The Relationship between Pulmonary Function Testing Including Cardiopulmonary Exercise Testing (CPET) and Outcomes in Patients with Oesophagogastric Cancer Undergoing Neo-adjuvant Chemotherapy

INTRODUCTION

he majority of cancer patients suffer from symptoms as a consequence of both their disease and its treatment. Neo-adjuvant chemotherapy has been recommended in the treatment of upper gastrointestinal malignancy in an attempt to downstage tumour activity in order to enhance respectability, as a precaution to destroy any micro-metastasis foci of the malignancy and to improve symptoms and survival.^1,2 It has, however, been shown that neo-adjuvant chemotherapy is complicated by toxicity and illness related to treatment e.g. neutropaenia and anaemia leading to an increased risk of mortality. ²

   There is continuing controversy about the advantage of using neo-adjuvant chemotherapy in cancer treatment.¹ In the respiratory field, studies suggest that neo-adjuvant chemotherapy increases the risk of respiratory complications after pneumonectomy ³ and it has been recommended that carbon monoxide transfer factor (TLCO) be assessed in lung cancer patients before and after chemotherapy induction since TLCO is a sensitive risk indicator of respiratory complications after surgery. ³ Conversely, it has been found that pre-operative chemotherapy did not impact on post-operative morbidity and mortality in lung cancer patients.⁴ Furthermorean upgrading in lung function and exercise capacity was noted after chemotherapy initiation in patients with malignant pleural mesothelioma ⁵, although this study was without post-chemotherapy surgery.

   In the gastro-oesophageal field, some studies suggest that there is no additional benefit of chemotherapy in the treatment of oesophageal cancer as there is no variation in anastomotic leaks, pulmonary or cardiac complications with pre-operative chemotherapy compared to surgery alone. ^{6, 7, 8} In addition, there is evidence of toxicity and pre-operative mortality related to chemotherapy in patients with oesophageal cancer, who underwent neo-adjuvant chemotherapy ⁹ and the post-oesophagectomy complication incidence is higher in those patients who had higher pre-operative chemotherapy toxicities. ¹⁰ By contrast, other studies showed that chemotherapy improves survival for gastro-oesophageal cancer. ^2,11,12 It has been found that reduction of pre-operative and especially post-operative oncological treatment toxicity is essential for the ongoing improvement of gastric cancer care.¹³ There was no apparentcause for the difference in results between these studies since they had the same location of cancer (e.g oesophageal cancer) or similar histology of cancer (e.g. gastric cancer is histologically similar to oesophagus cancer).

   Accordingly in the field of gastro-oesophageal cancer, the effect of chemotherapy treatment on patients’ cardiopulmonary fitness as well as on the incidence of post-operative cardiopulmonary complication remains controversial.

Aims of the study

The aim of the present study was to examine the effect of chemotherapy on cardiopulmonary fitness. In addition we have examined the association between pulmonary function measurements including CPET and outcomes in patients with gastro-oesophageal cancer undergoing neo-adjuvant chemotherapy. And to compare post chemotherapy CPET with surgical outcome.

PATIENTS

This is a case-control study. 41 Patients who were included in this study had been diagnosed with gastro-oesophageal cancer proven histologically by the Pathology laboratory, Glasgow Royal Infirmary. All patients were referred to the Pulmonary Function Laboratory, Respiratory Medicine, Glasgow Royal Infirmary between August 2008 and December 2011. These patients underwent chemotherapy as described below.

• 35 of the patients with gastro-oesophageal cancer underwent both pre- and post-chemotherapy CPET (this group was analysed to assess the effect of chemotherapy on cardiopulmonary fitness). 31 out of these 35 patients underwent pre- and post-chemotherapy CPET, followed by surgery.
• A further 6 patients with gastro-oesophageal cancer underwent chemotherapy followed by CPET and surgery but without a pre-chemotherapy CPET. In total, 37 patients underwent chemotherapy followed by a post-chemotherapy CPET and surgery (this group was analysed to compare post chemotherapy CPET with surgical outcome).

METHODS

The Neo-adjuvant chemotherapy study protocol is started by diagnosis followed by first CPET followed by neo-adjuvant chemotherapy followed by second CPET followed by surgery followed by post –operative outcome follow up

The regional multidisciplinary team referred the diagnosed patients for lung function testing and CPET in order to plan their treatment.

   At the pulmonary laboratory, all tests including anthropometric measurements, capillary blood sampling from ear (gas analysis and tHb) and the patients’ deprivation levels were determined by using the Scottish index of multiple deprivations (SIMD) 2012 calculator. Then flow-volume loop, transfer factor for carbon monoxide test (TLCO) and the cardiopulmonary exercise test (CPET) were performed {Peak VO2 (Oxygen consumption) and VO2 at anaerobic threshold (AT), Absolute AT and other CPET results as mentioned in Table 2}. CPET was conducted by using a metabolic exercise cart on an electrically braked bicycle ergometer. Flow and gas calibration were performed manually before CPET.  Electronic sphygmomanometer and 12- electrocardiogram electrodes were connected to the patient and the CPET method protocol as following:

• 3 minute rest (breathing flow & concentration analysis + ECG monitor)
• 1 minute unloaded cycling 50-60 rpm (breathing flow & concentration analysis + ECG
• Cycling 50-60 rpm with 10-20 watt/minute incremental load until symptom limiting the test or exhaustion
• Recovery  period (2-10 minutes) unloaded cycling

    ECG, Heart rate, respiratory exchange ratio and pulse oximetry were monitored and blood pressure was measured automatically every 2 minutes using sphygmomanometer. ^{14, 15}

   The test was ended before the patient reached exhaustion level if the patient signed that they had either chest pain or difficulty in breathing.  The test was also stopped if there was depression or elevation of ST segment ≥2 mm, T wave inversion or sustained ventricular tachycardia. ^{16, 17,18}

   Anaerobic threshold determination was by the V-slope method ^18,19,20 which was confirmed by ventilatory equivalent, end tidal partial pressure methods ^18,20 and respiratory exchange ratio (RER) changes. ²¹ These methods were observed initially by using 8–panel and then confirmed by 9-panel and 4-panel graph plots.

   The regional multidisciplinary team meeting decided that these patients either had an operable tumour but needed to be treated by chemotherapy before operation or these patients had an inoperable tumour and needed to be treated by chemotherapy treatment alone.  The patients were referred to the Oncologist at the Beatson West of Scotland Cancer Centre, Glasgow for chemotherapy. The following chemotherapeutic regimens were used by the oncologists to treat gastroesophageal, gastric cancers (the only first 3 regimens) and oesophageal cancer (all regimens), are:

• Epirubicin plus Cisplatin plus 5-FU called ECF……………or
• Epirubicin plus Cisplatin plus Capecitabine called ECX…...or
• Epirubicin plus Oxaliplatin plus 5-FU called EOF………….or
• Cisplatin plus 5-FU called  CF

    Patients who had operable oesophageal or oesophagogastric cancer received two to three cycles of one of the chemotherapy regimens described.  Operable gastric cancers patients were treated with three cycles of one regimen. While inoperable gastro-oesophageal cancers were treated by different numbers of chemotherapeutic cycles.  The courses of chemotherapy drugs were given at three-week intervals.  After completion of chemotherapy treatment, the team referred patients to undergo CT scan to assess disease progression.

   Patients who were being considered for surgery were referred back to the Pulmonary Function Laboratory, Respiratory Medicine, Glasgow Royal Infirmary to reassess their lung function and perform post-chemotherapy testing. These patients then underwent surgical resection in the form of transhiatal oesophagectomy, partial or subtotal gastrectomy and gastro-oesophagectomy depending on their disease location. One case only underwent palliative (Roux limb) gastroenterostomy. 

   Post-surgery the patients were admitted to the High Dependency Unit (HDU) or Intensive Care Unit (ICU) depending on patient’s general health.  When patients improved, they were transferred to a general surgical ward. Both the length of the high dependency unit stay and the intensive care stay were merged in this study under title of length of high dependency care stay.

   Patients were followed up for the first 30 days post-surgery and information about neo-adjuvant chemotherapy as well as the post-operative outcomes and complications that were recorded are illustrated in Table 1.

Table 1: Post-operative outcomes and related information in patients that underwent chemotherapy.

*1^st CPET= pre-chemotherapy CPET; 2^nd CPET= post-chemotherapy CPET

Statistical analysis

The study data are presented as numbers and percentage or medians and ranges.  Comparison of patient groups was carried out using non-parametric (Wilcoxon), parametric (paired samples test); a Mann-Whitney and chi square test and Pearson or Spearman as appropriate using SPSS software (IBM, SPSS, Version 19.0, USA), P ≤0.05 was considered significant.

RESULTS

For the 35 patients with gastro-oesophageal cancer who underwent pre- and post-chemotherapy CPET, the results are shown in Table (2).

   Median of carboxyhaemoglobin % (carbox-Hb %) was higher than normal range in both the pre- and post-chemotherapy groups. Absolute peak VO₂, peak VO₂ % predicted maximum VO₂, absolute AT and AT % predicted maximum VO₂ medians were lower than the normal range in both groups. A test of normality was done for each parameter.

   There were significant differences between both pre- and post-chemotherapy groups in arterial PCO₂ (4.5 vs. 4.7, respectively; p<0.01), t Hb (15 vs. 13, respectively; p<0.001) and heart rate at AT % maximum predicted HR (67 vs. 71, respectively; p<0.05). There were no significant differences in other variables.

   The 37 patients that underwent a 2^nd CPET (post-chemotherapy) followed by surgery were categorised depending on the development of post-operative complications into 11 (30%) patients with no post-operative complications and 26 (70%) patients with post-operative complications. The clinic-pathological characteristic indices, CPET parameters and post-operative complications are shown in Table 3 (This analysis did not include smoking status due to insufficient data).

   Median of body mass index (BMI) and carbox-Hb % were above the normal range in both groups. Absolute peak VO₂, peak VO₂ % predicted maximumVO₂, and absolute AT medians were lower than the normal range in both groups.  AT % predicted maximum VO₂was within normal range in the group without post-operative complications group while it was lower than normal in the group that had post-operative complications. All other variables were within normal range.

Table 2: The effect of chemotherapy on CPET and other related parameters in gastro-oesophageal cancer patients.

All values gives as median (range) Total patients’ numbers vary due to incomplete data.SA= surface area; AT= anaerobic threshold; VE= ventilatory equivalent; HR=heart rate. * HR/VO₂ at peak minus HR/VO₂ at anaerobic threshold.

   There was a significant association between post-operative complications and deprivation in patients with gastro-oesophageal cancer that underwent pre-operative chemotherapy (p<0.05). The patients with post-operative complications had a higher percentage of the most deprived patients and a lower percentage of the least deprived patients compared with those without post-operative complications. There were significant differences between patients without post-operative complications and those with, in length of high dependency care stay (8 vs. 11, respectively; p<0.01), in length of ward stay (5 vs. 9, respectively; p<0.05) and length of hospital stay (12 vs. 22, respectively; p<0.001). There were no significant differences between groups in other variables.

Table 3: The relationship between post chemo-CPET and other investigations parameters and post-operative complications in gastro-oesophageal cancer surgery patients (n=37).

All values given as median (range) Total patients’ numbers vary due to incomplete data. SA= surface area; AT= anaerobic threshold; VE= ventilatory equivalent. Mann-Whitney U test & Chi-square test.*is the difference between HR/VO₂ at peak and HR/VO₂ at anaerobic threshold.