treatments. I applaud the sponsors who put their resources into large randomized studies of such a rare disease; however, we must push for increased funding of preclinical research to identify compounds that inhibit known driver translocations that exist in several subtypes of sarcoma, and to identify new targets for those that do not. Researchers in breast cancer, lung cancer, melanoma, and many other malignancies are successfully chipping away at-and making substantial strides in understanding-rare subsets of their diseases. Yes, sarcoma is far rarer than those malignancies, but there are now three FDA-approved drugs for GIST, and an approved drug for dermatofibrosarcoma protuberans. The targeted approach will not work for every subset, as it hasn’t in other malignancies, but we can certainly better define which chemotherapy is best for which type of sarcoma and, we hope, identify new targeted therapies with better risk-benefit ratios.

Conclusion

The exact combination and order of drugs or the exact populations that benefit from one approach vs another may not be well defined in large randomized trials; however, Drs. Ravi, Patel, and Benjamin clearly explain how a series of smaller phase II trials and even statistically negative randomized trials of cytotoxic chemotherapy can guide treatment options for patients with adult soft-tissue sarcoma. The unfortunate fact remains that the main chemotherapy option for patients with adult soft-tissue sarcoma is doxorubicin, a drug first identified 4 decades ago. Thus, it is important to emphasize that randomized phase III trials may not be required for all drug approvals; funding organizations should strive to support basic scientists focusing on this rare disease, and sponsors should be commended for focusing their resources on rare subsets of a rare malignancy.

Financial Disclosure:Dr. Keedy has received grants for clinical trials sponsored by Johnson & Johnson and Janssen.

References:

1. Ravi V, Patel S, Benjamin RS. Chemotherapy for soft-tissue sarcomas. Oncology (Williston Park). 2015;29:43-50.

2. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet.1997;350:1647-54.

3. Frustachi S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian Randomised Cooperative Trial. J Clin Oncol. 2001;19:1238-47.

4. Gadd M, Casper E, Woodruff J, et al. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg. 1993:218:705-12.