The problem of inappropriate chemotherapy exists in advanced solid tumors. On the one hand, it is because the occurrence and regression of tumor is a complex process involving multiple factors and genes, and human understanding of tumor genomics and proteomics is still very incomplete, so individualized treatment is difficult to be realized in clinical practice, resulting in many patients experiencing ineffective chemotherapy in vain. The current clinical situation of palliative chemotherapy for colorectal cancer is now analyzed.
Just like other tumors, advanced colorectal cancer is often treated with chemotherapy because of short survival period. It has been proved that although combined chemotherapy can improve the recent efficacy of advanced colorectal cancer, the prolongation of long-term survival is very limited. Tumor chemotherapy has always advocated that “the effect does not change the formula”. Only when the tumor progresses is the indication to stop or change the treatment.
In fact, the efficacy of a chemotherapy regimen is often most obvious at 2-3 cycles, and subsequent chemotherapy can only consolidate the achieved efficacy, with the aim of prolonging the time to tumor progression (TTP), progression-free survival (PFS) and survival period (OS). In the clinical pursuit of the prolongation of these time indicators for evaluating survival, even patients who benefit from chemotherapy spend most of their remission time suffering from weeks and weeks of chemotherapy.
During this time, chemotherapy often has to be postponed or the drug dose reduced due to toxic side effects, along with symptomatic and supportive treatment, with a very poor quality of life. So, there is a great disagreement among physicians as to how long the duration of treatment should be for progression-free tumors after chemotherapy. A survey of 190 doctors in the UK showed that 30% of doctors would stop chemotherapy after 3 months of effective chemotherapy for advanced colorectal cancer; 50% of doctors would stop chemotherapy after 6 months of effective chemotherapy; the remaining 20% would choose to do chemotherapy indefinitely.
Nowadays, the oncology community has gradually recognized that patients’ quality of life should also be considered in the pursuit of prolonging survival. It is inappropriate to exchange the severe toxic side effects of chemotherapy and patients’ long-term poor quality of life for a limited extension of survival; however, it is also unwise to sacrifice longer survival in order to avoid or alleviate toxic side effects and ensure quality of life. Therefore, the pursuit of efficacy and survival benefit while taking into account the patient’s quality of life is the consensus in the internal medicine treatment of colorectal cancer today.
Many clinical studies for other tumor types have shown that shorter treatment duration shortens the time to tumor progression, but has little impact on survival. Recently, several trials have explored the StopandGo model of chemotherapy, in which the original regimen is discontinued after a few cycles of combination chemotherapy, maintained for a few cycles with a single agent or intermittently for a few cycles without treatment, and then the original regimen of chemotherapy is repeated.
The OPTIMOX1 trial demonstrated that after 6 cycles of chemotherapy with FOLFOX7 for advanced colorectal cancer, discontinuing platinum oxalate and maintaining only the LV5FU2 regimen for 12 cycles achieved the same near-term efficacy, PFS and survival as FOLFOX4 continuous chemotherapy until tumor progression. And, the original aim of this study was also achieved, i.e., the single agent maintenance group resulted in a significant reduction in 3rd and 4th degree neurotoxic responses because of the discontinuation of platinum oxalate for 12 cycles. It should be noted that the continuous chemotherapy group in this study was treated with the FOLFOX4 regimen, whereas the maintenance group was treated with 6 cycles of the FOLFOX7 regimen, so that the dose intensity of platinum oxalate was 37% higher in the maintenance group than in the continuous group, which may have compensated for the loss of effect due to discontinuation of platinum oxalate during the maintenance phase.
However, the comparable efficacy of first-line combination chemotherapy in the two groups suggests that the increase in dose intensity of platinum oxalate in the FOLFOX7 regimen had little effect on survival. In addition, the 5FU/LV dosing regimens were different in the two groups, and it is possible that maintenance therapy with simplified LV5FU2 (sLV5FU2) as maintenance therapy had a greater effect on clinical outcomes in the maintenance group, and previous studies have also found a more pronounced prolongation of PFS with this sLV5FU2 regimen.
Since combination chemotherapy followed by 5FU/LV monotherapy maintenance therapy can also be beneficial, in order to further reduce the toxicity of chemotherapy and improve the quality of life, an intermittent chemotherapy model was attempted based on the monotherapy maintenance therapy model, i.e., stopping chemotherapy after several cycles of combination chemotherapy and repeating the original chemotherapy regimen after a few cycles of interval. Although shortening the duration of chemotherapy may lead to a shortening of TTP, some studies have suggested that treatment with the same regimen again after tumor progression can benefit patients as well.
Maughan et al. were the first to randomize patients with colorectal cancer who had achieved stability or effectiveness with 12 weeks of single-agent chemotherapy into two groups: an intermittent group, in which chemotherapy was discontinued until tumor progression followed by chemotherapy with the same regimen; and a continuous group, in which chemotherapy was continued until tumor progression. As a result, patients in the intermittent group had significantly fewer toxic side effects and serious adverse events (SAEs) than those in the continuous group, but there was no significant difference in survival between the two groups. Although this study was for a single-agent regimen without much consideration of the cumulative toxicity of chemotherapy, the study would have been more meaningful if this StopandGo treatment concept was extended to CPT-11, platinum oxalate-based combination regimens. This is because high cost, high toxicity and low benefit are the main factors that limit the continuity of these combination regimens.
The results of the OPTIMOX2 trial [4] showed that, although the median PFS of patients in the intermittent chemotherapy group was significantly shorter compared to single-agent maintenance therapy after combination chemotherapy (28 weeks vs. 32 weeks, P=0.01), when calculated as the median disease control period (DDC,Durationofdiseasecontrol), i.e., progression-free with first-line chemotherapy with combination regimens of PFS plus the PFS of second-line chemotherapy again, there was no significant difference between the two groups (36 weeks vs. 41 weeks, P=0.17). It can be inferred that intermittent treatment, because of the interval of no treatment, although it may lead to faster tumor progression and shorter PFS, the re-treatment after progression, in turn, may compensate for the effect of the preceding interval of no treatment on survival, and at the same time, because of the interval of no treatment, patients have better quality of life, which is a compensation for the shortened time of tumor progression.
Harris et al. speculated that intermittent treatment may have delayed the emergence of drug-resistant clones, thus facilitating long-term control of the tumor. Another trial comparing the FOLFIRI regimen with two months of chemotherapy (4 cycles) and two months of intermittent (4 cycles) with the FOLFIRI regimen with continuous chemotherapy until tumor progression showed no significant difference in either PFS or OS between the two groups, further suggesting that this intermittent chemotherapy modality not only resulted in improved quality of life for patients but also reduced costs.
In comparing the efficacy of two treatment modalities, StopandGo and continuous chemotherapy, it is more appropriate to use the time-related study endpoint as the evaluation index. It is not suitable for the overall evaluation of the efficacy of several treatment stages after the change of treatment regimen or intermittent treatment; while OS is greatly influenced by the follow-up treatment, which is difficult to reflect the efficacy of a certain regimen.
The relationship between DDC and PFS has three cases: the first one is tumor progression after maintenance or intermittent treatment, and if the tumor is PR or SD after using the combination regimen again, DDC is equal to PFS plus the PFS of the second combination treatment; the second one is tumor progression after maintenance or intermittent treatment, and the tumor is PR or SD after using the combination regimen again. The second type is tumor progression after maintenance treatment or interval, and if the tumor gains PD after using the combination regimen again, then DDC equals PFS; the third type is tumor non-progression (PR or SD) after maintenance treatment or interval, and if the tumor gains PD after using the combination regimen again, then DDC equals PFS.
Most advanced tumors will eventually fail after multiple cycles of continuous chemotherapy due to the development of resistance or will be discontinued early due to the development of intolerable toxic side effects. In the future, maintenance therapy will focus more on the role of non-cytotoxic drugs such as signal transduction inhibitors, antisense drugs, and immunomodulators. This is because these non-cytotoxic drugs, although less effective in inducing tumor regression in the short term, can inhibit tumor cell growth, which may be beneficial in delaying the time of tumor progression and patient survival with less toxic side effects. Our basic study confirmed that the EGFR tyrosine kinase (EGFR-TK) inhibitor IRESSA can maintain the concentration of chemotherapeutic drugs in colorectal cancer cells for a considerable period of time and can inhibit the repair of DNA damage induced by chemotherapy (e.g., platinum oxalate, CPT-11, etc.).
Therefore, if IRESSA is given sequentially after the onset of chemotherapy, such a regimen is theoretically reasonable and may be beneficial for the prolongation of tumor growth time. For this reason, we conducted a clinical phase II trial of stopping chemotherapy and sequentially applying IRESSA treatment in patients with advanced lung cancer after obtaining PR or MR with chemotherapy [8]. As a result, 33 patients with evaluable efficacy and toxicities had an effective rate of 24.2%, a disease control rate of 93.9%, and one patient with PR with chemotherapy who achieved CR with subsequent IRESSA treatment. median TTP was 6.5 months, median OS was 8.5 months, and 1-year survival rate was 36.4%. most of the toxicities of IRESSA treatment were mild and reversible, and preliminary evidence shows that IRESSA not only consolidates the efficacy of chemotherapy in the majority of patients, but also improves the efficacy of nearly one quarter of patients.
Compared with continuous chemotherapy after effective conventional chemotherapy, stopping chemotherapy and applying IRESSA sequentially can maintain the efficacy of chemotherapy in most patients, prolong the validity of chemotherapy, and avoid the toxicity of chemotherapy. Although the biological characteristics of lung cancer and colorectal cancer are different, carrying out maintenance therapy with molecularly targeted drugs for colorectal cancer will undoubtedly be a means. Overseas, based on the OPTIMOX1 and OPTIMOX2 trials, the OPTIMOX3 trial has been recently initiated, which is the maintenance treatment after the benefit of combination therapy with monoclonal antibody Bevacizumab targeting VEGF and/or Erlotinib targeting EGFR tyrosine kinase, and we will closely follow the results of this study.
Recently, GrotheyA et al [9] analyzed data from 11 phase III clinical trials showing that patients with advanced colorectal cancer who had been treated with all three classes of drugs, including fluorouracil, CPT-11 and platinum oxalate, had significantly longer OS than patients who had received only one or two of these drugs (P=0.0001), and that whether all three classes had been used was more important than which chemotherapy regimen was chosen in first line ( CPT-11-based or platinum oxalate-based regimen) had a greater impact on OS.
The randomized clinical trial of GERCOR confirmed that Folfiri sequential to Folfox6 or Folfox6 sequential to Folfiri regimens had similar efficacy and survival. It is suggested that the treatment of advanced colorectal cancer may be less concerned about what regimen to choose in the first line or second line, and it is important to reasonably arrange the treatment of three classes of chemotherapeutic drugs and molecular targeted drugs according to the individual patient’s situation, and to carry out combination therapy, maintenance therapy or intermittent therapy in a phased and orderly manner.
In conclusion, the principles of traditional chemotherapy for advanced colorectal cancer are beginning to be shaken. In order to improve the quality of life, attention should be paid to the issue of moderate chemotherapy, especially for patients with advanced colorectal cancer who have already benefited from chemotherapy, and over-chemotherapy should be avoided. Therefore, exploring maintenance therapy with 5Fu-like monotherapy, or molecularly targeted drugs after benefit from combination chemotherapy, or even exploring intermittent chemotherapy with discontinuation of treatment after benefit from combination chemotherapy, as well as the duration of combination chemotherapy and the length of maintenance or intermittent treatment, will be the subject of future clinical research in colorectal cancer, both from pharmacoeconomics and medical ethics perspectives.