Cancer Research and Treatment

Original Articles

Real-World Experience of Weekly Carfilzomib in Combination with Cyclophosphamide and Dexamethasone in Multiple Myeloma Relapsed/Refractory to Bortezomib and Lenalidomide: Cheongin Yang, Changgon Kim, Kunye Kwak, Ka-Won Kang, Yong Park, Byung Soo Kim, Seong Hyun Jeong, Joon Seong Park, Yoon Seok Choi; Received April 17, 2025 Accepted April 24, 2025 Published online April 25, 2025; DOI: https://doi.org/10.4143/crt.2025.418 [Accepted]

Abstract PDF: Purpose
This retrospective study evaluated the efficacy and safety of a weekly carfilzomib, cyclophosphamide, and dexamethasone (KCd) regimen in patients with relapsed or refractory multiple myeloma (RRMM) who had been previously treated with both bortezomib- and lenalidomide-containing regimens.
Materials and Methods
We conducted a retrospective analysis of 33 patients with RRMM who received the KCd regimen between March 2020 and February 2024. All patients had prior exposure to both bortezomib and lenalidomide, and the majority (93.9%) were refractory to lenalidomide. Carfilzomib was administered once weekly at 70 mg/m² (after a step-up dose), along with oral cyclophosphamide and dexamethasone. Treatment response was assessed according to the International Myeloma Working Group (IMWG) criteria, and survival outcomes were analyzed.
Results
The overall response rate was 66.7%, including a complete response or better in 15.1% of patients and a very good partial response or better in 42.4%. With a median follow-up of 31.7 months, the median progression-free survival (PFS) was 13.5 months (95% CI, 11.47–15.53), while the median overall survival (OS) was not reached. The most common grade ≥3 adverse event was neutropenia (15.2%). Non-hematologic grade ≥3 toxicities were infrequent and manageable.
Conclusion
The weekly KCd regimen demonstrated encouraging efficacy and tolerability in a heavily pretreated RRMM population. These findings support its use as a feasible treatment option, particularly in patients refractory to lenalidomide.

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Low-Dose Cyclophosphamide Enhances the Tumoricidal Effects of 5-Day Spacing Stereotactic Ablative Radiotherapy by Boosting Antitumor Immunity: Hyunkyung Kim, Seok-Joo Chun, Sojung Sun, Haeun Cho, Tae-Jin Kim, Yoon-Jin Lee, Eui Kyu Chie, Kwangmo Yang, Mi-Sook Kim; Received August 21, 2024 Accepted November 7, 2024 Published online November 8, 2024; DOI: https://doi.org/10.4143/crt.2024.807 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aimed to investigate the potential role of low-dose cyclophosphamide (Cy) as a radiosensitizer by evaluating its impact on the immune response and the abscopal effect of stereotactic ablative radiotherapy through preclinical models.
Materials and Methods
CT26 tumors (immunologically hot) and 4T1 tumors (immunologically cold), grown in immunocompetent BALB/c and immunodeficient BALB/c–nude mice, were irradiated with 20 Gy in two fractions with 5-day spacing followed by intraperitoneal injections of 9 mg/kg Cy every 3 days. Immunological changes in CT26 tumors caused by the treatments were assessed using flow cytometry. Changes in the expression of hypoxia-inducible factor-1α (HIF-1α) in tumors were also assessed. Splenocytes and bone marrow–derived dendritic cells (DCs) were exposed to various concentrations of Cy to assess T cell proliferation and DC differentiation.
Results
The combination of Cy with radiotherapy (RT+Cy) significantly suppressed tumor growth compared to RT alone in immunocompetent mice, while that effect was not observed in immunodeficient mice. Additionally, RT+Cy effectively induced abscopal effects in hot and cold tumors, with increased CD8+ T cells in blood and tumors. Significantly higher expression levels of granzyme B, interferon γ, and tumor necrosis factor α were observed in RT+Cy group compared to the RT alone group. In vitro data indicated that low-dose Cy promotes DC differentiation. Low-dose Cy suppressed the radiation-induced upregulation of HIF-1α in the tumors.
Conclusion
Low-dose Cy enhances tumoricidal effects of 5-day spacing high-dose RT by increasing antitumor immune responses.

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Review Article

Improving Conventional or Low Dose Metronomic Chemotherapy with Targeted Antiangiogenic Drugs: Robert S. Kerbel; Cancer Res Treat. 2007;39(4):150-159. Published online December 31, 2007; DOI: https://doi.org/10.4143/crt.2007.39.4.150

Abstract PDF PubReader ePub

One of the most significant developments in medical oncology practice has been the approval of various antiangiogenic drugs for the treatment of a number of different malignancies. These drugs include bevacizumab (Avastin®), the anti-VEGF monoclonal antibody. Thus far, bevacizumab appears to induce clinical benefit in patients who have advanced metastatic disease only or primarily when it is combined with conventional chemotherapy. The reasons for the chemo-enhancing effects of bevacizumab are unknown, and this is a subject that we have been actively studying along with additional ways that antiangiogenic drugs may be combined with chemotherapy. In this respect, we have focused much of our effort on metronomic low dose chemotherapy. We have been studying the hypothesis that some chemotherapy drugs at maximum tolerated doses or other cytotoxic- like drugs such as acute "vascular disrupting agents" (VDAs) can cause an acute mobilization of proangiogenic cells from the bone marrow which home to and colonize the treated tumors, thus accelerating their recovery. These cells include endothelial progenitor cells. This systemic process can be largely blocked by a targeted antiangiogenic drug, e.g. anti-VEGFR-2 antibodies. In addition, metronomic chemotherapy, i.e., close regular administration of chemotherapy drugs at low non-toxic doses with no breaks, over prolonged periods of time not only prevents the acute CEP bone marrow response, but can even target the cells. This potential antiangiogenic effect of metronomic chemotherapy can also be boosted by combination with a targeted antiangiogenic agent. Treatment combinations of metronomic chemotherapy and an antiangiogenic drug have moved into phase II clinical trial testing with particularly encouraging results thus far reported in metastatic breast and recurrent ovarian cancer. Oral chemotherapy drugs such as cyclophosphamide (CTX), methotrexate are the main chemotherapeutics used for such trials. Oral 5-FU prodrugs such as UFT would also appear to be highly suitable based on long term adjuvant therapy studies in patients. Recent preclinical results using metronomic cyclophosphamide and metronomic UFT in models of advanced metastatic breast cancer suggest that this type of combination might be particularly promising for metronomic chemotherapy in this indication, particularly when combined with a targeted antiangiogenic drug.

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Original Articles

High-Dose Chemotherapy of Cyclophosphamide, Thiotepa and Carboplatin (CTCb) followed by Autologous Stem-Cell Transplantation as a Consolidation for Breast Cancer Patients with 10 or more Positive Lymph Nodes: a 5-Year follow-Up Results: Hee-Jung Sohn, Sang-Hee Kim, Gyeong-Won Lee, Shin Kim, Jin-Hee Ahn, Sung-Bae Kim, Sang-We Kim, Woo Kun Kim, Cheolwon Suh; Cancer Res Treat. 2005;37(3):137-142. Published online June 30, 2005; DOI: https://doi.org/10.4143/crt.2005.37.3.137

Abstract PDF PubReader ePub

Purpose

The benefit of consolidation high-dose chemotherapy (HDC) for high-risk primary breast cancer is controversial. We evaluated the efficacy and safety of consolidation HDC with cyclophosphamide, thiotepa and carboplatin (CTCb) followed by autologous stem-cell transplantation (ASCT) in resected breast cancer patients with 10 or more positive lymph nodes.

Materials and Methods

Between December 1994 and April 2000, 22 patients were enrolled. All patients received 2 to 6 cycles of adjuvant chemotherapy after surgery for breast cancer. The HDC regimen consisted of cyclophosphamide 1,500 mg/m²/day, thiotepa 125 mg/m²/day and carboplatin 200 mg/m²/day intravenous for 4 consecutive days.

Results

With a median follow-up of 58 months, 11 patients recurred and died. The median disease-free survival (DFS) and median overall survival (OS) were 49 and 69 months, respectively. The 5-year DFS and OS rates were 50% and 58%, respectively. The 12 patients with 10 to 18 involved nodes had better 5-year DFS (67%) and OS (75%) than 10 patients with more than 18 involved nodes (30% and 38%, respectively). The most common grade 3 or 4 nonhematologic toxicity was diarrhea, which occurred in 5 patients (23%). No treatment-related death was observed.

Conclusion

Consolidation HDC with CTCb followed by ASCT for resected breast cancer with more than 10 positive nodes had an acceptable toxicity but does not show promising survival.

Citations

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Real-world Experience of Improvement in the Survival of Lymphoma and Myeloma Patients with Autologous Stem Cell Transplantation over a 25-year Period
Hyungwoo Cho, Shin Kim, Kyoungmin Lee, Jung Sun Park, Cheolwon Suh
The Korean Journal of Medicine.2021; 96(6): 501. CrossRef
Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged <45)
X. Wang, J. Ren, J. Zhang, Y. Yan, N. Jiang, J. Yu, L. Di, G. Song, L. Che, J. Jia, X. Zhou, H. Yang, H. K. Lyerly
Clinical and Translational Oncology.2016; 18(1): 82. CrossRef

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High-Dose Chemotherapy of Cyclophosphamide, Thiotepa, and Carboplatin (CTCb) Followed by Autologous Stem-Cell Transplantation for Metastatic Breast Cancer Patients: A 6-Year Follow-Up Result: Hee-Jung Sohn, Sang-Hee Kim, Gyeong-Won Lee, Shin Kim, Hye Jin Kang, Jin-Hee Ahn, Sung-Bae Kim, Sang-We Kim, Woo Kun Kim, Cheolwon Suh; Cancer Res Treat. 2005;37(1):24-30. Published online February 28, 2005; DOI: https://doi.org/10.4143/crt.2005.37.1.24

Abstract PDF PubReader ePub

Purpose

The benefit of high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) is controversial. We evaluated the efficacy and safety of HDC with cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by autologous stem-cell transplantation (ASCT) for MBC patients.

Materials and Methods

From September 1994 to December 1999, 23 MBC patients were enrolled. All the patients received 2 to 10 cycles of induction chemotherapy. Before transplantation, 12 patients were in complete response (CR), nine were in partial response (PR), and two had progressive disease (PD). The HDC regimen consisted of cyclophosphamide 1,500 mg/m²/day, thiotepa 125 mg/m²/day and carboplatin 200 mg/m²/day intravenously for 4 consecutive days.

Results

After ASCT, 13 patients (56%) had a CR, five (22%) had a PR, three (13%) had no change, while two (9%) showed a PD. Seventeen patients relapsed or progressed during the median follow-up of 78 months. The median progression-free survival (PFS) time was 11 months and the median overall survival (OS) time was 23 months. The 5-year PFS and OS rates were 22% and 25%, respectively. On the multivariate analyses, less than 4 involved lymph nodes was predictive of a better PFS and OS.

Conclusion

HDC with CTCb for MBC has acceptable toxicity; however, this treatment does not show a survival benefit.

Citations

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Real-world Experience of Improvement in the Survival of Lymphoma and Myeloma Patients with Autologous Stem Cell Transplantation over a 25-year Period
Hyungwoo Cho, Shin Kim, Kyoungmin Lee, Jung Sun Park, Cheolwon Suh
The Korean Journal of Medicine.2021; 96(6): 501. CrossRef

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Hematologic malignancy

Cyclophosphamide, Bortezomib, and Dexamethasone Consolidation in Patients with Multiple Myeloma after Stem Cell Transplantation: The KMM130 Study: Jongheon Jung, Kihyun Kim, Sung-Hoon Jung, Sung-Soo Yoon, Jae Hoon Lee, Jin Seok Kim, Ho-Jin Shin, Soo-Mee Bang, Sang Kyun Sohn, Cheolwon Suh, Dok Hyun Yoon, Sun-Young Kong, Chang-Ki Min, Hyeon-Seok Eom, The Korean Multiple Myeloma Working Party; Cancer Res Treat. 2023;55(2):693-703.; DOI: https://doi.org/10.4143/crt.2022.952

Abstract PDF Supplementary Material PubReader ePub

Purpose
A three-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CVD) shows significant efficacy and manageable toxicity as induction therapy in patients with multiple myeloma.
Materials and Methods
In this phase II study, we enrolled 45 patients who achieved a very good partial response (VGPR) or partial response (PR) after autologous stem cell transplantation (ASCT) and evaluated the efficacy and toxicity of CVD consolidation. CVD consolidation comprised three cycles of cyclophosphamide 300 mg/m² orally on days 1, 8, and 15, and bortezomib 1.3 mg/m² subcutaneously on days 1, 8, 15, and 22, along with dexamethasone 20 mg orally or intravenously on days 1 and 2, 8 and 9, 15 and 16, and 22 and 23.
Results
At enrollment, 39 patients (86.7%) showed VGPR, and nine (13.3%) presented with PR. Nineteen patients (45.2%) achieved a complete response or better as their best response after the end of consolidation. Overall, 22 of 42 patients (52.4%) experienced an improved response status with CVD consolidation. Three-year overall survival and progression-free survival rates were 89.0% and 42.7%, respectively. The most common non-hematologic toxicities were peripheral neuropathy and infection (20.5%), with no grade ≥ 3 neuropathy observed.
Conclusion
These results showed that CVD consolidation therapy improved the response with reasonable toxicity in patients with residual disease after ASCT. This trial was registered with the Clinical Research Information Service, Republic of Korea (KCT0001327).

Citations

Citations to this article as recorded by

Is There Still a Role for Stem Cell Transplantation in Multiple Myeloma?
Morie A. Gertz
Hematology/Oncology Clinics of North America.2024; 38(2): 407. CrossRef
Ginsenoside Rg1 inhibits multiple myeloma and overcomes bortezomib resistance through AMPK-mTOR pathway
Li Lin, Dong Chen, Shuangyue Li, Tiantian Wang
Heliyon.2024; 10(13): e33935. CrossRef

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Case report

A Case of Triple-Alkylating Regimen and Peripheral Blood Stem Cell Transplantation for a Patient with Relapsed Ovarian Carcinoma: Jun Mo Lee, Seok Goo Cho, Jin No Park, Young Sun Hong, Hoon Kyo Kim, Sung Eun Namkoong, Kyung Shick Lee, Chun Choo Kim; J Korean Cancer Assoc. 2000;32(4):817-821.

Abstract PDF: Despite an aggressive surgical debulking followed by front-line chemotherapy, most patients with advanced ovarian carcinoma die of drug-resistant disease. Drug resistance can be overcome in a subset of patients with hematologic malignancies and lymphoma with high-dose therapy (HDT) and hematopoietic stem cell transplantation, suggesting that this therapy may also be value in ovarian carcinoma. We report the successful outcome of HDT and peripheral blood stem cell transplantation (PBSCT) in a 41-year-old nulliparous woman who initially was diagnosed with advanced ovarian carcicnoma with FIGO stage IIIc. Her disease relapsed after 19 months from initial therapy of definitive surgery and intra- and post-operative chemotherapy. Subsequently, she received optimal debulking surgery and salvage chemotherapy followed by HDT with triple- alkylating regimen, composed of cyclophosphamide (100 mg/kg), thiotepa (500 mg/m2), and melphalan (100 mg/m2). Her pretranplant characteristics were platinum-sensitive and complete response state. She showed rapid hematologic recovery and mild regimen-related toxicity (Bear man's toxicity criteria), stomatitis (grade I), cardiac toxicitiy (grade II). She has been followed up for 36 months after the inital therapy and is doing well without relapse.

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Original Articles

Results of CHOP-Bleo / CMED Alternating Chemotherapy for Aggressive Non - Hodgkin's Lymphoma: Suk Jin Kim, In Keun Choi, Sang Chul Oh, Jae Hong Seo, Byung Soo Kim, Sang Won Shin, Yeul Hong Kim, Jun Suk Kim; J Korean Cancer Assoc. 1998;30(2):350-356.

Abstract PDF: PURPOSE
To assess the efficacy and toxicity of a new protocol that consists of CHOP- Bleo alternated with a new regimen of Cyclophosphamide, methotrexate, etoposide, and dexamethasone(CMED) for aggressive Non-Hodgkin's Lymphoma(NHL). PATIENTS AND METHODS: Between January 1991 and December 1996, forty-six patients with Ann Arbor stages II-IV aggressive NHL were treated with alternating cycles of CHOP-Bleo and CMED for a total of 12 cycles. All eligible patients were evaluated for response, disease-free survival, and overall survival.
RESULTS
Twenty-two patients(47.8%) achieved a complete response and overall response rate was 83.9%. The range of survival duration was 1-68+months and the median survival time was 42 months. Overall 3-year survival rate was 54%. The range of disease-free survival time was 6-63+months and 3-year disease-free survival rate was 61%. The most common hematologic toxicity was leukopenia and the incidence of severe leukopenia(<1,000/mm3) was 11%. And alopecia(84.8%) was the most common non-hematologic toxicity.
CONCLUSION
The results of CHOP-Bleo/CMED alternating chemotherapy for patients with aggressive Non-Hodgkin's Lymphoma is not superior to other results of previous studies. Therefore further study will be warranted to determine clinical effectiveness of alternating chemotherapy.

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A Phase 2 Trial of EPOCH (Etoposide, Vincristine, Doxorubicin, Cyclophophamide and Prednisolone) Chemotherapy for Previously Treated Non - Hodgkin's Lymphoma: Baek Yeol Ryoo, Tae You Kim, Young Hyuk Im, Jhin Oh Lee, Taik Koo Yun, Keun Chil Park; J Korean Cancer Assoc. 1998;30(1):127-136.

Abstract PDF: PURPOSE
As a new strategy to modulate drug resistance in the treatment of relapsed or refractory non-Hodgkin's lymphoma(NHL), continuos infusion of drugs has been incorporated into the chemotherapy. We conducted a phase II study to determine the activity and safety of EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisolone) chemotherapy, in which the natursl products are administered as a continuous infusion, for previously treated NHL's of intermediate grade.
MATERIALS AND METHODS
EPOCH chemotherapy (etoposide 50 mg/m2/day 24 hour- continuous infusion, days 1~4, vincristine 0.4 mg/m2/day 24 hour-continuous infusion, days 1~4, doxorubicin 10 mg/m2/day 24 hour-continuous infusion, days 1~4, cyclophosphamide 750 mg/m2 i.v., day 5, prednisolone 60 mg/m2/day p.o. days 1-5) was given to eligible patients every 3 weeks and we assessed response and toxicity of the regimen.
RESULTS
Between June 1993 and December 1995, total 56 patients entered this trial and 49 were evaluable. The complete response rate was 41%(95% C.I.: 27-55%). After follow up of 9~50(median 38) months, progression free survival was 0~39+(median 7) months and the overall survival was 1~44+(median 14) months. The prognostic factor analyses showed that B symtoms and serum LDH level before treatment and response to previous treatment affected complete response rate, and patients' performance status and response to previous treatment affected progression free survival and overall survival. Toxicities of EPOCH regimen were leukopenia, stomatitis, nausea/vomiting and neurotoxicity, but they were tolerable. There was 1 case of treatment-related death due to sepsis. CONDUSION: EPOCH chemotherapy was safe and effective for the patients with relapsed NHL. However, the results of patients with NHL refractory to previous treatment were so poor that more intensive, novel treatment would be needed for this category of patients.

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Effect of Retinoic Acid on the Growth of Subcutaneously Injected C1300 Neuroblastoma and on the Survival of the Host A / J Mice: Hee Boong Park, Byeong Jun, Seung Hoon Choi; J Korean Cancer Assoc. 1994;26(1):113-119.

Abstract PDF: Deficiency of vitamin A and/or its precursors has been associated with increased cancer risk in animals and humans. Therapeutic trials of vitamin A and related compounds(retinoids) have demonstrated activities in several cancerous and precancerous conditions. We measured the effects of a retinoic acid on the growth of subcutaneously injected C1300 neuroblastoma and on the survival of the host A/J mice. The fifty A/J mice were inoculated with 10' of C- 1300 neuroblastoma cell in the right back. They were divided into five groups. One group received saline as a control. Two groups recieved 2 mg/kg and 5 mg/kg of retinoic acid. The other two groups recieved low dose(50 mg/kg and 100 mg/kg) cysclophosphamide. Tumor volume and survival were assessed. The survivals were significantly increased(p<0.05) in three groups, mice recieved 5 mg/kg of retinoic acid, 50 mg/kg and 100 mg/kg of cyclophosphamide. Tumor volumes of the mice treated with 5 mg/kg of retinoic acid were significantly lower than the control group(p<0.05). Retinoic acid suppressed the growth of neuroblastoma, it increased the survival of the treated mice if adequate doses were used.

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