Effects of food-based interventions in the management of chemoradiotherapy-induced nausea and vomiting: a systematic review.

BACKGROUND: Cancer treatment-related nausea and vomiting continue to be common and distressing symptoms for patients, despite improvements in antiemetics. Dietary modifications could potentially improve this symptom experience. Clinicians frequently provide dietary advice to patients, although the evidence base of such suggestions or recommendations is not clear. PURPOSE: This systematic review aimed to examine the current literature on food interventions associated with improvements in cancer treatment-related nausea and vomiting. METHODS: Eight electronic databases were searched with a specific search term strategy covering trials without time or language limitations. Eligible studies focused on a food substance, defined as any nutritious substance that people eat or drink to maintain life and well-being. Trials in children and adults during chemotherapy or radiotherapy were included. Cochrane risk of bias tool was used to assess trial quality and GRADE was used to assess the certainty in the effect of each outcome. RESULTS: Seventeen trials were included, 3 focusing on children and 14 on adults. Two trials included patients receiving radiation. Ten out of 17 trials (59%) had a high risk of bias. Strongest evidence with highest certainty was found for dietary counseling to meet macronutrient requirements in reducing incidence of radiotherapy-related nausea and vomiting in adults (n=2 studies; n=124 participants; GRADE level: moderate). There was also moderate certainty in the beneficial effect of protein supplementation on nausea and vomiting incidence in adults during radiotherapy (n=2 studies; n=124 participants; GRADE level: moderate). A significant positive effect on CINV incidence and/or severity in adults was also found for dietary counseling to meet macronutrient requirements during chemotherapy, a peppermint drink, scaly wood mushroom, chamomile, protein with ginger, and a colorless odorless diet (GRADE level: low to very low). CONCLUSIONS: The review identified food-based approaches that could improve the nausea and vomiting experience in patients with cancer and provide guidance to clinicians. However, confidence in these findings was low and studies were heterogeneous and mostly of low quality, requiring further investigation before stronger recommendations can be made. Future research is needed to confirm efficacy and safety. TRIAL REGISTRATION: PROSPERO CRD42022341154.

A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy.

The prognosis for patients with metastatic breast cancer remains poor. Metastatic breast cancer confined to the bones may have a better prognosis, especially hormone receptor-positive disease. We performed a prospective, randomized clinical trial to compare immediate consolidation with high-dose chemotherapy and hematopoietic support versus observation with high-dose consolidation at the time of disease progression in women with metastatic breast cancer and only bone metastases. The patients received chemotherapy with doxorubicin, 5-fluorouracil and methotrexate before randomization. In all, 85 patients were enrolled and 69 were randomized. The median follow-up is 8.1 years from randomization. The median event-free survival (EFS) for the immediate transplant arm is 12 months and for the observation arm is 4.3 months (P<0.0001). The median overall survival for the immediate transplant arm is 2.97 years and for the observation arm 1.81 years, a difference that is not statistically significant. Immediate high-dose chemotherapy and radiation therapy as consolidation offers a clinically and statistically significant improvement in EFS compared with radiation therapy alone following induction chemotherapy for women with metastatic breast cancer confined to the bones.

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support.

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci ( 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases ( 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind, dose-ranging study.

Uncontrolled clinical trials have shown that parenteral administration of GM-CSF reduces the frequency of chemotherapy-induced mucositis. The mechanism of this effect could be related to acceleration of haematopoiesis and/or increase in functional activation of WBC. We conducted a double-blind, placebo-controlled, dose ranging study of GM-CSF (mol-gramostim) mouthwash in patients with breast cancer during the first treatment cycle of a combination chemotherapy regimen which has historically produced dose-limiting (grade > or = 3) mucositis in approximately 39% of patients. Subjects were randomized to receive either placebo mouthwash (0.1 percent albumin) or one of four concentrations of GM-CSF mouthwash (0.01, 0.1, 1.0 or 10 mcg/ml). The primary endpoint was to evaluate the relationship between dose of GM-CSF mouthwash received and probability of grade > or = 3 mucositis using a logistic model. Solutions were administered four times daily starting within 24 hours of chemotherapy initiation and continuing until the end of the cycle (day 21). Mucositis was assessed on days 1-6, 10, 15 and 21. Day 6 plasma samples were assayed for GM-CSF. Forty-five patients were evaluable for response (nine per dosing group). A 42% risk (15/36) of mucositis grade > or = 3 was evident on day 15 in patients receiving GM-CSF compared to 2 of 9 patients on the placebo arm. No evidence of dose response was found by logistic regression. Five patients had a detectable plasma concentration of GM-CSF (56-209 pg/ml). A positive correlation between GM-CSF dose and leukocyte recovery was noted (P = 0.04).

Bone metastases from breast cancer: value of CT bone windows.

A pilot study was organized to compare the utility of scintigraphy, radiographic bone surveys, and conventional CT bone windows (CTBWs) in judging therapeutic response of bone lesions in patients with metastatic breast carcinoma. Twenty-six patients with stage IV disease and documented bone metastases were evaluated over a 2 year period. Discordance in the assessment of therapeutic response was greatest (56% discordance) between bone scans (BSs) and conventional CTBWs. In 77% of the discordant observations, the assessment by conventional CTBWs agreed with the patients' clinical response to therapy. Our preliminary results suggest that posttherapy review of conventional CTBWs provides useful clinical information about therapeutic response and exceeds the contribution of BSs in this regard.

4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial.

We designed an ex vivo bone marrow treatment for breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support (ABMS), using 4-hydroperoxycyclophosphamide (4-HC), an active derivative of cyclophosphamide with known activity against breast cancer. This phase I bone marrow purging trial used ficoll-separated mononuclear cells (MNC) (devoid of granulocytes and RBCs), as opposed to the buffy coat. Twenty-five patients with metastatic breast cancer were studied. Patients received three cycles of the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate (Duke AFM) regimen, followed by marrow harvest. An MNC fraction of marrow was prepared and treated with 4-HC in concentrations of 20 micrograms/mL (four patients), 40 micrograms/mL (four patients), 60 micrograms/mL (nine patients), or 80 micrograms/mL (eight patients) and cryopreserved. Patients then received high-dose systemic cyclophosphamide, cisplatin, and carmustine, followed by infusion of the purged marrow. The study end point was marrow engraftment, defined as WBC count greater than 1,000 cells per microliter. At the first three dose levels (20, 40, and 60 micrograms/mL 4-HC), there was no significant delay in time to engraftment (19, 20, and 23 days, respectively) compared with the unpurged historical controls (17 days). At 80 micrograms/mL, engraftment was significantly delayed compared with the lower concentrations (P = .027), and further escalation of 4-HC was not attempted. A significant correlation was observed between the time of leukocyte engraftment and the 4-HC concentration (P = .017). With a methylcellulose-based tissue culture assay, we demonstrated a statistically significant correlation between the colony-forming unit-granulocyte-macrophage (CFU-GM) content in the purged marrow and the days to engraftment. Ninety-five percent of patients responded clinically to the entire program, 55% of them completely. Longer follow-up is required to assess the ultimate benefit of intensive therapy on long-term survival.

The Duke AFM Program. Intensive induction chemotherapy for metastatic breast cancer.

Forty-five patients have completed treatment with AFM, an intensive induction chemotherapy regimen composed of Adriamycin (doxorubicin, Adria Laboratories, Columbus, Ohio), 5-fluorouracil, and methotrexate with folinic acid rescue. This regimen was designed to produce rapid and extensive tumor shrinkage prior to high-dose alkylating agent chemotherapy with autologous marrow support. The overall response rate was 91%, and 38% of patients achieved complete clinical responses after a mean of 70 days on treatment. Hematologic and mucosal toxicity were extensive, but no toxic deaths were noted. AFM is a potent remission induction regimen for metastatic breast cancer, but its considerable toxicity suggests caution in its use for routine breast cancer treatment.

High-dose carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support: excessive hepatic toxicity.

Intensive doses of carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support were given to four patients with advanced melanoma. Three developed clinically diagnosed, severe veno-occlusive liver disease, which was fatal in two cases. The dose of carboplatin (450 mg/m2) was comparable with that used in ambulatory regimens. At the doses and schedule employed, this three-drug combination produced excessive hepatic toxicity. Caution is suggested when giving carboplatin in combination with intensive doses of other chemotherapeutic agents with known hepatotoxic potential.

Neutrophil migration is defective during recombinant human granulocyte-macrophage colony-stimulating factor infusion after autologous bone marrow transplantation in humans.

We have previously reported that continuous intravenous (IV) administration of recombinant granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) to humans following high-dose alkylating agent chemotherapy and autologous bone marrow support (ABMS) results in myeloid bone marrow maturation, accelerated granulocyte recovery, and reduced treatment-related toxicity. However, we found that leukocyte counts declined rapidly after discontinuation of rHuGM-CSF therapy, which suggests possible growth factor effects on leukocyte margination and migration. For these reasons we studied granulocyte margination by using 111In-labeled autologous granulocytes and found similar granulocyte margination before (21.5% +/- 13.4%) and during continuous IV rHuGM-CSF infusion (23.3% +/- 9.6%). Phagocytosis of Cryptococcus neoformans and granulocyte hydrogen peroxide production was similar before and during rHuGM-CSF infusion and similar to patients treated with the same high-dose chemotherapy and ABMS but not receiving growth factor. However, migration of granulocytes to a sterile inflammatory site was markedly reduced during continuous rHuGM-CSF infusion (1.2 +/- 0.9 WBCs/cm2, 24 hr) as compared with baseline (39.6 +/- 17.7 WBCs/cm2/24 hr; P less than .0008). These findings may be of relevance when extravascular granulocytes are required for host defense.