• IJMPO

ISMPO Insights

August 2021 - 2

The world is a weird place which reminds us everyday that truth is indeed stranger than fiction. We see Afghanistan, the delta variant, an Indian athletics gold medal in Olympics and we rub our eyes.

In this issue of ISMPO insights, I have selected four recently published articles, two of them here and here potentially practice defining, one here giving us pause to think about our current clinical practice, and the last one here a strange situation that most of us have never encountered in our practice, but which promises to provide valuable biological insights. I thank my colleagues, Drs Shona Nag, Amita Maheshwari, Prabhat Bhargava and Tarini Sahoo for their excellent commentaries. I hope you will enjoy their take on these articles as much as I did.

Dr. Sudeep Gupta

Tata Memorial Centre, Mumbai

Email ID: sudeepgupta04@yahoo.com

1. Do Steroids Matter? A Retrospective Review of Premedication for Taxane Chemotherapy and Hypersensitivity Reactions

DOI: 10.1200/JCO.21.01200 Journal of Clinical Oncology, Published online August 06, 2021.

Olivia Lansinger, et al, from Stanford University School of Medicine, USA.

Purpose

Despite the widespread use of the taxanes paclitaxel and docetaxel for a variety of cancers and their well-known association with hypersensitivity reactions (HSRs), there is still significant variation in the prescribing practices of steroids for premedication. Premedication almost always includes dexamethasone, which can be associated with multiple adverse effects if taken for extended periods of time. This study reviews the pattern of steroid premedication in patients who received paclitaxel or docetaxel at Stanford Cancer Institute between January 2010 and June 2020.

Methods

We used an electronic query of the electronic medical record followed up with a manual review of patient charts to ask whether we could find a correlation between steroid premedication dosing and the incidence or severity of HSRs with the first taxane dose. Variables considered included steroid dose and route, dose and type of taxane, clinical cancer group, sex, and race.

Results

Five thousand two hundred seventeen patients were identified as having received paclitaxel or docetaxel, and 3,181 met criteria for our analysis. There were 264 (8.3%) HSRs. In adjusted multivariate analysis, we found no correlation of HSR rate or severity among any of the variables evaluated except gynecology oncology clinic patients, who had an increased risk (hazard ratio [HR] 1.34) of HSRs overall and high-grade HSRs (HR 2.34), and female patients, who had a higher rate of HSRs overall (HR 1.26), but not high-grade HSRs.

Conclusion

Neither dexamethasone dose nor route correlated with subsequent HSRs. Given the potential for adverse events from repeated high-dose steroids, our findings suggest that routine use of lower doses, such as a single 10 mg dose of dexamethasone, as premedication for taxanes to prevent HSRs is preferable to the current prescribing guidelines.

COMMENTARY BY:DR. SHONA NAG, CONSULTANT MEDICAL ONCOLOGIST, PUNE, INDIA

The article published by Lansinger et al., attempts to correlate the dosing of steroid premedication and the incidence and severity of Hypersensitivity reactions (HSR) during the first dose of taxane administration. Their major side effects include hypersensitivity reactions, most commonly seen with the first and second dose of administration. In order to circumvent and reduce these HSRs, a protocol for premedication before taxane use has been established and steroids form the backbone of this premedication protocol. The problem is the large cumulative steroid dose recommended as premedication which varies between 30 and 40 mg with every taxane administration. This big dose is troublesome especially with weekly Paclitaxel schedules and the short- and long-term side effects of steroid use cannot be overestimated.

This study is a retrospective analysis of 3181 patients treated with taxane chemotherapy from 2010 to 2020 at the Stanford Cancer Institute. The variables considered in the analysis were dose and route of steroid, type and dose of taxane, clinical cancer group, sex and race. The methodology for ascertainment of exposure to steroid was detailed and robust. Analysis was done by both adjusted and unadjusted multivariate analysis. Patients were divided into two groups based on the dose of steroid they received, 0-10mg Dexamethasone versus > 10-20mg Dexamethasone. In the unadjusted analysis, patients who received higher doses of Dexamethasone (> 10-20mg) had a higher rate of HSRs. This was also seen in those who were given Paclitaxel compared to Docetaxel. Patients who received steroid the day before had a lower rate of HSRs compared to those who received only IV Dexamethasone on the same day of chemotherapy administration. These differences however disappeared during the multivariate analysis and only patients with gynecologic malignancies and female patients were at a high risk of developing HSRs. Gynecologic oncology patients also tended to develop high grade sensitivity reactions. The strengths of this study lie in the large number of patients included and the long term follow up and rigorous methodology for data collection. The limitations include its retrospective nature and some incomplete data.

How does this study impact our routine practice? Certainly, it tells us with some confidence that we can reduce the dose of Dexamethasone in the premedication protocol for our patients, and that instead of 30-40 mg as previously recommended, a dose of 10 mg will work as well. Most of us actually do not use such large doses and routine use of steroids 24 hours prior to taxane doses is not uniformly practiced in most cancer centers in India. In fact, in some countries like Australia, steroids are used only for the first two weeks of weekly Paclitaxel administration and completely eliminated for the remaining doses. In our clinical setting, diabetes and infectious diseases are highly prevalent and lowering steroid dose during taxane premedication would prove to be a boon for patients and physicians alike.

2. Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants

DOI: 10.1056/NEJMoa2030391; N Engl J Med 2021; 384:42-50

Ayumu Arakawa, et al, from National Cancer Center, Tokyo, Japan

Summary

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child.

COMMENTARY BY:DR. AMITA MAHESHWARI, CONSULTANT GYNECOLOGIC ONCOLOGIST, TMC, MUMBAI, INDIA

Cancer associated with pregnancy is rare, with a reported incidence of 1/1000–2000 pregnancies. Transmission of cancer from mother to fetus is a rather rare phenomenon; haematogenous spread being the commonest mode. Although, fetal transmission of maternal genital tract cancer during vaginal delivery is theoretically possible but only anecdotal cases have been reported in the literature.

In January 7, 2021 issue of NEJM, Arakawa A et al., from Japan reported two highly unusual cases of paediatric lung cancers that probably developed as a result of aspiration of maternal cervical cancer cells by the infants. In both the cases, the diagnosis of maternal cervical cancer was missed antenatally and male babies were through vaginal route. Lung tumors of both the children had slow, indolent course with good clinical outcomes while the cervical tumors in the mothers had aggressive course. The diagnosis of maternal origin of fetal cancer was made incidentally based on the results of next-generation sequencing of paired samples of tumor and normal tissue since cases were enrolled on a prospective gene profiling trial on patients with advanced malignancies. The maternal origin of cancer was confirmed by the lack of Y chromosome in the tumors of children; and shared multiple somatic mutations, HPV genome, and SNP alleles (which were not inherited in the children’s germline), between their lung tumors with tumors from the mothers.

The first case, a 23-month-old boy, diagnosed with neuroendocrine carcinoma of lung with glandular differentiation that presented as multiple lung masses spread along the bronchi. As per his parents’ decision, the child was observed for one year without any active treatment. Interestingly, few lung lesions disappeared spontaneously during this watchful waiting but others persisted. He was treated with two lines of chemotherapy with partial response. Subsequently on disease progression, he was enrolled on immunotherapy trial and received nivolumab to which he experienced near complete disappearance of lung lesions. Lobectomy was done for the residual disease. Flow cytometric analysis of the resected tumor showed a higher fraction of immune cells (88%) compared with normal lung tissue (33%). A higher fraction of B cells (44%) as well as CD4+ and CD8+ T cells were also noted in the tumor consistent with a response to anti–programmed cell death protein 1 (PD-1) therapy. The child was free of disease at 12 months after lobectomy.

His mother who was diagnosed with cervical cancer3 months after delivery, was treated with surgery and chemotherapy. However, she experienced metastatic disease three years after the initial treatment and also received nivolumab.She experienced progressive disease on this treatmentand died five months later. Despite having similar tumors, the child and the mother had dramatically different responses to immunotherapy highlighting the importance of host’s immune response in immunotherapy-based treatment. Interestingly, immunohistochemical staining revealed that the tumors in the child and mother were negative for PD-1 and PD-L1.

The second patient was diagnosed with mucinous adenocarcinoma of hilar region of the left lung at the age of six years. The child was treated with multiple lines of chemotherapy and surgery (left pneumonectomy) and found to be free of disease at 15 months after treatment. His mother, who received the diagnosis of cervical adenocarcinoma three months after his deliver, was treated with surgery. But she died of the disease two years after initial treatment.

The two unusual cases reported here indicate the possibility of mother-to-infant transmission of uterine cervical cancer during vaginal delivery. The lack of literature on similar cases could be due to the current recommendation of caesarean section delivery for mothers diagnosed antenatally with cervical cancer.

3. Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer

DOI: 10.1056/NEJMoa2017699; N Engl J Med 2020; 383:2207-2218

Thierry Andre, et al., from multiple centres for the KEYNOTE-177 Investigators

Abstract

Background

Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H–dMMR advanced or metastatic colorectal cancer is unknown.

Methods

In this phase 3, open-label trial, 307 patients with metastatic MSI-H–dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil–based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.

Results

At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P=0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cut-off date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.

Conclusions

Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H–dMMR metastatic colorectal cancer, with fewer treatment-related adverse events.

COMMENTARY BY: DR. PRABHAT BHARGAVA, CONSULTANT MEDICAL ONCOLOGIST, TMC, MUMBAI, INDIA

Microsatellite instability is found in 5-15% of colorectal cancers, with a higher prevalence in right-sided tumors compared to left side tumors. One study from our institute showed the prevalence of only 1% in rectal cancers.1 MSI-H tumors are histologically poorly differentiated tumors and behave indolently till they invade the regional nodes, but once they metastasize, they are difficult to control with chemotherapy alone. Hence higher prevalence of MSI is seen in early-stage tumors but less than 5% prevalence in patients with advanced colorectal cancer. 2

Although trial results indicate that pembrolizumab increased PFS in patients with MSI-H advanced colorectal tumors, a few issues with the trial need to be kept in mind.

First, we can see an initial dip in the survival curve in the immunotherapy arm compared to the standard chemotherapy arm. We need to study further biomarkers which could help us identify these subsets of patients and thereby better patient management. Maybe this group of hyper progressors may benefit from an initial combination of chemotherapy with immunotherapy as tried in other solid tumors. Meanwhile, preliminary evidence of combined checkpoint inhibitors is encouraging.3 Ongoing randomized phase 3 trials combining PD-1 inhibitors with chemotherapy/ ipilimumab will further enlighten us.

Second, authors noted that RAS mutated tumors had less response to immunotherapy which is in contrast to previous studies of immunotherapy in RAS mutated colon cancer. 4

Third, we will have to keep in mind that overall survival benefit may not be seen in the trial as the tail end of the typical survival curve of an immunotherapy arm flattens over some time and then remains stable, which may happen in the control arm too due to 59% cross over. If overall survival benefit is not seen in this trial, then the confusion will not be whether to use immunotherapy in MSI-H tumors, but one can be confident in reserving it for the second line. This has more clinical implications in developing countries like ours where only 1.6% of the deserving patients can take immunotherapy in the present scenario due to financial toxicity.5

In the end, we appreciate the work done by T. André et al. in this controversial area. Although this trial has some limitations, a longer follow-up might help to clarify the survival benefit. A one-of-its-kind ongoing study initiated by our institute is trying to measure the impact low dose immunotherapy on overall survival in MSI-H solid tumors progressed on first-line therapy and the results are eagerly awaited.

References:
  • 1. Ostwal V, Pande NS, Engineer R, et al. Low prevalence of deficient mismatch repair (dMMR) protein in locally advanced rectal cancers (LARC) and treatment outcomes. J Gastrointest Oncol. 2019;10(1):19-29.
  • 2. Battaglin F, Naseem M, Lenz HJ, Salem ME. Microsatellite instability in colorectal cancer: an overview of its clinical significance and novel perspectives. Clin Adv Hematol Oncol. 2018;16(11):735-745.
  • 3. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018; 36: 773-9.
  • 4. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18:1182-91.
  • 5. Noronha V, Abraham G, Patil V et. al. A real-world data of Immune checkpoint inhibitors in solid tumors from India. Cancer Med. 2021 Mar;10(5):1525-1534.
    • 4. The Role of Adjuvant Chemotherapy in Metaplastic Breast Carcinoma: A Competing Risk Analysis of the SEER Database

      https://doi.org/10.3389/fonc.2021.572230, Front. Oncol., 26 April 2021

      Tian Lan, et al from multiple academic centers in China.

      Abstract

      Purpose: Chemotherapy is the clinically recommended treatment for patients with operable metaplastic breast carcinoma (MBC); however, its impact remains controversial. This study investigated the possible role of chemotherapy in the treatment of MBC.

      Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify the operable MBC patients. The competing risk analysis along with the propensity score matching (PSM) method was performed to evaluate the effect of chemotherapy. Moreover, a competing risk nomogram was built to identify prognosis in patients with MBC.

      Results: Of the 1137 patients with MBC, 775 received chemotherapy and 362 did not receive chemotherapy. The 5-year cumulative incidence of breast cancer-specific death (BCSD) showed similar outcomes in both the Chemo and No-Chemo groups (21.1 vs. 24.3%, p = 0.57). Chemotherapy showed no apparent association with BCSD (HR, 1.07; 95% CI, 0.72–1.60; p = 0.72), even after subgroup analysis or PSM. Race, tumor size, lymph node status, and radiation were identified as the significant factors for MBC after a penalized variable selection process. In addition, a competing risk nomogram showed relatively good accuracy of prediction with a C-index of 0.766 (95% CI, 0.700–0.824).

      Conclusion: Our findings demonstrated that chemotherapy did not improve BCSD for operable MBC patients. Thus, it may indicate the need to reduce exposure to the current chemotherapy strategies for patients with resectable MBC. Additionally, some novel treatment strategies are required urgently to identify and target the potential biomarkers.

      COMMENTARY BY: DR. TARINI P. SAHOO, CONSULTANT MEDICAL ONCOLOGIST, BHOPAL, INDIA

      Metaplastic breast cancer (MBC) is a rare subtype, constituting 1-2% of cancer breast. I recently encountered a case of operable MBC, postmenopausal, T3N0M0, ER positive, PR and Her-2/neu negative, for opinion regarding adjuvant chemotherapy. As a medical oncologist, the dilemma was whether to offer her any form of chemotherapy and if so what regimen?

      On literature search, the data is sparse and conflicting, but the general view one gets is the benefit of adjuvant chemotherapy is at best marginal. The paper by Lan etal., is a nice read, giving a comprehensive view of the data on adjuvant chemotherapy in MBC till date. They concluded that adjuvant chemotherapy does not benefit in reducing cancer specific mortality, but I feel that it has to be indivualized but definitely in an elderly or patient with multiple co-morbidities or a reluctant patient, this can be avoided without much deliberation.

      I decided to offer the lady adjuvant weekly paclitaxel for 12 weeks to be followed by hormonal therapy and radiotherapy. The available options ranged from a full dose anthracycline followed by taxane, anthracycline alone apart from what I had offered. Definitely not offering adjuvant CT was on the cards, especially with the available data.

      Have I offered the best possible regimen is anybody’s guess? As a medical oncologist, we often stand on similar crossroads, in tumor subtypes, where the data is inconclusive and we need to take a decision hoping that the best opinion has been offered.


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