Materials and methods

Patients

A total of 20 patients with haematological malignancies undergoing autologous HSCT at the Department of Haematology, Sahlgrenska University Hospital, Gothenburg, Sweden, were included between June 1998 and February 2002. Five patients who accepted inclusion performed the GE test only before transplantation and were therefore excluded from the analysis. The reasons for not performing the post transplant examination were unwillingness to complete the study without giving a specific reason (n=3), the patient died before follow up (n=1) or technical problems (n=1). Another 71 patients underwent autologous HSCT during the study period but were not enrolled in the study (declined enrolment, n=20; enrolment unintentionally missed for organizational reasons, n=49; language difficulties, n=2).

Apart from their haematological malignancies the patients were otherwise healthy. Two patients with hypertension were receiving a -blocker but no patients were on medication with drugs known to have a prokinetic effect (such as tacrolimus, erythromycin or cisapride) before or during the study period. No patient had a history of ischaemic heart disease and all patients were shown to have a normal ultracardiogram (UCG) before transplant. No patient fulfilled the criteria for diabetes mellitus before inclusion.

Baseline patient characteristics and conditioning of included (n=20) and excluded (n=71) patients will be found in Table 1.

Table 1 - Baseline clinical characteristics for included and not included patients.

Full table

The study protocol was approved by the Ethical Committee and the Isotope Committee of Sahlgrenska University Hospital and all patients gave informed, written consent before inclusion.

Methods

All patients received the same prophylactic antibiotics (orally administered ciprofloxacin 1000 mg/day from day -5 until engraftment, and aciclovir 1200 mg/day from day -7 to+100). Antifungal prophylaxis (fluconazole 100–200 mg/day) was restricted to patients colonized with fungi prior to transplantation. In total, 14 patients were already on medication with aciclovir at the time of inclusion.

Antiemetic therapy (ondansetron) was given during conditioning therapy. Total parenteral nutrition (TPN) was generally started when the daily, oral, caloric intake decreased below 50% of basic needs and was tapered off and stopped when the daily caloric intake exceeded 50% of basic needs.

GE test

GE was evaluated using radiopaque markers (ROMs) 1 week before and approximately 2 months after transplant. At 8.00 am, 20 cubic ROMs with density 1.13 g/cm³ and 3 mm side were given, together with a standard meal, which consisted of porridge and a soft drink (150 ml). The total energy content was 360 kcal. Emptying of ROMs was followed by hourly fluoroscopy, starting 4 h after ingestion until all ROMs were emptied. Emptying was regarded as delayed if any ROMs or more than 30% of ingested ROMs were retained after 6 h in men and women, respectively.¹³

Colonic transit time

In a subgroup of patients, colonic transit time was evaluated, using ROMs 1 week before (n=12) and approximately 2 months after transplant (n=9). It was evaluated by a single, plain, abdominal X-ray 7 days after the start of daily ingestion of 10 ring-shaped ROMs for 6 days. The number of retained ring markers divided by 10 (the daily dose) is the transit time in days.

Clinical GI toxicity

Clinical GI symptoms (nausea, vomiting, early satiety, obstipation and diarrhoea) were recorded prospectively by the patients during a 3-day period before transplant and during another 3-day period in connection with the post transplant, GE evaluation. During the same periods, patients recorded all oral intake. On the basis of these data, the mean, daily, oral energy intake was calculated for each individual. GI toxicity according to the WHO criteria¹⁴ was recorded prospectively by a nurse during the transplant course (from admission until discharge).

Intestinal permeability

GI permeability was assessed by a ⁵¹Cr-EDTA-absorption test¹⁵ before the start of the cytotoxic treatment and 4 days after the stem-cell infusion. The 24-h, urinary excretion of ⁵¹Cr-EDTA was expressed as the percentage of the dose given orally.

Malabsorption test (D-xylose test)

In 14 patients, small intestinal absorption was evaluated before and approximately 3 weeks after the stem-cell infusion, using a D-xylose test. Patients ingested 165 mmol of D-xylose in 500 ml of water and the amount of D-xylose excreted in a 5-h urine collection was measured.¹⁶

Statistics

Results are presented as meanss.d. For statistical comparisons, Fischer's exact test and the Mann–Whitney U-test were used. A P-value<0.05 was considered statistically significant.

Results

GE

Before transplant GE was within the reference range in all patients (including patients who did not complete the study). Post transplant GE (6927 days after stem-cell infusion) was delayed in three patients (15%).

Colonic transit time

In the subgroup of patients in whom colonic transit time was measured, all results were within the normal range (< 2.3. and < 4.3 days for men and women, respectively) before (n=12) and after transplant (64.229.3 days; n=9, data not shown). Three patients were not examined post transplant owing to unintentionally missed intake of ROMs (n=2) and unwillingness to complete the study (n=1).

Clinical toxicity

Gastrointestinal symptoms were recorded by all patients before and after transplant. No patients reported symptoms prior to transplant, but three patients (15%) reported either nausea (n=1) or nausea and vomiting (n=2) post transplant. No GI symptoms were reported by the five patients who did not perform the second GE evaluation. Oral intake was recorded by all patients included before and after transplant. There was a tendency to inferior, oral energy intake before transplant and a significantly greater need for total parenteral nutrition (TPN) during the transplant course among patients who developed gastroparesis after transplant, but clinical GI toxicity according to the WHO was not helpful in identifying patients who developed gastroparesis (Table 2).

Table 2 - Baseline characteristics and clinical outcome according to outcome of gastric emptying post transplant.

Full table

Post transplant GI symptoms did not discriminate between patients with or without gastroparesis since two out of three patients with delayed GE reported no GI symptoms. No patients developed insulin-dependent hyperglycemia or fulfilled the criteria for diabetes mellitus during or after the study period.

Intestinal permeability

Baseline permeability data were obtained from all patients, and on day 4 after stem-cell infusion from 14 patients. There was a significant increase in intestinal permeability on day 4, compared with the baseline (5.02.2% and 1.60.8%, respectively, P<0.0001), but there were no differences between patients with or without delayed GE post transplant (Table 2).

Malabsorption test (D-xylose test)

Baseline D-xylose tests were obtained from 14 patients, and post transplant (227 days after the stem-cell infusion) from nine patients. Missed values were due to nausea (n=2) or technical problems (n=3).

There was a significant decrease in D-xylose excretion post transplant, compared with the baseline (32.312.9 and 46.811.7 mmol/5 h, respectively, P=0.01). Only one patient with gastroparesis performed the post transplant test and therefore no comparisons between groups were made.

Discussion

The main finding in this prospective trial in patients undergoing autologous HSCT was that gastroparesis was diagnosed in only 15% of the patients 2 months post transplant. Furthermore, there was no correlation between gastroparesis and symptoms consistent with the diagnosis. However, patients who developed gastroparesis had nutritional difficulties even before, and during the transplant course.

Three out of 20 patients (15%) reported nausea and/or vomiting approximately 2 months post transplant, which touch upon the results of previous retrospective trials in HSCT patients. In these studies, mainly in allogeneic patients, the proportions of patients with gastroparesis among symptomatic patients have been high but have also varied considerably (53%¹⁰, 100%¹¹ and 80%¹²). One explanation may be that graft-versus-host disease (GVHD) in the upper GI tract may influence the symptoms reported and possibly contribute to gastroparesis.¹² In addition, the patients were selected for severity of symptoms, while in the present study the patients were prospectively included and showed mild GI symptoms not requiring therapy. In the light of the finding that two out of three patients with gastroparesis did not report typical symptoms, there is reason to believe that gastroparesis may be subclinical and that the correlation between delayed emptying and symptoms is very weak. This has also been shown to be the case in other subgroups of patients, for example, in those with diabetes.¹⁷

One of the shortcomings in retrospective trials has been the lack of evaluation of GE and symptoms before transplant, making it difficult to draw any conclusions as to whether delayed GE is caused by the treatment or depends on other factors. The finding in the present trial, that objective GI toxicity during the acute phase of the transplant course failed to predict the development of gastroparesis, gives support to the assumption that some patients may be prone to delayed GE after chemotherapy. On the other hand, the majority of patients with PPNV after HSCT with a conditioning containing cisplatinum for breast cancer turned out to have gastroparesis,¹¹ making it likely that the cause of delayed GE is due to both treatment-related and individual risk factors.

Methodological considerations (patients)

Patients undergoing allogeneic HSCT were not included, since GVHD in the upper GI tract and the use of drugs with prokinetic effect may exert an influence on the interpretation of symptoms and GE.^12,18

A large proportion of patients fulfilling the criteria for inclusion was not included in the study. The main reasons were organizational problems and the fact that the patients regarded the GE evaluation as complicated. This emphasises the need for less complicated methods of evaluating GE in this subset of patients. In this context, different breath tests ¹⁹ have been tried but their possible inaccuracy and the need for cumbersome calculations may cause problems and more reliable and simplified tests are under development.²⁰ It is unlikely that patient drop-out influenced the outcome significantly, since there were no differences in baseline clinical characteristics between those included or excluded. It is therefore, plausible that the results will apply to patients with haematological malignancies undergoing autologous HSCT.

Five of the patients included did not perform the GE evaluation post transplant but in no case was the reason nausea or vomiting, which otherwise might have led to underestimation of the frequency of post transplant gastroparesis.

Methodological considerations (methods)

Scintigraphy is probably regarded as the best method of measuring GE, but this method is expensive and of limited availability. However, measuring GE with ROMs has been shown to be well correlated with scintigraphy in both patients and healthy subjects.^13,21,22 Hence, it is unlikely that the use of scintigraphy would have enabled us to identify a greater proportion of patients with gastroparesis. It should be stressed that both methods necessitate separate reference values for men and women.^13,23

In conclusion, gastroparesis may be involved in some cases of severe, prolonged nausea and vomiting after autologous HSCT, but the incidence seems to be much lower than has been believed from previous retrospective studies. This prospective trial shows that delayed GE did not correlate with symptoms, and therefore alternative explanations of PPNV should be considered. Patients at risk of developing gastroparesis may be found among those with nutritional difficulties before and during the transplant course. The cause of gastroparesis after high-dose chemotherapy is still a puzzle, but it is most likely multifactorial, including both individual and treatment-related factors.

References

1. Snyder DS, Negrin RS, O'Donnell MR et al. Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase. Blood 1994; 84: 1672–1679. | PubMed | ISI | ChemPort |
2. Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups [see comments]. N Engl J Med 1995; 332: 217–223. | Article | PubMed | ISI | ChemPort |
3. Snyder DS, Nademanee AP, O'Donnell MR et al. Long-term follow-up of 23 patients with Philadelphia chromosome- positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia 1999; 13: 2053–2058. | Article | PubMed | ISI | ChemPort |
4. Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation [see comments]. N Engl J Med 2000; 343: 750–758. | Article | PubMed | ISI | ChemPort |
5. Nichols CR, Andersen J, Lazarus HM et al. High-dose carboplatin and etoposide with autologous bone marrow trans- plantation in refractory germ cell cancer: an Eastern Coopera-tive Oncology Group protocol. J Clin Oncol 1992; 10: 558–563. | PubMed | ISI | ChemPort |
6. Wardley AM, Jayson GC, Swindell R et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue [in process citation]. Br J Haematol 2000; 110: 292–299. | Article | PubMed | ISI | ChemPort |
7. Blijlevens NM, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant 2000; 25: 1269–1278. | Article | PubMed | ISI | ChemPort |
8. Rapoport AP, Miller Watelet LF, Linder T et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999; 17: 2446–2453. | PubMed | ISI | ChemPort |
9. Johansson JE, Ekman T. Gastro-intestinal toxicity related to bone marrow transplantation: disruption of the intestinal barrier precedes clinical findings. Bone Marrow Transplant 1997; 19: 921–925. | Article | PubMed | ISI | ChemPort |
10. Brand RE, DiBaise JK, Quigley EM et al. Gastroparesis as a cause of nausea and vomiting after high-dose chemotherapy and haemopoietic stem-cell transplantation [letter] [see comments]. Lancet 1998; 352: 1985. | Article | PubMed | ISI | ChemPort |
11. Hecht JR, Lembo T, Chap L. Prolonged nausea and vomiting after high dose chemotherapy and autologous peripheral stem cell transplantation in the treatment of high risk breast carcinoma. Cancer 1997; 79: 1698–1702. | Article | PubMed | ISI | ChemPort |
12. Eagle DA, Gian V, Lauwers GY et al. Gastroparesis following bone marrow transplantation. Bone Marrow Transplant 2001; 28: 59–62. | Article | PubMed | ISI | ChemPort |
13. Stotzer PO, Fjalling M, Gretarsdottir J, Abrahamsson H. Assessment of gastric emptying: comparison of solid scintigraphic emptying and emptying of radiopaque markers in patients and healthy subjects. Dig Dis Sci 1999; 44: 729–734. | Article | PubMed | ISI | ChemPort |
14. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. | Article | PubMed | ISI | ChemPort |
15. Bjarnason I, Peters TJ, Veall N. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test. Lancet 1983; 1: 323–325. | PubMed | ISI | ChemPort |
16. Craig RM, Ehrenpreis ED. D-xylose testing. J Clin Gastroenterol 1999; 29: 143–150. | Article | PubMed | ISI | ChemPort |
17. Nowak TV, Johnson CP, Kalbfleisch JH et al. Highly variable gastric emptying in patients with insulin dependent diabetes mellitus. Gut 1995; 37: 23–29. | PubMed | ISI | ChemPort |
18. Wakui M, Okamoto S, Ishida A et al. Prospective evaluation for upper gastrointestinal tract acute graft-versus-host disease after hematopoietic stem cell transplantation. Bone Marrow Transplantation 1999; 23: 573–578. | Article | PubMed | ISI | ChemPort |
19. Choi MG, Camilleri M, Burton DD et al. [13C]octanoic acid breath test for gastric emptying of solids: accuracy, reproducibility, and comparison with scintigraphy. Gastroenterology 1997; 112: 1155–1162. | Article | PubMed | ISI | ChemPort |
20. Lee JS, Camilleri M, Zinsmeister AR et al. A valid, accurate, office based non-radioactive test for gastric emptying of solids. Gut 2000; 46: 768–773. | Article | PubMed | ISI | ChemPort |
21. Feldman M, Smith HJ, Simon TR. Gastric emptying of solid radiopaque markers: studies in healthy subjects and diabetic patients. Gastroenterology 1984; 87: 895–902. | PubMed | ISI | ChemPort |
22. Bertrand J, Metman EH, Dorval ED et al. Étude du temps d'évacuation gastrique de repas normaux au moyen de granules radio-opaques. Applications cliniques et validation. Gastroenterol Clin Biol 1980; 4: 770–776. | ChemPort |
23. Hermansson G, Sivertsson R. Gender-related differences in gastric emptying rate of solid meals. Dig Dis Sci 1996; 41: 1994–1998. | Article | PubMed | ISI | ChemPort |

Acknowledgements

This study was supported by the Swedish Research Council (Grant no. 13409), by the funds of Jubileumskliniken at Sahlgrenska University Hospital and by the funds of Assar Gabrielsson.