ASCO 2018: 5 Noteworthy Colorectal Cancer Studies on Heated Chemotherapy, Chemotherapy–Smart Drug Decisions, Side Effects and Immunotherapy

1. Study: Surgery with heated chemotherapy for colon cancer (HİPEK)

Colorectal cancer is among cancers preventable through screening methods , alongside breast and cervical cancers, making 3 types. Its importance reflects both frequency and the metastatic stage, when effective treatments can still provide long survival.

The commonest metastatic site in colon cancer, at %50-70, is the liver , while %20 risk peritoneal involvement. The peritoneum has a very large surface, so involvement is an adverse risk factor, and untreated survival is below 6 months. Patients, relatives and physicians therefore feel an urgent need for aggressive treatment. Surgery plus chemotherapy is considered more effective: removing the peritoneum, affected organs and nodes, and potentially affected areas, alongside heated chemotherapy , is known as HİPEK (Hyperthermic İntraPEritoneal Khemotherapy). Only specialized surgeons in experienced centers perform it. Frequently used here, HİPEK is seen by patients and relatives as very promising for ovarian, stomach and colon cancers.

ASCO 2018 Congresswas preceded by the understanding that HİPEK is extremely difficult, requires extensive resection (peritoneum, spleen, widespread nodes, part of stomach and others), has no miraculous outcomes and, if not performed adequately, has serious side effects and life-threatening risks.

Patients and families always hope for innovations, including heated chemotherapy to eliminate cancer cells. Theoretically, chemotherapy heated to 43 degrees seems effective. Experienced centers have used it for approximately 15 years, but whether this burdensome treatment with severe side effects really prolongs survival remained the key question. Earlier reports from good centers suggested survival, normally under 6 months, could reach 40 months and even cure %16, increasing interest in comparative studies.

PRODIGE-7 , a clinical trial, is important in answering these questions. From 17 French centers, 265 patients with isolated peritoneal metastases were included. Among them, 133 received surgery followed by HİPEK with heated oxaliplatin , while 132 received surgery alone. Both groups had 6 months of preoperative neoadjuvant chemotherapy. Median age was 60, and postoperative mortality was identical at %1.5. Procedure-related complications were higher with HİPEK as expected, at %24.1 versus %13.6.

For the main question of overall survival, after approximately 5 years of follow-up, survival was 41.7 months with HİPEK and 41.2 without it, meaning no difference between treatments.

A brief comment : demanding surgery and heated chemotherapy like HİPEK are not ideal for every patient. If Peritoneal Cancer Index is low (< 11-25) and macroscopic tumor remains after surgery (> 1 mm), HİPEK has no positive survival effect. There is no survival advantage and procedure-related side effects are higher.

2. Study: Postoperative chemotherapy decisions in rectal cancer

The final 15 cm of the colon is the rectum . Unlike other colon regions, it lacks the protective serosa (comparable to the atmosphere protecting Earth from harmful sunlight), increasing recurrence and metastatic risk. To reduce this, rectal cancer uses strong combined strategies: first chemotherapy and radiotherapy are combined first, followed by surgery and then postoperative chemotherapy, bringing together strong treatment strategies.

The first questions are: “Should chemotherapy be given after surgery?” and “If so, which chemotherapy?”

The latter matters because oxaliplatin causes tingling, pins and needles and burning in hands and feet, worsened by cold air or water, medically called peripheral neuropathy . It may be so severe that walking and hand movement are impaired, even preventing holding a fork. Whether colon and rectal cancer could be treated effectively without oxaliplatin has therefore long been questioned. At ASCO 2018, ADORE answered which chemotherapy, though not every question.

ADORE compared treatment through the familiar port catheter over 2 days every 14 days, FOLFOX for 8 cycles (160 patients), with only 5-fluorouracil (FUFA), given for 5 days every 28 days for 4 cycles intravenously in stage 2 and 3 patients (161 patients). The oxaliplatin regimen was superior for disease-free survival to 5-fluorouracil alone: FOLFOX 6-year disease-free survival was %68.2 versus FUFA %56.8, statistically favoring FOLFOX. The difference was particularly meaningful in stage 3 (node-positive) patients. Adjuvant treatment is postoperative protection; adding oxaliplatin did not significantly improve overall survival.

3. Study: Do men or women have more colorectal treatment side effects?

On side effects, another valuable ASCO presentation answered “who has more chemotherapy side effects ?” Women or men?

An analysis also published in the leading journal JAMAexamined 28.000 stage 2 and 3 colon and rectal cancer patients receiving 5-fluorouracil, oxaliplatin and irinotecan chemotherapy. Nausea, vomiting, neutropenia, neuropathy and oral mucositis were more common in women . Most strikingly, dose reduction for side effects was needed in %25.9 of women versus %16.8 of men. The interpretation is that reductions lead to poorer effectiveness and survival outcomes in women.

4. Study: Timing of smart drugs in stage four colorectal cancer

After effectiveness with chemotherapy and biological smart molecules in metastatic disease, whether to stop or continue reduced chemotherapy or biological maintenance is debated. A major issue is that stage 4 patients already on intensive combinations cannot tolerate heavy treatment indefinitely. Therefore, for maintenance , reducing doses and agent numbers is essential. At ASCO, VALENTINO studied metastatic colon cancer with the RAS tumor mutation pathway inactive (RAS mutation-negative). After every 14 days for 8 cycles of FOLFOX plus panitumumab, one arm received 5-fluorouracil maintenance and the other panitumumab alone. Panitumumab was less favorable than 5-fluorouracil, with progression-free survival showing chemotherapy maintenance more effective. VALENTINO showed a chemotherapy-free arm or biological agent alone would not be effective maintenance in RAS-negative patients.

5. Study: Immunotherapy in colorectal cancer

As in other cancers, developments in using our T cells against colon cancer were expected. Approximately %10-15 have microsatellite instability (MSI) , related to inadequate DNA repair. In genomic instability caused by deficient mismatch repair (dMMR), T cells become more sensitive to tumors. For dMMR patients, nivolumab (Opdivo) and ipilimumab (Yervoy), immune checkpoint inhibitors, showed success last year in CheckMate-142. Long-term follow-up now showed sustained successful responses, leading to the bold statement that immunotherapy is standard for metastatic MSI-H colon cancer unresponsive to first-line chemotherapy and biological agents. Although early and ambitious for our country, immunotherapy offers future hope for this group, approximately %10-15 of colon cancers.

Related Topic:

• Colorectal cancer screening age should be lowered to 45 under the new ACS guideline
• What to know about colon and rectal cancer