9. Treatment recommendations for residual tumour, recurrence, second carcinoma and recurrent metastasis – Oropharyngeal and Hypopharyngeal Carcinoma
When treating local or locoregional recurrences, second carcinomas or residual squamous cell carcinomas of the oropharynx after primary treatment, different initial situations arise. The majority of patients with locoregional recurrences have undergone pretreatment consisting of surgery and/or postoperative radio- or radiochemotherapy or primary radio- or radiochemotherapy. Unless it is a rare second carcinoma in a different (new) location (defined according to the criteria of Warren and Gates, 1932, which are still valid today: 1: each of the tumours is malignant, 2: each must be at least 3 cm locally distant from the first carcinoma and 3: the probability that one is a metastasis of the other must be excluded. Field carcinogenesis, which has now been characterized by molecular biology, must also be taken into account. Overview: [562]), we are generally talking about new tumour growth in a previously treated area, which must be taken into account in a special way when making treatment decisions. According to the recently presented Odense-Birmingham definition, the following criteria are proposed for a recurrent tumour: 1: same anatomical subregion or adjacent subregion within 3 cm of the primary lesion, 2: time interval of occurrence not more than 3 years (from completed treatment of the primary lesion) and 3: same p16 status for oropharyngeal carcinoma [563]. A secondary carcinoma can occupy an intermediate position, as it is often a manifestation with sufficient local distance from the primary carcinoma after more than 3 years, but can still occur within the radiation field of the primary lesion or the more extensive surgical field in primary therapy.
The biological background of tissue changes after pre-treatment is diverse. Locoregional recurrences most frequently grow in areas that have been pre-irradiated with high doses, but less frequently in areas that have only been pre-operated on and not irradiated, and generally represent a particular challenge for further treatment. The literature provides ample evidence of the special situation after radiotherapy and less evidence of the situation after primary surgical treatment alone. For example, it has been shown that the in vitro radiosensitivity of recurrent squamous cell carcinoma cell lines established from a pre-irradiated area is significantly lower than the radiosensitivity of primary squamous cell carcinoma cell lines [564]. In animal models, tumour cells introduced by injection into a tissue pre-irradiated at a higher dose (e.g. 20 - 30 Gy single-time dose) grow significantly slower into a tumour of the same size than in a non-pre-irradiated area [565][566], which is referred to as the tumour bed effect. The reason for this is the reduced ability of the pre-irradiated tissue to provide sufficient neoangiogenesis for faster tumour growth. As a result, the tumours also tend to develop central tumour necrosis [567], i.e. tumour hypoxia, more quickly than in tissue that has not been pre-irradiated. This effect can also contribute to a reduced effect of radiotherapy or radiochemotherapy. In animal models, a significantly increased rate of the formation of distant metastases was also observed [565][567]. However, these tumour bed effects in the mouse model weaken with increasing distance from the pre-irradiation and are only slightly pronounced after 200 days [565][566]. In addition, there is the problem that the radiation tolerance of normal tissue is reduced when tumours in pre-irradiated tissue are re-irradiated. In an animal model, it has been shown that the tolerance of the cervical myelon in rhesus monkeys to re-radiation therapy increases again with a longer interval and is at least 61% of the original tolerance after 12 months [568]. For re-irradiation +/- chemotherapy of recurrences in the pre-irradiated area, the initial conditions are probably worse than in the context of primary therapy due to the lower radiation sensitivity of the tumours with simultaneous reduced tolerance of the normal tissue in analogy to the preclinical observations described above. In the case of persistent tumours in the high-dose irradiated area of radio- or radiochemotherapy, re-irradiation is hardly an option in the first 3-6 months, not only because of the low re-tolerance of the normal tissue, but also because of the obvious resistance of the irradiated tumours. With a longer interval (at least 6 months, preferably >1 year) to pre-irradiation and in the case of independent second tumours, the data from the animal models suggest somewhat more favourable starting conditions for re-irradiation +/- chemotherapy.
In general, it should be noted that the treatment of recurrent tumours and second carcinomas without distant metastases (any T, any N, not M1) after completion of primary therapy follows the same principles for both oro- (HPV-independent) and hypopharyngeal carcinomas - with special consideration of the changed initial situation in the pre-treated area - as primary therapy (Chapter 8). The previous therapy (surgery, primary or adjuvant radiotherapy or radiochemotherapy) and the particularities of renewed tumour growth in the previously treated area (scar recurrence; Section 9.1.1) must be taken into account. Unfortunately, recurrences after primary treatment in the oropharynx and hypopharynx are significantly less favourable prognostically than in the oral cavity and larynx [569][570][571][572]. It is therefore always necessary to check whether surgical treatment (R0 resection; salvage surgery) and, if necessary, adjuvant radio- or radiochemotherapy or definitive radio- or radiochemotherapy is still possible. If the locoregional recurrence is in an area that has been pre-irradiated with a higher dose, a new course of radiotherapy or radiochemotherapy can only be given with the understanding that the risk of late side effects is increased and, in some cases, that the total dose is reduced. If a meaningful resection is no longer possible due to the extent of the tumour, the option of re-radiation +/- chemotherapy is a potentially curative option [573][574][575][576][577][578]. If neither resection +/- radio- or radiochemotherapy, nor radio- or radiochemotherapy are feasible, there is the option of systemic therapy (drug-based tumour therapy). In drug-based tumour therapy, a distinction is made between first-line, second-line and possibly third-line therapy. First-line therapy is now internationally standardized (Section 9.2.1). In the case of distant metastases (M1), resection and targeted radiotherapy can be considered in the presence of individual metastases (oligometastasis). If this is also no longer possible, drug-based tumour therapy is also used in this situation. In the case of distant metastases, this can also be combined with targeted radiotherapy of metastases and, if necessary, resection.
Observation of the tissue situation in the pre-treated area: after surgery alone without radiotherapy
There is little data on the growth behaviour of locoregional recurrences in non-pre-irradiated tissue after surgery for oropharyngeal or hypopharyngeal carcinomas, and the available data are mainly for laryngeal carcinoma. In a case series of 29 recurrences of laryngeal carcinomas treated only surgically, the recurrent tumours predominantly showed diffuse, multicentric, and more frequent submucosal growth in different regions of the larynx, and in about half of the cases their extent was underestimated in imaging [579]. It is consistent with clinical experience and seems plausible that this altered growth pattern of recurrent tumours is also present in the majority of cases of oropharyngeal and hypopharyngeal carcinomas and makes it very difficult to determine the exact extent of the tumour. Whether the radiosensitivity of recurrent tumours that grow in non-irradiated tissue that has been scarred/altered by surgery increases has been little studied to date. An intrinsically reduced radiosensitivity at the cellular level does not appear plausible. However, scarring could lead to impaired blood flow, which would increase the likelihood of tumour hypoxia and the associated reduced radiosensitivity. Studies on patients have shown that keloids are usually hypoxic and hyperplastic (red) scars often have hypoxic areas. In contrast, no hypoxic areas were found in the area of white scars [580] [581][582]. The data suggest that hypoxic areas are not regularly present in healed scar tissue. The initial conditions for a good efficacy of radio- or radiochemotherapy are therefore better than after pre-irradiation, especially as there is also an unrestricted radiation tolerance of the normal tissue. However, the diffuse, often multicentric and submucosal tumour growth increases the risk of underestimating the extent of the tumour, which worsens the conditions for both salvage surgery and radio- or radiochemotherapy compared to primary therapy in an untreated area.
The considerations described above should not be underestimated in individual cases in view of the widespread lack of randomized studies and larger prospective registry data in the treatment of locoregionally limited recurrences of squamous cell carcinoma of the oropharynx and hypopharynx.
Definition of salvage surgery
In this context, the term "salvage surgery" should be explained in more detail, as it is commonly used to describe rescue surgery following failed radiotherapy. The term salvage surgery has become very prominent in the context of laryngeal organ preservation programs, in which laryngectomy was performed as salvage after tumour persistence or short-term recurrence following successful radiochemotherapy. However, current scientific consensus defines the term more broadly: "Salvage surgery is no longer limited to patients who failed radiotherapy or radiochemotherapy, but also includes patients who previously underwent surgical treatment for tumours located from the base of the skull to the lower neck areas (including thyroid cancer)" [517]. This means that even after sole surgical treatment of the initial carcinoma in the head and neck area in the event of a new recurrence/second tumour or locoregional metastases in the former resection area (scar), repeat surgery is also referred to as "salvage surgery".
9.1 Treatment recommendation if surgery or radiation is still an option
From a radiotherapeutic and surgical perspective, the biological characteristics of tumour recurrences or second carcinomas in previously treated areas cannot be equated with therapy-naïve, i.e. non-pretreated tissue situations in primary therapy.
- Consensus
- Strong consensus (100%)
In the special consideration of recurrence or second tumour therapy, some basic considerations/approaches have currently prevailed [583], which are listed below.
- From a radiotherapeutic and surgical point of view, the biological characteristics of tumour recurrences or second carcinomas in previously treated areas cannot be equated with therapy-naïve, i.e. non-pretreated tissue situations in primary therapy.
- In general, it should be noted that the treatment of recurrent tumours, secondary carcinomas without distant metastases (any T, any N, not M1) after completion of primary treatment of oropharyngeal and hypopharyngeal carcinoma follows the same principles as primary treatment with regard to testing R0 operability and radiation or radiochemotherapy capability - taking particular account of the changed initial situation in the pre-treated area.
- In the case of locoregional oropharyngeal and hypopharyngeal carcinoma recurrences or second carcinomas, the possibility of surgical treatment in patients without distant metastases should always be reviewed and, if R0 resection is likely to be achievable, favoured in the multidisciplinary tumour board.
- The term "salvage surgery" is no longer limited to indications in which radiotherapy or radiochemotherapy has failed, but also includes the treatment of patients who have previously undergone surgical treatment of tumours alone.
- Salvage surgery for oropharyngeal and hypopharyngeal carcinomas, especially in pre-irradiated areas, is subject to significantly higher complications, such as wound healing disorders, wound infections, secondary healing, persistent fistula formation, etc., than primary surgery in non-pretreated tissue and should therefore include reconstructions with transfer of non-pretreated tissue.
- The initial conditions for good efficacy of salvage surgery, radio- or radiochemotherapy in oropharyngeal and hypopharyngeal carcinoma recurrences or secondary carcinomas are better in solely preoperated areas than after additional pre-irradiation or primary radiochemotherapy, but worse overall than in therapy-naïve tissue.
- The diffuse, often multicentric and submucosal tumour growth in pre-treated areas increases the risk of underestimating the tumour extent and the actual degree of hypoxia, which worsens the conditions for salvage surgery as well as radio- or radiochemotherapy compared to primary therapy.
- Due to scarring in the previously treated area ("scar recurrence"), it is often difficult or impossible to show the exact extent of the tumour on imaging. Biopsy confirmation of the recurrence can be difficult due to the diffuse extension in the pre-treated area, as the tumour often eludes direct visualization during panendoscopy.
- If an urgent oropharyngeal or hypopharyngeal carcinoma recurrence/secondary tumour is suspected in pre-treated tissue and a targeted biopsy is not expedient due to diffuse tumour spread that is not visible externally/endoscopically, exploratory salvage surgery with limited resection of suspicious masses can be performed both in the pre-treated primary tumour and in the neck area for histological confirmation and visualization of the tumour spread.
- Recurrences after primary treatment in the oropharynx and hypopharynx are significantly less favourable prognostically than in the oral cavity and larynx.
9.1.1 Possibility of salvage surgery including neck dissection, adjuvant and primary radio- and radiochemotherapy
In principle, a biopsy or, depending on the scar, a limited excisional biopsy should be performed to histologically confirm a recurrent tumour/secondary carcinoma in a previously treated area.
If a targeted biopsy is not expedient as part of the clarification of an urgent suspected recurrent/secondary tumour in pre-treated tissue due to diffuse tumour spread that is not visible externally/endoscopically, exploratory salvage surgery with limited resection of suspicious masses in the oropharynx/hypopharynx as well as in the neck area can be performed for histological confirmation and visualization of the tumour spread.
- Consensus
- Strong consensus (100%)
In the case of locoregional recurrence in the pre-treated area, it should be checked whether a functionally meaningful R0 salvage resection is possible.
- Consensus
- Strong consensus (100%)
In the case of locoregional recurrences or double carcinomas in the oropharynx or hypopharynx in the pre-operated but not pre-irradiated area, resection +/- adjuvant radio- or radiochemotherapy should be performed if R0 resection is reasonably possible, or primary radio- or radiochemotherapy should be performed.
- Consensus
- Strong consensus (100%)
In the case of locoregional recurrences or double carcinomas in the oropharynx or hypopharynx in the pre-irradiated area, salvage resection should be preferred to non-surgical treatment if R0 resectability is functionally feasible.
Postoperative re-irradiation can be offered in particular after salvage resection if the following criteria are met:
- A long interval to the 1st radiation series (at least 6 months)
- No grade IV late effects of the 1st radiation series in the area to be re-irradiated
- No major wound healing disorders after salvage resection
- If risk factors are present (e.g. resection <5mm i.G., >1 affected LK or ECE)
- Consensus
- Strong consensus (95%)
If post-operative re-irradiation (possibly with combined chemotherapy) is performed after salvage resection, a total dose of at least 50 Gy (R0) - 60 Gy (R1/2) in 2 Gy equivalent dose for an alpha/beta value of 10 Gy should be aimed for.
In this situation, the CTV should be kept as small as reasonably possible (e.g. former tumour region 5-10 mm) in order to minimize the volume of normal tissue that cumulatively receives >100 Gy.
Simultaneous chemotherapy can be selected analogous to primary radiochemotherapy. With a short interval (6-12 months) to the previous chemotherapy, an alternative chemotherapy regimen should be preferred.
- Consensus
- Strong consensus (100%)
In the case of a locoregional recurrence of the cervical lymph nodes of an original oropharyngeal (regardless of HPV status) or hypopharyngeal carcinoma in a pre-irradiated/pre-operated area, a salvage neck dissection should be performed if functionally feasible.
- Consensus
- Strong consensus (100%)
The recommendation for the practical procedure in the case of locoregional recurrence (tumour and cervical lymph nodes) is based on the limited data presented above and clinical experience compiled in textbooks. Unfortunately, most of the groups are mixed, i.e. primary surgery +/- adjuvant radiotherapy or radiochemotherapy, or pre-treated with radiotherapy, so that the current data situation does not allow a clear standardized recommendation for the best treatment of locoregional recurrence in a pre-treated area. Randomized studies directly comparing salvage surgery +/- postoperative radio- or radiochemotherapy with radio- or radiochemotherapy are not available. Data from larger prospective registry studies are also not available. Therefore, the assessment of treatment effects is limited to case collections with mostly small case numbers (30 - 250) of mixed patient collectives [584][572] [585][586] that most frequently received resection with postoperative radio- or radiochemotherapy or primary radio- or radiochemotherapy as part of primary therapy (i.e. not recurrence therapy) as well as a few patients who were pretreated with surgery alone. Locoregional recurrences classified as resectable were predominantly treated surgically, whereas recurrences classified as non-resectable were treated with radio- or radiochemotherapy including brachytherapy or with chemotherapy alone or only with "best supportive care". This means that there is a clear bias in these case series to the disadvantage of non-surgical treatment methods, which should be taken into account in the already sparse data situation. However, if the results of different treatment methods are compared on this basis, meta-analyses show a clear survival advantage (10 - 30%) for salvage surgery compared to non-surgical treatment methods [587][588][589][569][590]. It should be noted that the majority of patients in these case series received postoperative radio- or radiochemotherapy despite pre-radiation. If R0 resection is successful, overall survival 5 years after salvage surgery is between 20 - 40% in the meta-analyses [587][587][569] [589] and even 50 - 60% for HPV16/p16-positive oropharyngeal carcinomas [589], thus demonstrating the high curative potential of the salvage surgery procedure. In the case of R1 resection [569], or if lymph node metastases with extracapsular growth are detected, the prognosis is significantly worse [586]. In contrast, a long interval between initial therapy and recurrence therapy is a favourable prognostic factor [589]. Second tumours have a better prognosis than recurrent tumours [591].
Despite all the previously described limitations of the data on the treatment of locoregional recurrences of oropharyngeal and hypopharyngeal carcinomas, the possibility of surgical treatment in patients without distant metastases should be reviewed and favoured if R0 resection is likely achievable. In the case of locoregional recurrences or second tumours in non-pre-irradiated tissues, radio- or radiochemotherapy alone is a sensible alternative, both in the case of resectability limitations and given resectability with a tumour extent that is clearly defined on imaging and can be easily confirmed via biopsy.
Recurrence or second tumour in previously treated scarred tissue
When surgically treating tumour recurrences or second carcinomas in previously treated tissue (scar carcinomas), the aspects discussed above must be taken into account from a radiotherapeutic and surgical perspective, which can be disregarded in the primary treatment of non-pretreated tissue. This must be taken into account in particular for larger resection areas (neck dissection, T2-4 primary tumour resection with reconstruction). Altered lymphatic drainage of the pre-treated tissue, poorer blood circulation in scar tissue and the often observed poorer oxygen supply (hypoxia) are often sufficient reasons to assume limited radiation effectiveness (see introductory text 9.1). The exact extent of the tumour in scar recurrences cannot be reliably depicted by imaging. Biopsy confirmation of the recurrence can be difficult due to the diffuse extent of the scar, as the tumour often eludes direct visualization during panendoscopy. For this reason, uncritical direct application of the principles of primary therapy in a non-pretreated area is not recommended, particularly in the case of scarring. Therefore, exploratory salvage surgery with resection of suspicious masses both in the HNSCC primary tumour area and in the locoregional neck area after/instead of an unsuccessful biopsy attempt is justified for the above-mentioned reasons and is explicitly recommended by leading head and neck oncologists (the mandate holders of this guideline also agreed 100% with this recommendation). Often, the exact extent of the tumour can only be determined by such a procedure, in which reasonable salvage resections can be performed without prior frustrating biopsy attempts (e.g. limited neck dissection, resection of a scarred tonsil bed after previous surgery, etc.). In this particular situation, exploratory surgery affects diagnostic and therapeutic criteria in equal measure. In experienced hands, this procedure also leads to relevant time savings in an otherwise very lengthy and inappropriate staging procedure characterized by biopsies in the wrong place. In addition, the subsequent histopathological description of the extent of the tumour provides a more precise planning basis for a possible subsequent resection and targeted adjuvant radio/radiochemotherapy or re-radiation.
Special aspects of salvage laryngopharyngectomy
Salvage laryngopharyngectomy for recurrences in the hypopharynx after primary radio(chemo)therapy is often the only curative treatment option for patients with advanced hypopharyngeal carcinomas and is an integral part of multimodal therapy for advanced hypopharyngeal carcinomas. Salvage laryngopharyngectomy is characterized by a more difficult intraoperative preparation, as the radiotherapy in the tissue leads to a scarred transformation and reduced blood supply to the tissue (analogous to chapter 7.7. S3 larynx guideline [2]). Salvage surgery, especially in pre-irradiated areas, is subject to a significantly higher degree of complications, such as wound healing disorders, wound infections, secondary healing, persistent fistula formation, etc., than surgery in non-pretreated tissue. In general, free and pedicled tissue transfer with non-pretreated, well-vascularized tissue and competent wound management are recommended [592][593][594][594][595][596][597][598][599]. There is no consensus in the literature as to which tissue transfer is optimal, particularly in the case of salvage laryngopharyngectomy for hypopharyngeal carcinoma recurrence/residual tumour after primary laryngeal organ-preserving multimodal therapy (reference to Section 7.7 of the S3 Guideline on Laryngeal Carcinoma [2]). Almost exclusively retrospective cohort studies are available. Most studies are available on the pectoralis major flap [600][601]. A few studies compare two different flap plasty techniques [601][602]. In a retrospective cohort analysis of 359 patients regarding pharyngeal fistulas after salvage laryngectomy, it was shown that the fistula rate after reconstruction using a pectoralis major flap (15%) was significantly lower than after reconstruction using a free flap (25%) or primary wound closure (34%). In patients who developed a fistula, the persistence of the fistula was significantly longer with primary closure (14 weeks) compared to pectoralis major flap reconstruction (9 weeks) or free flap reconstruction (6.5 weeks) [601]. A more recent study by Piazza et al. [603] described impressively low fistula rates after salvage surgery with free tissue transfer: 55 patients (mean age 66 years; male-to-female ratio 8:1) were included in the study. Prior treatments were radiotherapy in 22 (40%) patients, radiochemotherapy in 21 (38.2%) and partial laryngectomy followed by adjuvant (C)RT in 12 (21.8%). Reconstruction was achieved by radial forearm and anterolateral thigh flap (ALT) plasty in 16 (29.1%) and 39 (70.9%) patients, respectively. The success rate of flap plasty was 98.2% with only three pharyngocutaneous fistulas (5.4%) and one pharyngoesophageal stenosis (1.8%) [603].
It can therefore be concluded that in the context of salvage laryngopharyngectomy, the introduction of tissue from the non-irradiated area can significantly reduce the risk of fistula, although there is no evidence on the type of tissue transfer [601][604][605][606][607]. We now know from numerous recent reports that a hypopharyngeal carcinoma that is in principle resectable after primary radiochemotherapy does not necessarily have to be salvage-operable. According to recent reports, less than half of the previously resectable tumours proved to be no longer resectable/operable after radiochemotherapy [608]. Further information on the current techniques of reconstructive head and neck surgery was provided in Chapters 8.1.1 and 8.2.1.
For the recurrence detection of oropharyngeal and hypopharyngeal carcinomas in general, the few usable studies identified by IQWiG showed that PET had a significantly higher pooled sensitivity than the combination of CT and/or MRI in the technology comparison PET vs. combination of CT and/or MRI. Here, the specificity is reduced by false positive findings due to accumulation in inflammatory lesions. However, FDG-PET showed a higher reliability with a sensitivity of 100% and a specificity of 61-71% than CT and/or MRI [172]. (Section 7.3).
Planned neck dissection after definitive radiochemotherapy for node-positive oropharyngeal and hypopharyngeal carcinomas is a special situation. Here, salvage neck dissection should only be considered immediately after primary therapy if the FDG-PET-CT proves positive. The background and recommendations were explained in detail in chapter 7.3 (see recommendations 7.14 - 7.16, [202]).
Postoperative radiochemotherapy after salvage surgery
The value of postoperative radiochemotherapy after salvage surgery was investigated in one small randomized study (n=130) [609]. A statistically significant and clinically relevant advantage in locoregional tumour control and relapse-free survival was demonstrated by adjuvant radiochemotherapy, but a statistically significant survival benefit could not be demonstrated in the small number of cases. Radiochemotherapy was administered using the Chicago regimen, which is rarely used in Europe, with 60 Gy in 30 fractions over 11 weeks in combination with simultaneous 5-fluorouracil and hydroxyurea. In a multi-institutional evaluation of several US centres (216 patients), postoperative radiotherapy +/- chemotherapy (70%, predominantly cisplatin-based) with total doses >60 Gy did not show any benefit over total doses of 40 Gy - 60 Gy in terms of survival and locoregional relapse rate [610]. The rate of >= grade 3 late side effects was 24% for total doses <60 Gy compared to 32% for total doses above 60 Gy. The majority of patients in this case series were irradiated with 5 x 1.8-2.0 Gy per week, a smaller proportion with 2 x 1.5 Gy per day 5 x per week. With regard to the locoregional relapse rate, there was a trend (13% lower) in favour of hyperfractionated radiotherapy. Elective irradiation of unaffected adjacent lymph node levels did not improve the results.
Radio- or radiochemotherapy for functionally impractical R0 resectability
If R0 resection does not appear to be feasible for locoregional recurrences and second carcinomas, the possibility of radio- or radiochemotherapy should be examined for patients without distant metastases. For previously irradiated patients who were treated with re-radiation (in some cases also with brachytherapy) +/- chemotherapy without prior salvage surgery, overall survival after 2 years of 30% [611][584] to 41% [612] and after 5 years of 16% [587] were reported in meta-analyses. In the majority of case series, total doses of 45 Gy - 70 Gy (median 60 Gy) were achieved in conventional fractionation (1.8 - 2 Gy single dose) or, in some series, hyperfractionated radiotherapy with 2 x 1.5 Gy per day. Several case series have shown better survival and a lower locoregional recurrence rate with total doses of >50 Gy [613] or >60 Gy [577]. No advantage was seen for hyperfractionated radiotherapy with 2 x 1.5 Gy per day. In a larger case series (n=216), the effect of elective irradiation of adjacent, unaffected lymph node regions was investigated [577] and no benefit was found. Smaller case series on the use of hypofractionated stereotactic radiotherapy with total doses of 10 - 50 Gy in 1 - 8 fractions reported survival rates comparable to those of conventional fractionation [611]. Overall, however, there is significantly more experience with conventionally fractionated reirradiation. Re-irradiation with protons has theoretical advantages over photon therapy in terms of dose distribution. The first major published case series (n=242) showed results that are in the upper range of the data published with photon therapy [614]. Simultaneously with re-irradiation, systemic therapy with cisplatin, carboplatin, cetuximab, docetaxel, paclitaxel, 5-FU, capecitabine, hydroxyurea or a combination of two of these substances was used in the majority of patients in the aforementioned case series. It is not known which substances are most effective in combination with reirradiation and whether there is any benefit at all. However, due to the limitation of the total dose and volume of reirradiation, additional systemic therapy is considered a sensible option and was therefore frequently used in the case series cited. In particular, if no cisplatin was used during primary treatment, it makes sense to apply cisplatin-containing chemotherapy in combination with reirradiation. To date, there are no reliable data on the use of induction therapies prior to reirradiation +/- simultaneous chemotherapy and the use of immune checkpoint inhibitors in combination with reirradiation.
The acute toxicity of re-irradiation +/- chemotherapy does not differ significantly from the toxicity of therapy in patients who have not been previously irradiated. However, an increased risk of late toxicities is to be expected. The published rates of >=3 late effects are between approximately 10% and 40% in most studies [611][615] [612] [591]. The more frequent grade 3-4 late effects include trismus, fibrosis, pharyngeal stenosis and fistulas as well as osteoradionecrosis (up to 17%) [609]. Treatment-related deaths have been observed with these therapies in 0.1% - 8.4% of patients [611][615]. Mass bleeding from the carotid artery (carotid blowout syndrome) accounts for only a small proportion of these deaths, unless the carotid artery is largely overgrown by the recurrent tumour [616]. The grade 3-4 late side effects are often associated with a reduced quality of life due to predominantly poorer swallowing function. Total doses of re-irradiation of more than 60 Gy in conventional fractionation are associated with an approximately 10% increased risk of grade 3-4 late effects in both postoperative irradiation and definitive irradiation [577]. In the collectives that received postoperative re-radiation +/- chemotherapy, grade 3-4 late effects are on average approximately 5-20% higher than with re-radiation +/- chemotherapy alone [609][577]. When deciding which patients are suitable for re-irradiation +/- chemotherapy, it should be noted that in all of the studies and case series reported here, patients with grade 4 late effects of pre-irradiation were not treated with re-irradiation. In addition, the interval from the first radiotherapy in almost all patients was >6 months.
There are indications from some case series that grade 4 side effects occur more frequently in tissues that have been exposed to a cumulative dose of more than 120 Gy (2 Gy equivalent dose with the alpha/beta value of the respective normal tissue) [617]. This also applies to the "carotid blowout syndrome". Volumes receiving cumulative total doses of >120 Gy should therefore be kept as small as possible. Total cumulative doses of >130 Gy to a maximum of 137 Gy have only been reported in exceptional cases in the available case series [612]. The greater the distance from the previous irradiation and the fewer late effects from the previous therapies, the lower the risk of severe late effects can be estimated. The American Radium Society has published additional information on this topic [575]. The influence of additional simultaneous chemotherapy on the higher-grade late effects of re-radiation is insufficiently documented in the case series to make a conclusive assessment in this regard.
Radio- or radiochemotherapy in non-irradiated patients with recurrences after surgical therapy alone
Very little data is available on the effect of primary radiotherapy or radiochemotherapy in patients with recurrences after surgery alone who have not received prior radiotherapy. In a collection of cases (n=75) of locoregional recurrences of hypopharyngeal and laryngeal carcinomas [618], a 5-year survival proportion of 76% was observed after approximately 70 Gy in 2 Gy single dose +/- cisplatin-containing chemotherapy. This result is only slightly below the results expected in patients who were not previously treated. In this situation, radio- or radio-chemotherapy should be given according to the same principles and recommendations as for primary therapy (see Chapter 8), taking into account the possible altered lymphatic drainage due to the surgical procedure and the scar situation (as explained in detail above). In this particular situation, preference should therefore also be given to salvage surgery +/- adjuvant radiotherapy or radiochemotherapy, where this appears feasible.
9.1.2 Radiation reserve, re-irradiation
In the event of re-radiation, patients should be informed about the significantly increased risk of grade IV late effects of radiotherapy.
- Consensus
- Strong consensus (100%)
In the case of locoregional recurrences or second cancers in the oropharynx or hypopharynx in the previously irradiated area, where R0 resection is not feasible, re-irradiation can be carried out, if possible in combination with simultaneous chemotherapy, if the following criteria are met:
- a long interval to the 1st radiation series (at least 6 months)
- no grade IV late effects of the 1st radiation series in the area to be re-irradiated
Simultaneous chemotherapy can be selected in the same way as primary radiochemotherapy. With a short interval (6-12 months) to the previous chemotherapy, an alternative chemotherapy regimen should be preferred.
- Consensus
- Strong consensus (91%)
If re-irradiation is carried out with curative intent for a locoregional recurrence/secondary carcinoma, a total dose of approximately 60 Gy (2 Gy equivalent dose for an alpha/beta value of 10 Gy) should be aimed for.
In this situation, the CTV should be kept as small as reasonably possible (e.g. GTV + 5 mm) in order to minimize the volume of normal tissue that cumulatively receives >100 Gy.
In the event of re-irradiation, patients should be informed of the significantly increased risk of grade IV late effects of radiotherapy.
- Consensus
- Strong consensus (100%)
9.2 Treatment recommendation in case of non-operability or radiation option
Patients with a good general and performance status should be given palliative, usually cisplatin-based, systemic therapy if the options of salvage surgery and/or radio- or radiochemotherapy have been exhausted or are no longer possible. In patients with advanced, relapsed or metastatic oropharyngeal or hypopharyngeal carcinoma, response rates of 10-43% can be achieved with palliative chemotherapy, possibly in combination with immuno-checkpoint inhibitors [619] [620]. The selection of the active substances to be used currently depends on the expression of PD-L1 in the tumour tissue (CPS, TPS relevant for the immuno-checkpoint inhibitor pembrolizumab; see Section 7.5.2), the remission pressure at the time of therapy indication and the question of whether cisplatin-based radiochemotherapy has already taken place within the last 6 months. If more than 6 months have passed since the previous platinum-containing first-line combination, renewed platinum therapy (possibly also as a combination) can also be considered [621].
Special consideration of systemic drug therapy in recurrent or metastatic oropharyngeal carcinoma: influence of HPV status:
In patients with metastatic/recurrent oropharyngeal carcinoma, chemotherapy with docetaxel + cisplatin + cetuximab (TPEx) shows a survival benefit for patients with p16-positive compared to patients with p16-negative tumours (HR 0.61) [622]. For the combination FU + cisplatin + cetuximab (EXTREME), a difference in survival between patients with p16-positive versus p16-negative tumours has not been proven due to insufficient case numbers [623]. As the studies were not powered for this question, the significance is limited [624]. In patients with metastatic/relapsed oropharyngeal carcinoma, immunotherapy with PD1 or PD-L1 inhibitors (nivolumab, pembrolizumab, durvalumab) has shown no difference between patients with p16-positive and p16-negative tumours with regard to the endpoint "overall survival". However, the response to immunotherapy is generally better in p16-positive tumours than in p16-negative tumours [625] [626] [627].
9.2.1 "First line" drug-based tumour therapy
The antibody pembrolizumab, which is directed against the PD-1 receptor, is to be used in patients with metastatic or recurrent oropharyngeal and hypopharyngeal carcinoma with PD-L1-expressing tumour and immune cells (CPS ≥ 1) that cannot be treated locally as first-line monotherapy (especially in CPS ≥ 20 and with low disease burden) or in combination with platinum and 5-fluorouracil.
- Consensus
- Strong consensus (100%)
After 4-6 cycles of such combination therapy (recommendation 9.11), maintenance therapy should be given until progression or intolerance with pembrolizumab in PD-L1 positive patients or with cetuximab according to the EXTREME/TPEx protocol in negative PD-L1 status (CPS < 1) if the disease is not progressive.
- Consensus
- Strong consensus (100%)
In patients with metastatic or non-locally treatable recurrent oropharyngeal and hypopharyngeal carcinoma in good general condition (ECOG PS ≤ 1) who have no immunohistochemical evidence of PD-L1-expressing tumour or immune cells (CPS < 1) cetuximab should be used as first-line therapy in combination with platinum (preferably cisplatin) and 5-fluorouracil (EXTREME protocol) or with docetaxel instead of 5-FU (TPEx protocol).
- Consensus
- Strong consensus (100%)
After platinum-based prior therapy, nivolumab can also be considered as first-line monotherapy (regardless of PD-L1 expression) instead of monotherapy with pembrolizumab, particularly in patients who are not suitable for combined chemo(immune) therapy or in whom there is low remission pressure.
- Consensus
- Strong consensus
In patients with metastatic or recurrent oropharyngeal and hypopharyngeal carcinoma with CPS < 1 that cannot be treated locally and are unsuitable for combination therapy with cisplatin or 5-FU, combination therapy with docetaxel (or paclitaxel) and cetuximab, or nivolumab monotherapy (after prior platinum-based radio-chemotherapy or platinum-based chemotherapy alone) can be used.
- Consensus
- Strong consensus (100%)
In patients with metastatic or recurrent oropharyngeal and hypopharyngeal carcinoma that cannot be treated locally in a reduced general condition (ECOG PS ≥ 2) and given contraindications to immunotherapy, monotherapy, for example with docetaxel or cetuximab (off label), should primarily be considered and weighed against symptom-oriented supportive therapy alone.
- Consensus
- Strong consensus (100%)
Patients with early relapse after cisplatin-based radiochemotherapy can choose between immunotherapy with nivolumab [625] or pembrolizumab or monochemotherapy, for example with docetaxel or paclitaxel. Nivolumab can be administered here regardless of PD-L1 expression (approval in 2017). In patients with recurrence after (more than) 6 months or patients with a first diagnosis of R/M HNSCC without a curative option and CPS ≥ 1 (more detailed explanation of CPS in section 7.5.2), pembrolizumab is administered as monotherapy or in combination with chemotherapy (platinum and 5-FU). Pembrolizumab monotherapy can be considered for patients with PD-L1 expression of CPS ≥ 1 (further explanation of CPS in section 7.5.2) if there is no high time-to-remission pressure.
In the Keynote-048 study, the EXTREME protocol with subsequent cetuximab maintenance therapy was randomized against the PD1 inhibitor pembrolizumab alone and against the combination of pembrolizumab, cisplatin and 5-FU with subsequent pembrolizumab maintenance therapy [620]. The subgroup of patients with oropharyngeal and hypopharyngeal carcinomas amounted to approximately 48%. Pembrolizumab alone showed an improved overall survival of 12.3 versus 10.4 months compared to EXTREME in a population with a CPS ≥ 1. Pembrolizumab in combination with chemotherapy improved overall survival by 3 months (13.6 versus 10.6 months) in the population with CPS ≥ 1. Pembrolizumab as monotherapy in patients with high PD-L1 expression (CPS ≥ 20) led to an extension of overall survival from 10.7 to 14.9 months, with a significantly better side effect profile. Since more patients under pembrolizumab monotherapy than under concurrent or sole chemotherapy were primarily progressive, a combination of pembrolizumab with cisplatin and 5-FU is typically administered in cases of high time-to-remission pressure. This protocol corresponds to the current first-line standard and has replaced the previous standard (EXTREME protocol) at the highest level of evidence (evidence level A1) for the group of patients with CPS ≥ 1 [620].
The combination of pembrolizumab, cisplatin and 5-FU achieves a significant extension of overall survival with a comparable remission rate compared to the EXTREME protocol in patients with PD-L1 expression CPS ≥ 1. However, the rate of side effects is comparable to the EXTREME protocol and significantly higher than with pembrolizumab alone. The rate of side effects of the combination of pembrolizumab with platinum/5-FU is comparable to the side effect rate in the EXTREME arm and significantly higher than under monotherapy with pembrolizumab. Fatal treatment-related adverse events with pembrolizumab were reported in 1% (monotherapy) and 4% (in combination with chemotherapy) and in 3% with cetuximab in combination with chemotherapy [620]. Combined chemo-immunotherapy according to the protocol of the KN048 study has also prevailed over the previous EXTREME standard and replaced it at the highest level of evidence (evidence level A1) [628].
With regard to cisplatin-based combined systemic therapy, the combination of platinum with the monoclonal EGFR antibody cetuximab and 5-fluorouracil (with subsequent cetuximab maintenance therapy) had been considered the standard in this situation since 2008 based on data from the randomized phase III EXTREME trial [623], before the above-mentioned pembrolizumab monotherapy or chemotherapy combination was approved in 2019 on the basis of the Keynote 048 trial. The EXTREME triple combination was the first ever to show a significantly increased response rate, progression-free and overall survival (10.1 vs. 7.4 months with an HR of 0.8) compared to platinum in combination with 5-FU and was therefore positive in all effectiveness parameters. Patients' quality of life improved over the course of treatment, with at most an insignificant increase in toxicity, and tumour-related symptoms were reduced [629]. Maintenance therapy with cetuximab was well tolerated in this phase III study. A predictive biomarker for the selection of patients for this therapy has not yet been identified [624] [630]. Other EGFR antibodies such as panitumumab or the VEGF antibody bevacizumab were unable to achieve the results of the EXTREME trial, meaning that cetuximab is currently the only approved EGFR antibody in combination with platinum-containing chemotherapy in the palliative first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck region.
In the randomized phase II study TPExtreme [622], the long-standing standard EXTREME protocol was compared with a combination of cisplatin, docetaxel and cetuximab (TPEx). In 541 randomized patients, it was shown that replacing 5-FU with docetaxel significantly improved tolerability and treatment feasibility without reducing efficacy. With TPEx, chemotherapy was shortened from 6 cycles to 4 cycles and the total cisplatin dose was reduced by 50% compared to the EXTREME protocol. Since the publication of these study results, TPEx has been considered a valid alternative to the EXTREME protocol. The prophylactic administration of G-CSF is recommended as standard. Both protocols are currently still considered the first-line standard for patients with a PD-L1 expression of CPS < 1.
Monotherapy should be considered for patients with a reduced general condition. It has been shown that chemotherapy with cisplatin alone leads to a longer survival time compared to treatment with methotrexate, but has a higher toxicity [631]. Tyrosine kinase inhibitors such as gefitinib, erlotinib and afatinib have not been shown to provide significant benefit in the palliative systemic treatment of recurrent or metastatic head and neck squamous cell carcinoma, either as monotherapy or in combination with chemotherapy.
Patients with recurrent or metastatic squamous cell carcinoma of the head and neck should undergo regular cross-sectional imaging every 6-12 weeks during ongoing therapy in order to be able to switch to second-line therapy in good time.
9.2.2 "Second line" drug-based tumour therapy
After failure of primary platinum-containing combination therapy with cetuximab, second-line therapy with a checkpoint inhibitor (pembrolizumab [TPS>/=50%] or nivolumab as monotherapy) should be carried out
- Consensus
- Strong consensus (100%)
After failure of primary platinum-containing combination therapy with pembrolizumab, second-line therapy with docetaxel or paclitaxel, possibly in combination with cetuximab (off label), can be carried out.
- Consensus
- Strong consensus (100%)
After failure of first-line therapy with pembrolizumab or nivolumab as monotherapy, second-line therapy with platinum/5-FU and cetuximab or with docetaxel or paclitaxel and cetuximab can be carried out.
- Consensus
- Strong consensus (100%)
Patients who do not show tumour progression under second-line therapy including cetuximab or pembrolizumab or nivolumab should be offered continuation of therapy with the respective substance used until treatment failure (progression or intolerance).
- Consensus
- Strong consensus (100%)
For patients with progression after platinum-containing chemotherapy, the PD1 checkpoint inhibitor nivolumab significantly extended survival to 7.5 versus 5.1 months compared to monotherapy with a taxane, methotrexate or cetuximab (HR 0.70 p=0.01) [625]. Nivolumab has been approved independently of PD-L1 status in progression after platinum-containing therapy since 2017.
In an analogous study design, similar results were achieved for the PD1 inhibitor pembrolizumab, with the highest significance being achieved for patients with a PD-L1 TPS ≥ 50% [632]. For patients with a PD-L1 TPS ≥ 50%, the median overall survival of 11.6 months with pembrolizumab versus 6.6 months with taxane, MTX or cetuximab was highly significantly better, so that a comparatively strict approval was only granted for patients with TPS ≥ 50% with progression after platinum-containing prior therapy in 2018.
In this respect, nivolumab (regardless of PD-L1 expression) or pembrolizumab (TPS ≥ 50%) should be used in second-line therapy after platinum-based therapy (EXTREME or TPEx) in the absence of contraindications to a checkpoint inhibitor. After first-line therapy with pembrolizumab mono or platinum-5-FU-pembrolizumab, there is no standard therapy established by studies.
There are several other therapeutic agents in the literature, some of which are not approved in the EU, but are being discussed for use in recurrent/metastatic oropharyngeal and hypopharyngeal carcinomas (NCCN Guidelines Version 2.2023).
Combination therapies
- Cisplatin/Cetuximab [633]
- Cisplatin or carboplatin/docetaxel [634] or paclitaxel [635]
- Cisplatin/5-FU [635] [619]
- Cisplatin or carboplatin/docetaxel/cetuximab [622]
- Cisplatin or carboplatin/paclitaxel/cetuximab [636]
- Pembrolizumab/platinum (cisplatin or carboplatin)/docetaxel [620],[634]
- Pembrolizumab/platinum (cisplatin or carboplatin)/paclitaxel [635]
Monotherapy
9.3 Supportive therapy
This chapter is closely based on the extensive explanations of the two S3 guidelines on laryngeal and oral cavity carcinoma [1][2], which are largely compatible with the treatment of oropharyngeal and hypopharyngeal carcinoma.
In oropharyngeal and hypopharyngeal carcinoma, the various treatment options interact with each other and with many different normal tissues. Potential side effects (e.g. organ loss due to surgery in the case of a laryngopharyngectomy for advanced hypopharyngeal carcinoma, fibrosis after radiotherapy) have an influence on the therapy - in the primary decision, the combinability and the prognosis. Avoidance, treatment and support in the management of therapy consequences have a significant influence on the quality of life of patients with and after oropharyngeal and hypopharyngeal carcinoma. For this reason, side effects are also addressed in various ways in the other chapters of this guideline. This chapter deals with the prophylaxis and treatment of individual side effects of oropharyngeal and hypopharyngeal carcinoma therapy and general supportive measures, which are to be understood in a broader sense as supportive therapy.
A basic distinction must be made between side effects that occur during and immediately after treatment and those that either occur immediately and are long-lasting or occur over a longer period of time after treatment - the latter are particularly common after radiotherapy.
At this point, reference should be made to the S3 Guideline for Supportive Measures in Oncology, which is available in the current version from February 2020 [647] Many specific side effects are described in detail and provided with recommendations. To prevent overlapping updates, the following side effects of radiotherapy and chemotherapy will not be commented on here, even if they are relevant:
- Anemia / neutropenia
- Nausea/emesis
- Diarrhea
- Oral mucositis due to chemotherapy
- Tumour therapy-induced skin toxicity
- Chemotherapy-induced neurotoxicity (CIPN)
- Supportive therapy in radiation oncology
- Radiodermatitis
- Radiogenic osteonecrosis
- Radiogenic mucositis
- Radiogenic xerostomia
- Radiation effects on the brain and spinal cord
The diagnosis of oropharyngeal or hypopharyngeal carcinoma is shocking for most patients and can seriously change their life plans at a stroke. After the shock of the cancer diagnosis and the explanation of the expected therapy, including further postoperative treatments, the patient must come to terms with the information about the possible changes in swallowing function, voice production, breathing, facio-oral functions (smelling, blowing) and stigmatizing changes in the neck area (stoma). It is therefore important to show the patient rehabilitation and support options from the outset through social services, nursing staff, speech therapy, physiotherapy, physical therapy, psychosocial services and early contact with self-help groups. All these measures should be seen as an essential part of supportive therapy, which is not limited to drug treatment of normal tissue reactions that have occurred.
9.3.1 Prevention, side effects and their treatment
9.3.1.1 Specific supportive measures after surgery
In contrast to complications, the consequences of treatment are typical phenomena that can always be expected after surgery, even if they occur in varying degrees. Surgical treatment of oropharyngeal or hypopharyngeal carcinoma usually leads to functional impairments of varying degrees.
The least functional impairment occurs after transoral surgical techniques (TLM, TORS) for T1 carcinomas of the oropharynx and hypopharynx. The dysphonia or dysphagia that occurs afterwards usually regresses significantly after a few weeks, supported by speech therapy. Larger resections in the oropharynx can lead to permanent functional disorders of the tongue, palate closure, swallowing, voice production and articulation.
As the larynx separates the airway from the alimentary canal, aspiration is one of the frequent side effects after more extensive partial resections of smaller hypopharyngeal carcinomas, as the protective mechanisms of the laryngeal inlet are restricted. This problem does not occur with complete removal of the larynx, as in this situation the airway is separated from the alimentary canal. If a voice prosthesis is inserted, there is a risk of a pharyngo-tracheal fistula forming. Widening of the tracheoesophageal fistula occurs in early and late stages after the insertion of voice prostheses.
In some extensive procedures, shortness of breath due to tissue swelling close to the glottis can be a typical side effect that requires a temporary or even a permanent tracheostomy.
After a laryngopharyngectomy, there is a loss of smell due to the lack of nasal breathing and the risk of recurrent inflammation of the trachea due to the loss of the nose as a filter and humidifier. This can lead to the development of obstructive tracheitis, which requires intensive inpatient treatment. After a laryngectomy, the abdominal press is also not possible, e.g. when lifting heavy loads. Loss of voice after laryngectomy must be regarded as one of the serious side effects, which naturally cannot be avoided primarily due to the removal of the vocal organ. However, various rehabilitation measures are available to develop a replacement voice again. The specific supportive measures following laryngectomy (air humidification, nursing handling of tracheostoma, tracheostomy tubes, resuscitation in patients with tracheostoma) are described in detail in Chapter 7.9.1.1 of the S3 Guideline for Laryngeal Carcinoma [2].
A less frequently observed functional disorder after laryngectomy is stenosis of the hypopharynx, which can occur particularly after extensive resection of the hypopharynx and adjuvant radiotherapy and can then lead to considerable dysphagia and even aphagia.
Many of these typical side effects can be eliminated or reduced by intensive swallowing or voice training. In many cases, it is not possible to treat side effects with medication or surgery. In individual cases, postoperative adhesions of the tongue can be surgically removed and relevant hypopharyngeal stenoses can be eliminated by bougienage or dilatation plasty.
After a neck dissection, swelling may occur in the head and neck area due to congestion and drainage disorders in the lymph vessels. Movement of the head, e.g. turning and tilting, may also be restricted. This can occur mainly after adjuvant radiotherapy and the onset of radiation fibrosis, but also after lesions of the accessorius nerve. Physical and physiotherapeutic treatments can lead to an improvement, although there are no studies that prove the effect of lymphatic drainage. Damage to other nerves (hypoglossal nerve, lingual nerve, vagus nerve, border cord and phrenic nerve) can also occur [2].
9.3.1.2 Side effects and their treatment after radio(chemo)therapy
During radio(chemo)therapy, the acute side effects listed above (skin reaction, mucositis, xerostomia, radiation effects on nerve tissue) are in the foreground. Other side effects include loss of taste, nausea/vomiting, fatigue and weakness. It is not uncommon for pronounced side effects to lead to the patient wishing to discontinue or pause the therapy, both of which significantly compromise the effect of the therapy. Optimal prophylaxis and therapy are essential components of successful tumour therapy. The supportive measures in radiation oncology are described in detail in chapter 12 of [647].
There are also chronic side effects that can potentially occur in the long term, but whose probability can be reduced - at least in part - by adequate prophylaxis. This applies in particular to changes to the teeth and jaw, but also to chronic xerostomia and trismus. In addition, there are other chronic side effects of combined therapy such as lymphoedema, functional limitations of the neck and throat muscles and chronically delayed wound healing with a tendency to scarring and fistula formation. A variety of different changes can trigger chronic swallowing disorders, aspiration or hoarseness - examples include progressive fibrosis of the pharyngeal muscles; chronic mucosal oedema in the area of the laryngeal entrance, the ariepiglottic fold and the pocket folds; late oedema in the area of the entire larynx [648]; neuropathies and scarring of the mucosa; fibrosis of the entire oropharyngeal area and the masticatory muscles with consecutive difficulties in opening the mouth; cartilage necrosis in the laryngeal area.
All these side effects require close patient care, ideally by an interdisciplinary team. The sequence of measures is also important - dental restoration must take place before the start of radiotherapy, but the time window between surgery and adjuvant therapy should not be longer than 6 weeks without a compelling reason. If the preoperative presentation to the dentist takes place, tooth extractions can be performed during anaesthesia for tumour resection if necessary. It also helps with adherence if patients receive the same care instructions from all the doctors and other professional groups involved in their care. The benefits of early involvement of nutritional therapy and voice rehabilitation have been described elsewhere. Coordinated management is therefore necessary.
Once chronic changes have occurred, they tend to persist and increase in frequency over the long term, and there is little literature on incidence and treatment. Overall, it is recommended that patients with newly occurring symptoms after oncological therapy, including radiotherapy, should be presented to the radiotherapist in order to establish a connection if necessary and to provide information about treatment options [2]
9.3.1.3 Side effects and their treatment after drug-based tumour therapy
Very often, chemotherapy is administered simultaneously with radiotherapy (primary or adjuvant) and also alone in palliative treatment situations. Substances from immuno-oncology and EGFR targeting are also used (section 9.2.). The most common potential side effects of the substances used (tumour therapy-induced nausea and vomiting, diarrhea, altered hematopoiesis, oral mucositis due to systemic tumour therapy, skin toxicities, nephrotoxicity, chemotherapy-induced peripheral neuropathy, osseous complications, extravasations) are discussed in detail, excluding the specific toxicities of the checkpoint inhibitors approved to date (pembrolizumab, nivolumab) in the above-mentioned S3-LL Supportive Therapy [647].
Specific toxicities and their therapy of the PD-1 inhibitors pembrolizumab and nivulomab
Immune-mediated adverse events, including severe cases with sometimes fatal outcomes, have occurred in patients receiving pembrolizumab or nivolumab. Most immune-mediated adverse events that occurred during treatment with PD-1 inhibitors were reversible and manageable by discontinuation of pembrolizumab therapy, administration of corticosteroids and/or supportive measures. Immune-mediated side effects also occurred after administration of the last dose of the PD-1 inhibitor. Immune-mediated side effects can occur simultaneously in more than one organ system. Overview in [649].
If immune-mediated side effects are suspected, appropriate clarification should be ensured to confirm the aetiology or to exclude other causes. Depending on the severity of the side effect, the administration of PD-1 inhibitors should be interrupted and corticosteroids given. If improvement to grade 1 or less is observed, the corticosteroid dose should be reduced and discontinued for at least one month. Based on limited data from clinical trials in patients in whom the immune-mediated side effects could not be controlled with corticosteroids, the administration of other systemic immunosuppressants may be considered. Treatment with PD1 inhibitors should not be continued while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressants. Antibiotics should be given prophylactically to prevent opportunistic infections in patients receiving immunosuppressive treatment. Therapy with pembrolizumab/nivolumab can be resumed within 12 weeks of the last dose if the side effect improves to grade 1 or less and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day. PD-1 inhibitors should be permanently discontinued if another episode of any Grade 3 immune-mediated adverse reaction recurs or if any Grade 4 immune-mediated toxicity occurs, except in the case of endocrinopathies that can be controlled with hormone replacement therapy.
Immune-mediated pneumonitis
Pneumonitis has been reported in patients receiving PD-1 inhibitors. Patients should be monitored for signs and symptoms of pneumonitis. Any suspected pneumonitis should be confirmed by radiologic examination and other causes should be excluded. Corticosteroids should be given for grade ≥ 2 events (initial dose 1-2 mg/kg/day prednisone or equivalent with subsequent tapering). Treatment with PD-1 inhibitors should be interrupted in grade 2 pneumonitis and permanently discontinued in grade 3, grade 4 or recurrent grade 2 pneumonitis.
Immune-mediated colitis
Colitis has been reported in patients receiving PD-1 inhibitors. Patients should be monitored for signs and symptoms of colitis and other causes should be excluded. Corticosteroids should be given for grade ≥ 2 events (initial dose 1-2 mg/kg/day prednisone or equivalent with subsequent tapering). Treatment with PD-1 inhibitors should be interrupted in grade 2 or grade 3 colitis and permanently discontinued in grade 4 or repeated grade 3 colitis. The potential risk of gastrointestinal perforation should be considered.
Immune-mediated hepatitis
Hepatitis has been reported in patients receiving PD-1 inhibitors. Patients should be monitored for abnormalities in liver function (at baseline, periodically during treatment and when indicated by clinical evaluation) and for signs of hepatitis, and other causes of hepatitis should be excluded. Corticosteroids should be given at an initial dose of 0.5-1 mg/kg/day prednisone or equivalent for grade 2 events and 1-2 mg/kg/day prednisone or equivalent for grade ≥ 3 events with subsequent tapering. Depending on the severity of the liver enzyme elevation, treatment with PD-1 inhibitors should be interrupted or permanently discontinued.
Immune-mediated nephritis
Nephritis has been reported in patients receiving PD-1 inhibitors (see Section 4.8). Patients should be monitored for abnormalities in renal function and other causes of renal dysfunction should be excluded. Corticosteroids should be given for grade ≥ 2 events (initial dose 1-2 mg/kg/day prednisone or equivalent with subsequent tapering). Depending on the severity of the serum creatinine elevation, treatment with PD-1 inhibitors should be interrupted in grade 2 nephritis and permanently discontinued in grade 3 or 4 nephritis.
Immune-mediated endocrinopathies
Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism and hyperthyroidism have been observed during treatment with PD-1 inhibitors. In cases of immune-mediated endocrinopathies, long-term hormone replacement therapy may be necessary. Adrenal insufficiency (primary and secondary) has been reported in patients treated with PD-1 inhibitors, as has hypophysitis. Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypofunction of the pituitary gland) and other causes should be excluded. If clinically indicated, corticosteroids should be given to treat adrenal insufficiency and other hormones for replacement. PD-1 inhibitor therapy should be discontinued if grade 2 adrenal insufficiency or hypophysitis occurs until it is controlled with hormone replacement therapy. If grade 3 or 4 adrenal insufficiency or symptomatic hypophysitis, PD-1 inhibitors should be interrupted or permanently discontinued. Resumption of therapy with PD-1 inhibitors can be considered after corticosteroid therapy has been discontinued, if necessary. Pituitary function and hormone levels should be monitored to ensure adequate hormone replacement.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving PD-1 inhibitors. Patients should be monitored for hyperglycemia and other signs and symptoms of diabetes. Insulin should be given for type 1 diabetes. In cases of type 1 diabetes associated with grade ≥ 3 hyperglycemia or ketoacidosis, therapy with pembrolizumab should be interrupted until the metabolism is under control.
Disorders of thyroid function, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving PD-1 inhibitors and may occur at any time during treatment. Hypothyroidism is reported more frequently in patients with oro-, hypopharyngeal carcinoma and previous radiotherapy. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and when indicated by appropriate clinical evaluation) and for clinical signs and symptoms of thyroid disease. Hypothyroidism can be treated with hormone replacement therapy and does not require interruption of therapy or corticosteroid administration. Hyperthyroidism can be treated symptomatically. PD-1 inhibitors should be interrupted in grade ≥ 3 hyperthyroidism until improvement to grade ≤ 1. Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.
In patients with grade 3 or 4 endocrinopathies that have improved to Grade 2 or less and are under control with hormone replacement therapy if indicated, resumption of PD-1 inhibitor therapy may be considered after tapering off corticosteroid therapy if necessary. Otherwise, treatment should be discontinued.
Immune-mediated side effects on the skin
Immune-mediated severe skin reactions have been reported in patients receiving PD-1 inhibitors (see section 4.8). Patients should be monitored for suspected severe skin reactions, and other causes of severe skin reactions should be excluded. Depending on the severity of the adverse reaction, the administration of PD-1 inhibitors should be interrupted in grade 3 skin reactions until improvement to grade ≤ 1 or permanently discontinued in grade 4 skin reactions and corticosteroids should be administered.
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving PD-1 inhibitors. If SJS or TEN is suspected, administration of PD-1 inhibitors should be discontinued and the patient should be referred to an appropriate medical specialist for evaluation and treatment. If SJS or TEN is confirmed, PD-1 inhibitors should be permanently discontinued. Caution should be exercised when considering the use of PD-1 inhibitors in a patient who has previously experienced a serious or life-threatening skin side effect with other immunostimulatory drugs used to treat cancer.
Other immune-mediated adverse reactions
The following other clinically relevant immune-mediated adverse reactions have been reported in clinical trials or after the market launch of PD-1 inhibitors: Uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, hemolytic anaemia, sarcoidosis, encephalitis, myelitis, vasculitis, sclerosing cholangitis, gastritis, non-infectious cystitis and hypoparathyroidism.
Depending on the severity and type of side effect, therapy with PD-1 inhibitors should be interrupted for grade 2 or 3 events and corticosteroids should be administered.
PD-1 inhibitor therapy may be resumed within 12 weeks of the last dose if the adverse event improves to Grade 1 or less and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or its equivalent per day.
Treatment with PD-1 inhibitors should be permanently discontinued if any grade 3 immune-mediated adverse reaction recurs and for any grade 4 immune-mediated adverse reaction.
For grade 3 or 4 myocarditis, encephalitis or Guillain-Barré syndrome, PD-1 inhibitors should be permanently discontinued.
Detailed information on PD1 inhibitors pembrolizumab and nivolumab is available on the website of the European Medicines Agency (www.ema.europa.eu); [650] [651]. Further information can also be found in the specific ESMO guideline [652]
9.3.1.4 Supportive therapy teeth and gnatological system
In the treatment of oropharyngeal or hypopharyngeal carcinoma, the preservation and restoration of a functional stomatognathic system (teeth, oral cavity, jaw) plays an important role in maintaining quality of life. When preparing a patient for surgery or radiotherapy, the oral cavity should be germ-reduced by professional dental removal of soft and hard dental plaque. In the case of planned radiotherapy of the oropharyngeal or hypopharyngeal region (depending on the extent of the tumour and the affected lymphatic drainage pathways), different radiation exposure to the lower jaw and teeth is to be expected. This results in the classification of these patients into the "risk groups" according to Studer et al. [653]. The recommended prophylactic measures for the stomatognathic system can be found at [654] [655] [647].
For further information on specific dental supportive measures, please refer to Section 7.9.1.4. of the S3 Guideline for Laryngeal Guideline [2].
Patients who have undergone surgery and/or radiotherapy for oropharyngeal or hypopharyngeal carcinoma should have their chewing ability restored through masticatory rehabilitation with implants or conventional prosthetic restorations. Furthermore, these patients should be regularly monitored by a dentist. Dental surgery should be performed on these patients by specialists experienced in this clinical picture.
If radio- or radiochemotherapy is planned for oropharyngeal or hypopharyngeal carcinoma (primary or adjuvant), a dental check-up should be carried out before the start of treatment. The patient should be informed about prophylactic measures.
- Consensus
- Strong consensus (100%)
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