ISMPO Insights

October 2021 - 3

Dr. Maheboob M. Basade

Senior Medical Oncologist,

Head, Department of Medical Oncology,

Saifee Hospital Mumbai, Maharashtra, India

Email ID: basade@gmail.com

I. Patient-Reported Outcomes and Long-Term Nonadherence to Aromatase Inhibitors

Hershman DL, Neugut AI, Moseley A, Arnold KB, Gralow JR, Henry NL, Hillyer GC, Ramsey SD, Unger JM

Journal of the National Cancer Institute, Volume 113, Issue 8, August 2021, Pages 989–996, https://doi.org/10.1093/jnci/djab022


Nonadherence to aromatase inhibitors (AIs) is common and increases risk of breast cancer (BC) recurrence. We analyzed factors associated with nonadherence among patients enrolled in S1105, a randomized trial of text messaging.


At enrolment, patients were required to have been on an adjuvant AI for at least 30 days and were asked about financial, medication, and demographic factors. They completed patient-reported outcomes (PROs) representing pain (Brief Pain Inventory), endocrine symptoms (Functional Assessment of Cancer Therapy–Endocrine Symptoms), and beliefs about medications (Treatment Satisfaction Questionnaire for Medicine; Brief Medication Questionnaire). Our primary endpoint was AI nonadherence at 36 months, defined as urine AI metabolite assay of less than 10 ng/mL or no submitted specimen. We evaluated the association between individual baseline characteristics and nonadherence with logistic regression. A composite risk score reflecting the number of statistically significant baseline characteristics was examined.


We analyzed data from 702 patients; median age was 60.9 years. Overall, 35.9% patients were nonadherent at 36 months. Younger patients (younger than age 65 years) were more nonadherent (38.8% vs 28.6%, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.05 to 2.16; P = .02). Fourteen baseline PRO scales were each statistically significantly associated with nonadherence. In a composite risk model categorized into quartile levels, each increase in risk level was associated with a 46.5% increase in the odds of nonadherence (OR = 1.47, 95% CI =1.26 to 1.70; P < .001). The highest-risk patients were more than 3 times more likely to be nonadherent than the lowest-risk patients (OR = 3.14, 95% CI = 1.97 to 5.02; P < .001).


The presence of multiple baseline PRO-specified risk factors was statistically significantly associated with AI nonadherence. The use of these assessments can help identify patients for targeted interventions to improve adherence.


Patient reported outcome measure (PROM) is very important quantifying tool to gain insight into the patient's perspective. There have been many randomised trials done which incorporated the results of PROMs into the management of advanced cancer and it had shown to improve the overall survival if you act on them.

They reported out of 702 postmenopausal patients, 35.9% were non-adherent to the prescribed treatment. The trial noted that more patients from the age group less than 65 years, where found to be non-adherent to the treatment so also the patients of highest risk. Patients need to complete treatment to derive maximum benefit but they lose out due to non-adherence. The presence of multiple baseline PRO-specified risk factors was statistically significantly associated with AI nonadherence. To improve adherence to treatment, authors noted that PROM assessments will help to identify patients requiring interventions.

They also reported twice weekly text messaging did not improve compliance to the treatment.They suggested personalized approach in addressing issues faced by patients to improve compliance. [1]

Even in our practice we find such patients who donot adhere to the treatment. There are various social, economical, racial factors and side effects profile for non adherence in our patients. Trying to address each of these issues will try to improve the survival of such patients.

  • 1. Hershman DL, Unger JM, Hillyer GC, Moseley A, Arnold KB, Dakhil SR et al. Randomized trial of text messaging to reduce early discontinuation of adjuvant aromatase inhibitor therapy in women with early-stage breast cancer: SWOG S1105. Journal of Clinical Oncology. 2020 Jul 1;38(19):2122.
    • II. Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment: Results from the randomized FOCUS4-N trial

      Adams R, Fisher D, Graham J, Seligmann JF, Seymour M, Kaplan RS, Yates E, Richman SD, Quirke P, Butler R, Brown E

      Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 3504-3504.), DOI: 10.1200/JCO.2021.39.15_suppl.3504

      Background: There is extensive randomized evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy.

      Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 weeks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype.

      Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms.

      Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy.


      Most of the patients of metastatic colorectal cancer who are not operable cancers will receive chemotherapy with some biological therapy added in front line. Important question for the patients is how long to continue the treatment if they had shown the response or achieved stable disease to the initial induction therapy. Various time frames have been used either 4 months to 6 months of induction chemotherapy FOLFOX or FOLFIRI alongwith biological agent. Once therapy is over, there is a dilemma for the physician what to continue the next in maintenance. The toxicity pattern from the initial treatment decides the continuation of the therapy. Various trials have shown that continuation of capecitabine or 5FU along with the biological can prolong progression-free survival. Overall survival is not different if you stop the therapy.

      Focus4Ntrial specifically looked at oral maintenance with capecitabine versus active monitoring of the patients with metastatic colorectal cancer who are stable or responding after 16 weeks of first line therapy.

      Median PFS was 3.88 months (capecitabine maintenance arm) versus 1.87 months (active monitoring arm). Median OS was 13.9 months for capecitabine arm versus 13.3 months for active monitoring group.

      The conclusions from this study are that despite the strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected. This forms basis in providing a break into the treatment. It is safe management alternative for the patients who are stable or responding well to the first line therapy for the metastatic curative cancer. Therapies without bevacizumab can also be used for the maintenance therapy after 16 weeks.

      III. Cyclophosphamide-Free Adjuvant Chemotherapy for Ovarian Protection in Young Women with Breast Cancer: A Randomized Phase 3 Trial

      Yu KD, Ge JY, Liu XY, Mo M, He M, Shao ZM, SPECTRUM Investigators

      Journal of the National Cancer Institute, Volume 113, Issue 10, October 2021, Pages 1352–1359, https://doi.org/10.1093/jnci/djab065


      Chemotherapy-induced premature menopause leads to some consequences, including infertility. We initiated this randomized phase III trial to determine whether a cyclophosphamide-free adjuvant chemotherapy regimen would increase the likelihood of menses resumption and improve survival outcomes.


      Young women with operable estrogen receptor-positive HER2-negative breast cancer after definitive surgery were randomly assigned to receive adjuvant epirubicin and cyclophosphamidefollowed by weekly paclitaxel (EC-wP) or epirubicin and paclitaxel followed by weekly paclitaxel (EP-wP). All patients received at least 5-year adjuvant endocrine therapy after chemotherapy. Two coprimary endpoints were the rate of menstrual resumption at 12 months after chemotherapy and 5-year disease-free survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT01026116). All statistical tests were 2-sided.


      Between January 2011 and December 2016, 521 patients (median age = 34 years; interquartile range = 31-38 years) were enrolled, with 261 in the EC-wP group and 260 in the EP-wP group. The rate of menstrual resumption at 12 months after chemotherapy was 48.3% in EC-wP (95% confidence interval [CI] = 42.2% to 54.3%) and 63.1% in EP-wP (95% CI = 57.2% to 68.9%), with an absolute difference of 14.8% (95% CI = 6.37% to 23.2%, P < .001). The posthoc exploratory analysis by patient-reported outcome questionnaires indicated that pregnancy might occur in fewer women in the EC-wP group than in the EP-wP group. At a median follow-up of 62 months, the 5-year disease-free survival was 78.3% (95% CI = 72.2% to 83.3%) in EC-wP and 84.7% (95% CI = 79.3% to 88.8%) in EP-wP (stratified log-rank P = .07). The safety data were consistent with the known safety profiles of relevant drugs.


      The cyclophosphamide-free chemotherapy regimen might be associated with a higher probability of menses resumption.


      Younger premenopausal females suffering from variety of cancers have a fear of premature ovarian insufficiency and infertility because of the chemotherapy they receive. We always try to see how to minimize the side effects both long term and short term of the chemotherapy. Prevention of primary gonadal toxicity because of chemotherapy is the key. Not many trials have addressed this issue as the women want fertility preservation and they are interested in future family planning. Most common practice is to give gonadotropin-releasing hormone (GnRH) agonist before starting chemotherapy to reduce the risk of ovarian toxicity. But drugs like cyclophosphamide can cause ovarian damage and infertility. We need to have a balanced approach towards long-term disease control so also to prevent ovarian dysfunction. Yu and colleagues report the results of Substitution of PaclitaxEl for Cyclophosphamide on survival ouTcomes and ResUmption of Menses in young women with ER-positive breast cancer (SPECTRUM), a phase III randomized trial designed to evaluate a cyclophosphamide-free adjuvant chemotherapy regimen to reduce ovarian toxicity in young women with hormone receptor–positive and HER2-negative breast cancer.This trial was done to compare the differences in menses resumption rates as well as disease free survival between EC WP and eP WP. The inclusion criteria excluded the patients of TNBC and HER2 positive as they in any case might require chemotherapy devoid of cyclophosphamide. This has been very important study for younger women as from the study it was found that the patients who receive chemotherapy without cyclophosphamide have better chance of menstrual resumption at 12 months as compared to the patients receiving cyclophosphamide-based therapy and the disease-free survival at 5 years was also maintained. Such kind of studies are the need of an hour for the patients who wants to have the family.

      Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
      Editor-in-Chief - Dr. Padmaj Kulkarni
      Section Editor - Dr. Sneha Bothra
      Editorial Assistant - Devika Joshi