Según la arteria afectada y el tipo morfológico de lesión

CAPÍTULO IV. ANÁLISIS Y DISCUSIÓN DE LOS RESULTADOS

IV.2 Según la arteria afectada y el tipo morfológico de lesión

Gastrointestinal Cancers

04

23 Oesophageal Cancer

24 Gastric Cancer Chemotherapy

25 Pancreatic Cancer

26 Management of Colorectal Cancer After Surgery

27 Chemotherapy for Metastatic Colorectal Cancer

28 Liver Resection for Metastatic Colorectal Cancer

P R O B L E M

Case History

A 54-year-old woman with a long-standing history of gastro-oesophageal reflux disease presents with progressive dysphagia and weight loss. An oesophagogastroduodenoscopy confirms a mid-oesophageal tumour and biopsy confirms adenocarcinoma.

What initial investigations are needed? Outline the immediate management. If there is no evidence of metastatic disease what further staging investigations are needed before deciding to operate?

What are the treatment options if, after all investigations, there is no evidence of metastases and the cancer is considered to be operable?

How would the management change if the tumour is found to be locally advanced and inoperable?

Background

What initial investigations are needed? Outline the immediate management.

Initial investigations include upper gastrointestinal endoscopy and biopsies and computed tomography (CT).1_{An assessment of the severity of dysphagia is essential. If nutri-}

tional intake is severely limited rapid palliation of dysphagia can be achieved by dilatation, stent insertion or palliative radiotherapy.1 _{Parenteral nutrition may be}

required, which can be achieved by nasogastric feeding, percutaneous endoscopic gas- troscopy or jejunostomy.

Endoscopic stent insertion is relatively safe and non-invasive providing almost immediate results. Palliative radiotherapy is also usually well tolerated but is not without toxicity, and it can take longer than the other treatments before symptoms improve.

If there is no evidence of metastatic disease what further staging investigations are needed before deciding to operate?

Prognosis of oesophageal cancer is strongly stage dependent and accurate clinical staging is essential as is an assessment of operability. Endoscopic ultrasound provides the most accurate estimate of disease stage and is superior to CT at detecting lymph node metastases.1_{Laparoscopy is also increasingly being done and is especially helpful in identifying}

coeliac nodes and subcapsular liver metastases.

Positron emission tomography (PET) scanning with 18F-fluoro-deoxyglucose is used increasingly to detect distant metastases. It is non-invasive and more sensitive than CT, particularly at detecting occult metastases, obviating the need for aggressive treatments. However, evaluation of the primary site and loco-regional nodes is not as accurate.

What are the treatment options if, after all investigations, there is no evidence of metastases and the cancer is considered to be operable?

Surgery alone as a treatment option for locally advanced disease (T3 or T4) is considered suboptimal with 5-year survival rates of 15–20%. Preoperative and adjuvant treatment strategies are therefore important. Radiotherapy alone is of value in patients with locally advanced disease who are unfit for surgery or chemotherapy. In a study of 101 selected patients with local disease the 3-year and 5-year survival rates were 27% and 21%, respectively.2_{Most patients, however, benefit from preoperative chemotherapy or chemoradio-}

therapy.

A UK Medical Research Council (MRC) trial randomized 802 patients with operable oesophageal carcinoma to either resection alone or two cycles of preoperative CF (cisplatin and 5-fluorouracil) given every 3 weeks.3 _{The results are summarized in Table}

23.1. Overall survival was markedly greater in the patient group receiving chemotherapy. Resected specimens from patients who received chemotherapy were smaller, with less frequent extension into the surrounding tissue and less lymph node involvement. There have been many trials in which benefits of preoperative chemotherapy were not seen. One trial reported on 467 patients who were randomized to surgery alone or three cycles of CF-based preoperative chemotherapy.4_{The rates of complete response, median sur-}

vival and 1-year, 2-year and 3-year survival were not significantly different. As a result of the evidence from the MRC trial, preoperative chemotherapy with CF is widely used in the UK. There is interest in replacing cisplatin with oxaliplatin and trials are ongoing.

Surgery alone Preoperative chemotherapy + surgery

Patients undergoing surgery (%) 92 97 Patients with R0 resection (%) 54 60 2-year survival (%) 34 43 Median survival (months) 13.3 16.8 Frequency of local recurrence (%) 11 12

Table 23.1Results of the Medical Research Council trial comparing surgery alone with preoperative chemotherapy followed by surgery

Surgery alone Preoperative chemoradiotherapy

Median survival (months) 11 16 3-year survival (%) 6 32 Regional node involvement in surgical specimens (%) 82 42

Table 23.2Results of an Irish study investigating the role of preoperative chemoradiotherapy

In the USA, combined preoperative chemoradiotherapy is more commonly used. Only one trial has demonstrated a marked survival benefit with preoperative chemoradiotherapy prior to surgery.5_{This Irish study of 113 patients compared surgery alone}

with preoperative CF-based chemoradiotherapy. Complete pathological response was seen in 25% of patients treated with preoperative chemoradiotherapy and there was less regional node involvement seen in surgical specimens of this group as well (42% versus 82%, P < 0.001, respectively). The results are summarized in Table 23.2. Results in the surgery alone arm were inferior to other contemporary series.

Discussion

How would the management change if the tumour is found to be locally advanced and inoperable?

In patients with inoperable disease and no distant metastases, the optimum treatment is chemoradiotherapy. The chemotherapy sensitizes the tumour to radiotherapy and therefore there is a greater than additive effect. Almost all randomized trial data have been in squamous cell carcinoma.

A Radiation Therapy Oncology Group (RTOG) trial in which patients with locally advanced disease were randomized to either radiotherapy alone or concurrent chemo - radiotherapy (CF based) terminated earlier than planned after 121 patients had been recruited, as an interim analysis showed a marked survival benefit in the chemoradiotherapy arm.6_{An update on this study showed a much improved median survival (14}

months with chemoradiotherapy versus 9.3 months with radiotherapy) and 5-year survival (27% versus 0%, respectively).

If there is evidence of distant metastatic disease what are the management options?

The 5-year survival rate for advanced metastatic adenocarcinoma of the oesophagus is only 2%. The primary emphasis is on palliation of symptoms using a multidisciplinary approach. Palliation of dysphagia is similar to that for patients with locally advanced disease, although the potential risks of parenteral nutrition need to be considered in a patient who may only live for a few months.

Combination chemotherapy is usually given, and, in the UK, first-line treatment involves using the ECF regimen (epirubicin, cisplatin and infusional 5-fluorouracil). The evidence supporting this approach comes from a randomized controlled trial of 274 patients with advanced gastro-oesophageal cancer.7_{This trial compared the ECF regimen}

with FAMTX (5-fluorouracil, doxorubicin and methotrexate). The results are summarized in Table 23.3. An update of the trial, with a median 27-month follow-up, continues to show a survival advantage for the ECF regimen.8

ECF FAMTX

Response rate (%) 45 21 Median survival (months) 8.9 5.7 1-year survival (%) 36 21

Table 23.3 Comparison of the ECF and FAMTX regimens in a randomized trial

Early results from a phase III study (REAL-2) are encouraging for oxaliplatin and capecitabine.9_{REAL-2 was a 2}× 2 study that randomized patients with locally advanced

or metastatic oesophageal and gastric cancer to one of four regimens:

쎲 ECF (epirubicin, cisplatin and infusional 5-fluorouracil)

쎲 EOF (epirubicin, oxaliplatin and 5-fluorouracil)

쎲 ECX (epirubicin, cisplatin and capecitabine)

쎲 EOX (epirubicin, oxaliplatin and capecitabine).

Approximately 1000 patients were enrolled and median follow-up was 17.1 months. The study concluded that capecitabine was not inferior to 5-FU and that oxaliplatin was not inferior to cisplatin. A superior but not significant response rate was seen with EOX compared with ECF. As expected, there was less nephrotoxicity and haematological toxicity but greater gastrointestinal and neurotoxicity in patients receiving oxaliplatin. On the basis of this trial, it seems feasible to replace 5-FU and cisplatin with capecitabine and oxaliplatin, respectively.

Further randomized trials involving other cytotoxic agents are ongoing as well as those exploring the role of novel biological agents.

Suspected oesophageal cancer

OGD and biopsies CT scan to stage disease Severe dysphagia: consider dilatation, stent insertion or palliatve RT T1 or T2 operable disease T3 or T4 operable disease Locally advanced inoperable disease Metastatic disease

Surgery if fit Cisplatin and 5-FU based chemoradiotherapy Pre-operative chemotherapy with 2 cycles of CF Palliation of symptoms Consider pre-operative chemoradiotherapy If fit consider palliative chemotherapy ECF or EC capecitabine If elderly or poor PS: FAMTX or palliative RT

Figure 23.1 Flow chart for the management of patients with oesophageal cancer.

Conclusion

Chemoradiotherapy would be of benefit to this patient, whether or not the tumour is operable. If metastases are found, this indicates a very poor prognosis for the patient. An algorithm summarising the management of all stages of oesophageal cancer is shown in Figure 23.1.

Case History

A 68-year-old man presents with weight loss and persistent abdominal pain and is suspected of having gastric cancer. He undergoes gastric resection for a T3 N1 R0 adenocarcinoma of the stomach and has an uncomplicated postoperative recovery. What is initial management?

What other investigations would have been done at this time?

In the absence of metastatic disease is there a role for preoperative treatment? Are there any postoperative treatment options that may reduce his risk of recurrence?

A year later he presents with shortness of breath, fatigue and loss of appetite. Investigations reveal hepatic metastases with small-volume lung metastases. What options are available for treatment at his second presentation?

Background

What is initial management?

The patient should be resuscitated if necessary. A blood transfusion should be considered for symptomatic anaemia. Oesophagogastroduodenoscopy is usually the diagnostic procedure of choice. It has a higher sensitivity and specificity than double contrast barium meal and allows biopsy. A computed tomography (CT) scan of the chest and abdomen is important in staging the disease.

What other investigations would have been done at this time?

Endoscopic ultrasound provides greater accuracy in preoperative staging of gastric cancer. Pooled data on more than 2000 patients undergoing endoscopic ultrasound revealed 69% accuracy for nodal stage and 77% for staging the depth of invasion.1_{Laparoscopy is}

more invasive than CT or endoscopic ultrasound but it is possible to directly visualize the local lymph nodes, peritoneum and liver. It is usually considered in patients in whom definitive surgery is being planned.

24 Gastric Cancer Chemotherapy

Discussion

In the absence of metastatic disease is there a role for preoperative treatment?

Preoperative chemotherapy is usually given to ‘downstage’ a locally advanced tumour before attempted curative resection. Chemotherapy before surgery is usually given to patients whose disease is at a greater risk of metastasizing, i.e. T3 or T4 disease or those with nodal involvement. Most patients will have their disease reassessed radiologically prior to definitive surgery. A small percentage of these patients will still have inoperable disease or will have developed metastases in the interim, sparing them the morbidity of unnecessary gastrectomy.

A small randomized trial in which patients with operable gastric cancer were allocated to receive four cycles of FAMTX (5-fluorouracil [5-FU], doxorubicin and methotrexate) prior to surgery or surgery alone did not find a major benefit from preoperative chemotherapy.2 _{A total of 44% of patients could not complete chemotherapy and a}

greater proportion of curative resections were seen in the surgery-alone arm.

One randomized trial exploring preoperative chemotherapy (MAGIC) found a marked survival benefit (Table 24.1). In all, 503 patients were randomized to surgery alone or preoperative and postoperative chemotherapy;3 _{74% of patients had gastric cancer. The}

chemotherapy regimen was ECF (epirubicin, cisplatin and 5-FU) and it was planned to give patients three cycles of chemotherapy before and three cycles after surgery. Median follow-up was 3 years. Only 104 patients (42%) were able to complete surgery and all three cycles of postoperative chemotherapy. It would be interesting to compare this regimen with postoperative chemoradiation and trials are ongoing investigating this. However, this treatment is increasingly given in the UK on the basis of the MAGIC trial.

Surgery alone Chemotherapy + surgery

5-year survival (%) 23 36 Patients who underwent curative surgery (%) 79 70 T1/2 tumour (%) 52 38 N0/N1 disease (%) 84 76

Table 24.1 Results of the MAGIC trial

Preoperative radiotherapy has not been extensively investigated. A Chinese study of 370 patients who were randomly assigned to preoperative radiotherapy (40 Gy) or surgery alone showed a superior 5-year survival rate for the patients treated with radiotherapy (30% versus 20% for surgery alone).4

Are there any postoperative treatment options that may reduce his risk of recurrence?

In the UK there are no recommendations for adjuvant chemotherapy in gastric cancer. A meta-analysis of 19 trials estimated that the risk of death was reduced by 17% with adjuvant chemotherapy and this was even greater when the analysis was limited to

What options are available for treatment at his second presentation?

Metastatic disease is common at initial presentation with approximately half of patients affected. With regard to further treatment in patients with metastatic disease, the emphasis should be on palliation of symptoms. Simple measures such as pain control with anal- gesia, blood and/or iron replacement are recommended.

Palliative resection for bleeding or pain should only be considered if symptoms are otherwise uncontrolled. There is no survival benefit for radical gastrectomy in this set- ting. External beam radiotherapy can give quick relief from pain and bleeding. There are no randomized controlled trials comparing radiotherapy with endoscopic/palliative surgical techniques. Argon plasma coagulation can also be considered for haemorrhage.

In this case, if the patient is stable and has a good performance status then palliative chemotherapy should be considered. Combination chemotherapy is recommended due to better response rates but overall survival rates are similar with single-agent treatments. ECF was compared with FAMTX in a randomized controlled trial involving 274 patients7

(Table 24.3). More complications were associated with ECF due to the need for central line placement. In the UK this regimen is commonly used as first-line treatment in advanced gastric cancer.

17 trials that required complete resection of disease.5_{Adjuvant chemotherapy is toxic}

and the planned doses are often not achieved.

In the USA, postoperative adjuvant chemoradiotherapy is usually offered. One of the largest trials that support this was the INT-016 study,6_{in which 556 patients were ran-}

domized to observation or adjuvant combined chemoradiotherapy. Chemotherapy (5- FU with leucovorin) and radiotherapy were given (45 Gy in 1.8 Gy fractions). More than two-thirds of tumours were T3 or T4 and 85% of patients had nodal metastases. Table 24.2 summarizes the results. There were significant grade 3/4 toxicities and three patients (1%) died from treatment-related toxicities. The study was criticized for not stipulating that patients should have had an adequate surgical procedure. This factor probably explains the inferior survival seen.

Surgery alone Chemoradiotherapy

3-year disease-free survival (%) 31 48 Overall survival (%) 41 50 Median survival (months) 27 36

Table 24.2Results of the INT-016 trial

Response rate (%) Median survival (months)

ECF 45 8.9 FAMTX 21 5.7

Table 24.3Results of a randomized controlled trial comparing ECF and FAMTX

Newer options

Trials involving taxane combinations have yielded interesting results. The results of a multinational trial with 457 patients who received cisplatin + 5-FU with or without docetaxel8_{are summarized in Table 24.4.}

Early results from a phase III study have demonstrated encouraging results for oxaliplatin and capecitabine.9_{This was a 2}× 2 study that randomized patients with locally

advanced or metastatic oesophageal and gastric cancer to one of four regimens as dis- cussed in Chapter 23.

Conclusion

An algorithm summarising the management of all stages of gastric cancer is shown in Figure 24.1.

Case History

A 74-year-old man presents with weight loss, jaundice, dark urine and pale stools. A computed tomography (CT) scan confirms mass in the head of the pancreas with no

In document UNIVERSIDAD DE CIENCIAS MÉDICAS DE LA HABANA ICBP Victoria de Girón Facultad Playa. Centro de Investigaciones Médico Quirúrgicas. (página 69-73)

Según la arteria afectada y el tipo morfológico de lesión

CAPÍTULO IV. ANÁLISIS Y DISCUSIÓN DE LOS RESULTADOS

IV.2 Según la arteria afectada y el tipo morfológico de lesión

Gastrointestinal Cancers

04

Case History

Background

Discussion

Conclusion

Further Reading

Case History

Background

24

Gastric Cancer Chemotherapy

Discussion

Conclusion

Further Reading

Case History