The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases, including non-malignant ones. Despite the great success, there are several challenges surrounding CAR T-cell therapies, such as non-durable responses and high-grade toxicities. In addition, a new safety concern was added by the FDA on 28 November 2023 following reports of T-cell malignancies in patients previously treated with either anti-CD19 or anti-BCMA autologous CAR T-cell therapies both in clinical trials and in the real-world setting. Since then, several reports have been published presenting the incidence and analysing the risks of other secondary malignancies after CAR T-cell therapies. In this opinion article, the current landscape of secondary malignancies after CAR T-cell therapies is presented, along with a proposed strategy for future research aiming at potentially diminishing or abrogating the risk of developing secondary malignancies after CAR T-cell therapies.

Two by Two Factorial Design using Metformin and Curcumin for Second Primary Head and Neck Cancer Prevention Trial.

OBJECTIVE: The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without substantially increasing the required sample size. In view of the considerable preclinical evidence for Curcumin and Metformin in preventing the development and progression of head and neck squamous cell carcinoma (HNSCC), this study describes the protocol of the clinical trial towards applying the drug combination in prevention of second primary tumors. METHODS: We have applied the trial design to a large phase IIB/III double-blind, multi-centric, placebo-controlled, randomized clinical trial to determine the safety and efficacy of Metformin and Curcumin in the prevention of second primary tumours (SPT) of the aerodigestive tract following treatment of HNSCC (n=1,500) [Clinical Registry of India, CTRI/2018/03/012274]. Patients recruited in this trial will receive Metformin (with placebo), Curcumin (with placebo), Metformin, and Curcumin or placebo alone for a period of 36 months. The primary endpoint of this trial is the development of SPT, while the secondary endpoints are toxicities associated with the agents, incidence of recurrence, and identifying potential biomarkers. In this article, we discuss the 2x2 factorial design and how it applies to the head and neck cancer chemoprevention trial. CONCLUSION: 2x2 factorial design is an effective trial design for chemoprevention clinical trials where the effectiveness of multiple interventions needs to be tested parallelly.

Radiation Therapy Technology Advances and Mitigation of Subsequent Neoplasms in Childhood Cancer Survivors.

PURPOSE: In this Pediatric Normal Tissue Effects in the Clinic (PENTEC) vision paper, challenges and opportunities in the assessment of subsequent neoplasms (SNs) from radiation therapy (RT) are presented and discussed in the context of technology advancement. METHODS AND MATERIALS: The paper discusses the current knowledge of SN risks associated with historic, contemporary, and future RT technologies. Opportunities for research and SN mitigation strategies in pediatric patients with cancer are reviewed. RESULTS: Present experience with radiation carcinogenesis is from populations exposed during widely different scenarios. Knowledge gaps exist within clinical cohorts and follow-up; dose-response and volume effects; dose-rate and fractionation effects; radiation quality and proton/particle therapy; age considerations; susceptibility of specific tissues; and risks related to genetic predisposition. The biological mechanisms associated with local and patient-level risks are largely unknown. CONCLUSIONS: Future cancer care is expected to involve several available RT technologies, necessitating evidence and strategies to assess the performance of competing treatments. It is essential to maximize the utilization of existing follow-up while planning for prospective data collection, including standardized registration of individual treatment information with linkage across patient databases.

Chemotherapy for primary cancer can reduce the risk of head and neck second primary malignancy: a propensity-matched analysis.

OBJECTIVES: To investigate the effect of chemotherapy versus no chemotherapy on the risk of second primary head and neck malignancies (SPHNMs) in patients with locally advanced oral squamous cell carcinoma (OSCC) and to assess the survival outcomes of patients with SPHNM. MATERIALS AND METHODS: A total of 937 OSCC patients were divided into chemotherapy and nonchemotherapy groups by propensity score matching (PSM). In the presence of the competing event of non-SPHNM death, the fine and gray modified Cox proportional hazard model was fitted to detect the impact of various factors, including the history of chemotherapy, on SPHNM risk. The Kaplan-Meier method was used to assess the survival outcomes of patients. RESULTS: After PSM, the 10-year cumulative probability of SPHNM was 10.7% for patients who received chemotherapy and 22.1% for patients who did not. The fine and gray regression model showed that prior chemotherapy was associated with a 51% reduced risk of SPHNM (adjusted subdistribution hazard ratio (sHR): 0.49, 95% confidence interval (CI): 0.29-0.84, P = 0.1). The disease-free survival (DFS) rates did not differ significantly between the SPHNM and non-SPHNM groups. And there were no significant differences in DFS rates between the patients with and those without prior chemotherapy in the SPHNM group. CONCLUSIONS: Chemotherapy for locally advanced primary OSCC is associated with a decreased incidence of subsequent SPHNM. However, chemotherapy for the primary cancer does not improve DFS in patients with SPHNM. CLINICAL RELEVANCE: Chemotherapy plays a positive role in preventing SPHNMs for patients with oral squamous cell carcinoma. CLINICAL TRIAL REGISTRATION: Before January 2015, the data were retrieved retrospectively, while after January 2015, the data were collected prospectively in a POROMS database (ClinicalTrials.gov ID: NCT02395367).

Cancer Prevention for Survivors: Incidence of Second Primary Cancers and Sex Differences-A Population-Based Study from an Italian Cancer Registry.

BACKGROUND: The number of cancer survivors continues to increase, thanks to advances in cancer diagnosis and treatment. Unfortunately, the incidence of a second primary cancer (SPC) is also increasing, but limited studies reporting incidence data are available regarding multiple cancers. This study presents our observations on multiple primary malignant cancers, the associations between sites, and the inherent sex differences. PATIENTS AND METHODS: We report the data, disaggregated by sex, concerning the SPCs that were recorded in the "Registro Tumori Integrato" (RTI) a population-based cancer registry in Sicily, Italy, as observed in the period from 2003 to 2017, in a total population of approximately 2,300,000. SPCs were divided into synchronous and metachronous cancers. The International Classification of Diseases for Oncology, third edition (ICD-O-3), was used for topographical and morphological classifications. Multiple primary cancers with multi-organ primitiveness were selected from the database of the RTI by extracting patients with more than one diagnosis. SPCs had different histology or morphology from the particular cancer that was considered to be the index cancer case. Multicenter or multifocal cancers, or metastases, were excluded. The percentages of cancer by sex and topography, the average age of incidence, and a breakdown by age were computed. RESULTS: Differences were observed between sexes in terms of incidence and site for SPCs. The most frequent SPC was skin cancer (20% of the SPCs observed). The associations among sites of multiple cancers are reported. CONCLUSION: There are many gaps in our knowledge of sex differences in cancer. The study of multiple primary cancers could bring more likely opportunities for evaluation of the cancer burden and trends that can be used to identify new research areas by population health programs, as well as for clinical researchers.

Active exercise after polypectomy reduces the risk of metachronous advanced colorectal neoplasm.

BACKGROUND AND STUDY AIMS: Exercise is associated with a lower risk of colorectal neoplasm but its association with metachronous advanced colorectal neoplasm development after polypectomy remains unclear. We aimed to investigate associations between subjects' exercise habits and the risk of metachronous advanced colorectal neoplasm. PATIENTS AND METHODS: This study analyzed subjects older than 40 years who received screening colonoscopy with polypectomy and surveillance colonoscopy between January 2009 and December 2016. All participants completed a standard questionnaire containing exercise habits before surveillance colonoscopy. Subjects' exercise habits were quantified as weekly exercise amounts (metabolic equivalents of task-day/week) and dichotomized (active/sedentary exercise habit) using averages as the cut-off point. The associations between incidence of metachronous advanced colorectal neoplasm and exercise habits were evaluated using Kaplan-Meier analysis and Cox regression models. RESULTS: A total of 1820 subjects comprised the study cohort and 86 (4.73%) of them developed metachronous advanced colorectal neoplasm during the surveillance period. An active exercise habit after polypectomy was associated with a lower risk of metachronous advanced colorectal neoplasm (adjusted hazard ratio [aHR] 0.57, 95% confidence interval [CI] 0.35-0.91). Furthermore, this protective effect from exercise was specific for subjects having advanced neoplasm at screening colonoscopy (aHR 0.32, 95% CI 0.11-0.94). CONCLUSIONS: An active exercise habit after polypectomy, a surrogate for a more active lifestyle, is associated with a lower risk for developing metachronous advanced colorectal neoplasm. A positive lifestyle modification, such as maintaining/establishing an active exercise habit, should be advised after polypectomy, especially for those with advanced colorectal neoplasm during screening.

Surgery and prophylactic surgery in hereditary breast cancer.

Women with hereditary breast cancer are at increased risk of second primary cancers in the ipsilateral and contralateral breast. The level of risk varies with mutation and age at first breast cancer diagnosis. These factors as well as life expectancy should be considered when selecting the surgical approach.

[Hairy cell leukemia: What are the best treatment options for relapsed or refractory patients?] / Leucémie à tricholeucocytes : quelles sont les meilleures options thérapeutiques pour les patients en rechute ou réfractaires ?

Hairy cell leukemia is a rare form of leukemia: three hundred new cases are diagnosed each year in France. The diagnosis is based on: (1) morphological examination of the blood and bone marrow smear, (2) analysis by flow cytometry of hairy cells, which express three or the four following markers: CD11c, CD25, CD103 and CD123, (3) identification of the BRAFV600E mutation, a true molecular marker of the disease. The management of treatment has evolved considerably in recent years. As of today, the purine analogues remain the standard treatment in the first line. Relapses are however observed in about 40% of cases. In the event of a first relapse, the preferred option is treatment with immunochemotherapy i.e. a combination of cladribine plus rituximab. Subsequent relapses are treated with moxetumomab pasudotox or BRAF inhibitors which provide indisputable benefits if third-line treatment is required. We will discuss in patients with relapsed/refractory hairy cell leukemia the needs for personalized medicine and the advantages and disadvantages of each treatment modality. The good prognosis for LT requires treatments that are not immunosuppressive, non-myelotoxic, and do not increase the risk of secondary cancers.

Young Adult Cancer Survivorship: Recommendations for Patient Follow-up, Exercise Therapy, and Research.

Survivors of adolescent and young adult cancers (AYAs) often live 50 to 60 years beyond their diagnosis. This rapidly growing cohort is at increased risk for cancer- and treatment-related 'late effects' that persist for decades into survivorship. Recognition of similar issues in pediatric cancer survivors has prompted the development of evidence-based guidelines for late effects screening and care. However, corresponding evidence-based guidelines for AYAs have not been developed. We hosted an AYA survivorship symposium for a large group of multidisciplinary AYA stakeholders (approximately 200 were in attendance) at Princess Margaret Cancer Centre (Toronto, Ontario, Canada) to begin addressing this disparity. The following overview briefly summarizes and discusses the symposium's stakeholder-identified high-priority targets for late effects screening and care and highlights knowledge gaps to direct future research in the field of AYA survivorship. This overview, although not exhaustive, is intended to stimulate clinicians to consider these high-priority screening and care targets when seeing survivors in clinical settings and, ultimately, to support the development of evidence-based late effects screening and care guidelines for AYAs.

Helicobacter pylori eradication prevents secondary gastric cancer in patients with mild-to-moderate atrophic gastritis.

BACKGROUND AND AIM: Whether Helicobacter pylori eradication prevents metachronous recurrence after endoscopic resection (ER) of early gastric cancer remains controversial. This multicenter retrospective study aimed to evaluate the long-term (> 5 years) effects of H. pylori eradication by stratifying patients' baseline degrees of atrophic gastritis. METHODS: A total of 483 H. pylori-positive patients who had undergone ER for early gastric cancer were divided into two groups-(i) those having undergone successful H. pylori eradication within 1 year after ER (eradicated group, n = 294) and (ii) those with failed or not attempted H. pylori eradication (non-eradicated group, n = 189). The cumulative incidences of metachronous gastric cancer between the two groups were compared for all patients, for patients with mild-to-moderate atrophic gastritis (n = 182), and for patients with severe atrophic gastritis (n = 301). RESULTS: During a median follow-up of 5.2 years (range 1.1-14.8), metachronous cancer developed in 52 (17.7%) patients in the eradicated group and in 35 (18.5%) patients in the non-eradicated group (P = 0.11, log-rank test). In patients with mild-to-moderate atrophic gastritis (111 and 71 in the eradicated and non-eradicated groups, respectively), the cumulative incidence of metachronous cancer was significantly lower in the eradicated group than that in the non-eradicated group (P = 0.03, log-rank test). However, no significant intergroup difference was observed in patients with severe atrophic gastritis (P = 0.69, log-rank test). CONCLUSIONS: Helicobacter pylori eradication had a preventive effect on the development of metachronous gastric cancer in patients with mild-to-moderate atrophic gastritis.

Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.

BACKGROUND: Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data. AIM: Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7. METHODS AND RESULTS: We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months. CONCLUSIONS: These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.

Impact of radiation techniques on lung toxicity in patients with mediastinal Hodgkin's lymphoma.

PURPOSE: Mediastinal radiotherapy (RT), especially when combined with bleomycin, may result in substantial pulmonary morbidity and mortality. The use of modern RT techniques like intensity-modulated radiotherapy (IMRT) is gaining interest to spare organs at risk. METHODS: We evaluated 27 patients who underwent RT for Hodgkin's lymphoma between 2009 and 2013 at our institution. For each patient, three different treatment plans for a 30-Gy involved-field RT (IFRT) were created (anterior-posterior-posterior-anterior setup [APPA], 5­field IMRT, and 7­field IMRT) and analyzed concerning their inherent "normal tissue complication probability" (NTCP) for pneumonitis and secondary pulmonary malignancy. RESULTS: The comparison of different radiation techniques showed a significant difference in favor of standard APPA (p < 0.01). The risk of lung toxicity was significantly higher in plans using 7­field IMRT than in plans using 5­field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5­field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7­field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7­field IMRT over 5­field IMRT (Burman: 0.6%). Further analysis showed an increase in risk for secondary pulmonary malignancies to be statistically significant (p < 0.01); mean induction probability for pulmonary malignoma was 0.1% higher in plans using 5­field IMRT than APPA and 0.19% higher in plans using 7­field IMRT than APPA as well as 0.09% higher in plans using 7­field IMRT than 5­field IMRT. During a median follow-up period of 65 months (95% confidence interval: 53.8-76.2 months), only one patient developed radiation-induced pneumonitis. No secondary pulmonary malignancies have been detected to date. CONCLUSION: Radiation-induced lung toxicity is rare after treatment for Hodgkin lymphoma but may be influenced significantly by the RT technique used. In this study, APPA RT plans demonstrated a decrease in potential radiation pneumonitis and pulmonary malignancies. Biological planning using NTCP may have the potential to define personalized RT strategies.

Considerations for Child Cancer Survivors and Immunocompromised Children to Prevent Secondary HPV-associated Cancers.

Survivors of childhood cancer and other immunocompromised children are at high risk for the development of secondary human papillomavirus (HPV)-associated cancers. In this overview, the authors examine the epidemiology of vaccine efficacy, the natural history of HPV infections, and accelerated HPV-associated cancer development in these populations. The authors highlight the opportunities for preventive care and future research directives.

Successful Eradication of Helicobacter pylori Could Prevent Metachronous Gastric Cancer: A Propensity Matching Analysis.

BACKGROUND AND AIM: Helicobacter pylori is the leading cause of gastric cancer, but it is still uncertain whether eradicating H. pylori in early gastric cancer (EGC) patients who underwent endoscopic resection can prevent metachronous gastric cancer (MGC). This study aimed to investigate the effect of H. pylori eradication to prevent MGC after endoscopic submucosal dissection (ESD). METHODS: In this propensity-matched retrospective observational study, 770 patients with EGC who received ESD were enrolled. The outcome was the incidence of MGC; this was compared between the persistent and eradicated groups. RESULTS: MGC was detected in 27 patients (7.8%) during a median period of 39.0 months (range 26.0-64.0). After propensity matching, 126 pairs of patients in each group were analyzed. The 5-year cumulative incidence rates of MGC were 13.2 and 3.9% in the persistent and eradicated groups, respectively (p= 0.021, log-rank test). On multivariate analysis, H. pylori eradication prevented MGC significantly (hazard ratio [HR] 0.32; p = 0.029). The results remained robust after inverse probability of treatment weighting analysis (HR 0.30; p = 0.020). CONCLUSIONS: Successful H. pylori eradication could prevent MGC after ESD for EGC.

Proton pencil beam scanning reduces secondary cancer risk in breast cancer patients with internal mammary chain involvement compared to photon radiotherapy.

PURPOSE: Proton pencil beam scanning (PBS) represents an interesting option for the treatment of breast cancer (BC) patients with nodal involvement. Here we compare tangential 3D-CRT and VMAT to PBS proton therapy (PT) in terms of secondary cancer risk (SCR) for the lungs and for contralateral breast. METHODS: Five BC patients including supraclavicular (SVC) nodes in the target (Group 1) and five including SVC plus internal-mammary-nodes (IMNs, Group 2) were considered. The Group 1 patients were planned by PT versus tangential 3D-CRT in free-breathing (FB). The Group 2 patients were planned by PT versus VMAT considering both FB and deep-inspiration breath hold (DIBH) irradiation. The prescription dose to the target volume was 50 Gy (2 Gy/fraction). A constant RBE = 1.1 was assumed for PT. The SCR was evaluated with the excess absolute risk (EAR) formalism, considering also the age dependence. A cumulative EAR was finally computed. RESULTS: According to the linear, linear-exponential and linear-plateau dose response model, the cumulative EAR for Group 1 patients after PT was equal to 45 ± 10, 17 ± 3 and 15 ± 3, respectively. The corresponding relative increase for tangential 3D-CRT was equal to a factor 2.1 ± 0.5, 2.1 ± 0.4 and 2.3 ± 0.4. Group 2 patients showed a cumulative EAR after PT in FB equal to 65 ± 3, 21 ± 1 and 20 ± 1, according to the different models; the relative risk obtained with VMAT increased by a factor 3.5 ± 0.2, 5.2 ± 0.3 and 5.1 ± 0.3. Similar values emerge from DIBH plans. Contrary to photon radiotherapy, PT appears to be not sensitive to the age dependence due to the very low delivered dose. CONCLUSIONS: PBS PT is associated to significant SCR reduction in BC patients compared to photon radiotherapy. The benefits are maximized for young patients with both SVC and IMNs involvement. When combined with the improved sparing of the heart, this might contribute to the establishment of effective patient-selection criteria for proton BC treatments.

Cancer progression and the invisible phase of metastatic colonization.

Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.

Second primary breast cancer after unilateral mastectomy alone or with contralateral prophylactic mastectomy.

BACKGROUND: An increasing number of patients undergo contralateral prophylactic mastectomy (CPM) for unilateral breast cancer. However, the benefit of CPM has not been quantified in the setting of contemporary breast cancer therapy. METHODS: We performed an analysis of 180 068 patients in the Surveillance, Epidemiology, and End Results (SEER) database, diagnosed with unilateral ductal breast carcinoma between 1998 and 2013 and treated with unilateral mastectomy (UM) or CPM. UM was performed in 146 213 patients (81.2%); CPM was performed in 33 855 patients (19.8%). Primary outcome of interest was cumulative incidence of a second primary breast cancer in the ipsilateral or contralateral breast greater than 3 months after initial diagnosis. Cumulative incidence analysis was based on a Cox proportional model to generate curves of second primary breast cancer in any breast, ipsilateral breast only, or contralateral breast only. RESULTS: Patients who underwent CPM had a significantly reduced incidence of second primary breast cancer 10 and 15 years after surgery (CPM 0.93% [0.73%, 1.12%] vs UM 4.44% [4.28%, 4.60%]). Patients who underwent CPM had significantly lower adjusted hazard of second primary breast cancer when compared with UM (HR 0.38 vs 1.0, P < .0001). CONCLUSIONS: CPM offers some protection from a second primary breast cancer, attributable to a reduced incidence in the contralateral breast. These findings provide additional information to providers and patients as they make decisions regarding surgical management. They should also be interpreted in the context of the absolute incidence of second primary breast cancer after UM and previous literature demonstrating no survival benefit.