Unique Aspects of Maintenance Therapy in Oncology Require Careful Consideration

Maurie Markman, MD

The term "maintenance therapy" has been applied to disease treatment in an increasing number of tumor types and clinical settings. But what is maintenance therapy and how does it differ from other strategies in cancer care?

Maintenance therapy aims to maintain a response attained with the preceding antineoplastic drug regimen. Despite observed clinical benefits—for instance, elimination or substantial reduction of cancer-related symptoms or objective regression of measurable tumor masses—continuing certain regimens may not be feasible because of associated toxicities.

An example is administering carboplatin or cisplatin in treating advanced-stage ovarian cancer. Despite the major activity of the platinum drugs in this malignancy (with some therapies having an objective response rate above 80%), continuing treatment beyond 6 to 8 cycles likely will result in severe adverse effects (AEs) including peripheral neuropathy, renal dysfunction, and worsening emesis. Therefore, the goal of maintenance therapy would be maintaining the maximum clinical benefit achieved from the preceding cytotoxic strategy.

It is important to distinguish maintenance therapy from treatments that follow completion of an effective cytotoxic antineoplastic regimen. For example, clinicians may consider consolidation therapy for patients with hematologic malignancies who are highly responsive to chemotherapy. This approach is designed to intensify a treatment (eg, stem cell transplantation following a response to induction chemotherapy in acute myelocytic leukemia) with the goal of curing the malignancy. In this setting, 1 or possibly 2 cycles of an aggressive antineoplastic treatment will be administered, hopefully achieving this aim—a far different approach from the concept of maintenance.

Given the fundamental goals of maintenance therapy, there are additional issues to consider. First, an effective maintenance therapy regimen will be associated with a toxicity profile deemed acceptable over an extended period. This could be years rather than months in certain clinical settings, assuming the absence of disease progression.

Second, the extended delivery strategy inherent in a maintenance approach should be accomplished while minimizing time and effort required of patients. Weekly clinic visits or intermittent hospitalizations during initial cytotoxic treatment for a life-threatening malignancy may be appropriate. However, this would not be a rational approach for a maintenance strategy of 2 or 3 years. Monthly drug infusions or, preferably, oral regimens would be more in line with achieving goals of a maintenance approach to cancer treatment.¹

The toxicity profile of such extended treatment programs must be carefully considered. AEs considered acceptable for a highly effective induction regimen may be unacceptable in the maintenance setting. For example, patients with BRCA-mutant ovarian cancer may tolerate occasional intense emesis associated with platinum agents administered every 3 to 4 weeks for a maximum of 5 to 6 treatment courses. However, it is unlikely that even minimal nausea lasting several hours with each daily or twice-daily oral treatment with a PARP inhibitor would be acceptable for 2 to 3 years, despite the demonstrated efficacy of this maintenance strategy.¹

For decades, anticancer drug trials have focused on acute short-term AEs during a limited number of treatment cycles. Therefore, one must question whether these toxicity profiles objectively capture the negative effect on quality of life when delivered for several years in the maintenance setting.

The effects of longer-term and more chronic AEs associated with a maintenance strategy were highlighted in a study (NCT00003120) comparing 2 monthly paclitaxel regimens in women with ovarian cancer who had achieved a clinically defined complete response to platinum-based cytotoxic chemotherapy.² With delivery of a 3-hour drug infusion once every 28 days minimizing the time patients spent in clinic or a physician’s office for therapy, investigators compared 3 monthly cycles of single-agent paclitaxel vs 12 monthly cycles. The longer regimen significantly improved the time to subsequent disease progression; however, the extended maintenance approach was associated with considerable risk for developing clinically significant grade 2/3 peripheral neuropathy. This was unlikely to be acceptable for patients and oncologists.²

Finally, one must consider specific therapeutic goals justifying this cancer treatment approach beyond simply hoping to maintain a response, either objective (eg, decrease in size of tumor masses, reduction in ascites, decrease in biomarkers of cancer) or subjective (eg, reduction in cancer symptoms). Permitting a patient to maintain an acceptable quality of life (as defined by the individual) for more prolonged periods than would be possible without a maintenance regimen is a legitimate goal of treatment. A critical point is that the patient defines what acceptable quality of life is, and not investigators on a peer-reviewed publication. Issues to be considered are the resulting AEs including low-grade events vs discontinuation of all antineoplastic therapy and observing the subsequent clinical course; time and effort required of the patient (and potentially family members) to receive therapy; and cost of the management program.

A statistically defined (P < .05) improvement in time to disease progression may be observed in a clinical trial of a maintenance strategy compared with an observation or placebo control. However, if the prolonged treatment period is associated with potentially distressing symptoms (eg, daily emesis), overall decreased quality of life (as defined by the patient), or if duration of benefit is modest (median of several months), one must critically ask what this approach has accomplished. for most patients (and their oncologists).

A further consideration is understanding the effect of reintroducing alternative active antineoplastic regimens when there is documented progression but without the maintenance approach. If such therapy can rapidly reduce or eliminate recurrent signs and symptoms of disease with acceptable toxicity, it might challenge the benefits of a maintenance approach. This would be supported further if benefits of a maintenance strategy were anticipated to be limited in duration.

Conversely, such an outcome would be considered a therapeutic success if patients could resume many daily activities experienced prior to cancer diagnosis, AEs are manageable, and duration of outcomes is based on clinical trial data measured in many months or considerably longer. This has been documented, for example, in patients with ovarian cancer with a BRCA mutation or homologous recombination repair defects treated with oral PARP inhibitors.^1,3

Nothing inherent in the concept of maintenance therapy suggests overall survival (OS) cannot or will not be improved by employing the approach. However, such an outcome should not be mandated in a phase 3 randomized trial evaluating and defining the clinical benefit of maintenance therapy. Delivery of 1 or more possible active treatments to patients in the experimental maintenance and control study arms following completion of trial-based therapy may make it difficult, if not impossible, to document a statistically significant effect on OS associated with the investigative regimen.

Finally, outcomes of maintenance therapy will vary greatly based on tumor type, status of disease, and available therapeutics—even with documenting what appears to be the same molecular defect (eg, BRCA mutation) and employing the identical therapeutic (eg, PARP inhibitor) in different tumor types. This phenomenon is demonstrated by the striking improvement in progression-free survival associated with delivery of one of several PARP inhibitors in BRCA-mutated ovarian cancer vs administering the same class of drugs as maintenance in BRCA-mutated pancreatic cancer.^1,3,4 However, it is reasonable to anticipate that future research efforts will discover alternative molecular markers that can be therapeutically targeted by delivering the novel agents as a maintenance strategy in cancer management.

References

1. Pothuri B, O’Cearbhaill R, Eskander R, Armstrong D. Frontline PARP inhibitor maintenance therapy in ovarian cancer: a Society of Gynecologic Oncology practice statement. Gynecol Oncol. 2020;159(1):8-12. doi:10.1016/j. ygyno.2020.07.097
2. Markman M, Liu PY, Wilczynski S, et al; Southwest Oncology Group; Gynecologic Oncology Group. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21(13):2460-2465. doi:10.1200/JCO.2003.07.013
3. Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(30):3468-3493. doi:10.1200/JCO.20.01924
4. Golan T, Hammel P. Management of BRCA mutation carriers with pancreatic adenocarcinoma. J Natl Compr Canc Netw. 2021;19(4):469-473. doi:10.6004/jnccn.2021.7031 19():469-473.