Probleme actuale privind aplicarea protocolului de tratament în cancerul de rect

The authors wish to discuss some problems that currently appear in the clinical practice during the treatment of patients with rectal cancer when implementing the treatment protocols. In this article, we will take into consideration both the treatment Guidelines of the Ministry of Health, and also the American National Comprehensive Cancer Network (NCCN) guidelines.

The treatment guideline of rectal cancers elaborated by the Ministry of Health (Annex 11, available at www.ms.gov.ro/documente/Ghid%2011) recommends the following protocol in rectal neoplasms:

• Rectal cancer stage I - T1-2 N0 Mo
  • Surgical treatment
  •  Postoperative chemotherapy.
• Rectal cancer stage II - T3 N0 M0 and stage III - T3-4 and/or N1-2
  •  Preoperative radiotherapy
  •  Surgical intervention
  •  Postoperative chemotherapy.
• Inoperable rectal tumour, no metastases:
  • A)  radio-chemotherapy (with a favourable response)
    •   surgery
    •   postoperative chemotherapy
  • B)  radio-chemotherapy (with a non-favourable response)
    •   chemotherapy
• Operable rectal tumour, with metastases:
  •  radical surgery of the tumour with resection of the hepatic or lung metastasis
  •  radio-chemotherapy
  •  radio-chemotherapy followed by surgical treatment.
• Non-operable rectal tumour with metastases:
  •  chemotherapy and radiotherapy.

• short-course preoperative radiotherapy - the Swedish method:
  •  25 Gy, with 5 Gy per fraction, for a week
  •  immediate surgical intervention
  •  after that, adjuvant chemotherapy for 6 months.
• long-course preoperative radiotherapy:
  •  45-50 Gy, administered in 25 fractions (1.8-2 Gy/fraction)
  •  after 4-8 weeks: surgical intervention
  •  after that, ulterior adjuvant chemotherapy for 4 months.
• preoperative chemo-radiotherapy, long-course type:
  •  45-50 Gy administered in 25 fractions
  •  folic acid - 20 mg/m², 5-FU 350 mg/m² (week 1+5)
  •  after 4-8 weeks: surgical intervention.

Optional: radical surgery followed by adjuvant radio-chemotherapy (2 cycles FU-FOL Mayo, followed by ERT 50 Gray, 18.3 Gray/fraction). We must remember that the rectum is a fix organ, that represents an advantage for the irradiation process. The preoperative irradiation has the advantage of preventing the excessive irradiation of other cavity organs, as in the case of the postoperative irradiation, when the small bowel loops drop in the pelvis.

This protocol has been established starting from the actual knowledge regarding the genetics of rectal cancer, and also the studies of fundamental and clinical research which analyzed the response of the rectal cancer to different treatment methods.

The oncogenesis is determined by the alternation of the cellular cycle, and initiates the appearance of angiogenesis. Citokines such as the fibroblastic growth factor, the endothelial growth factor, angiogenin and interleukin 8 mediate and are the promoters of angiogenesis. Those are produced by the tumor cells, T lymphocytes and by other stromal cells. Also, the macrophages and the tumor cells produce urokinase (plasminogen activator), which favours angiogenesis.

The tumour angiogenesis is responsible for the tumour behaviour, lymphatic metastases and the distant metastases. This is the reason why we consider necessary the establishment of the angiogenesis score (number of vessels/unit), and also that of the tumour stage, the differentiation degree, the status of the lymphatic invasion⁽¹⁾.

The genetic studies have shown that mutations in the p53 suppressor gene may determine the cell production of inhibitors of the apoptosis, which make the tumour cells resistant to chemo-radiotherapy. The evaluation of the status of the p53 gene might allow the appreciation of the tumour aggressiveness in case of a partially located lesion, the response to PCT (5FU), the survival after curative resection, and of the prognostic⁽²⁾. Also, the BRAF mutation, which appears in 8-10% of the cases of colorectal cancer, indicates a weak response to chemotherapy and mutations in the k-ras gene are associated with:

• a bigger recurrence rate
• an increased mortality
• a weak response to anti-EGFR therapy (Epidermal Growth Factor Receptor): 
  • Bevacizumab (Avastin), panitumumab (Vectibix) and Cetuximab (Erbitux) administered in colorectal cancer (with or without metastases)
  • One recommends the personalised therapy of these cases (Selumetinib) - Valtorta et al., 2013; Petrelli et al., 2013.

• The cellular apoptosis through disruptions at the DNA level and through the production of free oxygen radicals.
• The cellular destructions that affect tumour proliferation.
• The fibrosis and the densification of the rectal wall.
• The obliterating arteritis through hyalinisation process.
• The blockage of the cells which block the apoptosis.
• The destruction of the micro-angiogenesis net­work.

• The tumour dimensions
• The tumour differentiation degree
• The cellular phenotype
• The tumour angiogenesis.

• The mitotic rate versus the apoptotic rate/the extensive tumour necrosis
  •  The frequent apoptosis and the extensive necrosis indicate the intense mitotic and vascular-genetic activity, and also show inefficient repair.
  •  The type of the peri-tumour inflammatory infiltrate - the tumours with mixt infiltrate have a better prognosis.
  •  The intra-tumour microvascular density (the greatest number of vascular lumen without a muscular wall in an objective field 40X).
  •  A small number of vessels → big chances of a treatment response.
  •  A big number of vessels → an aggressive tumour behaviour.

• CD34 for microvascular density (number of lumina and endothelial cells/m²);
• MMR proteins (MLH1, MSH2, MSH6, PMS2) – mechanism of repair DNA defect → a bigger opportunity of response to radiotherapy (RT);
• The couple blc2-p53; tumour cells may be classified into 4 classes:

1. bcl2+/p53- → Dukes A/B, pN+;
2. blc2-/p53- → probably, tumours with a non-aggressive behaviour, responsive to neoadjuvant chemotherapy;
3. blc2+/p53+ (co-expression or different tumour cells) → resistance to chemotherapy;
4. bcl2-/p53+ → Dukes C/D, resistant to radiotherapy.

• cyclin D1 → its overexpression → mechanism of acquired resistance to radiotherapy.

• Macroscopic:
  •  The decrease of the tumour dimensions
  •  Conversions to a more inferior stage.
• Clinic:
  •  The decrease of the rates of local relapse
  •  The decrease of the inferior oncology margin to 2 cm
  •  The “sterilisation” of the lymph nodes.

• R1 - total regression: the absence of the tumour cells which was found in 6-8% of the cases.
• R2 - nearly complete regression: rare neoplastic residual cells, found in 73% of the cases.
• R3 - partial regression: the post-radiation fibrosis is more accentuated than the remaining tumour, which is found in 10% of the cases.
• R4 - insufficient regression (non-responsive tu­mours): the remaining tumour is bigger than the post-radiation fibrosis, met in nearly 9% of the cases. 
• R5 - the absence of the regression.

In R1 and R2, the 3-year survival is 90-95%.

In R3 and R4, the 3-year survival is 55%.

In a study performed by us and published in Surgery, the fraction between the response to radiotherapy and the initial stage of the cancer was:

• The radiotherapy response R1+R2 was obtained in 86.66% of the patients who were in stage II, and R3 (partial regression) - in 13.34%.
• A good response to R2 radiotherapy (almost complete regression) was achieved in nearly 28.57% of the patients who were in stage III, and in the rest of 71.43% of patients, the regression was insufficient or absent.

Therefore, we can say that the radiotherapy response was correlated directly with the initial stage of the disease, being favourable for patients in stage II of evolution and weak for those in stage III⁽³⁾.

Under these conditions, a very important problem is the identification of the degree of response to radiotherapy of the tumour and also to the metastases potential, as long-term radiotherapy lasts approximately 4 weeks, to which one may add around a minimum of 4-8 weeks until the moment in which the patient will be operated on, a total of 8-12 weeks. If the tumour has a low potential for the radiotherapy response, but a high potential for metastases, the benefit of radiotherapy will be decreased and the risk of metastasis will increase exponentially, taking into account the fact that radiotherapy is a form of local treatment and does not prevent metastases. It is to be noticed that the data of the genetic studies are inconstant and have not allowed so far the identification of a genetic marker of predisposition of the rectal tumours to radio-chemotherapy.

Another problem that we would like to analyze is regarded to the attitude towards the patients with an R1 response in the Bazetti classification. In the treatment guide of the Ministry of Health for colorectal carcinoma in stage I TNM (T1-2N0M0), it is mentioned that, in carefully selected cases which are correctly staged preoperatively, in centres with experience, one might choose local transanal resection, exclusive radiotherapy or a combination between radiotherapy and limited surgery.

The NCCN guidelines (Ryan R et al. Histopathology 2005; 47(2):141-6), version 2/2017 - rectal cancer, classifies post-radiation regression into 4 grades (R0, R1, R2, R3), which correspond to the grades described by Bazetti; one mentions as a possible option the watchful waiting (wait-and-see).

The post-radiotherapy regression R0 and its follow-up (wait-and-see) has the advantage that the patients are spared the complications of surgery and there are two studies mentioned (Habr-Gama et al., 2004, 2010)⁽⁴⁾ which conclude that this attitude does not have to be a routine one. Nevertheless, we must state the fact that the surgical treatment in rectal cancer may assume the following complications:

• Abdominal perineal resection:
  •  Permanent colostomy
  •  Impair of the sexual activity
  •  Decrease of the quality of life
  •  Para-stomal hernia.
• The anterior low and ultralow resection
  •  Anastomotic fistula
  •  Pelvic abscess
  •  Protection ileostomy for  3-6 months
  •  The suppression of the ileostomy
  •  Partial anal incontinence temporary or total, which appears in more than 60% of the patients, and in 30% appear very severe forms (anterior resection syndrome)
  •  An anastomosis presenting with with stenosis
  •  Associated complications.

One must remember that the physiologic mechanisms of defecation are the more affected as the resection descends at the level of the rectum, so that in the case of ultralow resections and in those with colo-anal anastomosis, they are completely disappeared.

Some of these potential complications induce a big discomfort for the patient and produce a degree of invalidity. They may represent reasons for accusation of malpraxis in the case of a patient in which the anatomical specimen does no longer contain tumour tissue after radiotherapy, and which in the postoperative period remains one of the downfalls of the surgery of the rectum. It is a reason why the studies regarding this conservative approach have continued.

Therefore, a study from 2010 (Maas et al.)⁽⁵⁾ has shown that:

• In batch I - 21 patients who responded completely to radiotherapy out of 192 (11%) were not operated on.
• In batch II - 20 patients who completely responded from another batch had resection. 
• Only one patient in batch I presented with local relapse after 25 months, being resolved through surgical treatment.
• For two years, there weren’t any important differences between the two batches regarding the relapses and the survival, but the functional effect was significantly better in non operated patients. 
• In a retrospective study performed by us on 141 patients admitted and treated for rectal cancer in the I^st Clinic of Surgery of the “Prof. Dr. Al. Trestioreanu” Institute of Oncology Bucharest, between October 2007 and 31^st of December 2013, nine patients (6.38%) presented with a complete response to preoperative radiotherapy. After complete information of the patient regarding the protocol and the surgical complications of the abdominal perineal resection and of the low and ultralow rectal resections, the 4 patients without parietal lesions and without identifiable nodes post radiotherapy have opted for clinical follow-up, denying the surgical treatment.
• Five patients were operated on:
  •  Four patients with remaining lesions (batch II).
  •  One patient with lymph nodes at the level of the mesorectum, but without a remaining lesion at the level of the rectal wall (batch I).

The pathology exam:

• In the patient with increased lymph node noticed on MRI post-RT, a cancerous lesion was confirmed at the level of the lymph node.
• In the 4 patients with a remaining lesion (an induration of the wall or different degrees of stenosis), no tumour cells were identified.
• The patients were re-biopsied after radiotherapy.

The evolution of the non-operated patients after radiotherapy:

• One patient with liver metastases after one year, treated with radiofrequency ablation and chemotherapy without any relapse or a continuation of evolution 3 years after radiofrequency ablation.
• Three patients with favorable outcome with no local recurrence or metastasis to 4, 3 and 2 years of diagnosis after the diagnosis.

The evolution of the patients with a complete response who were operated on:

• One patient with liver metastases at 1 year postoperatively through radio-ablation and resection plus chemotherapy.
• Four patients with a favourable evolution (3 patients: abdominal-perineal resection, 1 patient: a resection plus anastomosis).

After correlating the data from our own experience with data from literature, we consider that, in order to apply the non operative treatment strategy (wait-and-see), the patient must meet the following criteria:

1. The lack of the lesion at the level of the rectal mucosa post-radiotherapy or small ulcerations with a negative biopsy.

2. The absence of the lesions at the level of the rectal wall and of the increased lymph nodes at the MRI exam, and on the post-radiotherapy rectal ultrasound⁽⁶⁾.

3. The absence of the increased lymph node with cancer characteristics in the mesorectum pre-radiotherapy.

4. A CEA tumour marker <0.5 ng/dl post-radiotherapy, for patients in which CEA was more increased before radiotherapy.

5. The absence of the KRAS and BRAF mutations.

Conclusions

1. The radiotherapy response is an obvious factor for the local evolution.

2. Radiotherapy does not influence and may worsen the distant evolution with metastases through the delay of other associated treatment, surgery or chemotherapy.

3. Because, so far, we do not have a biologic, histologic or genetic marker, in order to predict the tumour response of rectal tumors to radio-chemotherapy it is necessary to:

• Establish an angiogenesis score which correlates with the tumour regression judged by the tumour volume, the depth of the invasion, the incidence of the local and distal metastases.
• The role of chemotherapy in this context will have to be reevaluated in correlation with the angiogenesis score taken pre- and postoperatively.

4. The attentive follow-up of the patients with a complete response to radiotherapy respects the criteria aforementioned, allows to avoid the surgical treatment and protects from the complications of the low and ultralow anastomoses, and the non-benefit of the abdominal-perineal resection of the rectum.

5. In order to implement an attitude as such, it is compulsory to respect a treatment protocol for the post-radiotherapy evaluation, such as:

• Clinical rectal examination.
• Rectoscopy with biopsy in patients with small ulcerations or small scars at the level of the mucosa.
• The pelvic MRI exam.
• The trans-rectal ultrasound must certify the absence of the cancer lesions at the level of the rectal wall and at the level of the lymph nodes.
• The biology and paraclinical investigations are included in follow-up protocols of the patient with a rectal neoplasm, for 5 years.

6. In the process of the decision making, the patient has an important role: after the correct communication of the possibility of evolution in the case of the non-surgery, but also of the possible complications of the surgical treatment in the case of medium and inferior rectal tumours, he may opt for the watchful waiting.