Obligatory—this is not medical advice
Treating patients with sarcoma is about finding out where our expertise, what’s been proven, and what is safe meets the individual and their preferences. Depending upon the values of the patient, multiple paths can be entirely valid. It’s important that we review these options as best we can, understanding that there’s a whole world of information to know, and, unfortunately, a very limited time allowed for a patient visit—this is mediated by administrative and insurance pressures, and sadly has been taken from the physician and the patient over the last few decades. Part of the force behind this substack is to allow more nuanced dissemination of sarcoma specific information to patients in a relatively comprehensive, yet digestible format. There’s a lot here to review already.
Oral treatment offers many advantages that I can’t possibly list entirely here, but, amongst them include:
Increased autonomy for patients and their caregivers
Decreased number of visits
Lessened duration of encounters (infusion appointments are lengthy)
Improved access to medications (unfortunately, insurance companies can still be a barrier here)
Reduced transportation/travel costs for patients and caregivers
The difference between oral and IV treatment, aside from the obvious logistical elements, is that oversight of administration, while capable of being improved, is nonetheless ultimately done by the patient. The patient takes the medications at home in most cases where it is just they, themselves, and their loved ones ensuring the intervals prescribed. There can be reminders, prompts, and all sorts of digital wizardry to improve compliance (adherence to the dosage and frequency), but, this system still is far from perfect.
Below, I’ll mention some of the most commonly used oral treatments, and others that are being studied. I apologize if I do not touch on everything, there are certainly more.
Types of Treatment
Generally speaking, at least how it exists practically today, there are two forms of medications that can be given orally:
Targeted therapy: a type of treatment that uses medications that selectively targets specific molecules on cancer cells
Cytotoxic Chemotherapy: medications that act to impact the ability of cancer cells to divide by causing DNA damage altered DNA replication, etc.
Realize that the definitions here become blurry. Some medications thought to purely cause DNA damage have been discovered to have new, previously unknown mechanisms.1 I would venture to say that nothing is as simple as we initially imagined it to be. An upcoming post on one of our more commonly applied medications, doxorubicin, will emphasize this.
Pazopanib
Pazopanib is one of the most prescribed medications for soft tissue sarcoma after the completion of the PALETTE, a randomized, double-blind, placebo-controlled phase 3 study.2 It is a targeted therapy, a tyrosine kinase inhibitor. The PALETTE study was a herculean effort that incorporated the enrollment of 372 patients, randomized 2:1 to pazopanib over placebo. The primary end point here was progression free survival, which is a composite endpoint incorporating:
Growth of the tumor by 30% in sum of diameters at any point (including after tumor shrinkage)
Death
Figure 2, which shows a significant improvement in progression free survival is above. There was not an improvement in overall survival, indicating that patients did not live longer while on therapy. Additionally, given that this trial included nearly all subtypes of soft tissue sarcoma, it may not be as directly applicable, but there are many patients with advanced leiomyosarcoma who can do well with pazopanib. Side effects, however, can be significant, as the following table will show. This is why monitoring with biweekly labs for a few months is necessary.
This can be a good medication for many patients with soft tissue sarcoma, and, in fact may even be used in the first line in some cases such as for older adults. 3
Temozolomide
Temozolomide is a cytotoxic chemotherapy whose mechanism of action involves alkylation of DNA. It has been shown to be effective in multiple contexts as cytotoxic chemotherapy and is usually given as an oral formulation. Dosing can vary depending on indication. 4
As with pazopanib, temozolomide underwent study in a broad population of patients with soft tissue sarcoma that was unresectable or metastatic.5 Phase 2 data incorporated 25 patients who were given temozolomide twice daily for 5 days as an oral dose of 200mg/m2 followed by 9 doses of 90mg/m2 every 4 weeks (14 days of oral treatment, varying doses).
This phase 2 study utilized a 2-stage design which attempts to quickly terminate trials on ineffective medications. It accrued to its planned total of patients. On trial, there were 2 partial responses, 2 mixed responses, and 3 patients with stable disease > 6 months. All responding patients had leiomyosarcoma of uterine or other origin.
Toxicity was consistent with prior trials of temozolomide. Largely hematologic, but with nausea (which can be protracted), fatigue, diarrhea. See table 2 above. In general, I would say that temozolomide alone is not commonly given, but can be suitable for the right patient. There have been multiple approvals since the early 2000s which have superseded temozolomide for patients with LMS in earlier lines of treatment. See prior posts.
Temozolomide and Olaparib
Data published at the ASCO 2021 meeting for patients with uterine leiomyosarcoma, the phase 2 NCI protocol #10250, were encouraging.6 This study used a combination of temozolomide and Olaparib, a poly ADP ribose polymerase inhibitor (PARP). 22 patients were recruited who had progressed on at least one line of prior therapy. They received temozolomide 75mg/m2 daily with 200mg of Olaparib bid on days 1-7 of a 21 day cycle. The primary endpoint was ORR within 6 months, which was 23% with a median progression free survival (see above) of 6.9 months. The duration of response, for the 23% of patients with a response, was 12 months. Hematologic toxicity was severe, including grade 3 and 4 neutropenia in 77% of patients. The authors remark that it was manageable, but that does not entirely paint the picture of the experience of patients (limited as it may be by the abstract format).
The results led to initiation of a Phase III clinical trial here for patients with uterine leiomyosarcoma.7
Temozolomide and Cabozantinib
Again, temozolomide is used, but this time with cabozantinib, a tyrosine kinase inhibitor that abrogates multiple targets, including VEGF. The combination of chemotherapy with anti-VEGF has long been applied to multiple types of solid cancers.89 While some successes have been made in progression free survival, many of these studies have not shown an overall survival signal. Again, this varies significantly on the type of cancer tested. Unsurprisingly, not all forms of treatment work for all conditions. An abstract presented at the ACO 2015 meeting indicated a complete response rate of 20%, a partial response rate of 20% and a rate of stable disease for at least 3 months of 45%.10 This, again, was in patients with heavily pretreated uterine leiomyosarcomas. Toxicity is not well described in this abstract.
These were encouraging and a similar study is ongoing in patients with unresectable and metastatic leiomyosarcoma, as well as other sarcomas.11 This will be presented at ASCO 2023.
Conclusions
While there are advantages and disadvantages to oral treatment for patients with leiomyosarcomas, it is our responsibility to communicate each option to patients. Various forms of oral targeted and cytotoxic treatments may be given at different steps of their treatment journey. It is important to know that, although these medications may be administered orally, they still bear a significant degree of toxicity that can culminate in hospital admissions, cessation of treatment, or worse. Again, as sarcoma medical oncologists, we must be transparent about the risks and benefits of these therapies so that our patients are informed and can be empowered to make the best decisions. Insurance authorization, although not heavily referenced here, can often impede accessibility to these medications and interfere with this process.
https://www.nature.com/articles/ncomms2921
https://pubmed.ncbi.nlm.nih.gov/22595799/
https://pubmed.ncbi.nlm.nih.gov/32840417/
www.accessdata.fda.gov/drugsatfda_docs/label/2016/021029s031lbl.pdf
https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.11506
https://clinicaltrials.gov/ct2/show/NCT05432791